Diseases caused by deficiencies of mineral nutrients An enormous ...
Diseases caused by deficiencies of mineral nutrients An enormous ...
Diseases caused by deficiencies of mineral nutrients An enormous ...
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<strong>Diseases</strong> <strong>caused</strong> <strong>by</strong> <strong>deficiencies</strong> <strong>of</strong> <strong>mineral</strong> <strong>nutrients</strong><br />
<strong>An</strong> <strong>enormous</strong> literature exists on the subject <strong>of</strong> <strong>mineral</strong> nutrient <strong>deficiencies</strong> in animals and it is<br />
not possible to review it all here. However, some general comments should be made. The era <strong>of</strong><br />
large-scale <strong>deficiencies</strong> affecting very large numbers <strong>of</strong> animals and comprising single elements<br />
has now largely passed in developed countries. The diagnostic research work has been done and<br />
the guidelines for preventive programs have been outlined and put into action in the field, so that<br />
the major breakthroughs have already been made, and what remains is in many ways a tidying-up<br />
operation after large-scale control campaigns. The loose edges needing to be refined include<br />
correcting overzealous application <strong>of</strong> <strong>mineral</strong>s, which can produce toxicoses, sorting out the<br />
relative importance <strong>of</strong> the constituent elements in combined <strong>deficiencies</strong>, which are characterized<br />
<strong>by</strong> incomplete response to provision <strong>of</strong> single elements, and devising means <strong>of</strong> detecting marginal<br />
<strong>deficiencies</strong>.<br />
At least 15 <strong>mineral</strong> elements are nutritionally essential for ruminants. The macro<strong>mineral</strong>s are<br />
calcium, phosphorous, potassium, sodium, chlorine, magnesium, and sulfur. The trace elements,<br />
or micro<strong>mineral</strong>s, are copper, selenium, zinc, cobalt, iron, iodine, manganese, and molybdenum.<br />
INCIDENCE AND ECONOMIC IMPORTANCE<br />
Despite increasing experimental evidence that anomalies in trace element supply can influence<br />
growth, reproductive performance or immunocompetence <strong>of</strong> livestock, few data exist from which<br />
the incidence and economic significance <strong>of</strong> such problems can reliably be assessed. Most<br />
published reports <strong>of</strong> the more readily recognized trace element-related diseases continue to<br />
provide insufficient quantitative information to assess their incidence and true economic impact.<br />
Despite these <strong>deficiencies</strong> in information, the FAO/WHO <strong>An</strong>imal Health yearbooks indicate that,<br />
<strong>of</strong> the countries providing information on animal diseases, 80% report nutritional diseases <strong>of</strong><br />
moderate or high incidence, and trace element <strong>deficiencies</strong> or toxicities are involved in more than<br />
half <strong>of</strong> those whose causes were identified. In the United Kingdom it has been estimated that,<br />
despite the activities <strong>of</strong> its nutritional and veterinary advisory services and extensive policies <strong>of</strong><br />
ration supplementation, characteristic clinical signs <strong>of</strong> copper deficiency develop annually in<br />
about 0.9% <strong>of</strong> the cattle population. In light <strong>of</strong> recently described evidence that copper deficiency<br />
can predispose to increased mortality due to infectious diseases in lambs, the economic losses<br />
from copper deficiency may be grossly underestimated.<br />
DIAGNOSTIC METHODS AND STRATEGIES<br />
In developed countries with highly developed animal industries, the emphasis is on disease<br />
prevention rather than therapy, and elimination or economical control <strong>of</strong> trace element<br />
<strong>deficiencies</strong> is a matter <strong>of</strong> education rather than research. However, because copper, cobalt,<br />
selenium, and iodine <strong>deficiencies</strong> can affect reproductive performance, appetite, early postnatal<br />
growth, and immunocompetence on a herd or Hock basis, increasing emphasis is being placed on<br />
diagnostic methods that will identify a developing risk long before specific clinical manifestations<br />
appear. In addition, it is not good enough to merely define the distribution <strong>of</strong> animal populations<br />
with an abnormal trace element status indicated <strong>by</strong> blood or tissue analysis, or to detect a<br />
deficiency <strong>of</strong> the trace element in the diet. The only feasible way <strong>of</strong> monitoring the preclinical<br />
stages <strong>of</strong> trace element deficiency is the identification <strong>of</strong> a biochemical indicator which reflects<br />
changes in the activity <strong>of</strong> the enzyme involved or the concentration in tissues <strong>of</strong> its substrate or<br />
products. The demand is growing for techniques that will predict when the likely pathological<br />
outcome <strong>of</strong> such anomalies justifies the introduction <strong>of</strong> protective measures. For example, recent
observations indicate that a high proportion <strong>of</strong> grazing cattle become hypocupremic if maintained<br />
on forage, but fail to develop characteristic clinical signs <strong>of</strong> deficiency and, furthermore, only<br />
1481<br />
a small percentage cf these animals exhibit any physiological response to the administration <strong>of</strong><br />
copper. This illustrates the lack <strong>of</strong> understanding <strong>of</strong> the variables involved in the development <strong>of</strong><br />
clinical manifestations <strong>of</strong> copper deficiency and whether they are induced <strong>by</strong> a simple dietary<br />
deficiency <strong>of</strong> copper or <strong>by</strong> specific copper antagonists present in the diet. A relatively new and<br />
interesting area <strong>of</strong> development is the observation <strong>of</strong> genetic variation in dietary requirements for<br />
copper among different breeds <strong>of</strong> sheep and that sheep can be selected for a high or tow<br />
concentration <strong>of</strong> plasma copper, which in turn will have pr<strong>of</strong>ound physiological consequences in<br />
the low group. There is now evidence that heredity is involved in the utilization <strong>of</strong> trace elements<br />
<strong>by</strong> animals. A small amount is necessary, but a larger amount may be toxic, and there is a need to<br />
determine the optimal economic balance.<br />
Thus, it is likely that trace element <strong>deficiencies</strong> are widespread, but their incidence and<br />
importance are probably underestimated because subclinical forms <strong>of</strong> deficiency can occur and go<br />
unnoticed or prolonged periods.<br />
DEFICIENCIES IN DEVELOPING COUNTRIES<br />
In developing countries, the trace element problem is confounded <strong>by</strong> the common <strong>deficiencies</strong> <strong>of</strong><br />
energy, protein, phosphorus and water, which affect post¬natal growth and reproductive<br />
performance. Undernutrition is commonly accepted as the most important limitation to herbivore<br />
livestock production in tropical countries. However, <strong>mineral</strong> <strong>deficiencies</strong> or imbalances in soils<br />
and forages have long been held responsible for low production and reproduction problems among<br />
grazing tropical cattle. Cattle grazing forages in areas severely deficient in phosphorus, cobalt, or<br />
copper are even more limited <strong>by</strong> lack <strong>of</strong> these elements than either that <strong>of</strong> energy or protein.<br />
PATHOPHYSIOLOGY OF TRACE ELEMENT DEFICIENCY<br />
The physiological basis <strong>of</strong> trace element deficiency is complex. Some elements are involved in a<br />
single enzyme, some in many more, and a lack <strong>of</strong> one element may affect one or more metabolic<br />
processes. Furthermore, there are wide variations in how individual animals respond clinically to<br />
lowered blood or tissue levels <strong>of</strong> a trace element. For example, two animals in a herd or flock with<br />
the same copper levels in their blood may be in different bodily condition. The susceptibility to<br />
clinical disease may be a function <strong>of</strong> the stage <strong>of</strong> physiological development at which they occur,<br />
genetic differences within a species, and interrelationships with other trace elements. There is now<br />
good evidence to show that the amounts <strong>of</strong> dietary copper adequate for some breeds <strong>of</strong> sheep were<br />
deficient for others, and even toxic to others.<br />
A dietary deficiency does not necessarily lead to clinical disease. Several factors predispose the<br />
animal to clinical disease and they include:<br />
•The age at which the deficiency occurs (for example fetal lambs are highly susceptible to<br />
demyelination due to copper deficiency in late fetal life)<br />
•Differences in genotype requirements<br />
•Discontinuous demands for trace elements because <strong>of</strong> changes in environment<br />
•The challenge <strong>of</strong> infections, diet, and production demands<br />
•Individual variations in response to the deficiency, the use <strong>of</strong> alternative path ways <strong>by</strong> the body in<br />
the face <strong>of</strong> a deficiency<br />
•Size <strong>of</strong> the functional reserves.
The trace elements are involved as component parts <strong>of</strong> many tissues, and one or more enzyme<br />
activities and their deficiency leads to a wide variety <strong>of</strong> pathological consequences and metabolic<br />
defects. These arc summarized in Table 29.1.<br />
Table 29.1 Principal pathological and metabolic defects in essential trace element <strong>deficiencies</strong><br />
(1)<br />
Deficiency Pathological consequence Associated metabolic defect<br />
Copper Defective melanin production<br />
Tyrosine/DOPA oxidation<br />
Defective keratinization; ha ir, wool -SH oxidation to S-S<br />
Connective tissue defects<br />
Lysyl oxidase<br />
Ataxia, myelin aplasia<br />
Cytochrome oxidase<br />
Growth failure<br />
?<br />
<strong>An</strong>emia<br />
?<br />
Uricemia<br />
Urate oxidase<br />
Cobalt <strong>An</strong>orexia<br />
Methyl malonyl CoA mutase<br />
Impaired oxidation <strong>of</strong> propionate<br />
<strong>An</strong>emia<br />
Tetrahydr<strong>of</strong>olate methyl transferase<br />
Selenium Myopathy; cardiac/skeletal<br />
Peroxide/hydroperoxide destruction Glutathione<br />
Liver necrosis<br />
peroxidase<br />
Defective neutrophil function<br />
OH; O2 generation<br />
Zinc <strong>An</strong>orexia, growth failure<br />
?<br />
Parakeratosis<br />
Polynucleotide synthesis, transcription,<br />
Perinatal mortality<br />
Thymic involution<br />
Defective cell-mediated immunity<br />
translation?<br />
Iodine Thyroid hyperplasia<br />
Reproductive failure Hair,<br />
wool loss<br />
Thyroid hormone synthesis<br />
Manganese<br />
Skeletal/cartilage defects<br />
Reproductive failure<br />
Chondroitin sulfate synthesis?<br />
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The soil-plant -animal interactions in relation to the incidence <strong>of</strong> trace element <strong>deficiencies</strong><br />
in livestock are being examined. The soil and its parent materials are the primary sources <strong>of</strong> trace<br />
elements on which soil-plant-animal relationships are built. The natural ranges in concentration <strong>of</strong><br />
most trace elements in soils are wide and range from deficient soils to those which are potentially<br />
toxic. The availability <strong>of</strong> trace elements to plants is controlled <strong>by</strong> their total concentration in the<br />
soil and their chemical form. Certain species <strong>of</strong> plants take up more trace elements than do others.<br />
The ingestion <strong>of</strong> soil can have a pr<strong>of</strong>ound effect on trace element nutrition and metabolism.<br />
Geochemical surveys can now assist in the identification <strong>of</strong> areas in which livestock are exposed<br />
to excessive ingestion or <strong>deficiencies</strong> <strong>of</strong> trace elements.<br />
The dose-response trial will continue to play a significant role in the delineation <strong>of</strong> trace<br />
element <strong>deficiencies</strong> because it is <strong>of</strong>ten difficult to determine the role <strong>of</strong> individual trace elements.<br />
A deficiency <strong>of</strong> one trace element may result in clinical disease, which may be indistinguishable<br />
from a deficiency <strong>of</strong> more than one trace element. Many <strong>of</strong> the trace element <strong>deficiencies</strong> may
produce nonspecific as well as specific effects.<br />
A dose-response trial can be defined as the application <strong>of</strong> a test and a control substance to a<br />
group, or replicates, <strong>of</strong> individuals and the measurement <strong>of</strong> the response to the treatment. The<br />
requirements for a reliable dose-response trial include a careful appraisal <strong>of</strong> the basis for<br />
conducting the trial, a suitable form <strong>of</strong> the test substance for treatment, the careful selection <strong>of</strong><br />
animals for the test, a reliable biochemical method for monitoring the response to the trace<br />
element, a measurable production response, an adequate system for measurement <strong>of</strong> the variable<br />
that may influence the response, and a means <strong>of</strong> measuring the economic impact.<br />
The ad hoc field observations made <strong>by</strong> veterinarians who make a diagnosis <strong>of</strong> a trace element<br />
deficiency, followed <strong>by</strong> treatment or dietary changes, are subjective and usually lack controls but<br />
are nevertheless <strong>of</strong> value in indicating the magnitude and variability <strong>of</strong> response that might be<br />
expected in future experimental studies. Dose-response trials help to establish a link between a<br />
trace element and certain clinical signs; they may identify factors which modify the response to a<br />
trace element and, <strong>of</strong> paramount impotance, give an indication <strong>of</strong> the economic importance <strong>of</strong><br />
adequate supplementation <strong>of</strong> the element in the diet.<br />
There are major problems in the diagnosis and anticipation <strong>of</strong> trace element <strong>deficiencies</strong> in<br />
grazing livestock. Because <strong>of</strong> the interplay between the constituents <strong>of</strong> the diet and the<br />
homeostatic mechanisms <strong>of</strong> the body, it is <strong>of</strong>ten impossible to predict from dietary composition<br />
alone whether a particular nutritional regimen will result in clinical disease. The assessment <strong>of</strong> the<br />
absorbable, rather than the total, concentration <strong>of</strong> elements in the diet is now considered to be<br />
more important in understanding the nutritional basis for the <strong>deficiencies</strong>.<br />
LABORATORY DIAGNOSIS OF MINERAL DEFICIENCIES<br />
The diagnosis <strong>of</strong> <strong>mineral</strong> <strong>deficiencies</strong>, particularly trace element <strong>deficiencies</strong>, will depend heavily<br />
on the interpretation <strong>of</strong> the biochemical criteria <strong>of</strong> the trace element status. This is because<br />
<strong>deficiencies</strong> <strong>of</strong> any one or more <strong>of</strong> several trace elements can result in non-specific clinical<br />
abnormalities, such as loss <strong>of</strong> weight. growth retardation, anorexia, and inferior reproductive<br />
performance.<br />
The interpretation <strong>of</strong> biochemical criteria <strong>of</strong> trace element status are governed <strong>by</strong> three<br />
important principles: relationship with intake, time, and function.<br />
1. Relationship between the tissue concentrations <strong>of</strong> a direct marker and the dietary intake<br />
<strong>of</strong> the element willgenerally besigmoidin shape (a dose-response curve). The important point on<br />
the curve is the intake at which the requirement <strong>of</strong> the animal is passed, which is the intake <strong>of</strong> the<br />
nutrient needed to maintain normal physiological concentrations <strong>of</strong> the element and/or avoid<br />
impairment <strong>of</strong> essential functions. For several markers <strong>of</strong> trace element status, the position on the<br />
X-axis at which requirement is passed coincides with the end <strong>of</strong> the lower plateau <strong>of</strong> the response<br />
in marker concentration. Under these conditions, the marker is an excellent index <strong>of</strong> sufficiency<br />
and body reserves, but an insensitive index <strong>of</strong> a deficiency. If requirement is passed at the<br />
beginning <strong>of</strong> the upper plateau, the marker is a poor index <strong>of</strong> sufficiency, but a good index <strong>of</strong><br />
deficiency. This principle allows direct markers to be divided into storage and non-storage types<br />
corresponding to the former and latter positions on the x-axis.<br />
2.Non-storage criteria can be divided into indicators <strong>of</strong> acute and chronic deficiency and two<br />
types <strong>of</strong> relationships can be distinguished:a rapid,early decline in marker concentration followed<br />
<strong>by</strong> a plateau, and a slow, linear rate <strong>of</strong> decline. Markers with a slow, linear response will be good<br />
indices <strong>of</strong> a chronic deficiency, but unreliable indices <strong>of</strong> acute deficiency, because they cannot
espond quickly enough. Conversely, the marker with a rapid, early decline will be a good index<br />
<strong>of</strong> acute deficiency, but an unreliable indicator for chronic deficiency if the low plateau is reached<br />
before functions are unpaired. Those biochemical criteria that are based on metalloenzyme or<br />
metalloprotein concentrations in erythrocytes are <strong>of</strong> the slow type because the marker is<br />
incorporated into the erythrocyte before its release into the bloodstream, and thereafter its half-life<br />
is determined <strong>by</strong> that <strong>of</strong> the erythrocyte that is 150 days or more. Metalloenzymes or<br />
metalloproteins in the plasma with short half-lives provide markers <strong>of</strong> the rapid type.<br />
3.A deficiency can be divided into four phases:depletion,deficiency(marginal), dysfunction and<br />
clinical disease.<br />
Depletion is a relative term describing the failure <strong>of</strong> the diet to maintain the trace element status<br />
<strong>of</strong> the body, and it may continue for weeks or months without observable clinical effects when<br />
substantial body reserves exist. When the net requirement for an essential element exceeds the net<br />
flow <strong>of</strong> absorbed clement across the intestine then depletion occurs. The body processes may<br />
respond <strong>by</strong> improving intestinal absorption or decreasing endogenous losses. During the depletion<br />
phase there is a loss <strong>of</strong> trace element from any storage sites, such as the liver, during which time<br />
the plasma concentrations <strong>of</strong> the trace element may remain constant. The liver is a common store<br />
for copper, iron, and vitamins A and B12.<br />
If the dietary deficiency persists, eventually there is a transition from a state <strong>of</strong> depletion to one<br />
<strong>of</strong> deficiency, which is marked <strong>by</strong> biochemical indications that<br />
1483<br />
the homeostatic mechanisms are no longer maintaining a constant level <strong>of</strong> trace elements<br />
necessary for normal physiological function. After variable periods <strong>of</strong> time, the concentrations or<br />
activities <strong>of</strong> trace element-containing enzymes will begin to decline leading to the phase <strong>of</strong><br />
dysfunction. There may be a further lag period, the subclinical phase, before the changes in<br />
cellular function are manifested as clinical disease. The biochemical criteria can be divided,<br />
according to the phase during which they change, into indicators <strong>of</strong> marginal deficiency and<br />
dysfunction. The rate <strong>of</strong> onset <strong>of</strong> clinical disease will depend on the intensity <strong>of</strong> the dietary<br />
deficiency, the duration <strong>of</strong> the deficit and the size <strong>of</strong> the initial reserve. If reserves are non-existent,<br />
as with zinc metabolism, the effects may be acute and the separate phases become superimposed.<br />
The application <strong>of</strong> these principles to the interpretation <strong>of</strong> biochemical criteria <strong>of</strong> trace element<br />
status are presented later in this chapter where applicable under each <strong>mineral</strong> nutrient.<br />
The definitive etiological diagnosis <strong>of</strong> a trace element deficiency will depend on the response<br />
in growth and health obtained following parenteral treatment or supplementation <strong>of</strong> the diet. The<br />
concurrent measurement <strong>of</strong> biochemical markers will aid in the interpretation and validation ol<br />
those markers for future diagnosis. The strategies for anticipating and preventing trace element<br />
<strong>deficiencies</strong> include regular analysis <strong>of</strong> the feed and soil, winch are not highly reliable, and<br />
monitoring samples from herds and flocks to prevent animals from entering the zone <strong>of</strong> marginal<br />
trace element <strong>deficiencies</strong> which precedes the onset <strong>of</strong> functional deficiency. The decision to<br />
intervene can be safely based on the conventional criteria <strong>of</strong> marginal trace element status.<br />
REVIEW LITERATURE<br />
Suttle, N. F. (1986) Problems in the diagnosis and anticipation <strong>of</strong> trace element <strong>deficiencies</strong> in<br />
grazing livestock. Vet. Rec, 119, 148-152.<br />
COBALT DEFICIENCY<br />
Cobalt deficiency is a disease <strong>of</strong> ruminants ingesting a diet deficient in cobalt, which is required
for the synthesis <strong>of</strong> vitamin B12. The disease is characterized clinically <strong>by</strong> inappetence and loss <strong>of</strong><br />
body weight. Some effects on reproductive performance in sheep have been reported.<br />
Synopsis<br />
Etiology. Dietary deficiency <strong>of</strong> cobalt resulting in a deficiency <strong>of</strong> vitamin Bl2.<br />
Epidemiology. Occurs primarily in cattle and sheep unsupplemented with cobalt worldwide<br />
where soils are deficient in cobalt. Associated with ovine white liver disease.<br />
Signs. Inappetence, gradual loss <strong>of</strong> body weight, pica, marked pallor <strong>of</strong> the mucous membranes.<br />
Wool and milk production decreased. Decreased lambing percentage.<br />
Clinical pathology. Cobalt, or vitamin B12. concentration <strong>of</strong> liver. Cobalt concentrations.<br />
Methylmalonic acid in plasma and urine. Formiminoglutamic acid in urine. <strong>An</strong>emia.<br />
Lesions. Emaciation, hemosiderosis <strong>of</strong> spleen.<br />
Diagnostic confirmation. Vitamin B12 and cobalt <strong>of</strong> liver.<br />
Differential diagnosis list:<br />
Common causes <strong>of</strong> ill-thrift in ruminants:<br />
•Copper deficiency<br />
•General nutritional deficiency (protein<br />
and energy)<br />
•Johne's disease<br />
•Intestinal helminthiasis.<br />
Treatment. Oral dosing with cobalt or parenteral injections <strong>of</strong> vitamin B12.<br />
Control. Dietary supplementation with<br />
cobalt. Cobalt-heavy pellets.<br />
ETIOLOGY<br />
The disease is <strong>caused</strong> <strong>by</strong> a deficiency <strong>of</strong> cobalt in the diet which results in a deficiency <strong>of</strong> vitamin<br />
B12.<br />
EPIDEMIOLOGY<br />
Occurrence<br />
Cobalt deficiency occurs in Australia, New Zealand, the United Kingdom and North America, and<br />
probably occurs in mainy other parts <strong>of</strong> the world (1). Where the deficiency is extreme, large<br />
tracts <strong>of</strong> land are unsuitable for the raising <strong>of</strong> ruminants, and in certain areas suboptima] growth<br />
and production may be limiting factors in the husbandry <strong>of</strong> sheep and cattle. The concentration <strong>of</strong><br />
cobalt in the soil can vary widely as, for example, in Irish cattle farms where the soil cobalt<br />
content varied between 0.2 and 18 mg/kg dry matter (DM), the forage had marginal to normal<br />
cobalt content, and low or very low blood vitamin B12 status was found in 55% <strong>of</strong> herds sampled<br />
(2). However, the significance <strong>of</strong> the cobalt deficiency clinically is uncertain (3).<br />
Cattle and sheep are similarly affected and the signs are similar in both species. Cattle are<br />
slightly less susceptible than sheep, and lambs and calves are more seriously affected than adults.<br />
Frank deficiency is unlikely to occur in pigs, or in other omnivores or carnivores, because vitamin<br />
B12 is present in meat and other animal tissues, but there are some reports <strong>of</strong> improved weight<br />
gains following supplementation <strong>of</strong> the ration with cobalt. Horses appear to be unaffected.<br />
Although the disease occurs most commonly in ruminants at pasture in severely deficient areas,<br />
sporadic cases occurin marginal areas, especially after long periods <strong>of</strong> stable feeding. Bulls, rams,<br />
and calves are the groups most commonly affected, although dairy cows kept under the same<br />
conditions may develop a high incidence <strong>of</strong> ketosis.
Risk factors<br />
Dietary and environmental factors<br />
Pastures containing less than 0.07 and 0.04 mg/kg DM result in clinical disease in sheep and cattle,<br />
respectively. The daily requirement for sheep at pasture is 0.08 mg/kg DM <strong>of</strong> cobalt; for growing<br />
lambs the need is somewhat greater and at pasture levels <strong>of</strong> less than 0.10 mg/kg DM inefficient<br />
rates <strong>of</strong> gain are likely. For growing cattle, an intake <strong>of</strong> 0.04 mg/kg DM in the feed is just below<br />
requirement levels (4). Variations in the cobalt content <strong>of</strong> pasture occur with seasonal variations in<br />
pasture growth and with drainage conditions. The increased incidence <strong>of</strong> the disease, which has<br />
been observed in the spring, may be related to domination <strong>of</strong> the pasture <strong>by</strong> rapidly growing<br />
grasses, which have a lower cobalt content than legumes. There is also a great deal <strong>of</strong> variation<br />
between years in the severity <strong>of</strong> the losses encountered due to variations in the cobalt status <strong>of</strong> the<br />
animals. Forage grown on well-drained soils has a greater cobalt content than that grown on<br />
poorly drained soils <strong>of</strong> the same cobalt status. Plant growth is not visibly affected <strong>by</strong> a low cobalt<br />
content <strong>of</strong> the soil, but the addition <strong>of</strong> excessive quantities may retard growth.<br />
Cobalt is also protective against the liver damage in sheep exposed to annual ryegrass (5).<br />
Primary cobalt deficiency occurs only on soils which are deficient in cobalt. Such soils do<br />
not appear to have any geological similarity,varying from<br />
1484<br />
windblown shell sands to soils derived from pumice and granite. Japanese soils composed largely<br />
<strong>of</strong> volcanic ash are seriously deficient. A survey in New Brunswick, Canada, revealed the average<br />
value for grass samples was 0.028 mg/kg DM, and for legume samples, 0.088 mg/kg DM, which<br />
justifies supplementation <strong>of</strong> ruminant diets with cobalt. The soils in New Brunswick are naturally<br />
acidic and with the heavy annual rainfall <strong>of</strong> 120 cm the cobalt content <strong>of</strong> the soil is decreased <strong>by</strong><br />
leaching. Outbreaks <strong>of</strong> cobalt deficiency have occurred in cattle grazing on pastures on the<br />
granite-derived northern tablelands <strong>of</strong> New South Wales in Australia, and in sheep grazing pasture<br />
on soils derived from weathered rhyolite and ignimbrite, the former being inherently-low in cobalt.<br />
Cobalt deficiency is now-occurring in areas where it has never before been diagnosed, and in<br />
seasons <strong>of</strong> lush spring and summer pasture growth, cobalt deficiency should be suspected as a<br />
cause <strong>of</strong> unthriftiness. Lambs grazing cobalt-deficient pastures <strong>of</strong> the Northern Netherlands are 6.7<br />
times more likely to die if unsupplemented with cobalt than supplemented lambs (6).<br />
Although soils containing less than 0.25 mg/kg cobalt are likely to produce pastures containing<br />
insufficient cobalt, the relationship between levels <strong>of</strong> cobalt in soil and pasture is not always<br />
constant. The factors governing the relationship have not been determined, although heavy liming<br />
is known to reduce the availability <strong>of</strong> cobalt in the soil. Manganese appears to have a similar<br />
action, but the agricultural significance <strong>of</strong> the relationship is unknown.<br />
Ovine white liver disease<br />
A specific hepatic dysfunction <strong>of</strong> sheep has been described in New Zealand, Australia, the United<br />
Kingdom (7), and Norway (8). It has been called 'white liver disease' because <strong>of</strong> the grayish color<br />
<strong>of</strong> the liver. Clinically, it is manifested<strong>by</strong> pho-tosensitization when the disease is acute, and<br />
anemia and emaciation when the disease is chronic. It seems likely that the disease is a toxic<br />
hepatopathy against which adequate levels <strong>of</strong> dietary cobalt are protective (9).<br />
PATHOGENESIS<br />
Cobalt is unique as an essential trace element m ruminant nutrition because it is stored in the body<br />
in limited amounts only and not in all tissues. In the adult ruminant, its only known function is in
the rumen and it must, therefore, be present continuously in the feed.<br />
The effect <strong>of</strong> cobalt in the rumen is to participate in the production <strong>of</strong> vitamin Bl2<br />
(cyanocobalamin), and compared to other species the requirement for vitamin B]2 is very much<br />
higher in ruminants. In sheep, the requirement is <strong>of</strong> the order <strong>of</strong> 11ug/day, and probably 500<br />
ug/day arc-produced in the rumen, most being lost in the process. <strong>An</strong>imals in the advanced stages<br />
<strong>of</strong> cobalt deficiency are cured <strong>by</strong> the oral administration <strong>of</strong> cobalt or <strong>by</strong> the parenteral<br />
administration <strong>of</strong> vitamin B12. On cobalt-deficient diets the appearance <strong>of</strong> signs is accompanied <strong>by</strong><br />
a fall <strong>of</strong> as much as 90% in the vitamin 13,, content <strong>of</strong> the feces, and on oral dosing with cobalt the<br />
signs disappear and vitamin B12 levels in the feces return to normal. Parenteral administration <strong>of</strong><br />
cobalt is without appreciable clinical effect, although some cobalt does enter the alimentary tract<br />
in the bile and leads to the formation <strong>of</strong> a small amount <strong>of</strong> cobalamin.<br />
The essential defect in cobalt deficiency in ruminants is an inability to metabolize propionic acid,<br />
which is accompanied <strong>by</strong> a failure <strong>of</strong> appetite and death from inanition. The efficiency <strong>of</strong> cobalt m<br />
preventing staggers m sheep grazing pasture dominated <strong>by</strong> (Phalaris tuberosa) and possibly <strong>by</strong><br />
canary grass {Phalaris minor) or rhompa grass, a hybrid Phalaris spp., is also unexplained. A<br />
suggestion that a dietary deficiency <strong>of</strong> cobalt can lead to the development <strong>of</strong> polio-ence<br />
phalomalacia appears not to be valid.<br />
The pathogenesis <strong>of</strong> ovine white liver disease is unclear. It is unknown if the disease is a simple<br />
cobalt deficiency, or a hepatotoxic disease in cobalt/vitamin B12-deficient lambs. Marginal to<br />
deficient cobalt-deficient grass is essential for the development <strong>of</strong> the disease (8). Cobalt<br />
fertilization <strong>of</strong> deficient pastures results in an increase in vitamin BP in lambs (9). Hepatic<br />
dysfunction occurs in affected sheep (10). Affected lambs generally have higher serum levels <strong>of</strong><br />
copper than in cobalt/vitamin B12-supplemented lambs grazing the same pastures (11). Dosing<br />
affected lambs with copper oxide needles resulted in toxic levels <strong>of</strong> liver copper (12). It is<br />
suggested that the disease is a manifestation <strong>of</strong> Bl2 deficiency made worse <strong>by</strong> factors triggering<br />
early hepatic fatty change, resulting in more severe liver damage and loss <strong>of</strong> intracellular<br />
homeo-stasis, rendering the hepatocytes more vulnerable to other elements such as copper (13).<br />
The amount <strong>of</strong> fructan in the pasture may be an important factor in the pathogenesis <strong>of</strong> the lesion<br />
(4). One hypothesis suggests that the high level <strong>of</strong> fructan may initiate hepatic lipodystrophy,<br />
leading to hepatic insufficiency, growth reduction and ovine white liver disease (4). Vitamin B12 is<br />
therapeutic (14).<br />
CLINICAL FINDINGS<br />
No specific signs arc characteristic <strong>of</strong> cobalt deficiency. A gradual decrease in appetite is the only<br />
obvious clinical sign. It is accompanied <strong>by</strong> loss <strong>of</strong> body weight, emaciation and weakness, and<br />
these are <strong>of</strong>ten observedin the presence <strong>of</strong> abundant green feed. Pica is likely to occur, especially<br />
in cattle. There is marked pallor <strong>of</strong> the mucous membranes and affected animals are easily<br />
fatigued. Growth, lactation, and wool production are severely retarded, and the wool may be<br />
tender or broken. In sheep, severe lacrimation with pr<strong>of</strong>use outpouring <strong>of</strong> fluid sufficient to mat<br />
the wool <strong>of</strong> the face is one <strong>of</strong> the most important signs in advanced cases. Signs usually become<br />
apparent when animals have been on affected areas for about 6 months and death occurs in 3-12<br />
months after the first appearance <strong>of</strong> illness, although severe wasting may be precipitated <strong>by</strong> the<br />
stress <strong>of</strong> parturition or abortion.<br />
Cobalt deficiency in pregnant ewes can result m decreased lambing percentage, increased<br />
percentage <strong>of</strong> stillbirths, and increased neonatal mortality (15). Lambs from deficient ewes are
slower to start sucking, have reduced concentrations <strong>of</strong> serum colostra] immunoglobulins, and<br />
have lower serum vitamin BI2 and higher methylmalonic acid concentrations than lambs from<br />
cobalt-adequate dams.<br />
CLINICAL PATHOLOGY<br />
Estimation <strong>of</strong> the cobalt or vitamin B12 content <strong>of</strong> the liver, as described under necropsy findings,<br />
is the most valuable diagnostic test available. All tests suffer from the disadvantage that tissue<br />
cobalt levels will reflect the cobalt intake for a considerable time prior to the estimation, and<br />
animals suffering from acute cobalt deficiency may be observed to have normal tissue levels <strong>of</strong><br />
the clement. Estimations <strong>of</strong> the cobalt content <strong>of</strong> soils and pasture have limited value because <strong>of</strong><br />
the seasonal variations that occur.<br />
1485<br />
Cobalt concentrations<br />
Cobalt concentrations in the plasma <strong>of</strong> normal sheep are <strong>of</strong> the order <strong>of</strong> 1-3 ug/dL (0.17-0.51<br />
umol/L), and in deficient animals these are reduced to 0.03-0.41 umol/L. Clinical signs <strong>of</strong> cobalt<br />
deficiency in sheep are associated with serum vitamin B12 levels <strong>of</strong> less than 0.20 mg/mL, and<br />
serum vitamin B12 levels are used as a laboratory test <strong>of</strong> cobalt status in animals. Levels <strong>of</strong><br />
0.2-0.25 ug/L are indicative <strong>of</strong> cobalt deficiency. These rise rapidly to 0.5-1.0 ug/L on treatment.<br />
The value <strong>of</strong> serum vitamin B12 assay as a diagnostic tool is in some doubt, but correctly<br />
interpreted they appear to be worthwhile. Radioassay methods for measuring serum and liver<br />
vitamin B12 in cattle and sheep have now replaced the microbiological assays. Serum vitamin B12<br />
values greater than 0.2 ug/L are indicative <strong>of</strong> a normal vitamin Bl2 status in cattle. Deprivation <strong>of</strong><br />
feed from sheep for 24 hours results in a marked increase in serum vitamin B12. The serum<br />
vitamin B12 levels <strong>of</strong> sheep at pasture are unreliable indicators <strong>of</strong> liver vitamin B12.<br />
Methylmalonic acid<br />
Because <strong>of</strong> some <strong>of</strong> the difficulties with the interpretation <strong>of</strong> serum vitamin B12 levels, other<br />
biochemical tests, especially methylmalonic acid (MMA) in plasma and urine as diagnostic and<br />
prognostic indicators and formiminoglutamic acid (FIGLU) tests are now used (16). The<br />
determination <strong>of</strong> MMA has the potential to distinguish between subchmically and clinically<br />
affected animals, which serum vitamin B12, cannot do. Methylmalonic acid is ordinarily<br />
metabolized in ruminants <strong>by</strong> a vitamin B12 enzyme system. <strong>An</strong> elevated plasma concentration <strong>of</strong><br />
MMA is a comparatively early indicator <strong>of</strong> functional vitamin B12 deficiency (17). It is<br />
recommended that 10 umol/L be an upper limit <strong>of</strong> normality for plasma MMA in barley-fed<br />
animals, and 5 umol/L be the upper limit for grass-fed animals (17). A comparison <strong>of</strong> serum<br />
vitamin Bl2 and serum MMA as diagnostic measures <strong>of</strong> cobalt status in cattle indicates that =2<br />
umol/L is normal, 2-4 umol/L represents subclinical deficiency, and =4 umol/L reprcsents<br />
deficiency (18). In a cobalt-deficient animal the methylmalonic content <strong>of</strong> urine is abnormally<br />
high and this has some merit as a test for the presence <strong>of</strong> the deficiency (9). Cobalt-adequate<br />
lambs have plasma MMA levels <strong>of</strong> less than 5 umol/L, urinary MMA less than 120 umol/L and<br />
urinary MMA/creatinine values <strong>of</strong> less than 0.022 umol MMA/mmol <strong>of</strong> urinary creatinine. <strong>An</strong><br />
unequivocal result for methylmalonic acid is a concentration <strong>of</strong> greater than 30 ug/mL for ten<br />
animals selected randomly from a flock. If the urine is kept for more than 24 hours it should be<br />
acidified to avoid degradation <strong>of</strong> the methylmalonic acid. Commercial kits are now available for<br />
assay <strong>of</strong> vitamin B12in ruminant blood.
Formiminoglutamic acid<br />
The concentration <strong>of</strong> formiminoglutamic acid in urine is a reliable indicator <strong>of</strong> the cobalt status <strong>of</strong><br />
lambs. Levels <strong>of</strong> 0.08-20 umol/mL in the urine <strong>of</strong> affected lambs return to zero rapidly after<br />
treatment. However, the concentration <strong>of</strong> formiminoglutamic acid increases in the urine <strong>of</strong> lambs<br />
only in the later stages <strong>of</strong> cobalt deficiency when there is weight loss and ill-thrift. <strong>An</strong>imals with<br />
subclinical cobalt deficiency do not produce urinary formiminoglutamic acid at levels that would<br />
be useful diagnostically. Neither MMA nor formiminoglutamic acid is a normal constituent <strong>of</strong><br />
urine and their presence in urine, without the need for a quantitative measurement, is probably a<br />
positive indication <strong>of</strong> cobalt deficiency.<br />
Hematology<br />
Affected animals are anemic, but their hemoglobin and erythrocyte levels are <strong>of</strong>ten within the<br />
normal range because <strong>of</strong> an accompanying hemoconcentration. The anemia is normocytic and<br />
normochromic. There is also a decrease in cellularity <strong>of</strong> the bone marrow in cobalt-deficient sheep.<br />
It is not repaired <strong>by</strong> the administration <strong>of</strong> vitamin B12 or <strong>by</strong> the parenteral administration <strong>of</strong> cobalt.<br />
Affected animals are also hypoglycemic (less than 60 mg glucose per dL <strong>of</strong> plasma) and have low<br />
serum alkaline phosphatase levels (less than 20 U/L). The response to cobalt administration is<br />
matched <strong>by</strong> a very rapid return to normal <strong>of</strong> these levels. Unfortunately, there are too many other<br />
factors affecting their concentration for them to be <strong>of</strong> much value in diagnostic work.<br />
NECROPSY FINDINGS<br />
At necropsy, emaciation is extreme. The livers <strong>of</strong> sheep affected with white liver disease are pale<br />
and fatty. In most cases <strong>of</strong> cobalt deficiency the spleen is dark due to the accumulation <strong>of</strong><br />
hemosiderin. The microscopic changes <strong>of</strong> ovine white liver disease include hepatocellular<br />
dissociation and intracytoplasmic accumulations <strong>of</strong> lipid and ceroid-lip<strong>of</strong>uscin within hepatocytes.<br />
The ultrastructural changes <strong>of</strong> experimentally-induced ovine white liver disease have also been<br />
documented (19).<br />
Biochemical assays reveal very high iron levels in the liver and spleen, and low cobalt levels in<br />
the liver. In normal sheep, cobalt levels in the liver are usually above 0.20 mg/kg DM, but m<br />
affected sheep are typically less than 0.05 mg/kg DM. Liver cobalt levels in cattle fed excessive<br />
amounts <strong>of</strong> cobalt and thought to be affected <strong>by</strong> cobalt poisoning can be as high as 69 mg/kg DM.<br />
Normal levels <strong>of</strong> the vitamin <strong>of</strong> cattle in New Zealand are 0.70-1.98 mg/kg <strong>of</strong> liver. After oral<br />
dosing with cobalt, "the level <strong>of</strong> the element in the liver rises, but returns to the pretreatment level<br />
in 10-30 days. Since serum B]2 levels reflect cobalt status, it is <strong>of</strong>ten useful to submit sera from<br />
surviving herdmates when attempting to confirm the diagnosis.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
•Toxicology-50 gliver(ASSAY(Co)), 2 mL serum (ASSAY (B12)).<br />
•Histology - formalin-fixed liver (LM).<br />
DIFFERENTIAL DIAGNOSIS<br />
Cobalt deficiency must be differentiated from other causes <strong>of</strong> ‘ill-thrift' or ‘enzootic marasmus'.<br />
Ill-thrift<br />
In young animals, in which this situation is most <strong>of</strong>ten encountered, nutritional <strong>deficiencies</strong> <strong>of</strong><br />
copper, selenium and vitamin D are possible causes <strong>of</strong> ill-thrift. Lack <strong>of</strong> total digestible <strong>nutrients</strong><br />
is the commonest cause <strong>of</strong> thin animals, but owners are usually aware <strong>of</strong> the shortage and do not<br />
present their animals for diagnosis. However, it does happen, especially with urban people who<br />
become farmers and are unaware <strong>of</strong> the actual
1486<br />
needs <strong>of</strong> animals. So it is best to check the feed supply and also to check whether or not the<br />
animals have any teeth. These circumstances are seen so commonly in today's era <strong>of</strong> hob<strong>by</strong> farms<br />
that a new disease category 'hob<strong>by</strong> farm malnutrition' is warranted.<br />
Internal parasitism<br />
Careful necropsy or fecal examination will determine the degree <strong>of</strong> helminth infestation, but<br />
cobalt-deficient animals are more susceptible to parasitism and the presence <strong>of</strong> a heavy parasite<br />
load should not rule out the diagnosis <strong>of</strong> primary cobalt deficiency. It is also common for parasitic<br />
disease and cobalt deficiency to occur together in the one animal. It is then necessary to make two<br />
diagnoses and conduct two control programs. In sheep, special care is needed to differentiate the<br />
disease from Johne's disease. The differential diagnosis <strong>of</strong> anemia has been discussed elsewhere<br />
(pp. 416, 1295).<br />
Dietary supplementation response<br />
The most conclusive method <strong>of</strong> determining if animal production is being affected <strong>by</strong> the<br />
deficiency <strong>of</strong> a trace <strong>mineral</strong> is to measure the response <strong>of</strong> a production parameter, such as weight<br />
gain, milk production, wool production, or reproductive performance following supplementation<br />
<strong>of</strong> animals with the element under consideration (20). However, if the degree <strong>of</strong> response can be<br />
related to a tissue level <strong>of</strong> the element, or its metabolites, then tissue analyses can replace the need<br />
for field trials, which require considerable expertise and resources and can take several months to<br />
monitor the results and obtain a quantitative outcome.<br />
Growth response curve to supplementation A new approach to defining <strong>mineral</strong> <strong>deficiencies</strong> is<br />
based on constructing response curves for any specified level <strong>of</strong> serum vitamin B12 that can be<br />
used to determine liveweight response to supplementation and the probability <strong>of</strong> obtaining a<br />
response (20). The technique closely relates the tissue <strong>mineral</strong> or biochemical indicator with the<br />
degree <strong>of</strong> production response to treatment. The advantages <strong>of</strong> this method over the traditional<br />
method have been described (20). The results from published and unpublished cobalt/vitamin B12<br />
weight response trials in young sheep grazing pasture in New Zealand have been reviewed (20).<br />
No significant weight gain responses occurred to vitamin B,? or cobalt treatment in trials with<br />
serum vitamin B12 levels above 500 pmol/L or liver vitamin B12<br />
levels greater than 500 nmol/kg. The fitted response curve approached 0 g/day at 500 pmol/L for<br />
serum vitamin B12 and 375 nmol/kg for liver vitamin B12. The minimum vitamin B12 at which an<br />
economic response to treatment (=10 g/day BW gain) is not likely is 336 pmol/L for serum and<br />
282 nmol/kg for liver (20). Variable responses to cobalt or vitamin B12 include age, breed, sex,<br />
energy intake, concurrent disease, and length <strong>of</strong> pasture. Higher soil contamination on short<br />
pastures may result in increased cobalt intake and reduced response to vitamin B12 or cobalt.<br />
Serum vitamin B12 levels may also increase following prolonged yarding, and within 24-48 hours<br />
after changes in dietary cobalt.<br />
TREATMENT<br />
Cobalt and vitamin B12<br />
Affected animals respond satisfactorily to oral dosing with cobalt or the IM injection <strong>of</strong> vitamin<br />
B12. Oral dosing with vitamin B12 is effective, but much larger doses are required. Oral dosing<br />
with cobalt sulfate is usually at the rate <strong>of</strong> about 1 mg cobalt/day in sheep and can be given in<br />
accumulated doses at the end <strong>of</strong> each week. Intervals <strong>of</strong> 2 weeks between dosing are inadequate<br />
for the best possible response. On the other hand, the monthly dosing <strong>of</strong> lambs with oral doses <strong>of</strong>
300 mg <strong>of</strong> cobalt is sufficient greatly to reduce deaths and permit some growth at suboptimal<br />
levels. The response to dosing is very quick, significant elevation <strong>of</strong> serum vitamin B12 levels<br />
being evident within 24 hours. When large doses <strong>of</strong> cobalt are administered to some sheep, other<br />
undosed sheep on the same pasture may find sufficient additional cobalt on the pasture from the<br />
feces <strong>of</strong> their Hock-mates to meet their needs. No exact data are available on dose rates for cattle<br />
but ten times the prophylactic rate should be effective. Vitamin B12 should be given in 100-300 ug<br />
doses for lambs and sheep at weekly intervals. Vitamin B12,, therapy is not likely to be used<br />
generally because <strong>of</strong> the high cost and the comparable effect <strong>of</strong> oral cobalt administration.<br />
However, vitamin B12 (hydroxycobalainin) may be a suitable therapeutic agent. One injection <strong>of</strong> 1<br />
mg provides protection to lambs for 14 weeks, and for weaners protection for up to 40 weeks.<br />
Treatment <strong>of</strong> lambs with ovine white liver disease with hydroxycobalamin results in an immediate<br />
beneficial response and treatment is repeated 10 days later (7).<br />
Cobalt toxicity<br />
Overdosing with cobalt compo inds is unlikely, but toxic signs <strong>of</strong> loss <strong>of</strong> weight, rough hair coat,<br />
listlessness, anorexia, and muscular incoordination appear in calves at dose rates <strong>of</strong> about 40-45<br />
mg <strong>of</strong> elemental cobalt per 50 kg BW per day. Sheep appear to be much more resistant to the toxic<br />
effects <strong>of</strong> cobalt than are cattle. Pigs have tolerated up to 200 mg cobalt/kg <strong>of</strong> diet. At intakes <strong>of</strong><br />
400 and 600 mg/kg there is growth depression, anorexia, stiff legs, incoordination, and muscle<br />
tremors. Supplementation <strong>of</strong> the diet with methionine, or with additional iron, manganese, and<br />
zinc alleviates the toxic effects.<br />
CONTROL<br />
The recommended safe level <strong>of</strong> cobalt in the diet for sheep and cattle is 0.11 mg cobalt kg/DM<br />
diet. If this is not available, supplementation <strong>of</strong> the diet with cobalt is necessary. Calves reared on<br />
cobalt-deficient pastures require cobalt or vitamin B12, supplementation prior to weaning. Cobalt<br />
deficiency in grazing animals can be prevented most easily <strong>by</strong> the top-dressing <strong>of</strong> affected pasture<br />
with cobalt salts. The amount <strong>of</strong> top-dressing required will vary with the degree <strong>of</strong> deficiency.<br />
Recommendations include 400-600 g/ hectare cobalt sulfate annually or 1.2-1.5 kg/hectare every 3<br />
-4 years. The response to pasture treatment is slow, requiring some weeks to complete. Affected<br />
animals should be treated orally or <strong>by</strong> injection <strong>of</strong> vitamin B12 to obtain a quick, interim response.<br />
In New Zealand, the requirement for cobalt <strong>of</strong> ruminants grazing on the pumice soils <strong>of</strong> the<br />
Central Plateau was established in the 1930s and top-dressing to increase the cobalt intake was<br />
widely practiced for many years. <strong>An</strong> on-farm survey conducted in 1978-1979 indicated that cobalt<br />
inputs could be halved because adequate reserves <strong>of</strong> soil cobalt had accumulated. However, the<br />
economic downturn in agriculture resulted in less use <strong>of</strong> cobalt, and follow-up surveys indicated a<br />
general overall decline in soil and pasture cobalt levels, which was pronounced in areas with a<br />
poor history <strong>of</strong> cobalt top-dressing. There is now a need to increase the soil level <strong>of</strong> cobalt to<br />
prevent cobalt<br />
1487<br />
deficiency in grazing ruminants. A regular cobalt input is required to build up reserves. This input<br />
requirement is about 350 g cobalt sulfate/hectare for 7-10 years on the most deficient areas.<br />
Individual farm to farm variation exists within an area and it is necessary to monitor their soil,<br />
pasture, and animal cobalt status. To achieve a level <strong>of</strong> cobalt <strong>of</strong> 0.08 mg/kg DM in pasture (the<br />
critical level for sheep) a soil cobalt level <strong>of</strong> 1.7 and 2.2 mg/kg DM is required for the<br />
yellow-brown pumice soils and yellow-brown loams, respectively (21).
Supplementation <strong>of</strong> the diet with 0.1 mg cobalt/day for sheep and 0.3-1.0 mg/day for cattle is<br />
required, and can be accomplished <strong>by</strong> inclusion <strong>of</strong> the cobalt in salt or a <strong>mineral</strong> mixture. Cobalt<br />
can also be supplied to cattle in their drinking water supply.<br />
Cobalt-heavy pellet<br />
The use <strong>of</strong>'heavy pellets' containing 90% cobalt oxide is an alternative means <strong>of</strong> overcoming the<br />
difficulty <strong>of</strong> maintaining .\n adequate cobalt intake in a deficient area. I he pellet is m the form <strong>of</strong><br />
a bolus (5 g for sheep, 20 g for cattle) which, when given <strong>by</strong> mouth, lodges in the reticulum and<br />
gives <strong>of</strong>f cobalt continuously m very small but adequate amounts. Reports on their use in sheep<br />
and cattle indicate that they are effective. Adminisation <strong>of</strong> the pellets to lambs and calves less than<br />
2 months old is likely to be ineffective because <strong>of</strong> failure to retain them in the undeveloped<br />
reticulum. The problem <strong>of</strong> cobalt deficiency in sucking animals can be overcome in part if the<br />
dams are treated because <strong>of</strong> the increased vitamin B12 content <strong>of</strong> their milk, but the daily intake <strong>of</strong><br />
the lambs will still be much below the minimal requirement. In about 5% <strong>of</strong> animals the pellets do<br />
not lodge in the reticulum and approximately 20% are rejected during the year after administration.<br />
If no response occurs, retreatment is advisable. A further possible cause <strong>of</strong> failure is where pellets<br />
become coated with calcareous material, particularly if the drinking water is highly <strong>mineral</strong>ized or<br />
it pasture top-dressing is heavy. The effects <strong>of</strong> pellet coating can be overcome <strong>by</strong> simultaneous<br />
dosing with an abrasive metal pellet. The cost is relatively high and, where top-dressing <strong>of</strong><br />
pastures is practiced, addition <strong>of</strong> cobalt to the fertilizer is the cheaper form <strong>of</strong><br />
administration.Pellets are preferred in extensive range-grazing where top-dressing is impracticable<br />
and animals are seen only at infrequent intervals.<br />
Controlled release glass boluses <strong>of</strong> cobalt<br />
Boluses <strong>of</strong> controlled release glass containing cobalt are available for oral administration to cattle<br />
and sheep. The boluses are retained in the forestomachs for up to several months and slowly<br />
release cobalt.<br />
Combine cobalt with administration <strong>of</strong> anthelmintics<br />
<strong>An</strong>thelmintics are convenient and efficient vehicles for supplementing the diet with selenium and<br />
cobalt on a regular basis, because both the selenium and cobalt status <strong>of</strong> lambs decline as they<br />
become dependent on forage, with its adherent nematode larvae, for their <strong>nutrients</strong>. As a result, the<br />
periods <strong>of</strong> highest incidence <strong>of</strong> cobalt and selenium deficiency and helminthiasis coincide. In one<br />
trial, there were lasting responses to selenium but transient, though significant, responses to the<br />
cobalt in the form <strong>of</strong> increases in plasma vitamin B12, In some trials, the administration <strong>of</strong> a<br />
monthly bolus <strong>of</strong> 250 mg cobalt was more effective than the cobalt in the anthelmintic. The<br />
optimum level <strong>of</strong> cobalt supplementation <strong>of</strong> an anthelmintic ranges from 20 to 100 mg cobalt per<br />
treatment. When the anthelmintic is given at 3-weekly intervals there may be a cumulative effect.<br />
A comparison <strong>of</strong> giving 500 ug cyanocobalamin subcutaneously to one group <strong>of</strong> lambs, with 2.5<br />
mg cobalt orally in an anthelmintic to another group, revealed that even the lowest dose <strong>of</strong> cobalt<br />
in anthelmintics will be <strong>of</strong> some nutritional benefit (22).<br />
REFERENCES<br />
(1)McDonald, I. W. (1993) Aust.J. AXr. Res.,44, 347.<br />
(2)Mcc.J. F. & Rogers. P. A. M. (1996) IrishVet.J., 49, 160.<br />
(3)Mee.J. F. & Rogers, P. A. M. (1996) IrishVet.J., 49, 529.<br />
(4)Uvlund, M. J. & Pestalozzi, M. (1990) AdaVet. Scand., 31, 373.<br />
(5) Davits, S. C. ct al. (1993) Ami. Vet.J., 70, 1866.
(6)Vellema, P. ct al. (1997) Vet. Quart., 19,1.<br />
(7)Dannatt, L. & Porter, T. A. (1996) Vet.Rec., 7.!9, 371.<br />
(8)Uvlund. M.J. & Pestaloxzzi, M. (1990) Acta Vet. Scand., 31. 257.<br />
(9) Uvlund, M.J. (1990) Ada Vet. Scand., 31, 267.<br />
(10)Uvlund, M.J. (1990) Acta Vet. Scand., 31,277.<br />
(11)Uvlund, M.J. (1990) Acta Vet. Scand., 31,297.<br />
(12)Uvlund, M.J. (1990) Acta Vet. Scand., 31,287.<br />
(13)Uvlund, M.J. (1990) Ada Vet. Scand., 31,309.<br />
(14)Uvlund, M.J. (1990) Ada Vet. Scand., 31,369.<br />
(15)Fisher, G. E. ik MacPherson, A. (1991)Res. Vet. Set., 50, 319.<br />
(16)McGhie.T. K. (1991)J. Chmmatograph.Biomed. Appi, 566, 215.<br />
(17)O'Harte, F. R M. ct al. (1989) Br.J. Nutr.,62, 729.<br />
(18)Paterson.J. E. & MacPherson, A. (1990)Vet. Rec, 126, 329.<br />
(19)Kennedy, S. et al. (1997) Vet. Hatlwl., 34,575.<br />
(20)Clark, R. Ci. et al. (1989) NZ Vct.J., 37,7.<br />
(21)Hawke, M. F. et al. (1994) Proc. NZGrassland Assoc, 56, 249.<br />
(22)Suttle, N. F. et al. (1990) Vet. Rec, 126,192.<br />
COPPER DEFICIENCY<br />
Synopsis<br />
Etiology. Primary copper deficiency due to inadequate levels in diet. Secondary copper deficiency<br />
due to conditioning factors such as excess molybdenum and sulfur in diet. Epidemiology.<br />
Primarily in young pastured ruminants in spring and summer. Primary deficiency occurs in sandy<br />
soil and heavily weathered areas; secondary in peat or muck soil areas. Feed and water supplies<br />
may contain molybdenum, sulfate and iron salts, which interfere with copper metabolism. May be<br />
congenital in newborn lambs (swayback) if ewes deficient or delayed in nursing lambs (enzootic<br />
ataxia). Some breeds <strong>of</strong> sheep highly susceptible.<br />
Signs. Herd problem. Young growing ruminants on pasture. Unthriftiness, changes in hair color,<br />
chronic diarrhea in molybdenosis (secondary deficiency), chronic lameness, neonatal ataxia,<br />
anemia later stages <strong>of</strong> deficiency, and falling disease in adult cattle.<br />
Clinical pathology. Low serum and hepatic copper. Ceruloplasmin. <strong>An</strong>emia.<br />
Lesions. <strong>An</strong>emia, emaciation, hemosiderosis, osteodystrophy, demyelination in enzootic ataxia,<br />
myocardiopathy.<br />
Diagnostic confirmation. Low serum and hepatic copper and response to treatment.<br />
1488<br />
Differential diagnosis list<br />
Copper deficiency must be differentiated from herd problems associated with the following<br />
clinical findings:<br />
•Unthriftiness due to intestinal parasitism (Chapter 26)<br />
•Malnutrition due to energy-protein deficiency (p. 100)<br />
•Lameness <strong>caused</strong> <strong>by</strong> osteodystrophy due to calcium, phosphorus and vitamin D imbalance (pp.<br />
561, 1533)<br />
•<strong>An</strong>emia due to pediculosis (p. 1398)<br />
•Neonatal ataxia in lambs (congenital swayback and enzootic ataxia) from border disease (p.<br />
1238); cerebellar hypoplasia (daft lamb disease) (p. 1740); hypothermia (pp. 52, 129); meningitis
(p. 538)<br />
•Sudden death due to other causes(p. 75).<br />
Treatment. Copper sulfate orally; copper glycinate parenterally.<br />
Control. Provide source <strong>of</strong> copper <strong>by</strong> oral dosing or dietary supplementation in feed or on pasture.<br />
Parenteral administration <strong>of</strong> copper at strategic times. Copper oxide needles orally for prolonged<br />
effectiveness. Controlled-release boluses. Genetic selection. Removal <strong>of</strong> sulfates from water<br />
supply.<br />
ETIOLOGY<br />
Copper deficiency may be primary, when the intake in the diet is inadequate, or secondary<br />
(conditioned) when the dietary intake is sufficient but the utilization <strong>of</strong> the copper <strong>by</strong> tissues is<br />
impeded.<br />
Primary copper deficiency<br />
The amount <strong>of</strong> copper m the diet may be inadequate when the forage is grown on deficient soils or<br />
on soils in which the copper is unavailable.<br />
Secondary copper deficiency<br />
In secondary copper deficiency, the amount <strong>of</strong> copper in the diet is adequate, but conditioning<br />
dietary factors interfere with the utilization <strong>of</strong> the copper. Such secondary copper <strong>deficiencies</strong> are<br />
summarized in Table 29.2. The administration <strong>of</strong> copper is preventive and curative. The<br />
conditioning factor is known only in some instances, but a dietary excess <strong>of</strong> molybdenum is one <strong>of</strong><br />
the most common. A high molybdenum intake can induce copper deficiency even when the<br />
copper content <strong>of</strong> the pasture is quite high, and a higher copper intake can overcome the effect <strong>of</strong><br />
the molybdenum. Conversely, supplementation <strong>of</strong> the diet with molybdenum can be used to<br />
counteract the copper intake when its content in the diet is dangerously high. There are species<br />
differences in response to high copper and molybdenum intake; sheep are much more susceptible<br />
to copper poisoning, cattle to excess molybdenum.<br />
Zinc, iron, lead, and calcium carbonate are also conditioning factors, and in New Zealand the<br />
administration <strong>of</strong> selenium to sheep on copper-deficient pastures increases copper absorption and<br />
improves the growth rate <strong>of</strong> lambs. The use <strong>of</strong> zinc sulfate for the control <strong>of</strong>ficial eczema may<br />
cause a depression <strong>of</strong> plasma copper levels, which can be alleviated <strong>by</strong> the injection <strong>of</strong> copper<br />
glycinate.<br />
Dietary inorganic sulfate in combination with molybdenum has a pr<strong>of</strong>ound effect on the<br />
uptake <strong>of</strong> copper <strong>by</strong> ruminants. Sheep consuming a complete diet, low in sulfur and molybdenum<br />
and with a modest I 2-20 mg copper/kg dry matter (DM), may die from copper toxicity, while<br />
others grazing pasture <strong>of</strong> similar copper content but high in molybdenum and sulfur can give birth<br />
to lambs affected with the copper deficiency disease sway-back (1). <strong>An</strong> increase <strong>of</strong> sulfate<br />
concentration m a sheep diet from 0.1 to 0.4% can potentiate a molybdenum content as low as 2<br />
mg/kg (0.02 mmol/kg) to reduce copper absorption to below normal levels. Additional sulfate in<br />
the diet also has a depressing effect on the absorption <strong>of</strong> selenium so that areas <strong>of</strong> a country with<br />
marginal copper and selenium levels in the soil may produce deficiency syndromes in animals if<br />
sulfate is added; this is likely to happen when heavy dressings <strong>of</strong> superphosphate are applied. Such<br />
combined <strong>deficiencies</strong> are becoming more common. The possibility <strong>of</strong> interaction between copper<br />
and selenium must also be considered because <strong>of</strong> the reported failure <strong>of</strong> animals to respond to<br />
treatment unless both elements are provided.<br />
EPIDEMIOLOGY
Occurrence<br />
Copper deficiency is endemic worldwide and causes diseases <strong>of</strong> economic importance that may be<br />
severe enough to render large areas <strong>of</strong> otherwise fertile land unsuitable for grazing <strong>by</strong> ruminants<br />
<strong>of</strong> all ages, but primarily young, growing ruminants. Based on serum copper surveys <strong>of</strong> cattle<br />
herds in Britain, copper deficiency constitutes a serious problem requiring vigilance. It is<br />
estimated that characteristic clinical signs <strong>of</strong> copper deficiency develop annually in about 0.9% <strong>of</strong><br />
the cattle population in the United Kingdom. In some surveys, the lowest levels <strong>of</strong> serum copper<br />
were in heifers being reared as heifer replacements. Although heavy mortalities occur m affected<br />
areas, the major loss is due to failure ot animals to thrive. Enzootic ataxia may affect up to 90% <strong>of</strong><br />
a lamb flock in badly affected areas and most <strong>of</strong> these lambs die <strong>of</strong> inanition. In falling disease, up<br />
to 40% <strong>of</strong> cattle in affected herds may die.<br />
Geographical distribution<br />
Primary copper deficiency<br />
The diseases <strong>caused</strong> <strong>by</strong> ciency <strong>of</strong> copper in a primary deficiency <strong>of</strong> copper in ruminants are<br />
enzootic ataxia <strong>of</strong> sheep in Australia, New Zealand and the United States, licking sickness, or<br />
liksucht <strong>of</strong> cattle in Holland, and falling disease <strong>of</strong> cattle in Australia.<br />
Table 29.2 Secondary copper deficiency status<br />
Disease Country Species affected Copper level in Probable<br />
liver<br />
conditionin<br />
g factor<br />
Swayback Britain,united states Sheep<br />
Low<br />
Unkonw<br />
Renguerra Peru<br />
Sheep<br />
Low<br />
Unkonw<br />
Teart<br />
Britain<br />
Sheep and cattle Unkonw Molybdenu<br />
Scouring disease Holland<br />
Cattle<br />
Unkonw m<br />
Peat scours New zealand<br />
Cattle<br />
Low<br />
Unkonw<br />
Peat scours Britain<br />
Cattle<br />
Unkonw,low Molybdenu<br />
level in blood m<br />
Peat scours Canada<br />
Cattle<br />
Unkonw Unkonw<br />
Salt sick<br />
Pine (unthrifty)<br />
United states(florida)<br />
Scotland<br />
Cattle<br />
Cattle<br />
Unkonw<br />
Low<br />
Moiybdenu<br />
m<br />
Unkown<br />
Unkonw<br />
1489<br />
A concurrent deficiency <strong>of</strong> both copper and cobalt occurs in Australia (coast disease) and<br />
Florida in the United States (salt sickness) and is characterized <strong>by</strong> the appearance- <strong>of</strong> clinical signs<br />
<strong>of</strong> both <strong>deficiencies</strong> in all species <strong>of</strong> ruminants. The disease is controlled <strong>by</strong> supplementation <strong>of</strong><br />
the diet with copper and cobalt.<br />
In pigs, copper deficiency may cause anemia in sucking pigs, and reduced growth rate and<br />
cardiac disease in growing pigs. Adult horses are unaffected, but abnormalities <strong>of</strong> the limbs and<br />
joints <strong>of</strong> foals reared in copper-deficient areas do occur. Osteochondrosis is associated with a<br />
copper deficiency in young, farmed red deer and wapiti X red deer hybrids in New Zealand (2).
Secondary copper deficiency<br />
The diseases <strong>caused</strong> <strong>by</strong> secondary copper deficiency, mostly due to high dietary intakes <strong>of</strong><br />
molybdenum and sulfate, arc-listed in Table 29.2. They include syndromes characterized <strong>by</strong><br />
diarrhea or <strong>by</strong> unthriftiness. Yellow calf, a disease <strong>of</strong> nursing calves occurs on Hawaii's<br />
range-land where copper content <strong>of</strong> forages ranges from 2.6 to 11.8 mg/kg and the molybdenum<br />
from less than 1 to 39 mg/kg. Swayback <strong>of</strong> lambs in the United Kingdom has been classed as a<br />
secondary copper deficiency, but no conditioning factor has been determined. While swayback is<br />
a naturally occurring disease <strong>caused</strong> <strong>by</strong> a primary deficiency <strong>of</strong> copper, identical lesions occur<br />
experimentally <strong>by</strong> feeding molybdenum and sulfate to the ewes. There is some evidence that<br />
heavy lime dressing <strong>of</strong> a pasture may predispose to swayback. A wasting disease similar to peat<br />
scours, and preventable <strong>by</strong> the administration <strong>of</strong> copper, and unthriftiness ('pine') <strong>of</strong> calves, occur<br />
in the United Kingdom, but in both instances the copper and molybdenum intakes are normal.<br />
Molybdenum appears to be the conditioning agent in enzootic ataxia in the United States. A<br />
dietary excess <strong>of</strong> molybdenum is known to be the conditioning factor in the diarrheic diseases,<br />
peat scours in New Zealand, California, and Canada, and 'teart' in Britain.<br />
A survey in Saskatchewan, Canada, found that 67% <strong>of</strong> slaughter cattle had liver levels lower<br />
than 10 mg copper/kg on a wet weight (ww). A survey <strong>of</strong> the copper status <strong>of</strong> the fetuses and<br />
livers from adult animals found that 20% <strong>of</strong> steers, 54% <strong>of</strong> pregnant cows, 52%) <strong>of</strong> heifers, and<br />
77% <strong>of</strong> non-pregnant cows had liver levels less than 25 mg/kg DM (3). The concentrations <strong>of</strong><br />
copper in the liver <strong>of</strong> the fetuses were directly proportional to the liver copper concentrations in<br />
the darns (3). Liver copper levels <strong>of</strong> fetuses from dams with liver copper greater than 25 mg/kg<br />
DM were higher than those in fetuses from dams with liver copper levels lower than 25 mg/kg<br />
DM. During gesta¬tion, the level <strong>of</strong> copper progressively increased in the fetal liver and decreased<br />
in the maternal liver. The concentration <strong>of</strong> copper in fetal livers increased with increasing fetal age<br />
and at term the new¬born calf has high levels <strong>of</strong> liver copper to meet postnatal requirements<br />
because cows' milk is a poor source <strong>of</strong> copper. The magnitude <strong>of</strong> copper deficiency in \ some<br />
areas is extensive and emphasizes the importance <strong>of</strong> adequate copper nutrition in pregnant cattle in<br />
order to maintain adequate fetal levels <strong>of</strong> copper.<br />
Seasonal incidence<br />
Both primary and secondary copper deficiency occur most commonly in spring and summer<br />
coinciding with the lowest levels <strong>of</strong> copper in the pasture.<br />
Large monthly variations occur in the serum levels <strong>of</strong> copper in both beet and dairy cattle and<br />
are commonly correlated with the rainfall; the higher the rainfall the lower the copper level.<br />
The incidence <strong>of</strong> secondary copper deficiency may be highest at other times, depending upon<br />
the concentration <strong>of</strong> the conditioning factor in the forage. For example, the molybdenum content<br />
may be highest in the autumn when rains stimulate a heavy growth <strong>of</strong> legumes.<br />
Risk factors<br />
Several factors influence the plasma and tissue concentrations <strong>of</strong> copper, particularly in ruminants,<br />
including:<br />
•Age <strong>of</strong> animal<br />
•Demands <strong>of</strong> pregnancy and lactation<br />
•Stage <strong>of</strong> growth<br />
•Copper sources available to the animals<br />
•Mineral composition <strong>of</strong> feed
•Season <strong>of</strong> the year<br />
•Soil characteristics and its <strong>mineral</strong> composition<br />
•Breed <strong>of</strong> animal<br />
•Concentration <strong>of</strong> <strong>mineral</strong>s, such as sulfur and molybdenum, which can interfere with the<br />
availability <strong>of</strong> copper (4, 5).<br />
<strong>An</strong>imal factors<br />
Age susceptibility<br />
Young animals are more susceptible to primary copper deficiency than adults. Calves on dams fed<br />
deficient diets may show signs at 2-3 months <strong>of</strong> age. As a rule, the signs are severe in calves and<br />
yearlings, less severe in 2-year-olds, and <strong>of</strong> minor degree in adults. Enzootic ataxia is primarily a<br />
disease <strong>of</strong> sucking lambs whose dams receive insufficient dietary copper. Ewes with a normal<br />
copper status take some time to lose their hepatic reserves <strong>of</strong> copper after transfer to<br />
copper-deficient pastures and do not produce affected lambs for the first 6 months. The occurrence<br />
<strong>of</strong> the disease in sucklings, and its failure to appear after weaning, point to the importance <strong>of</strong> fetal<br />
stores <strong>of</strong> copper and the inadequacy <strong>of</strong> milk as a source <strong>of</strong> copper. Milk is always a poor source <strong>of</strong><br />
copper and when it is the sole source <strong>of</strong> nourishment the intake <strong>of</strong> copper will be low. Milk from<br />
normal ewes contains 20-60 ug/dL (3.1-9.4 umol/L) copper, but under conditions <strong>of</strong> severe copper<br />
deficiency this may be reduced to 1 2 (0.16-0.31 umol/L).<br />
Breed susceptibility<br />
There are marked genetic differences in copper metabolism between breeds <strong>of</strong> sheep. The Welsh<br />
Mountain ewe can absorb copper 50% more efficiently than the Scottish blackface (6), and the<br />
Texel cross blackface 145% more efficiently than pure blackface lambs (6). The susceptibility to,<br />
or protection from, the effects <strong>of</strong> copper deficiency, and also copper poisoning, is influenced from<br />
birth <strong>by</strong> genetic effects. These affect copper status <strong>of</strong> the lamb at birth, through the maternal<br />
environment controlled <strong>by</strong> the dam's genes and through the effect <strong>of</strong> the lamb's own genes. Later<br />
in life, the animal's own genes become the predominant influence determining its copper status on<br />
any given nutritional regimen. These genetic differences have physiological consequences<br />
reflected in differences m the incidence <strong>of</strong> swayback, both between and within breeds, and in<br />
effects on growth and possibly on reproduction. The differences observed are due to genetic<br />
differences in the efficiency <strong>of</strong> absorption <strong>of</strong> dietary copper.<br />
The genetic effects determining the copper status <strong>of</strong> the lamb are already present in utero, and<br />
the effects are not con-<br />
1490<br />
trolled <strong>by</strong> the lamb's own genotype but <strong>by</strong> that <strong>of</strong> its dam. The maternal effect is still present at<br />
weaning at 9 weeks <strong>of</strong> age, but disappears after weaning when the genetic differences are due to<br />
the sheep's own genotype.<br />
The existence <strong>of</strong> genes determining plasma copper has been shown <strong>by</strong> the successful continued<br />
selection for high and low concentrations in closed lines <strong>of</strong> a single breed type. Ram selection is<br />
made on the basis <strong>of</strong> plasma copper concentrations at 18 and 24 weeks <strong>of</strong> age. The proportion <strong>of</strong><br />
the normal variation in plasma copper that is heritable is 0.3. I he high-line female sheep retain<br />
more copper in the liver than the low-line females, <strong>caused</strong> <strong>by</strong> a positive correlation between the<br />
concentration <strong>of</strong> copper in plasma and the efficiency <strong>of</strong> absorption (7).<br />
The genetic variation in the copper metabolism <strong>of</strong> sheep has important physiological<br />
consequences. Breeds show wide variation in their susceptibility to sway-back; the incidence <strong>of</strong>
swayback may vary from 0 to 40% between breeds within one Hock, and the incidence according<br />
to breed type is closely related to the differences in the concentration <strong>of</strong> copper in the liver than in<br />
blood. When these high and low female lines are placed on improved and limed pasture, which<br />
can induce a severe copper deficiency, soon after birth there are indications <strong>of</strong> sway-back, general<br />
dullness, lack <strong>of</strong> vigor and mortality m the lambs. By 6 weeks <strong>of</strong> age the mortality rate is higher in<br />
the lambs from the low copper line than in those from the high copper line. In addition, at 6 weeks<br />
<strong>of</strong> age, lambs from the low line are 2 kg lighter than those in the high line.<br />
Certain breeds <strong>of</strong> cattle, e.g. the Simmental and Charolais, may haw: higher copper<br />
requirements than other breeds, e.g. <strong>An</strong>gus, and these differences may be related to differences in<br />
copper absorption in the gastrointestinal tract (8, 9).<br />
Fetal liver copper<br />
During gestation, the copper concentration increases progressively in the ovine and bovine fetal<br />
liver and decreases in the maternal liver (10). The developing bovine fetus obtains its copper <strong>by</strong><br />
placenta] transfer and at birth the liver concentration <strong>of</strong> copper is high and declines postnatally<br />
to adult levels within the first few months (3). Placental transfer is less efficient in sheep, and<br />
lambs are commonly born with low liver reserves, making the neonatal lambs susceptible to<br />
copper deficiency (10). In copper-deficient cattle, the accumulation <strong>of</strong> liver copper in the fetus<br />
continues independent <strong>of</strong> the dam's liver copper until the fetus is about 180 days, then a gradual<br />
decline in fetal liver copper occurs. The liver copper concentration in fetuses from dams on a<br />
copper-adequate diet continues to increase and not decline at 180 days <strong>of</strong> gestation. All <strong>of</strong> this<br />
indicates an increase in copper requirements <strong>by</strong> the dam during pregnancy; during the last month<br />
<strong>of</strong> pregnancy, the daily requirement for copper in cattle increases to approximately 70% above the<br />
mainte¬nance requirements, which means that the dietary allowance <strong>of</strong> 10 mg/kg DM needs to be<br />
increased up to 25 mg/kg DM during pregnancy (10). The concentrations <strong>of</strong> copper, iron,<br />
manganese, and zinc are consistently lower than normal in the livers <strong>of</strong> aborted fetuses, indicating<br />
a non-specific change in trace element status which is probably an effect <strong>of</strong> abortion, and not a<br />
cause (11).<br />
Colostrum is rich in copper, allowing the newborn with its preferential ability to absorb copper<br />
to increase hepatic stores. Later, the copper content <strong>of</strong> milk declines rapidly so that it is usually<br />
insufficient to meet the requirements <strong>of</strong> the sucking neonate for copper. The young milk-fed<br />
animal is able to absorb about 80% <strong>of</strong> its copper intake, but the efficiency <strong>of</strong> absorption declines<br />
with age as the rumen becomes functional, when only 2-10% <strong>of</strong> available copper is absorbed.<br />
Dietary factors<br />
Pasture composition<br />
The absorption (or availability) <strong>of</strong> copper is influenced <strong>by</strong> the type <strong>of</strong> diet, the pres¬ence <strong>of</strong> other<br />
substances in the diet such as molybdenum, sulfur and iron, the interaction between the type <strong>of</strong><br />
diet and the chemical composition <strong>of</strong> the diet, and the genetic constitution <strong>of</strong> the animals (6).<br />
Copper is well-absorbed from diets ' low in fiber, such as cereals and brassicas, but poorly<br />
absorbed from fresh forage. Conservation <strong>of</strong> grass as hay or silage generally improves its<br />
availability. This explains why copper deficiency is a problem <strong>of</strong> the grazing animal and seen only<br />
rarely in housed ruminants receiving diets that are commonly adequate in copper.<br />
Molybdenum and sulfur<br />
Only small increases in the molybdenum and sulfur concentration <strong>of</strong> grass will cause major<br />
reductions in the availability <strong>of</strong> copper (6). This is especially notable in ruminants grazing
improved pastures in which the molybdenum and sulfur concentrations were increased. The<br />
copper content <strong>of</strong> feedstuffs should be expressed in terms <strong>of</strong> available copper concentration, using<br />
appropriate equations, which permits a more accurate prediction <strong>of</strong> clinical disease and can be<br />
used for more effective control strategies.<br />
The effect <strong>of</strong> changes in molybdenum and sulfur concentrations m grass on the availability <strong>of</strong><br />
copper is changed <strong>by</strong> conservation. At a given concentration <strong>of</strong> sulfur, the antagonistic effect <strong>of</strong><br />
molybdenum is proportionately less in hay than in fresh grass. At a low concentration <strong>of</strong><br />
molybdenum the effect <strong>of</strong> sulfur is more marked in silage than in fresh grass. The use <strong>of</strong><br />
formaldehyde as a silage additive may weaken the copper sulfur antagonism and yield material <strong>of</strong><br />
high availability (6). Thus, fields <strong>of</strong> herbage high in molybdenum should be used for conservation<br />
when possible, and sulfuric acid should not be used as an additive for silage unless accompanied<br />
<strong>by</strong> a copper salt because it significantly raises the sulfur concentration <strong>of</strong> the silage.<br />
Copper in diet<br />
For general purposes, pasture containing less than 3 mg/kg DM <strong>of</strong> copper will result in signs <strong>of</strong><br />
deficiency m grazing ruminants. Levels <strong>of</strong> 3-5 mg/kg DM can be considered as dangerous, and<br />
levels greater than 5 mg/kg DM (preferably 7 12) are safe unless complicating factors cause<br />
secondary copper deficiency. The complexity <strong>of</strong> minimum copper requirements, affected as they<br />
are <strong>by</strong> numerous conditioning factors, necessitates examination under each particular set <strong>of</strong><br />
circumstances. For example, plant molybdenum levels are related directly to the p}l reaction <strong>of</strong><br />
the soil. Grasses grown on strongly acidic molybdenum-rich soils are characterized <strong>by</strong> low<br />
molybdenum values (less than 3 mg/kg DM), whereas those associated with alkaline<br />
molybdenum-poor soils may contain up to 17 mg/kg DM. Thus, it seems likely that conditioned<br />
copper deficiency can be related to regionally enhanced levels <strong>of</strong> plant available rather than soil<br />
molybdenum.Heavily limedpastures are <strong>of</strong>ten<br />
1491<br />
associated with a less than normal copper intake and a low copper status <strong>of</strong> sheep grazing them.<br />
Secondary copper deficiency is also recorded in pigs whose drinking water contains very large<br />
amounts <strong>of</strong> sulfate.<br />
Dietary iron<br />
A dietary intake <strong>of</strong> iron can interfere with copper metabolism (12). Dietary levels <strong>of</strong> iron in the<br />
range <strong>of</strong> 500-1500 mg/kg DM, within the range <strong>of</strong> their fluctuation in silage and forage, and<br />
higher levels, are a risk <strong>of</strong> inducing copper deficiency in ruminants, especially when the copper<br />
intake is marginal. Ruminants obtain iron from ingested soil and <strong>mineral</strong> supplements and, in<br />
areas where hypocuprosis is likely to occur, the risk can be minimized <strong>by</strong> avoiding the use <strong>of</strong><br />
<strong>mineral</strong> supplements <strong>of</strong> high iron content, minimizing the use <strong>of</strong> bare winter pasture and avoiding<br />
the excessive contamination <strong>of</strong> silage with soil during harvesting.<br />
Molybdenum-induced secondary copper deficiency in cattle occurred when motor oil<br />
containing molybdenum bisulfide was spilled on a pasture located on the side <strong>of</strong> a railway bed<br />
near the farm (13).<br />
Stored feeds<br />
Livestock that are housed are in a different position to those on pasture. Concentrates and<br />
proprietary feeds usually contain adequate copper. Pasture is less likely to contain sufficient<br />
copper, especially in early-spring when the grass growth is lush, and silage and haylage may be<br />
deficient. lay is more mature and usually contains more <strong>of</strong> all <strong>mineral</strong>s, so that animals housed for
the winter are protected against copper deficiency for ,a few weeks after they come out onto<br />
pasture in the spring. Young, growing animals will be first affected. These comments should not<br />
be interpreted to mean that housed or feedlot animals cannot be affected <strong>by</strong> hypocuprosis; they<br />
can if the locally produced feed is copper-deficient, or more likely has a high concentration <strong>of</strong><br />
molybdenum. Both are likely to be prevented, or less severe, it there is some supplementary<br />
feeding.<br />
Soil characteristics<br />
Copper deficiency<br />
In general, there are two types <strong>of</strong> soil on which copper-deficient plants are produced. Sandy soils,<br />
poor in organic matter and heavily weathered, such as on the coastal plains <strong>of</strong> Australia, and in<br />
marine and river silts, are likely to be deficient in copper as well as other trace elements,<br />
especially cobalt.<br />
The second important group <strong>of</strong> soils are 'peat' or muck soils reclaimed from swamps, and<br />
are soils more commonly associated with copper deficiency in the United States, New Zealand,<br />
and Europe. Such soils may have an absolute deficiency <strong>of</strong> copper, but more commonly the<br />
deficiency is relative in that the copper is not available and the plants growing on the soils do not<br />
contain adequate amounts <strong>of</strong> the element.<br />
The cause <strong>of</strong> the lack <strong>of</strong> availability <strong>of</strong> the copper is uncertain, but is probably the formation <strong>of</strong><br />
insoluble organic copper complexes. <strong>An</strong> additional factor is the production <strong>of</strong> secondary copper<br />
deficiency on these soils due to their high content <strong>of</strong> molybdenum. A summary <strong>of</strong> the relevant<br />
levels <strong>of</strong> copper in soils and plants is given in Table 29.3.<br />
Molybdenum excess<br />
Pastures containing less than 3 mg/kg DM <strong>of</strong> molybdenum are considered to be safe, but disease<br />
may. occur at 3-10 mg/kg DM if the copper intake is low. Pastures containing more than 10 mg/kg<br />
DM <strong>of</strong> molybdenum are dangerous unless the diet is supplemented with copper. Excess<br />
molybdenum may occur in soils up to levels <strong>of</strong> 10 and even 100 mg/kg. Perhaps more dangerous<br />
is the risk that overzealous application <strong>of</strong> molybdenum to pasture to increase bacterial nitrogen<br />
fixation may have similar effects, which are likely to be long-lasting.<br />
In the United Kingdom appreciable land is underlain <strong>by</strong> marine black shales rich in<br />
molybdenum, resulting in a high content <strong>of</strong> molybdenum in the soil and pastures, and in a<br />
secondary copper deficiency that, potentially, limits livestock performance. Secondary<br />
(conditioned) copper deficiency is now recognized in cattle in many parts <strong>of</strong> Canada. Large areas<br />
<strong>of</strong> west-central Manitoba are underlain <strong>by</strong> molybdeniferous shale bedrocks and the soils contain<br />
up to 20 mg/kg <strong>of</strong> molybdenum. However, in the same geographical location, hypocupremia may<br />
be associated with a primary deficiency <strong>of</strong> copper in the forage, or a secondary copper deficiency<br />
clue to molybdenum in the forages.<br />
PATHOCLNES1S<br />
Effects on tissues<br />
Copper is necessary in tissue oxidation <strong>by</strong> either supplementing cytochrome oxidase systems or<br />
entering into their formation. Ceruloplasmin is the copper-containing enzyme through which<br />
copper exerts its physiological function. The pathogenesis <strong>of</strong> most <strong>of</strong> the lesions <strong>of</strong> copper<br />
deficiency has been explained in terms <strong>of</strong> faulty tissue oxidation because <strong>of</strong> failure <strong>of</strong> these<br />
enzyme systems. This role is<br />
Table 29.3 Copper levels <strong>of</strong> soils and plants in primary and secondary copper deficiency
Condition Area<br />
Normal<br />
Primary copper<br />
deficiencyWes<br />
Secondary copper<br />
deficiency<br />
-<br />
West Australia<br />
New Zealand<br />
New Zealand<br />
HollandSand<br />
New Zealand<br />
Britain<br />
Britain<br />
Britain<br />
Ireland<br />
Holland<br />
Canada<br />
Soil type Soil copper<br />
mg/kg<br />
-<br />
various<br />
Sand<br />
Peat<br />
Sand<br />
Peat<br />
Peat<br />
Limestone<br />
Stiff clay<br />
Shale deposits,<br />
peat marine alluvial soils<br />
sand<br />
Burned-over peat<br />
18-22<br />
1-2<br />
0.1-0.6<br />
-<br />
-<br />
5<br />
-<br />
-<br />
-<br />
-<br />
20-60<br />
Plant<br />
copper<br />
(mg/kg dry<br />
matter)<br />
11<br />
3-5<br />
3<br />
3<br />
5<br />
10-25<br />
1492<br />
exemplified in the early stages <strong>of</strong> copper deficiency <strong>by</strong> the changes in the wool <strong>of</strong> sheep.<br />
Wool<br />
The straightness and stringiness <strong>of</strong> this wool is due to inadequate keratinization, probably due to<br />
imperfect oxidation <strong>of</strong> free thiol groups. Provision <strong>of</strong> copper to such sheep is followed <strong>by</strong><br />
oxidation <strong>of</strong> these free thiol groups and a return to normal keratinization within a few hours.<br />
Body weight<br />
In the later stages <strong>of</strong> copper deficiency the impairment <strong>of</strong> tissue oxidation causes interference with<br />
intermediary metabolism and loss <strong>of</strong> condition or failure to grow.<br />
Diarrhea<br />
The pathogenesis <strong>of</strong> copper deficiency in causing diarrhea is uncertain and there is little evidence<br />
that a naturally-occurring primary copper deficiency will cause diar-rhea. There are no histologica]<br />
changes in gut mucosa, although villous atrophy is recorded in severe, experimentally produced<br />
cases. Diarrhea is usually only .a major clinical finding in secondary copper deficiency associated<br />
with molybdenosis.<br />
<strong>An</strong>emia<br />
The known importance <strong>of</strong> copper in the formation <strong>of</strong> hemoglobin accounts for the anemia in<br />
copper deficiency. The presence <strong>of</strong> hemosiderin deposits in tissues <strong>of</strong> copper-deficient animals<br />
suggests that copper is necessary for the reutilization <strong>of</strong> iron liberated from the normal breakdown<br />
<strong>of</strong> hemoglobin. There is no evidence <strong>of</strong> excessive hemolysis in copper-deficiency states. <strong>An</strong>emia<br />
may occur in the later stages <strong>of</strong> primary copper deficiency, but is not remarkable in the secondary<br />
form unless there is a marginal copper deficiency, as occurs in peat scours in New Zealand. The<br />
unusual relation¬ship in New Zealand between copper deficiency and postparturient<br />
hemoglobinuria is unexplained. Heinz body ane-mia in lambs with <strong>deficiencies</strong> <strong>of</strong> copper or
selenium and moved from improved pasture to rape (Brassicaa napus) has been reported.<br />
Bone<br />
The osteoporosis that occurs in some natural cases <strong>of</strong> copper deficiency is <strong>caused</strong> <strong>by</strong> the<br />
depression <strong>of</strong> osteoblastic activity (14).<br />
In experimentally induced primary copper deficiency, the skeleton is osteoporotic and there is a<br />
significant increase in osteoblastic activity. There is a marked overgrowth <strong>of</strong> epiphyseal cartilage,<br />
especially at costochondral junctions and in metatarsal bones. This is accompanied <strong>by</strong> beading <strong>of</strong><br />
the ribs and enlargement <strong>of</strong> the long bones. There is also an impairment <strong>of</strong> collagen formation.<br />
When the copper deficiency is secondary to dietary excesses <strong>of</strong> molybdenum and sulfate, the<br />
skeletal lesions are quite different and characterized <strong>by</strong> widening <strong>of</strong> the growth plate and<br />
metaphysis, and active osteoblastic activity.<br />
Copper deficiency in foals causes severe degenerative disease <strong>of</strong> cartilage, characterized <strong>by</strong><br />
breaking <strong>of</strong> articular and growth plate cartilage through the zone <strong>of</strong> hypertrophic cells, resulting in<br />
osteochondrosis <strong>of</strong> the articular-epiphyseal complex (A-E complex) (5). The incidence and<br />
severity <strong>of</strong> osteochondrosis in foals can be decreased <strong>by</strong> supplementation <strong>of</strong> the diets <strong>of</strong> mares<br />
during the last 3-6 months <strong>of</strong> pregnancy and the first 3 months <strong>of</strong> lactation (4). Foals from<br />
non-supplemented mares have separation <strong>of</strong> the thickened cartilage from the subchondral bone.<br />
Clinical, radiographic, and biochemical differences occur between copper-deficient and<br />
copper-supplemented foals (16), and there may be a relationship between low copper intakes in<br />
rapidly growing horses, inferior collagen quality, biomechanically weak cartilage, and<br />
osteochondritis (17).<br />
Copper is essential for metalloenzyme lysyl oxidase, which produces aldehydic groups on<br />
hydroxylysine residues as a prerequisite for eventual cross-link formation in collagen and elastin.<br />
Similar lesions in foals have been attributed to zinc toxicity from exposure <strong>of</strong> affected animals to<br />
pasture polluted <strong>by</strong> smelters. Experimentally, the addition <strong>of</strong> varying amounts <strong>of</strong> zinc to the diet <strong>of</strong><br />
foals containing adequate copper will result in zinc-induced copper deficiency (5), but there are no<br />
effects with zinc intakes up to 580 ppm and it is suggested that 2000 ppm or higher are necessary<br />
to affect copper absorption in horses (18). Similar lesions <strong>of</strong> osteochondrosis have occurred in<br />
young tanned red deer and wapiti X red deer hybrids in New Zealand (2).<br />
Connective tissue<br />
Copper is a component <strong>of</strong> the enzyme lysyl oxidase, secreted <strong>by</strong> the cells involved in the synthesis<br />
<strong>of</strong> the elastin component <strong>of</strong> connective tissues and has important functions in maintaining the<br />
integrity <strong>of</strong> tissues such as capillary beds, ligaments, and tendons.<br />
Heart<br />
The myocardia] degeneration <strong>of</strong> falling disease may be a terminal manifestation <strong>of</strong> anemic anoxia,<br />
or be due to interference with tissue oxidation. In this disease it is thought that the stress <strong>of</strong> calving<br />
and lactation contribute to the development <strong>of</strong> heart block and ventricular fibrillation when there<br />
has already been considerable decrease in cardiac reserve. Experimentally induced copper<br />
deficiency in piglets causes a marked reduction in growth and hematocrit, and cardiac pathology<br />
and electrical disturbances (19).<br />
Blood vessels<br />
Experimentally produced copper deficiency has also <strong>caused</strong> sudden death due to rupture <strong>of</strong> the<br />
heart and great vessels in a high proportion <strong>of</strong> pigs fed a copper-deficient diet. The basic defect is<br />
degeneration <strong>of</strong> the internal elastic laminae. I here is no record <strong>of</strong> a similar, naturally occurring
disease. A similar relationship appears to have been established between serum copper levels and<br />
fatal rupture <strong>of</strong> the uterine artery at parturition in aged mares.<br />
Pancreas<br />
Lesions <strong>of</strong> the pancreas may be present in normal cattle with a low blood copper status. The<br />
lesions consist <strong>of</strong> an increase in dry matter content and a reduction in the concentrations <strong>of</strong> protein<br />
and copper in wet tissue. The cytochrome oxidase activity and protein: RNA ratio are also reduced.<br />
There are defects in acinar basement membranes, splitting and disorganization <strong>of</strong> acini, cellular<br />
atrophy and dissociation, and stromal proliferation.<br />
Nervous tissue<br />
Copper deficiency halts the formation <strong>of</strong> myelin and causes demyelination in lambs, probably <strong>by</strong> a<br />
specific relationship between copper and myelin sheaths. Defective myelination can commence as<br />
early as the midpoint <strong>of</strong> the fetus's uterine life. The focus <strong>of</strong> lesions in the white matter shifts from<br />
the cerebrum in lambs affected at birth (congenital swayback) to the spinal cord in delayed cases,<br />
which may reflect respective peaks <strong>of</strong> myelin<br />
1493<br />
development at those sites at 90 days <strong>of</strong> gestation and 20 days after birth. The postnatal<br />
development <strong>of</strong> delayed sway-back has been confirmed through its control <strong>by</strong> copper<br />
supplementation after birth. In experimental animals it has been shown that copper deficiency<br />
does interfere with the synthesis <strong>of</strong> phospholipids. While anoxia is a cause <strong>of</strong> demyelination, an<br />
anemic anoxia is likely to occur in highly deficient ewes, and anemic ewes produce a higher<br />
proportion <strong>of</strong> lambs with enzootic ataxia, there is <strong>of</strong>ten no anemia in ewes producing lambs with<br />
the more common subacute form <strong>of</strong> the disease. Severely deficient ewes have lambs affected at<br />
birth .and in which myelin formation is likely to have been prevented. The lambs <strong>of</strong> ewes less<br />
severely deficient have normal myelination at birth, and develop demyelination in postnatal life.<br />
Reproductive performance<br />
There is no evidence that copper deficiency causes reproductive failure in dairy cows. Copper<br />
glycinate given to dairy cattle does not affect the average interval in days between calving and<br />
first observed heat, services per conception, or first service conception rate compared to untreated<br />
cows in the same population. Experimentally, the addition <strong>of</strong> molybdenum to the diet <strong>of</strong> heifers<br />
delayed the onset <strong>of</strong> puberty, decreased the conception rate, and <strong>caused</strong> anovulation and anestrus<br />
in cattle without accompanying changes in copper status or in liveweight gain. Thus, the presence<br />
<strong>of</strong> molybdenum rather than low copper status may affect reproductive performance <strong>of</strong> cattle.<br />
Geo-chemical data indicate that approximately 10% <strong>of</strong> the cultivated area <strong>of</strong> England and Wales<br />
have soils that may result in forage molybdenum concentrations similar to those used in the above<br />
experimental diet. It appears inadvisable to ascribe poor reproductive performance to subclinical<br />
hypocuprosis on the evidence <strong>of</strong> blood copper analysis alone. Other factors, such as management<br />
and energy and protein intake, should be examined.<br />
Immune system<br />
Copper deficiency results in decreased humoral and cell-mediated immunity, as well as decreased<br />
non-specific immunity regulated <strong>by</strong> phagocytic cells, such as macrophages and neutrophils. The<br />
decreased resistance to infection in sheep is amenable to treatment with copper and genetic<br />
selection. In lambs genetically selected for low and high concentrations <strong>of</strong> plasma copper, the<br />
mortality from birth to 24 weeks <strong>of</strong> age in the high line was half that in the low line. Most <strong>of</strong> the<br />
losses were due to a variety <strong>of</strong> microbial infections. Experimental viral and bacterial infections <strong>of</strong>
cattle can cause a rapid, though transient, increase in serum ceruloplasmin and plasma copper in<br />
copper-replete animals, suggesting a major protective role for copper in infectious diseases (20).<br />
These changes in copper metabolism evolve from an interleukin-1 mediated increase in hepatic<br />
synthesis and release <strong>of</strong> ceruloplasmin, an acute phase protein (20). Copper concentrations in<br />
organs involved in immune regulations such as liver, spleen, thymus, and lung are substantially<br />
reduced <strong>by</strong> copper deficiency, suggesting that copper-deficient animals are at greater risk for<br />
infection than copper-adequate animals. Experimental copper depletion and repletion did not<br />
affect neutrophil or lymphocyte function in growing beef cattle heifers (21).<br />
The severity <strong>of</strong> copper depletion needed for immune dysfunction is less than required to induce<br />
clinical signs <strong>of</strong> copper deficiency, and endogenous copper may contribute to the regulation <strong>of</strong><br />
both non-immune and immune inflammatory responses. Low molecular weight complexes may<br />
have an anti-inflammatory effect in animal models <strong>of</strong> inflammation, and it is postulated that the<br />
elevation <strong>of</strong> plasma copper-containing components during inflammatory disease represents a<br />
physiological response.<br />
Sequence <strong>of</strong> clinical signs development<br />
In experimental copper deficiency in calves, beginning at 6 weeks <strong>of</strong> age, sub-clinical and<br />
clinical abnormalities appear after the following intervals: hypocupremia at 15 weeks, growth<br />
retardation from 15 to 18 weeks, rough hair coat at 17 weeks, diarrhea at 20 weeks, and leg<br />
abnormalities at 23 weeks. These signs correlate well with the onset <strong>of</strong> hypocupremia and are<br />
indicative <strong>of</strong> a severe deficiency. Even with these signs <strong>of</strong> deficiency, the histological<br />
abnormalities may be only minor in degree.<br />
In experimental primary copper deficiency in calves, beginning at 12 weeks <strong>of</strong> age, clinical<br />
signs <strong>of</strong> the deficiency may not become apparent for about 6 months. Musculoskeletal<br />
abnormalities include a stilted gait, a ‘knock-kneed' appearance <strong>of</strong> the forelimbs, overextension <strong>of</strong><br />
the flexors, splaying <strong>of</strong> the hooves, and swellings around the etacarpophalangeal and<br />
carpometacarpal joints. Changes in hair pigmentation occur after about 5 months, and diarrhea<br />
between 5 and 7 months. The diarrhea ceased 12 hours after oral administration <strong>of</strong> a small amount<br />
(10 mg) <strong>of</strong> copper.<br />
Copper-molybdenum-sulfate relationship<br />
The interaction between copper, molybdenum, and sulfur in ruminant nutrition is unique in its<br />
effects on health and production. Copper, molybdenum, and sulfur from organic or inorganic<br />
sources can combine in the rumen to form an unabsorbable triple complex, copper<br />
tetrathiomolybdate, and deplete the host tissues <strong>of</strong> copper (1).<br />
Secondary or conditioned copper deficiency occurs when the dietary intake <strong>of</strong> copper is<br />
adequate, but absorption and utilization <strong>of</strong> the copper are inadequate because <strong>of</strong> the<br />
presence <strong>of</strong> interfering substances in the diet (1). Molybdenum and sulfate alone orin<br />
combination can affect copper metabolism and the mechanisms <strong>by</strong> which this occurs are now<br />
being clarified. This effect also operates in the fetus and interferes with copper storage in the fetal<br />
liver. Besides the relationship with molybdenum, an interaction between the absorption <strong>of</strong> copper<br />
and selenium has been demonstrated, the administration <strong>of</strong> selenium to sheep on copper-deficient<br />
pastures causing an improvement in copper absorption.<br />
The toxicity <strong>of</strong> any level <strong>of</strong> dietary molybdenum is affected <strong>by</strong> the ratio <strong>of</strong> the dietary<br />
molybdenum to dietary copper. The critical copper:molybdenum ratio in animal feeds is 2, and<br />
feeds or pasture with a lower ratio may result in conditioned copper deficiency. In some regions <strong>of</strong>
Canada, the copper: molybdenum ratio will vary from 0.1 to 52.7 (5). Higher critical ratios closer<br />
to 4.1-5.1 have been recommended for safety (5). The influence <strong>of</strong> dietary molybdenum on copper<br />
metabolismin ponies has been examined experimentally.<br />
The copper status <strong>of</strong> growing calves can also be affected to a similar degree <strong>by</strong> the inclusion <strong>of</strong><br />
appropriate levels <strong>of</strong> sup-<br />
1494<br />
plementary iron or molybdenum in the diet. Following such inclusion, the liver and plasma<br />
concentrations <strong>of</strong> copper will decline within 12-16 weeks to levels indicating severe copper<br />
deficiency. The clinical signs <strong>of</strong> copper deficiency, as indicated <strong>by</strong> reduced growth rate and<br />
changes in the hair texture and color, are evident after 16-20 weeks only in animals supplemented<br />
with molybdenum. The reduced growth rate was accompanied <strong>by</strong> a decreased feed intake and<br />
reduced efficiency <strong>of</strong> feed utilization.<br />
Copper absorption<br />
On the basis <strong>of</strong> a response to copper injections and no response to copper administered orally to<br />
sheep on a high molybdenum intake, it is suggested that interference occurs with the absorption <strong>of</strong><br />
copper from the gut.<br />
It is proposed that thiomolybdates from in the rumen from the reaction <strong>of</strong> dietary molybdenum<br />
compounds with sulfides produced from the reduction <strong>of</strong> dietary sulfur compounds <strong>by</strong> rumen<br />
bacteria. The thiomolybdates reduce the absorption <strong>of</strong> dietary copper from the intestine and also<br />
inhibit a number <strong>of</strong> copper-containing enzymes. including ceruloplasmin, cytochrome oxidase,<br />
superoxide dismutase, and tyrosine oxidase.<br />
Copper utilization<br />
Sulfate and molybdate can interfere with mobilization <strong>of</strong> copper from the liver, inhibition <strong>of</strong><br />
copper intake <strong>by</strong> the tissues, inhibition <strong>of</strong> copper transport both into and out <strong>of</strong> the liver, and<br />
inhibition <strong>of</strong> the synthesis <strong>of</strong> copper-storage complexes and ceruloplasmin.<br />
The clinical signs <strong>of</strong> hypocuprosis (such as steely wool) can occur in sheep on diets containing<br />
high levels <strong>of</strong> molybdenum and sulfate, even though blood copper levels are high. Tins suggests<br />
that under these circumstances copper is not utilizable in tissues and the blood copper rises in<br />
response to the physiological needs <strong>of</strong> the tissues for the element. In pigs, a copper-molybdenum<br />
complex can existin animals and that in this form the copper is unavailable. This would interfere<br />
with hepatic metabolism <strong>of</strong> copper and the formation <strong>of</strong> copper-protein complexes such as<br />
ceruloplasmin.<br />
Hepatic storage<br />
The copper status <strong>of</strong> the liver depends on whether the animals are receiving adequate dietary<br />
copper. With adequate dietary levels, the liver copper levels are less in the presence <strong>of</strong> molybdate<br />
and sulfate. If the animals are receiving a copper-deficient diet such that copper is being removed<br />
from the liver, then the molybdate plus sulfate animals retain more copper in their liver than<br />
copper-deficient animals not receiving sulfate plus molybdate. This supports the hypothesis that<br />
molybdate and sulfate together impair the movement <strong>of</strong> copper into or out <strong>of</strong> the liver, possibly <strong>by</strong><br />
affecting copper transport. Sulfate alone exerts an effect. <strong>An</strong> increasein intake reduces hepatic<br />
storage <strong>of</strong> both copper and molybdenum.<br />
Phases <strong>of</strong> copper deficiency<br />
The development <strong>of</strong> a deficiency can be divided into tour phases:<br />
1.Depletion
2.Deficiency (marginal)<br />
3.Dysfunction<br />
4.Disease.<br />
During the depletion phase there is loss <strong>of</strong> copper from any storage site, such as liver, but the<br />
plasma concentrations <strong>of</strong> copper may remain constant. With continued dietary deficiency the<br />
concentrations <strong>of</strong> copper in the blood decline during the phase <strong>of</strong> marginal deficiency. However, it<br />
may be some time before the concentrations or activities <strong>of</strong> copper-containing enzymes in the<br />
tissues begin to decline and it is not until this happens that the phase <strong>of</strong> dysfunction is reached.<br />
There may be a further lag before the changes in cellular function are manifested as clinical signs<br />
<strong>of</strong> disease.<br />
Summary<br />
The overall effect <strong>of</strong> these interactions is as follows. Molybdate reacts with sulfides to produce<br />
thiomolybdatesin the rumen.The subsequent formation <strong>of</strong> copper-thiomolybdate complexes<br />
isolates the copper from being biologically available (1). The thiomolybdates reduce the<br />
effectiveness <strong>of</strong> enzymes containing copper and there are some significant interactions between<br />
copper, zinc, and iron.<br />
CLINICAL FINDINGS<br />
The general effects <strong>of</strong> copper deficiency are the same in sheep and cattle, but in addition to these<br />
general syndromes there are specific syndromes more or less restricted to species and to areas.<br />
What follows is a general description <strong>of</strong> the disease <strong>caused</strong> <strong>by</strong> copper deficiency, in turn followed<br />
<strong>by</strong> the specific syndromes <strong>of</strong> enzootic ataxia, swayback, falling disease, peat scours, teart, and<br />
unthriftiness (pine).<br />
Cattle<br />
Subclinical hypocuprosis<br />
No clinical signs occur, blood copper levels are marginal or below 57 mg/dL (9.0 mmol/L) and<br />
there is a variable response in productivity after supplementation with copper. Some surveys in<br />
copper-deficient areas found that about 50% <strong>of</strong> beef herds and 10% <strong>of</strong> dairy herds within the same<br />
area have low blood levels <strong>of</strong> blood copper associated with low copper intake from natural forages.<br />
The deficiency is likely to be suspected only if production is monitored and found to be<br />
supoptimal.<br />
A perplexing feature <strong>of</strong> subclinical hypocuprosis is the wide variation in improved growth rate<br />
obtained when cattle <strong>of</strong> the same low copper status are given supplementary copper under field<br />
conditions.<br />
General syndrome<br />
Primary copper deficiency<br />
Primary copper deficiency causes unthriftiness. loss <strong>of</strong> milk production, and anemia in adult cattle.<br />
The coat color is affected, red and black cattle changing to a bleached, rusty red. and the coat itself<br />
becomes rough and staring. In severely deficient states, which are now uncommon, calves grow<br />
poorly, and there is an increased tendency for bones to fracture, particularly the limb bones and<br />
the scapula. Ataxia may occur after exercise, with a sudden loss <strong>of</strong> control <strong>of</strong> the hindlimbs and<br />
the annual tailing or assuming a sitting posture. Normal control returns after rest. Itching and<br />
hair-licking are also recorded as manifestations <strong>of</strong> copper deficiency in cattle. Although diarrhea<br />
may occur, persistent diarrhea is not characteristic <strong>of</strong> primary copper deficiency and its occurrence<br />
should arouse suspicion <strong>of</strong> molybdenosis or helminthiasis. In some affected areas, calves develop
stiffness and enlargement <strong>of</strong> the joints and contraction <strong>of</strong> the flexor tendons causing the affected<br />
animals to stand on their toes. These signs may be present at birth or occur before weaning.<br />
Paresis and incoordination are not evident.<br />
<strong>An</strong> increased occurrence <strong>of</strong> postparturient hemoglobinuria is also recorded,<br />
1495<br />
but only in New Zealand, and may be unrelated to copper deficiency.<br />
Secondary copper deficiency<br />
This syndrome includes the signs <strong>of</strong> primary copper deficiency, except that anemia occurs less<br />
commonly, probably due to the relatively better copper status in the secondary state, anemia being<br />
largely a terminal sign in primary copper deficiency. For example, anemia occurs in peat scours <strong>of</strong><br />
cattle in New Zealand, but in this instance the copper intake is marginal. In addition to the other<br />
signs, however, there is a general tendency for diarrhea to occur, particularly in cattle. Because<br />
diarrhea is not a major sign in naturally occurring primary copper deficiency it is possible that it is<br />
due to the conditioning factor, which reduces the availability <strong>of</strong> copper. For example, the severity<br />
<strong>of</strong> the diarrhea is roughly proportional to the level <strong>of</strong> intake <strong>of</strong> molybdenum.<br />
Falling disease<br />
The characteristic behavior in falling disease is for cows in apparently good health to throw up<br />
their heads, bellow, and fall. Death is instantaneous in most cases, but some fall and struggle<br />
feebly on their sides for a few minutes with intermittent bellowing, and running movement<br />
attempts to rise. Rare cases show signs for up to 24 hours or more. These animals periodically<br />
lower their heads and pivot on the front legs. Sudden death usually occurs during one <strong>of</strong> these<br />
episodes.<br />
Peat scours (‘teart')<br />
Persistent diarrhea with the passage <strong>of</strong> watery, yellow-green to black feces with an in<strong>of</strong>fensive<br />
odor occurs soon after the cattle go on to affected pasture, in some cases within 8-10 days. The<br />
feces are released without effort, <strong>of</strong>ten without lifting the tail. Severe debilitation is common,<br />
although the appetite remains good. The hair coat is rough and depigmentation is manifested <strong>by</strong><br />
reddening or gray flecking, especially around the eyes, in black cattle. The degree <strong>of</strong> abnormality<br />
varies a great deal from season to season and year to year, and spontaneous recovery is common.<br />
Affected animals usually recover in a few days following treatment with copper.<br />
Unthriftiness (pine) <strong>of</strong> calves<br />
The earliest signs are a stiffness <strong>of</strong> gait and unthriftiness. The epiphyses <strong>of</strong> the distal ends <strong>of</strong> the<br />
metacarpus and metatarsus may be enlarged and resemble the epiphysitis <strong>of</strong> rapidly growing<br />
calves deficient in calcium and phosphorus or vitamin D. The epiphyses are painful on palpation<br />
and some calves are severely lame. The pasterns arc upright and the animals may appear to have<br />
contracted flexor tendons. The unthriftiness and emaciation are progressive and death may occur<br />
in 4-5 months. Grayness <strong>of</strong> the hair, especially around the eyes in black cattle, is apparent.<br />
Diarrhea may occur in a few cases.<br />
Sheep<br />
General syndrome<br />
Primary copper deficiency<br />
Abnormalities <strong>of</strong> the wool are the first observed signs, and may be the only sign in areas <strong>of</strong><br />
marginal copper deficiency. Fine wool becomes limp, glossy and loses its crimp, developing a<br />
straight, steely appearance. Black wool shows depigmentation to gray or white, <strong>of</strong>ten in bands
coinciding with the seasonal occurrence <strong>of</strong> copper deficiency. The straight, steely defect may<br />
occur in similar bands, and the staple may break easily. There appear to be some differences<br />
between breeds in susceptibility to copper deficiency. Merino sheep appearing to have a higher<br />
copper requirement than mutton sheep. The fleece abnormalities <strong>of</strong> Merino sheep in Australia<br />
have not been observed in Romney Marsh sheep in copper-deficient areas in New Zealand, but<br />
this may be due in part to the difficulty <strong>of</strong> detecting abnormality in wool that is normally rather<br />
straight and steely. <strong>An</strong>emia, scouring, unthriftiness, and infertility may occur in conditions <strong>of</strong><br />
extreme deficiency, but in sheep the characteristic findings are in the lamb, the disease enzootic<br />
ataxia being the major manifestation. Retardation <strong>of</strong> growth, diarrhea, delay to marketing, and<br />
increased mortality are common clinical findings in lambs genetically selected for low plasma<br />
copper and placed on improved and limed upland pastures. Osteoporosis, with increased tendency<br />
<strong>of</strong> the long bones to fracture, has also been recorded under conditions <strong>of</strong> copper deficiency<br />
insufficient to cause enzootic ataxia.<br />
Swayback and enzootic ataxia in lambs and goat kids<br />
These diseases have much in common, but there are differences in epidemiology and some subtle<br />
clinical ones.<br />
SWAYBACK is the only authentic manifestation <strong>of</strong> a primary nutritional deficiency <strong>of</strong> copper in<br />
the United Kingdom. The incidence can vary greatly among breeds <strong>of</strong> sheep, reflecting the genetic<br />
differences in copper metabolism both between and within breeds <strong>of</strong> sheep. The disease occurs in<br />
several forms.<br />
A congenital form, cerebrospinal swayback, occurs only when the copper deficiency is<br />
extreme. Affected lambs are born dead or weak and unable to stand and suck. Incoordination and<br />
erratic movements are more evident than in enzootic ataxia and the paralysis is spastic in type.<br />
Blindness also occurs occasionally. There is s<strong>of</strong>tening and cavitation <strong>of</strong> the cerebral white matter<br />
and this probably commences about day 120 <strong>of</strong> gestation.<br />
Progressive (delayed) spinal swayback begins to develop some weeks after birth with lesions<br />
and clinical signs appearing at 3-6 weeks <strong>of</strong> age.<br />
Postnatal acute fatal swayback may be a third form <strong>of</strong> the disease, and appears to occur only in<br />
Wales. It resembles the more usual delayed form, but develops suddenly. There is a sudden onset<br />
<strong>of</strong> recumbency with death occurring 1-2 days later due to acute swelling <strong>of</strong> the cerebrum.<br />
ENZOOTIC ATAXIA affects only un-weaned lambs. In severe outbreaks the lambs may be<br />
affected at birth, but most cases occur in the 1-2-month age group. The seventy <strong>of</strong> the paresis<br />
decreases with increasing age at onset. Lambs affected at birth or within the first month usually<br />
die within 3-4 days. The disease in older lambs may last for 3-4 weeks and survival is more likely,<br />
although surviving lambs always show some ataxia and atrophy <strong>of</strong> the hindquarters. The first sign<br />
to appear in enzootic ataxia is incoordination <strong>of</strong> the hindlimbs. appearing when the lambs are<br />
driven. Respiratory and cardiac rates are also greatly accelerated <strong>by</strong> exertion. As the disease<br />
progresses, the incoordination becomes more severe and may be apparent after walking only a few<br />
yards. There is excessive flexion <strong>of</strong> joints, knuckling over <strong>of</strong> the fetlocks, wobbling <strong>of</strong> the<br />
hindquarters and finally falling. The hindlegs are affected first and the lamb may be able to drag<br />
itself about in a sitting posture. When the forelegs eventually become involved recumbency<br />
persists and the lamb dies <strong>of</strong> inanition. There is no true paralysis, the lamb being able to<br />
1496
kick vigorously even in the recumbent stage.the appetite remains unaffected.<br />
Enzootic ataxia due to copper deficiency has been reported in young goat kids. The disease is<br />
similar in most respects to the disease in lambs. Kids may be affected at birth, or the clinical signs<br />
may be delayed until the animals are several weeks <strong>of</strong> age. Cerebellar hypoplasia is a frequent<br />
finding in goats.<br />
Other species<br />
Deer<br />
Enzootic ataxia in red deer is remarkably different from the disease in lambs in that it develops<br />
in young adults well past wearning age, and in adults. The clinical signs include ataxia, swaying <strong>of</strong><br />
the<br />
hindquarters, a dog-sitting posture and,eventually, inability to use the hindlimbs.Spinal cord<br />
demyelination and midbrain neuronal degeneration are characteristic. osteochondrosis <strong>of</strong> young,<br />
farmed deer with copper deficiency is characterized <strong>by</strong> lameness, one or more swollen joints, and<br />
an abnormal ‘bunny-hopping' gait or ‘cow-hocked' stance (2). Copper deficiency in red deer in<br />
Australia during a period <strong>of</strong> drought <strong>caused</strong> loss <strong>of</strong> weight in lactating hinds after calving and<br />
steely hair coats (the hair had a lustre resembling that <strong>of</strong> so-called steely wool <strong>of</strong> copper-deficent<br />
sheep). Both adult and yearling stags had normal hair coats but those <strong>of</strong> the yearling hinds were<br />
patchy, with large areas <strong>of</strong> harsh, light colored, steely hair (22). The high sulfur content <strong>of</strong> the diet<br />
and possible accidental iron ingestion from being fed on the ground may have resulted in<br />
secondary copper deficiency.<br />
Pigs<br />
Naturally occurring enzootic ataxia has occurred in growing pigs 4-6 months <strong>of</strong> age. Posterior<br />
paresis progresses to complete paralysis in 1-3 weeks. Dosing with copper salts had no effect on<br />
the clinical conditions, but hepatic copper levels were 3-14 mg/kg (0.05-0.22 mmol/kg). Copper<br />
deficiency in piglets 5-8 weeks <strong>of</strong> age has been reported and was characterized clinically <strong>by</strong> ataxia,<br />
posterior paresis, nystagmus, inability to stand, paddling movements <strong>of</strong> the limbs and death in 3-5<br />
days. Demyelination <strong>of</strong> the spinal cord, and degenerative lesions <strong>of</strong> the elastic fibers <strong>of</strong> the walls<br />
<strong>of</strong> the aorta and pulmonary arteries were present.<br />
The inclusion <strong>of</strong> copper sulfate, at levels <strong>of</strong> 125-250 mg/kg <strong>of</strong> copper, in the diets <strong>of</strong> pigs 11-90 kg<br />
liveweight and fed ad libitum, results in slight improvements in growth rate and feed efficiency,<br />
but has no significant effect on carcass characteristics (23). The supplemental copper causes a<br />
marked increase in liver copper concentration which poses a potential hazard and it is<br />
recommended that copper supplementation be limited to starter and grower diets fed to pigs<br />
weighing less than 50 kg liveweight.<br />
Horses<br />
Adult horses are unaffected <strong>by</strong> copper deficiency, but there are unconfirmed reports <strong>of</strong><br />
abnormalities <strong>of</strong> limbs <strong>of</strong> foals. Foals in copper-deficient areas may be unthrifty and slow-growing,<br />
with stiffness <strong>of</strong> the limbs and enlargement <strong>of</strong> the joints. Contraction <strong>of</strong> the flexor tendons causes<br />
the animal to stand on its toes. There is no ataxia or indication <strong>of</strong> involvement <strong>of</strong> the central<br />
nervous system. Signs may be present at birth or develop before weaning. Recovery occurs slowly<br />
after weaning and foals are unthrifty for up to 2 years.<br />
CLINICAL PATHOLOGY<br />
The laboratory evaluation <strong>of</strong> the copper status <strong>of</strong> form animals is complex because the<br />
biochemical values are <strong>of</strong>ten difficult to interpret and to correlate with the clinical state <strong>of</strong> the
animal. Interpretation <strong>of</strong> the copper status <strong>of</strong> an individual animal is more difficult than <strong>of</strong> a herd.<br />
The guidelines for the laboratory diagnosis <strong>of</strong> primary and secondary copper deficiency in cattle<br />
and sheep are summarized in Table 29.4.<br />
HERD DIHAGNOSIS The diagnosis <strong>of</strong> copper deficiency in a herd <strong>of</strong> animals is based on a<br />
combination <strong>of</strong> collection and interpretation <strong>of</strong> the history, clinical examination <strong>of</strong> the affected<br />
animals, laboratory tests on serum and liver samples, and examination <strong>of</strong> the environment<br />
including analysis <strong>of</strong> the feed and water supplies, and perhaps soil analysis (24).<br />
It is necessary to be especially careful when collecting specimens for copper analysis to avoid<br />
contamination <strong>by</strong> needles, copper distilled water, vial caps, cans for liver specimens, and other<br />
possible sources <strong>of</strong> copper. <strong>An</strong> additional problem is the possible effect <strong>of</strong> intercurrent disease on<br />
plasma levels <strong>of</strong> copper.<br />
TREATMENT RESPONSE TRIAL A comparison <strong>of</strong> health and production variables in a group<br />
<strong>of</strong> animals treated with copper, and a similar group not treated with copper, is also desirable.<br />
Variables include calf growth rates, calf mortality, and reproductive performance.<br />
COPPER STATUS OF HERD In order to assess the copper status <strong>of</strong> herd, a standard practice is<br />
to take blood samples at random from at least 10% <strong>of</strong> clinically affected animals and from 10% <strong>of</strong><br />
normal animals. however, this may be inapprot<br />
Table 29.4 Copper levels in body tissues and fluids in primary and secondary copper deficiency<br />
Species and tissue Normal level Primary copper Secondary copper<br />
deficiency<br />
deficiency<br />
Cattle<br />
1.26±31<br />
Less than 0.5 and as Less than 0.5 and as<br />
Blood plasma More than 100 low as 0.1-0.2 low as 0.2-0.3<br />
(fig/mL) (convert to (usually 200) Less than 20 and as Less than 10<br />
SI units <strong>by</strong><br />
0.05-0.20<br />
low as 4<br />
5.5<br />
multiplying<br />
6.6-10.40.7-1.3More 0.01-0.02<br />
0.4-0.7<br />
<strong>by</strong> 15.7 which gives than 200 (usually 1.8-3.4<br />
15-19<br />
nmol/L). Adult liver 350+)<br />
0.1-0.2<br />
(mg/kg dry matter)<br />
(convert to SI units <strong>by</strong><br />
multiplying <strong>by</strong> 0.0157<br />
which gives mmol/kg)<br />
Milk (mg/L) Hair<br />
(mg/kg)<br />
Sheep<br />
Blood plasma (ug/mL)<br />
Adult liver (mg/kg dry<br />
matter)<br />
20<br />
1497<br />
priate when there may be a wide variation in the serum copper concentration within a herd. In<br />
some cases, a 10% sample may be too large and in other cases too small. The minimal sample size<br />
for random samples from a finite population <strong>of</strong> a normal continuously distributed variable has<br />
been calculated as follows:<br />
[n = Nt2cv2/[(N-1)E2 t2cv2 ]]
Where n = minimal sample size; N= herd size; = Student t value; cv = coefficient <strong>of</strong> variation; and<br />
E = allowable error. Initial testing can be used to estimate variability <strong>of</strong> serum copper<br />
concentration within a herd, and a minimal sample size may be calculated. Each class <strong>of</strong> animal<br />
according to age groups, diet, and production status should also be sampled. Follow-up samples<br />
should be taken from the same animals following therapy or the institution <strong>of</strong> control measures.<br />
Laboratory diagnosis<br />
Historically, the laboratory diagnosis <strong>of</strong> copper deficiency in cattle and sheep centered on the<br />
determination <strong>of</strong> serum or plasma copper and liver copper. However, it is now known that serum<br />
copper levels alone are not reliable as indicators <strong>of</strong> copper status, and liver samples collected<br />
either <strong>by</strong> liver biopsy or at slaughter should be used to accurately assess copper status in cattle (25,<br />
26). Clinically normal animals may have marginal levels <strong>of</strong> serum copper, or unthrifty animals<br />
may have marginal or deficient serum levels <strong>of</strong> copper. Furthermore, when either the normal<br />
animals with the marginal levels <strong>of</strong> copper or the unthrifty animals with the marginal or deficient<br />
levels are treated with copper there may or may not be an improvement in weight gain as might be<br />
expected in the former, or improvement in clinical condition in the latter.<br />
Phases<br />
The development <strong>of</strong> a deficiency can be divided into four phases:<br />
1.Depletion<br />
2.Deficiency (marginal)<br />
3.Dysfunction<br />
4.Disease.<br />
During the depletion phase, there is loss <strong>of</strong> copper from any storage site, such as liver, but the<br />
plasma concentrations <strong>of</strong> copper may remain constant. With continued dietary deficiency the<br />
concentrations <strong>of</strong> copper in the blood will decline during the phase <strong>of</strong> marginal deficiency.<br />
However, it may be some time before the concentrations or activities <strong>of</strong> copper-containing<br />
enzymes in the tissues begin to decline, and it is not until this happens that the phase <strong>of</strong><br />
dysfunction is reached. There may be a further lag before the changes in cellular function are<br />
manifested as clinical signs <strong>of</strong> disease.<br />
Interpretation <strong>of</strong> laboratory results<br />
The three principles governing the interpretation <strong>of</strong> biochemical criteria <strong>of</strong> trace element status<br />
include:<br />
•The relationships between the concentration <strong>of</strong> the marker and the intake <strong>of</strong> the element<br />
•The time the animal is on an adequate diet<br />
•Disturbances <strong>of</strong> tissue function.<br />
From these principles, the concentrations <strong>of</strong> liver copper are insensitive indices <strong>of</strong> deficiency,<br />
but good indicators <strong>of</strong> excess. Plasma copper less than 57µg/dL (9 µmol/L) is a good index <strong>of</strong><br />
marginal deficiency, but values may have to fall to below 19µg/dL.(3µmol/L) before there is a risk<br />
<strong>of</strong> dysfunction and loss <strong>of</strong> production in sheep and cattle. However, these are only guidelines. The<br />
range <strong>of</strong> values and the cut-<strong>of</strong>f levels above which animals are normal, or below which they<br />
are deficient, have not been well-established. There is considerable biological variation<br />
dependent on the species, the breed <strong>of</strong> animal, the length <strong>of</strong> time over which the depletion has<br />
occurred, and the presence <strong>of</strong> intercurrent disease.<br />
Concentrations <strong>of</strong> copperin liver and blood may be <strong>of</strong> diagnostic value but should be interpreted<br />
with caution since clinical signs <strong>of</strong> copper deficiency may appear before there are significant
changes in the levels <strong>of</strong> copper in the blood and liver. Conversely, the plasma levels <strong>of</strong> copper<br />
may be very low in animals that are otherwise normal and performing well. There is a tendency to<br />
overestimate the presence <strong>of</strong> copper deficiency because veterinarians use a diagnostic threshold<br />
for copper deficiency that is too high (27). Among veterinary laboratories, there is a wide<br />
variation in the normal range currently used for equine serum copper values (28).<br />
Plasma and hepatic copper levels<br />
Cattle and sheep<br />
In cattle and sheep, plasma copper levels between 19µ g/dL and 57 µg/dL (3.0 and 9.0 µmol/L)<br />
represent marginal deficiency, and levels below 19µg/dL (3 µmol/L) represent functional<br />
deficiency or hypocuprosis. The internationally recognized threshold to assess copper deficiency<br />
is 9.4µ mol/L (27). In both species。a value for plasma or serum <strong>of</strong> 11.0 µmol/L can be associated<br />
with a liver concentration from 789 to 3786 µmol/kg DM (50-240 mg/kg). By contrast, a value <strong>of</strong><br />
9.3µ mol/L will usually be associated with liver copper values <strong>of</strong> 315-789 µmol (20-50 mg/kg<br />
DM), which are regarded as marginally inadequate. Plasma copper levels <strong>of</strong> 49.9 µg/dL (7.85<br />
µmol/L) or less are indicative <strong>of</strong> low liver copper levels. Plasma copper levels above 90.2 µg/dL<br />
(14.2 µmol/L) are usually associated with liver levels above 38.1 mg/kg (0.6 mmol/kg) DM. Of<br />
the two estimations, that on liver is the most informative as levels in blood may remain normal for<br />
long periods after liver copper levels commence to fall and early signs <strong>of</strong> copper deficiency appear.<br />
Levels <strong>of</strong> copperin adult liver above 200 mg/kg DM (3.14 mmol/kg) in sheep, and above 100<br />
mg/kg DM (1.57 mmol/kg) in cattle are considered to be normal.. Levels <strong>of</strong> less than 80 mg/kg<br />
DM (1.5 mmol/kg) in sheep, and less than 30 mg/kg DM (0.5 mmol/kg) in cattle are classed as<br />
low. Liver copper levels in fetuses and neonates are usually much higher than in adults, and<br />
normal foals have had levels <strong>of</strong> 219 mg/kg (3.4 mmol/kg DM) compared to a normal <strong>of</strong> 31 mg/kg<br />
(0.49 mmol/kg DM) in adults.<br />
Milk and hair copper<br />
The levels <strong>of</strong> copper in milk and hair are also lower in deficient than in normal cattle and<br />
estimation <strong>of</strong> the copper content <strong>of</strong> hair is now acceptable as a diagnostic aid. It has the advantage<br />
<strong>of</strong> providing an integrated progressive record <strong>of</strong> nutritional intake. The levels <strong>of</strong> copper in bovine<br />
hair are more markedly depressed when extra molybdenum is fed.<br />
Ceruloplasmin<br />
The difficulty <strong>of</strong> interpreting plasma levels <strong>of</strong> copper led to the estimation <strong>of</strong> plasma levels <strong>of</strong><br />
copper-protein complexes, especially ceruloplasmin. Ceruloplasmin<br />
1498<br />
contains greater than 95% <strong>of</strong> the circulating copper in normal animals. There is a highly<br />
significant correlation between plasma copper levels and plasma ceruloplasmin activity, which is a<br />
less complicated and more rapid procedure than plasma copper. The regression analyses indicate a<br />
strongly positive correlation coefficient <strong>of</strong> ceruloplasmin with serum <strong>of</strong> cattle and sheep <strong>of</strong> 0.83<br />
and 0.92,respectively. The correlation between serum ceruloplasmin activity and hepatic copper<br />
concentrations in cattle was only 0.35, indicating an unreliable relationship. Normal plasma<br />
ceruloplasmin levels in sheep are in the region <strong>of</strong> 45-100 mg/L. Normal levels <strong>of</strong> serum<br />
ceruloplasmin activity in cattle range from 120 to 200 mg/L. The mean copper and ceruloplasmin<br />
levels are higher in plasma than serum; the percentage <strong>of</strong> copper associated with ceruloplasmin is<br />
lessin serum (55%) thanin plasma (66%). Normal plasma ceruloplasmin levelsin sheep range from<br />
4.5 to 10 mg/dL. In experimental primary copper deficiencyin calves, rapid decreases occurin
plasma ceruloplasmin activity at least 80 days before overt clinical signs <strong>of</strong> deficiency.<br />
Erythrocyte dismutase<br />
The measurement <strong>of</strong> the activity <strong>of</strong> erythrocyte superoxide dismutase (ESOD), a<br />
copper-containing enzyme, is now being evaluated as a procedure for the diagnosis <strong>of</strong> copper<br />
deficiency. The activity <strong>of</strong> this enzyme decreases more slowly than plasma or liver copper in<br />
copper-deficient animals and may be more closely correated with the presence <strong>of</strong> imminence <strong>of</strong><br />
hypocuprosis. In marginal deficiency, the ESOD value ranges from 2 to 5 U/mg hemoglobin, and<br />
in functional deficiency the value is below 2 (29).<br />
Hepatic copper<br />
Because the liver is a storage compartment for copper, the concentrations <strong>of</strong> liver copper indicate<br />
the state <strong>of</strong> depletion rather than deficiency. There is no particular threshold value for liver copper<br />
below which the performance and health <strong>of</strong> livestock are likely to be impaired. A broad range <strong>of</strong><br />
values may, for example, coincide with the marginally deficient state, e.g. 5.1-20.3 mg (0.08-0.32<br />
mmol) copper/kg liver DM. The concentration <strong>of</strong> hepatic copper in sheep is uniform, and a single<br />
biopsy sample should be representative <strong>of</strong> the whole liver. The technique <strong>of</strong> liver biopsy for<br />
assessing the copper status <strong>of</strong> sheep has been evaluated. Frequency <strong>of</strong> biopsy does not affect<br />
copper concentration, the variability between successive samples is small, and the biopsy<br />
procedure does not reduce body weight or rate <strong>of</strong> gain. Copper concentrations in the kidney cortex<br />
may be <strong>of</strong> more diagnostic value because concentrations are normally within a narrow range <strong>of</strong><br />
12.7-19.0 mg/kg DM (0.2-0.3 mmol/kg DM). Thus, concentrations below 12.7 mg/kg DM (0.2<br />
mmol/kg DM) in the kidney may be a more reliable indicator <strong>of</strong> dysfunction than liver copper<br />
concentration.<br />
Horses<br />
A threshold level <strong>of</strong> plasma copper <strong>of</strong> 16 umol/L is used to distinguish between the normal and<br />
subnormal values (30). Liver copper from horses sampled at slaughter vary widely about a mean<br />
<strong>of</strong> 113.7n.mol/kg WW (30). The threshold <strong>of</strong> 52.5 umol/kg WW <strong>of</strong> copper in liver is proposed to<br />
distinguish deficient from marginal liver copper status. Many healthy horses have serum values<br />
between 12 and 16 umol/L.<br />
The mean hepatic copper concentrations <strong>of</strong> horses fed diets containing 6.9-15.2 mg copper/kg<br />
DM were 17.1-21.0 µg/g DM (0.27-0.33 umol/g DM) tissue. The plasma copper concentrations<br />
ranged from 3.58 to 4.45 ug/dL (22.8-28.3 umol/L). There was no simple mathematical<br />
relationship between plasma and hepatic copper concentrtions. The range <strong>of</strong> serum copper<br />
concentrations in Thoroughbred horses at grass was 63-196 ug/dL (9.91-30.85 mmol/L), and in<br />
stabled Thoroughbreds the range was 47-111 ug/dL (7.40-17.47 mmol/L).<br />
Hematology<br />
<strong>An</strong>emia may occur in advanced cases <strong>of</strong> primary copper deficiency, hemoglobin levels being<br />
depressed to 50- 80 g/L and erythrocytes to 2-4 X 10 12 /L. A high proportion <strong>of</strong> cows in problem<br />
herds may have a Heinz-body anemia without evidence <strong>of</strong> hemoglobinuria, and the severity <strong>of</strong> the<br />
anemia will be related to the hypocupremia.<br />
NECROPSY FINDINGS<br />
The characteristic gross findings in copper deficiency <strong>of</strong> ruminants are those <strong>of</strong> anemia and<br />
emaciation. Hair and wool abnormalities may be present as already described. Extensive deposits<br />
<strong>of</strong> hemosiderin can cause darkening <strong>of</strong> the liver, spleen and kidney in most cases <strong>of</strong> primary<br />
copper deficiency, and in the secondary form if the copper status is sufficiently low. In lambs
there may be severe osteoporosis and long bone fractures. Osteoporosis is less evident in cattle,<br />
but can be confirmed radiographically and histologically. In naturally occurring secondary copper<br />
deficiency in cattle, associated with high dietary molybdenum and sulfate, there is widening <strong>of</strong> the<br />
growth plates due to abnormal <strong>mineral</strong>ization <strong>of</strong> the primary spongiosia, resulting in a grossly<br />
rachitic appearance to the bones.<br />
The most significant finding in enzootic ataxia is the degeneration <strong>of</strong> axons and myelin within<br />
the cerebellar and motor tracts in the spinal cord, a change only evident at the microscopic level.<br />
Chromatolysis <strong>of</strong> neurons in a variety <strong>of</strong> locations within the central nervous system is usually<br />
detectable. In a few extreme cases, and in most cases <strong>of</strong> sway-back, the myelin loss also involves<br />
the cerebrum, where there is destruction and cavitation <strong>of</strong> the white matter. There is marked<br />
internal hydrocephalus in such cases and the convolutions <strong>of</strong> the cerebrum are almost obliterated.<br />
Acute cerebral edema with marked brain swelling and cerebellar herniation, reminiscent <strong>of</strong><br />
polioencephalomalacia, may also accompany the more typical myelopathy and multifocal cerebral<br />
leukomalacia in lambs with hypocuprosis.<br />
In falling disease, the heart is flab<strong>by</strong> and pale. There is generalized venous congestion and the<br />
blood may appear watery. The liver and spleen are enlarged and dark. Histological examination<br />
reveals atrophy <strong>of</strong> the cardiac muscle fibers and considerable cardiac fibrosis. Deposits <strong>of</strong><br />
hemosiderin are present in the liver, spleen and kidney.<br />
Necropsy findings associated with copper deficiency in non-ruminant species are not<br />
well-documented. Degenerative changes with subsequent rupture <strong>of</strong> the aorta have been<br />
experimentally induced in swine, but this has not been described as a naturally occurring disease.<br />
A myelopathy with white matter changes similar to those <strong>of</strong> enzootic ataxia has also been reported<br />
in 4-5-month-old copper-deficient pigs. Musculoskeletal changes<br />
1499<br />
similar to those described for calves have also been reported in foals with hypocuprosis.<br />
Necropsy examinations should include assay <strong>of</strong> copper in viscera .The levels <strong>of</strong> copper in liver<br />
are usually low (see Table 29.4), and in secondary copper deficiency there may be a high level <strong>of</strong><br />
copper in the kidney, and high levels <strong>of</strong> molybdenum in the liver, kidney, and spleen. Copper<br />
levels in body tissues and Hinds in primarm and secondary copper deficiency are listed in Table<br />
29.4.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
•Toxicology - 50 g liver, kidney(ASSAY (Cu) (Mo)).<br />
•Histology - formalin-fixed samples <strong>of</strong>:long bone (including growth plate),skin, liver, spleen.<br />
Enzootk ataxia/<br />
swaybaik: halt <strong>of</strong> midsagittally-sectioned brain, lumbar and cervical spinal cord. Falling disease:<br />
heart (several sections), bone marrow, spleen(LM).<br />
DIFFERENTIAL DIAGNOSIS<br />
The clinical findings which are common in young, growing ruminants, include a herd problem <strong>of</strong><br />
unthriftiness and progressive loss <strong>of</strong> weight, changes in hair coat color or texture <strong>of</strong> wool, chronic<br />
lameness, neonatal ataxia in lambs and kids, and terminal anemia. In adult cattle on pasture with<br />
excess molybdenum, chronic diarrhea is charactic. A combination <strong>of</strong> serum and liver copper, and<br />
serum molybdenum, are major diagnostic aids in distinguishing between copper deficiency and<br />
the other diseases.<br />
Several disease complexes that are herd or flock problems in cattle and sheep may resemble
oth primary and secondary copper deficiency. The emphasis is on many animals being affected at<br />
about the same time, with a chronic debilitating disease complex, under the same dietary and<br />
seasonal circumstances.<br />
Cattle<br />
Unthriftiness and progressive weight loss may be due to protein-energy malnutrition and<br />
examination <strong>of</strong> the diet will reveal the cause.<br />
Changes in hair coat color in young growing cattle is <strong>caused</strong> only <strong>by</strong> copper deficiency.<br />
Chronic lameness in young growing cattle may be <strong>caused</strong> <strong>by</strong> a calcium, phosphorus and<br />
vitamin D imbalance,which is determined <strong>by</strong> examination <strong>of</strong> the diet and radiography <strong>of</strong> the long<br />
bones. The radiographic changes in cattle with secondary copper deficiency consist <strong>of</strong> widened<br />
irregular epiphyseal plates with increased bone density in the metaphysis and metaphyseal lipping.<br />
These findings are similar to those described for rickets and secondary nutritional<br />
hyperparathyroidism in cattle.<br />
Chronic diarrhea in young cattle may be due to intestinal parasitism and fecal examination<br />
and response to therapy are diagnostic. Diarrhea in a group <strong>of</strong> adult cattle on pasture known to be<br />
high in molybdenum is probably due to secondary copper deficiency and response to therapy is<br />
diagnostic.<br />
Winter dysentery <strong>of</strong> cattle, salmonellosis, coccidiosis and mucosal disease are acute diseases<br />
characterized <strong>by</strong> diarrhea but are accompanied <strong>by</strong> other signs and clinicopathological findings<br />
which facilitate their identification. Many poisons, particularly arsenic, lead and salt, cause<br />
diarrhea in ruminants but there are usually additional diagnostic signs and evidence <strong>of</strong> access to<br />
the poison. Assay <strong>of</strong> feed and tissues helps to confirm a diagnosis <strong>of</strong> poisoning.<br />
A diagnosis <strong>of</strong> peat scours is usually made if there is an immediate response to oral dosing<br />
with a copper salt.<br />
Falling disease occurs only in adult cattle and must be differentiated from other causes <strong>of</strong><br />
sudden death. Poisoning <strong>by</strong> the gidgee tree (Acacia georginaa) produces a similar syndrome in<br />
cattle.<br />
Sheep and goats<br />
Unthriftiness and abnormal wool or hair as a flock or herd problem are characteristic <strong>of</strong> copper<br />
deficiency in sheep and goats, which must be differentiated from protein-energy malnutrition,<br />
intestinal parasitism, cobalt deficiency, and external parasites.<br />
Lameness in a group <strong>of</strong> lambs several weeks <strong>of</strong> age must be differentiated from nutritional<br />
osteodystrophy due to a calcium, phosphorus and vitamin D deficiency or imbalance, stiff lamb<br />
disease due to enzootic muscular dystrophy.<br />
Neonatal ataxia <strong>caused</strong> <strong>by</strong> congenital swayback and enzootic ataxia in newborn lambs and kids<br />
due to maternal copper deficiency must be differentiated from border disease <strong>of</strong> newborn lambs,<br />
characterized <strong>by</strong> an outbreak <strong>of</strong> newborn lambs with hairy fleece and tremors, cerebellar<br />
hypoplasia (daft lamb disease), and hypothermia.<br />
TREATMENT<br />
The treatment <strong>of</strong> copper deficiency is relatively simple, but it advanced lesions are already present<br />
in the nervous system or myocardium complete recovery will not occur. Oral dosing with 4 g <strong>of</strong><br />
copper sulfate for calves from 2 to 6 months <strong>of</strong> age and 8-10 g for mature cattle given weekly for<br />
3-5 weeks is recommended tor the treatment <strong>of</strong> primary or secondary copper deficiency.<br />
Parenteral injections <strong>of</strong> copper glycinate may also be used and the dosages are given under control.
The diet <strong>of</strong> affected animals should also be supplemented with copper. Copper sulfate may be<br />
added to the <strong>mineral</strong>-salt mix at a level <strong>of</strong> 3-5% <strong>of</strong> the total mixture. A commonly recommended<br />
mixture for cattle is 50% calcium-phosphorus <strong>mineral</strong> supplement. 45% cobalt-iodized salt, and<br />
3-5% copper sul-tate. This mixture is <strong>of</strong>fered free <strong>of</strong> choice or can be added to a complete diet at<br />
the rate <strong>of</strong> 1% <strong>of</strong> the total diet.<br />
CONTROL<br />
Dietary requirements<br />
The minimum dietary requirement for copper for cattle is 10 mg copper/kg DM and 5 mg/kg DM<br />
for sheep.<br />
The requirement necessary to prevent subclinical or clinical copper deficiency will depend on<br />
the presence <strong>of</strong> interfering substances such as molybdenum, sulfur and iron in the diet and<br />
possibly the genotype <strong>of</strong> the animal. Copper sulfate is considered a better supplement than copper<br />
oxide needles or injectable copper for cattle consuming diets containing excess molybdenum or<br />
molybdenum plus sulfur. Although there is a marked difference between breeds <strong>of</strong> sheep in their<br />
susceptibility to hypocuprosis, this would not seem to have an immediate practical application.<br />
The estimated copper requirement in the diet <strong>of</strong> mature ponies is 3.5 mg/kg DM.<br />
Copper can he supplied <strong>by</strong> several different methods as outlined below. The dose rates given<br />
are those recommended for the control <strong>of</strong> primary copper deficiency, and these may have to be<br />
increased or treatment given more frequently in some instances <strong>of</strong> secondary copper deficiency. In<br />
these circumstances it is <strong>of</strong>ten necessary to determine the most satisfactory dosing strategy <strong>by</strong> a<br />
field trial.<br />
Copper sulfate<br />
Oral closing<br />
Oral dosing with copper sulfate (5 g tocattle, 1.0 g to sheep, weekly) is adequate<br />
1500<br />
as prophylaxis and will prevent the occurrence <strong>of</strong> swayback in lambs if the ewes are dosed<br />
throughout pregnancy. Lambs can be protected after birth <strong>by</strong> dosing with 35 mg <strong>of</strong> copper sulfate<br />
every 2 weeks. However, regular oral dosing with copper sulfate is laborious and time-consuming<br />
and is no longer widely practiced.<br />
Dietary supplementation<br />
The copper sulfate may be mixed with other <strong>mineral</strong>s into a <strong>mineral</strong> premix, which is then<br />
incorporated into the concentrate part <strong>of</strong> the ration. The final concentration <strong>of</strong> copper is usually<br />
adjusted to provide an overall intake <strong>of</strong> at least 10 ppm <strong>of</strong> copper in the DM <strong>of</strong> the final ration. If<br />
the forage components <strong>of</strong> the ration contain much less than 10 ppm, the concentrate part <strong>of</strong> the<br />
ration may need to contain much larger concentrations <strong>of</strong> copper. Where a secondary copper<br />
deficiency is due to molybdenum in the forage, up to 1200 mg copper (approximately 5 g <strong>of</strong><br />
hydrated copper sulfate) is added to the concentrate daily. When sheep are grazing toxic lupin<br />
stubble, the signs <strong>of</strong> lupinosis may be exacerbated <strong>by</strong> the supplementation <strong>of</strong> only 10 mg<br />
copper/kg DM as copper sulfate, and therefore the supply <strong>of</strong> copper in the absence <strong>of</strong> suitable<br />
amounts <strong>of</strong> molybdenum and sulfur should be kept to a minimum (31).<br />
If animals are not receiving concenrates containing copper, an alternative is to provide free<br />
access to a <strong>mineral</strong> mixture or salt-lick containing 0.25-0.5% <strong>of</strong> copper sulfate for sheep and 2%<br />
for cattle, which will supply sufficient copper provided an adequate intake <strong>of</strong> the mixture is<br />
assured. The <strong>mineral</strong> mixture usually contains iodized salt, cobalt, calcium, phosphorus, and other
trace <strong>mineral</strong>s.<br />
In some deficient areas, an effective method <strong>of</strong> administering copper is <strong>by</strong> the annual<br />
top-dressing <strong>of</strong> pasture with 10 kg/hectare copper sulfate, although the amount required mayvary<br />
widely with the soil type and the rainfall. Top-dressing may cause copper poisoning if livestock<br />
are turned onto pasture while the copper salt is still adherent to the leaves. Treated pasture should<br />
be left unstocked for 3 weeks or until the first heavy rain. It is also possible that chronic copper<br />
poisoning may result if the copper status <strong>of</strong> the soil increases sufficiently over a number <strong>of</strong> years.<br />
Addition <strong>of</strong> copper salts to drinking water is usually impractical because the solution corrodes<br />
metal piping, and maintenance <strong>of</strong> the correct concentration <strong>of</strong> copper in large bodies <strong>of</strong> water is<br />
difficult. However, if the need is great, some way around these difficulties can usually be found<br />
and a system has been devised for automatic supplementation for short periods via the drinking<br />
water, and has been effective in controlling copper deficiency in cattle. Copper pellets which<br />
provide 2-3 mg copper/L <strong>of</strong> water have been recommended for cattle. Calves can tolerate copper<br />
in milk replacers at a concentration <strong>of</strong> 50 ppm but there is no advantage in providing more than 10<br />
ppm.<br />
There is no evidence that copper or molybdenum supplementation <strong>of</strong> the diets <strong>of</strong> pregnant ewes<br />
and lambs at 10 mg/kg DM had any effect on selenium status.<br />
Removal <strong>of</strong> sulfates<br />
The removal <strong>of</strong> sulfates from drinking water <strong>by</strong> water purification, using a process <strong>of</strong> reverse<br />
osmosis, may have a positive effect on the copper status <strong>of</strong> beef cows. Cows drinking desulfated<br />
water had an increased availability <strong>of</strong> copper compared to those drinking water containing a large<br />
concentration <strong>of</strong> sulfates.<br />
Parenteral injections <strong>of</strong> copper<br />
To overcome the difficulty <strong>of</strong> frequent individual dosing or top-dressing <strong>of</strong> parture, periodic<br />
parenteral injection <strong>of</strong> copper compounds that release copper gradually has given good results.<br />
They can be given at strategic times depending on the circumstances. They also have the<br />
advantage <strong>of</strong> avoiding fixation <strong>of</strong> copper <strong>by</strong> molybdenum in the alimentary tract. Injectable<br />
preparations <strong>of</strong> copper are now the method <strong>of</strong> choice for the prevention <strong>of</strong> swayback in lambs. The<br />
following have been evaluated under field conditions:<br />
•Copper calcium ethylenediamine tetra-acetate (copper calcium<br />
edetate)<br />
•Copper methionate<br />
•Copper heptonate<br />
•Copper glycinate<br />
•Copper oxyquinoline sulfonate.<br />
The criteria used to judge these injections are minimal damage at the site <strong>of</strong> injections,<br />
satisfactory liver storage (90-100%) <strong>of</strong> the administered dose, and a safe margin between<br />
therapeutic and toxic doses. The dose <strong>of</strong> copper in any <strong>of</strong> the compounds for cattle is 400 mg and<br />
for sheep 150 mg. Copper heptonate at the rate <strong>of</strong> 25 mg <strong>of</strong> copper in 2 mL <strong>of</strong> preparation given<br />
<strong>by</strong> IM injection to ewes in mid-pregnancy was successful in preventing swayback in lambs.<br />
Copper calcium edetate has the advantage <strong>of</strong> giving maximum copper storage very quickly - 1<br />
week after injection - and blood levels are elevated within a few hours. Because <strong>of</strong> the rapidity <strong>of</strong><br />
the absorption, toxic effects can be encountered unless proper dose levels are observed. As well as<br />
deaths from serious overdosing, some deaths occur in groups <strong>of</strong> sheep for unexplained reasons. It
is suggested that stress be minimized and simultaneous other therapy be avoided.<br />
A marked local reaction occurs at the site <strong>of</strong> injection so that SC injection is preferable in<br />
animals to be used for meat, although to avoid an unsightly blemish, breeding animals should<br />
receive an IM injection. The injections are a small risk for precipitating blackleg in cattle on farms<br />
where this disease occurs. For sheep, a single injection <strong>of</strong> 45 mg <strong>of</strong> copper as copper glycinate in<br />
midpregnancy is sufficient to prevent swayback in the lambs.<br />
The SC injection <strong>of</strong> copper calcium edetate or copper oxyquinoline sulfonate into sheep<br />
results in a rapid increase in the concentration <strong>of</strong> copper in whole blood, serum, and urine within<br />
the first 24 hours. Following the injection <strong>of</strong> copper methionate, the concentration <strong>of</strong>. copper in<br />
blood and serum rises steadily over a period <strong>of</strong> 10 days, and there is no detectable increase in<br />
urinary copper. After the injection <strong>of</strong> any <strong>of</strong> the three compounds, there is a steady increase in<br />
serum ceruloplasmin activity over a period <strong>of</strong> 10-20 days, followed <strong>by</strong> a slow fall to preinjection<br />
activity <strong>by</strong> 40 days. The lower toxicity <strong>of</strong> copper injected as methionate compared with that as<br />
copper calcium edetate or copper oxyquinoline sulfonate is due to the slower absorption and<br />
transport <strong>of</strong> the copper to the liver and kidney. Death has occurred in sheep following the<br />
parenteral administration <strong>of</strong> diethylamine oxyquinoline sulfonate at recommended doses. Affected<br />
sheep manifested signs <strong>of</strong> hepatic encephalopathy, and at necropsy there was acute, severe,<br />
generalized, cen-<br />
1501<br />
trilobular hepatocellular necrosis. The use <strong>of</strong> copper disodium edetate at recommended doses in<br />
calves has also resulted in deaths associated with liver necrosis and clinical signs <strong>of</strong> hepatic<br />
encephalopathy.<br />
Injectable copper glycinate is an excellent source <strong>of</strong> supplementary copper for increasing the<br />
concentration <strong>of</strong> copper in the serum <strong>of</strong> copper-deficient cattle and maintaining grazing cattle in<br />
an adequate copper status. One dose <strong>of</strong> copper glycinate will maintain adequate copper levels for<br />
about 60-90 days. The recommended dose in beef herds is 120 mg <strong>of</strong> copper for adult cattle and<br />
60 mg <strong>of</strong> copper for calves. A supplemental source <strong>of</strong> copper is required for the calf during the<br />
pasture season because milk is a poor source <strong>of</strong> copper, particularly from copper-deficient cows,<br />
and calves do not have the opportunity to increase or maintain body stores <strong>of</strong> copper while grazing.<br />
When the dam is severely hypocupremic in the spring, the calf is also severely hypocupremic or<br />
copper-deficient. Insufficient copper is secreted into the milk <strong>of</strong> copper-treated cows. Therefore,<br />
where the dam has not received an adequate copper intake during pregnancy, direct treatment <strong>of</strong><br />
the calf will be required in early life. The copper reserves <strong>of</strong> newborn calves are increased in fetal<br />
liver at the expense <strong>of</strong> copper stores in the dam's liver, which are dependent on the availability ot<br />
dietary or supplemental copper to the dam. Calves usually have sufficient liver copper at birth and<br />
do not need an injection <strong>of</strong> 50 mg until they are 6 weeks old. Because <strong>of</strong> the higher requirements<br />
for copper during the last trimester <strong>of</strong> pregnancy (demands <strong>of</strong> the fetal liver), a program <strong>of</strong> copper<br />
supplementation should involve the use <strong>of</strong> copper supplements, throughout the year as required.<br />
One dose <strong>of</strong> copper glycinate is sufficient when cattle are grazing forage that contains no more<br />
than 3 mg/kg DM <strong>of</strong> molybdenum and 3 g/kg DM <strong>of</strong> sulfur. With higher levels <strong>of</strong> molybdenum<br />
and sulfur, repeated injections <strong>of</strong> copper glycinate are recommended. The injectable copper may<br />
be supplemented <strong>by</strong> the use <strong>of</strong> copper sulfate in a <strong>mineral</strong> supplement at a level <strong>of</strong> 1%. The<br />
inclusion <strong>of</strong> copper sulfate in the <strong>mineral</strong> supplement may be adequate for cows, but the calves<br />
may not consume an adequate amount <strong>of</strong> <strong>mineral</strong> and injectable copper. The level <strong>of</strong>
supplementation required to prevent a drop in serum copper over the pasture season will depend<br />
upon the concentration <strong>of</strong> dietary molybdenum and sulfur and their effect upon the coefficient <strong>of</strong><br />
absorption <strong>of</strong> copper.<br />
Injectable copper complex compounds have been evaluated as supplementary copper for<br />
grazing beef cattle under Canadian conditions. Copper edetate at 100 mg <strong>of</strong> copper, copper<br />
glycinate at 120 mg, and copper methionate at 120 mg were used and were equally effective in<br />
improving copper status <strong>of</strong> copper-deficient cattle and maintaining them in an adequate copper<br />
status for 90 days (32). The copper methionate was least acceptable because <strong>of</strong> the incidence and<br />
severity <strong>of</strong> reactions at the site <strong>of</strong> injection.<br />
Controlled-release glass<br />
Death due to poisoning is one <strong>of</strong> the dangers <strong>of</strong> parenteral administration because it is difficult to<br />
control the rate at which the supplement releases the copper, especially if the controlling<br />
mechanism is chemical binding. Methods used to control the release include the development <strong>of</strong><br />
soluble controlled-release glass for oral administration to sheep and cattle. The copper is slowly<br />
released, absorbed, and stored in the liver. Initial field evaluations indicate that the boluses may<br />
not contain sufficient copper to maintain normal levels <strong>of</strong> copper for a sufficient length <strong>of</strong> time<br />
compared to the use <strong>of</strong> copper oxide needles.<br />
Boluses <strong>of</strong> a soluble copper-containing controlled-release glass have been devel¬oped and<br />
evaluated. The boluses are based on a phosphate-type glass into which appropriate quantities <strong>of</strong><br />
trace elements are incorporated. The boluses lodge in the rumen and release copper at a slow rate.<br />
They can provide additional supplies <strong>of</strong> copper to ruminants at an almost uniform rate for many<br />
months. One commercial product contains selenium and cobalt, and in one experiment increased<br />
ceraloplasmin activity for at least 1 year. In one field study, the admin¬istration <strong>of</strong> two<br />
commercial soluble glass boluses containing copper and selenium, the selenium levels were<br />
increased from marginal to adequate, but adequate copper levels were not maintained.<br />
Copper oxide needles<br />
Copper oxide needles or wire particles (fragments <strong>of</strong> oxidized copper wire up to 8 mm in length<br />
and 0.5 mm in diameter) are used for oral dosing and one <strong>of</strong> the most effective and safest methods<br />
for the control <strong>of</strong> copper deficiency in ruminants. Its major advantages are prolonged effectiveness<br />
and low cost. A single treatment can be effective for an entire summer or winter season. The<br />
needles are retained in the forcstomachs and aboma-sum for up to 100 days or more and the<br />
copper is slowly released, absorbed, and stored in the liver. A dose <strong>of</strong> 0.1g/kg live weight (5g) in<br />
sheep is safe and does not induce copper toxicity in the susceptible North Ronaldsay breed. The<br />
response in liver copper concentrations is dose-dependent. In sheep given doses ranging from 2.5<br />
to 20 g per animal, the liver cop¬per concentrations will peak 10 weeks after administration and<br />
will thereafter decline in a linear fashion over the next 40 weeks. A single dose <strong>of</strong> 20g <strong>of</strong> copper<br />
oxide needles to hypocupremic suclder cows was sufficient to maintain adequate copper status for<br />
at least 5 months. The use <strong>of</strong> 20 g <strong>of</strong> copper oxide needles to young cattle weighing 190 kg<br />
effectively prevented growth retardation and severe hypocuprcrma, which occurred in an undosed<br />
control over a 70-day trial period. The currently recommended doses for beef cattle are 5 g for<br />
calves, 10 g for yearlings and 20 g for heavier or adult cattle, which will give protection for at<br />
least 6 months. A single oral dose <strong>of</strong> 20 g <strong>of</strong> copper oxide needles at the beginning <strong>of</strong> the grazing<br />
season is effective in increasing or maintaining stores <strong>of</strong> copper in the liver <strong>of</strong> grazing cows and<br />
calves consuming low-copper, high-molybdenum forage and high-sulfate water supplies. The use
<strong>of</strong> 50 g <strong>of</strong> needles in adult cows (55 kg BW) sustained higher levels <strong>of</strong> plasma concentrations than<br />
the SC injection <strong>of</strong> copper glycinate, and 100, 200 or 300 g <strong>of</strong> needles given orally did not cause<br />
clinical effects. The administration <strong>of</strong> a single dose <strong>of</strong> 2 g cupric oxide needles orally to lambs<br />
between 3 and 5 weeks <strong>of</strong> age is an effective method for the prevention <strong>of</strong> induced hypocuprosis<br />
manifested as ill-thrift in lambs grazing pastures improved <strong>by</strong> liming and reseed-ing. The<br />
treatment maintained the lambs in norrnocupremia, provided adequate liver copper reserves,<br />
prevented clinical signs <strong>of</strong> hypocuprosis, and produced a liveweight gain advantage. The<br />
administration <strong>of</strong> the needles to ewes in the first half <strong>of</strong> pregnancy is also effective for the<br />
1502<br />
prevention <strong>of</strong> swayback in their lambs. The administration <strong>of</strong> cupric oxide needles to ewes at<br />
parturition is effective in preventing hypocupremia for up to 17 weeks in animals on pasture<br />
previously shown to cause a molybdenum-sulfur-induced copper deficiency. The treat-ment <strong>of</strong> the<br />
ewes at parturition also resulted in higher concentrations <strong>of</strong> cop- per in the milk in the initial<br />
weeks <strong>of</strong> lactation. However, this increase in milk copper will not be effective in preventing<br />
hypocupremia and hypocuprosis in the lambs, which can be treated with cupric oxide needles at 6<br />
weeks <strong>of</strong> age. Because some breeds <strong>of</strong> sheep may have a propen-sity to concentrate excess<br />
quantities <strong>of</strong> copper in the liver, it is important to adhere to the recommended dosage. Cupric<br />
oxide needles at a dose <strong>of</strong> 4 g per animal have also been used for the prevention <strong>of</strong> swayback in<br />
goats, and to maintain liver copper levels for up to 5 months in farmed red deer grazing on a<br />
marginally copper-deficient pasture.<br />
Copper oxide powder<br />
Copper oxide powder administered in the form <strong>of</strong> experimental, sustained-release rumen boluses<br />
significantly increased blood and liver copper concentrations in growing sheep, in out-wintered<br />
stickler cows during late pregnancy and early lactation, and m growing cattle at grass in the<br />
summer periods over periods <strong>of</strong> at least 170 and 123 days, respectively (33).<br />
Genetic selection<br />
It is now possible to manipulate trace element metabolism <strong>by</strong> genetic selection in farm animals.<br />
Within a period <strong>of</strong> 5 years, selection <strong>of</strong> sheep based on plasma concentration <strong>of</strong> copper resulted in<br />
two divergent sets <strong>of</strong> progeny, one with a high level <strong>of</strong> copper status, the other with a low level,<br />
which resulted in clinical manifestations <strong>of</strong> copper deficiency in the low level and protection in<br />
the high level.<br />
General guidelines<br />
Several rules <strong>of</strong> thumb are important and useful.<br />
•A dietary intake <strong>of</strong> copper equivalent to l0mg/kg DM will prevent the<br />
occurrence <strong>of</strong> primary copper deficiency in both sheep and cattle •Diets containing less than 5<br />
mg/kg DM will cause hypocuprosis<br />
•Diets with copper: molybdenum ratios <strong>of</strong> less than 5:1 are conducive to conditioned (secondary)<br />
hypocuprosis<br />
•The newborn calf is protected against neonatal hypocuprosis <strong>by</strong> donations from the dam, but<br />
newborn lambs assume the same copper status as the ewe •Cattle are more susceptible to copper<br />
deficiency than are sheep.<br />
REVIEWUTERATUE Gooneratne, S. R., Buckley, W. T. & Christensen, D. A. (1989) Review <strong>of</strong><br />
copper<br />
deficiency and metabolism in ruminants. Can.J.<strong>An</strong>im.Sci.,69,819-5. Smart, M. E., Cymbaluk, N. .
f& Christensen,<br />
D. A. (1992) A review <strong>of</strong> copper status <strong>of</strong> cattle in Canada ami recommendations for<br />
supplementation. Can. Vet.J, 33, 163-170. Suttle, N. F. (1986) Problems in the diagnosis and<br />
anticipation <strong>of</strong> trace element <strong>deficiencies</strong> in grazing livestock. Vet.Rec, It9, 148-152.<br />
Suttle, N. F. (1986) Copper deficiency in ruminants, recent developments. Vet. Rec, 119, 519-522.<br />
Suttle, N. F. (1987) The nutritional requirement for copper in animals and man. In: Copper in<br />
<strong>An</strong>imals and Mem. Volume I. Eds HoweU,<br />
M. & Gawthorne, J. M. Boca Raton, FL:<br />
CRC Press, pp. 21-43. Suttle, N. F. (1991) The interactions between copper, molybdenum, and<br />
sulphur in ruminant nutrition. <strong>An</strong>n. Rcir. Nutr., 1 /, 121-140.<br />
Suttle, N. F. (1994) Meeting the copper requirements <strong>of</strong> ruminants: In: Recent Advances in<br />
<strong>An</strong>imal Nutrition. Eds Garnsworthy, P. C. & Cole, D.J. A.<br />
Nottingham: Nottingham Univ. Press, pp. 173-187. Wikse, S. E., Herd, IX, Field, R. & Holland, P.<br />
(1992) Diagnosis <strong>of</strong> copper deficiency m cattle./ Am. Vet. Med. Assoc, 200, 1625-1629.<br />
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(19)Wildman, R. E. C. et al. (1996) Biol. Trace Element. Res., 55, 55.<br />
(20)Stabel.J. R. et al. (1993)/ <strong>An</strong>im. Sci., 11, 1247.<br />
(21)Arthington.J. D. ct al. (1995) /. <strong>An</strong>im. Sci., 13, 2079.<br />
(22)Fyffe.J.J. (1996) Aust. Vet.J., 13, 188.<br />
(23)BowlandJ. V. (1990) % News & Info., 11, 163.<br />
(24)Wikse, S. E. et al. (1992) /. Am. Vet. Med. Assoc, 200, 1625.<br />
(25)Vermunt, J. J. ik West, D. M. (1994) NZ Vet.J., 42, 194.<br />
(26)Clark, R. G. & Ellison, R. S. (1993) NZ Vet.J., 41, 98.<br />
(27)Suttle, N. F. (1993) Vet. Rec, 133, 123.<br />
(28)Mee.J. F. & McLaughlm, J. (1995) Vet. Rec, 136. 275.
(29)Suttle, N. F. (1986) Vet. Rec, 119, 148.<br />
(30)Suttle, N. F. et al. (1996) Equine Vet.J..2H, 497.<br />
(31)White. C. F. et al. (1994) Ausl.J. Agr.Res., 45, 279.<br />
(32)Boila, R. J. et al. (1984) Can.}. Arum. Sci.,64. 365.<br />
(33)Parkins, J. J. et al. (1994) Br. Vet.J., 150,547.<br />
IODINE DEFICIENCY<br />
Synopsis<br />
Etiology. Primary dietary deficiency <strong>of</strong>iodine or secondary toconditioning factors such as calcium,<br />
Brassica plants, or bacterial pollution <strong>of</strong> water. Epidemiology. In all species, most common in<br />
continental land masses. Neonatal animals. Diets <strong>of</strong> dams deficient in iodine or containing<br />
conditioning factors such as certain plants.<br />
Signs. Goiter as palpable enlargement <strong>of</strong> thyroid gland. Neonatal mortality due to stillbirths, weak<br />
neonates may not be able to suck and die in few days, alopecia at birth, myxedema. Clinical<br />
pathology. Blood iodine levels.<br />
Lesions. Thyroid enlargement, alopecia, myxedema. Diagnostic confirmation. Goiter and iodine<br />
deficiency.<br />
Differential diagnosis list:<br />
•Weak calf syndrome<br />
•Abortion<br />
1503<br />
•Congenital defects (Chapter 34).<br />
Treatment. Not usually undertaken.<br />
Control. Insure dietatry intake <strong>of</strong> iodine in pregnant animals<br />
ETIOLOGY<br />
Iodine deficiency may be due to deficient iodine intake or secondarily conditioned <strong>by</strong> a high<br />
intake <strong>of</strong> calcium, diets consisting largely <strong>of</strong> Brasska spp., or gross bacteial pollution <strong>of</strong> feedstuffs<br />
or drinking water. A continued intake <strong>of</strong> a low level <strong>of</strong> cyanogenetic glycosides, e.g. in white<br />
clover, is commonly associated with a high incidence <strong>of</strong> goitrous <strong>of</strong>fspring. Lmamann, a glycoside<br />
in linseed meal, is the agent producing goiter in newborn lambs born from ewes fed the meal<br />
during pregnancy. A continued intake <strong>of</strong> the grass Cynodon aethiopicus with low iodine and high<br />
cyanogenetic glucoside contents may cause goiter in lambs. Rapeseed and rapeseed meal are also<br />
goitrogenic.<br />
EPIDEMIOlOGY<br />
Occurrence<br />
Goiter <strong>caused</strong> <strong>by</strong> iodine deficiency occurs in all <strong>of</strong> the continental land masses. It is not ot major<br />
economic importance because <strong>of</strong> the ease <strong>of</strong> recognition and correction, but if neglected may<br />
cause heavy mortalities in newborn animals. The most common cause <strong>of</strong> iodine deficiency in<br />
farm animals is the failure to provide iodine in the diet. The sporadic occurrence <strong>of</strong> the disease<br />
in marginal areas attracts most attention. <strong>An</strong> epi-demiological survey in Germany found up to<br />
10% <strong>of</strong> cattle and sheep farms, and 15% <strong>of</strong> swine herds were affected with iodine deficiency,<br />
which were both primary and secondary due to the presence <strong>of</strong> nitrates, thiocyanates or<br />
glucosinolates in the diet (1).<br />
The importance <strong>of</strong> subclinical iodine deficiency as a cause <strong>of</strong> neonatal mortality could be much<br />
greater than clinical disease. For example, in southern Australia ewes supplemented with iodine
y the single injection <strong>of</strong> iodine in oil, have had less mortality in the lambs, have grown larger<br />
lambs, or performed the same as controls.<br />
Young animals are more likely to bear goitrous <strong>of</strong>fspring than older ones and this may account<br />
for the apparent breed susceptibility <strong>of</strong> Dorset Horn sheep, which mate at an earlier age than other<br />
breeds.<br />
A simple deficiency <strong>of</strong> iodine in the diet and drinking water may occur and is related to<br />
geographical circumstances. Areas where the soil iodine is not replenished <strong>by</strong> cyclical accessions<br />
<strong>of</strong> oceanic iodine include large continental land masses and coastal areas where prevailing winds<br />
are <strong>of</strong>fshore. In such areas, iodine deficiency is most likely to occur where rainfall is heavy and<br />
soil iodine is continually depleted <strong>by</strong> leaching. Soil formations rich in calcium or lacking in humus<br />
are also likely to be relatively deficient in iodine. The ability <strong>of</strong> soil to retain iodine under<br />
conditions <strong>of</strong> heavy rainfall is directly related to their humus content, and limestone soils arc, in<br />
general, low in organic matter. A high dietary intake <strong>of</strong> calcium also decreases intestinal<br />
absorption <strong>of</strong> iodine, and in some areas heavy applications <strong>of</strong> lime to pasture are followed <strong>by</strong> the<br />
development <strong>of</strong> goiter in lambs. This factor may also be important in areas where drinking water<br />
is heavily <strong>mineral</strong>ized.<br />
Risk factors<br />
Dietary and environmental factors<br />
There are several situations in which the relationship between iodine intake and the occurrence <strong>of</strong><br />
goiter is not readily apparent. Goiter may occur on pasture containing adequate iodine; it is then<br />
usually ascribed to a secondary or conditioned iodine deficiency. A diet rich in plants <strong>of</strong> the<br />
Brassica spp., including cabbages and brussels sprouts, may cause simple goiter and<br />
hypothyroidism in rabbits, which is preventable <strong>by</strong> administered iodine. Hypothyroidism has also<br />
been produced in rats <strong>by</strong> feeding rape-seed, and in mice <strong>by</strong> feeding rapeseed oil meal, heeding<br />
large quantities <strong>of</strong> kale to pregnant ewes causes a high incidence <strong>of</strong> goiter and hypothyroidism,<br />
also pre¬ventable <strong>by</strong> administering iodine in the newborn lambs. The goitrogenic substance in<br />
these plants is probably a glu-cosinolate capable <strong>of</strong> producing thiocyanate in the rumen. The<br />
thio-cyanate content, or potential content, varies between varieties <strong>of</strong> kale, being much less in<br />
rape-kale, which also does not show the two-fold increase in thiocyanate content other varieties<br />
show in autumn. Small young leaves contain up to five times as much thiocyanate as large, fully<br />
formed leaves. Some <strong>of</strong> these plants are excellent sources <strong>of</strong> feed, and in some areas it is probably<br />
economical to continue feeding them, provided suitable measures are taken to prevent goiter in the<br />
newborn. Although kale also causes mild goiter in weaned lambs this does not appear to reduce<br />
their rate <strong>of</strong> gain.<br />
A diet high in linseed meal (20% <strong>of</strong> ration) given to pregnant ewes may result in a high<br />
incidence <strong>of</strong> goitrous lambs, which is preventable with iodine or thyroxine. Under experimental<br />
conditions, groundnuts are goitrogenic for rats, the goitrogenic substance being a<br />
glyco-side-arachidoside. The goitrogenic effect is inhibited <strong>by</strong> supplementation <strong>of</strong> the diet with<br />
small amounts <strong>of</strong> iodine. Soybean <strong>by</strong>products are also considered to be goitrogenic. Gross<br />
bacterial contamination <strong>of</strong> drinking water <strong>by</strong> sewage is a cause <strong>of</strong> goiter in humans in countries<br />
where hygiene is poor. There is a record <strong>of</strong> a severe outbreak <strong>of</strong> goitrous calves from cattle<br />
running on pasture heavily dressed with crude sewage. Prophylactic dosing <strong>of</strong> the cows with<br />
potassium iodide prevented further cases. Feeding sewage sludge is also linked to the occurrence<br />
<strong>of</strong> goiter.
Goiter in lambs may occur when permanent pasture is plowed and resown. This may be due to<br />
the sudden loss <strong>of</strong> decomposition and leaching <strong>of</strong> iodine-binding humus in soils <strong>of</strong> marginal iodine<br />
content. In subsequent years the disease may not appear. There may be some relation between this<br />
occurrence <strong>of</strong> goiter and the known variation in the iodine content <strong>of</strong> particular plant species,<br />
especially if new pasture species are sown when the pasture is plowed. The maximum iodine<br />
content <strong>of</strong> some plants is controlled <strong>by</strong> a strongly inherited factor and is independent <strong>of</strong> soil type<br />
or season. Thus, in the same pasture, perennial rye grass may contain 146 µg iodine per 100 g dry<br />
matter (DM) and Yorkshire for grass only 7µg/100 g DM. Because goiter has occurred in lambs<br />
when the ewes are on a diet containing less than 30 µg iodine per 100 g DM, the importance <strong>of</strong><br />
particular plant species becomes apparent. A high incidence <strong>of</strong> goiter associated with heavy<br />
mortality has been observed in the new¬born lambs <strong>of</strong> ewes grazing on pasture dominated <strong>by</strong><br />
white clover and <strong>by</strong> subterranean clover and perennial ryegrass.<br />
Congenital goiter has been observed in foals born to mares on low iodine intake, but also to<br />
mares fed an excessive amount <strong>of</strong> iodine during pregnancy.<br />
1504<br />
PATHOGENESIS<br />
Iodine deficiency results in a decreased production <strong>of</strong> thyroxine and stimulation <strong>of</strong> the secretion <strong>of</strong><br />
thyrotropic hormone <strong>by</strong> the pituitary gland. This commonly results in hypcrplasia <strong>of</strong> thyroid tissue<br />
and a considerable enlargement <strong>of</strong> the gland. Most cases <strong>of</strong> goiter <strong>of</strong> the newborn are <strong>of</strong> this type.<br />
The primary deficiency <strong>of</strong> thyroxine is responsible for the severe weakness and hair abnormality<br />
<strong>of</strong> the affected animals. Although the defect is described as hairlessness, it is truly hypoplasia <strong>of</strong><br />
the hairs, with many very slender hairs present and a concurrent absence and diminution in size <strong>of</strong><br />
hair follicles. A hyperplastic goiter is highly vascular and the gland can be felt to pulsate with the<br />
arterial pulse and a loud murmur may be audible over the gland. Colloid goiter is less common in<br />
animals and probably represents an involutional stage after primary hyperplasia.<br />
Other factors, particularly the ingestion <strong>of</strong> low levels <strong>of</strong> cyanide, exert their effects <strong>by</strong> inhibiting<br />
the metabolic activity <strong>of</strong> the thyroid epithelium and restricting the uptake <strong>of</strong> iodine. Thiocyanates<br />
and sulfocyanates are formed during the process <strong>of</strong> detoxication <strong>of</strong> cyanide in the liver and these<br />
substances have a pronounced depressing effect on iodine uptake <strong>by</strong> the thyroid. Some pasture and<br />
fodder plants, including white clover, rape and kale, are known to have a moderate content <strong>of</strong><br />
cyanogenetic glucosides. These goitro-genic substances may appear in the milk and provide a<br />
toxic hazard to both animals and man. The inherited form in cattle is due to the increased activity<br />
<strong>of</strong> an enzyme that deiodinatesiodotyrosines so rapidly that the formation <strong>of</strong> thyroxine is inhibited.<br />
Iodine is an essential element for normal fetal brain and physical development in sheep. A<br />
severe iodine deficiency in pregnant ewes causes reduction in fetal brain and body weight from 70<br />
days <strong>of</strong> gestation to parturition. The effects are mediated <strong>by</strong> a combination <strong>of</strong> maternal and fetal<br />
hypothyroidism, the effect <strong>of</strong> maternal hypothyroidism being earlier than the onset <strong>of</strong> fetal thyroid<br />
secretion (2). There is also evidence <strong>of</strong> fetal hypothyroidisms, and absence <strong>of</strong> wool growth and<br />
delayed skeletal maturation near parturition.<br />
CLINICAL FINDINGS<br />
Although loss <strong>of</strong> condition, decreased milk production, and weakness might be anticipated these<br />
signs are not usually observed in adults. Loss <strong>of</strong> libido in the bull, failure to express estrus in the<br />
cow, and a high incidence <strong>of</strong> aborted, stillborn or weak calves have been suggested as
manifestations <strong>of</strong> hypothyroidism m cattle, whereas prolonged gestation is reported in mares, ewes,<br />
and sows.<br />
A high incidence <strong>of</strong> stillbirths and weak, newborn animals is the most common manifestation<br />
<strong>of</strong> iodine deficiency. Partial or complete alopecia and palpable enlargement <strong>of</strong> the thyroid gland<br />
are other signs that occur with varying frequency in the different species. Affected foals have a<br />
normal hair coat and little thyroid enlargement, but are very weak at birth. In most cases they are<br />
unable to stand without support and many are too weak to suck. Excessive flexion <strong>of</strong> the lower<br />
forelegs and extension <strong>of</strong> lower parts <strong>of</strong> the hindlegs has also been observed in affected foals.<br />
Defective ossification has also been reported, the manifestation is collapse <strong>of</strong> the central and third<br />
tarsal bones leading to lameness and deformity <strong>of</strong> the hock. Enlargement <strong>of</strong> the thyroid also occurs<br />
commonly in adult horses in affected areas, Thoroughbreds and light horses being more<br />
susceptible than draft animals.<br />
In cattle, the incidence <strong>of</strong> thyroid enlargement in adults is much lower than in horses and the<br />
cardinal manifestations are gross enlargement <strong>of</strong> the thyroid gland and weakness in newborn<br />
calves. If they are assisted to suck for a few days, recovery is usual, but if they are born on the<br />
range during inclement weather many will die. In some instances, the thyroid gland is sufficiently<br />
large to cause obstruction to respiration. Partial alopecia is a rare accompaniment.<br />
In pigs, the characteristic findings are birth <strong>of</strong> hairless, stillborn or weak piglets <strong>of</strong>ten with<br />
myxedema <strong>of</strong> the skin <strong>of</strong> the neck. The hairlessness is most marked on the limbs. Most affected<br />
piglets die within a few hours <strong>of</strong> birth. Thyroid enlargement may be present but is never<br />
sufficiently great to cause visible swelling in the live pig. Survivors arc-lethargic, do not grow<br />
well, have a waddling gait and leg weaknesses due to weakness <strong>of</strong> ligaments and joints.<br />
Adult sheep in iodine-deficient areas may show a high incidence <strong>of</strong> thyroid enlargement but are<br />
clinically normal in other respects. Newborn lambs manifest weakness, extensive alopecia and<br />
palpble, if not visible, enlargement <strong>of</strong> the thyroid glands. Goats present a similar clinical picture,<br />
except that all abnormalities are more severe than in lambs. Goat kids are goitrous and alopecic.<br />
The degree <strong>of</strong> alopecia varies from complete absence <strong>of</strong> hair, through very fine hair, to hair that is<br />
almost normal.<br />
<strong>An</strong>imals surviving the initial danger period after birth may recover, except for partial<br />
persistence <strong>of</strong> the goiter. The glands may pulsate with the normal arterial pulse and may extend<br />
down a greater part <strong>of</strong> the neck and cause some local edema. Auscultation and palpation <strong>of</strong> the<br />
jugular furrow may reveal the presence <strong>of</strong> a murmur and thrill, the 'thyroid thrill', due to the<br />
increased arterial blood supply <strong>of</strong> the glands.<br />
Experimental hypothyroidism produced in horses <strong>by</strong> surgical excision <strong>of</strong> the gland results in a<br />
syndrome <strong>of</strong> poor growth, cold sensitivity, long, dull hair coat, docility, lethargy, edema <strong>of</strong><br />
hindlimbs and a coarse, thick appearance <strong>of</strong> the face. The rectal temperature is depressed and<br />
blood cholesterol levels are high. Administration <strong>of</strong> thyroprotein reverses the syndrome.<br />
CLINICAL PATHOLOGY<br />
Estimations <strong>of</strong> iodine levels in the blood and milk are reliable indicators <strong>of</strong> the thyroxine status <strong>of</strong><br />
the animal. Organic or protein-bound iodine is estimated in serum or plasma and used as an index<br />
<strong>of</strong> circulating thyroid hormone, provided access to exogenous iodine in the diet, or as treatment, is<br />
adequately controlled. There may be between-breed differences in blood iodine levels but levels <strong>of</strong><br />
2.4-14 µg <strong>of</strong> protein-bound iodine per 100 mL <strong>of</strong> plasma appear to be in the normal range. In ewes,<br />
an iodine concentration in milk <strong>of</strong> below 8 µg/L indicates a state <strong>of</strong> iodine deficiency.
Levels <strong>of</strong> thyroxine in the blood have not been much used to measure thyroid gland sufficiency<br />
in animals. Work in ewes has shown that normal lambs at birth have twice the serum thyroxine<br />
levels <strong>of</strong> their dams, but goitrous lambs have levels less than those <strong>of</strong> their dams. However, low<br />
mean thyroxine levels (50 nmol/L is normal) are not a definitive indication <strong>of</strong> iodine deficiency<br />
because <strong>of</strong> the variety <strong>of</strong> factors affecting thyroxine levels. These levels fall rapidly soon after<br />
birth and approximate the dam's levels at 5-6 weeks <strong>of</strong> age.<br />
Bloodcholesterollevelshavebeen<br />
1505<br />
used as an indicator <strong>of</strong> thyroid function in humans but are not used in the investigation <strong>of</strong> goiter in<br />
animals.<br />
In determining the iodine status <strong>of</strong> an area, iodine levels in soil and pasture should be obtained<br />
but the relationship between these levels, and between them and the status <strong>of</strong> the grazing animal,<br />
may be complicated <strong>by</strong> conditioning factors.<br />
NECROPSY FINDINGS<br />
Macroscopic thyroid enlargement, alopecia and myxedema may be evident. The weights <strong>of</strong><br />
thyroid glands have diagnostic value. In full-term normal calves the average fresh weight is 6.5g,<br />
in lambs 2g is average. The iodine content <strong>of</strong> the thyroid will also give some indication <strong>of</strong> the<br />
iodine status <strong>of</strong> the animal. At birth a level <strong>of</strong> 0.03% <strong>of</strong> iodine on a wet weight basis (0.1% on dry<br />
weight) can be considered to be the critical level in cattle and sheep. On histological examination,<br />
hyperplasia <strong>of</strong> the glandular epithelium may be seen. The hair follicles will be found to be<br />
hypoplastic. Delayed osseous maturation, manifested <strong>by</strong> absence <strong>of</strong> centers <strong>of</strong> ossification, is also<br />
apparent in goitrous newborn lambs.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
•Toxicology - 1 thyroid gland (ASSAY(Iodine))<br />
•Histology - skin, thyroid (LM).<br />
DIFFERENTIAL DIAGNOSIS<br />
Iodine deficiency is easily diagnosed if goiter is present but the occurrence <strong>of</strong> stillbirths without<br />
obvious goiter may be confusing. Abortion due to infectious agents in cattle and sheep must be<br />
considered in these circumstances. In stillbirths due to iodine deficiency, gestation is usually<br />
prolonged beyond the normal period, although this may be difficult to determine in animals bred<br />
at pasture. Inherited defects <strong>of</strong> thyroid hormone synthesis are listed under the heading <strong>of</strong> inherited<br />
diseases. Hyperplastic goiter without gland enlargement has been observed in newborn foals in<br />
which rupture <strong>of</strong> the common digital extensor tendons, forelimb contracture, and mandibular<br />
prognathism also occur. The cause <strong>of</strong> the combination <strong>of</strong> defects in unknown.<br />
TREATMENT<br />
Treatment <strong>of</strong> neonates with obvious clinical evidence <strong>of</strong> iodine deficiency is usually not<br />
undertaken because <strong>of</strong> the high case fatality rate. When outbreaks <strong>of</strong> iodine deficiency occur in<br />
neonates, the emphasis is usually on providing additional iodine to the pregnant dams. The<br />
recommendations for control can be adapted to the treatment <strong>of</strong> affected animals.<br />
CONTROL<br />
The recommended dietary intake <strong>of</strong> iodine for cattle is 0.8-1.0 mg/kg DM <strong>of</strong> feed for lactating and<br />
pregnant cows, and 0.1-0.3 mg/kg DM <strong>of</strong> feed for non-pregnant cows and calves.<br />
Iodine can be provided in salt or a <strong>mineral</strong> mixture. The loss <strong>of</strong> iodine from salt blocks may be<br />
appreciable and an iodine preparation that is stable but contains sufficient available iodine is
equired. Potassium iodate satisfies these requirements and should be provided as 200 mg <strong>of</strong><br />
potassium iodate per kg <strong>of</strong> salt. Potassium iodide alone is unsuitable, but when mixed with<br />
calcium stearate (8% <strong>of</strong> the stearate in potassium iodide) it is suitable for addition to salt - 200<br />
mg/kg <strong>of</strong> salt.<br />
Individual dosing <strong>of</strong> pregnant ewes, on two occasions during the 4th and 5th months <strong>of</strong><br />
pregnancy, with 280 mg potassium iodide or 370 mg potassium iodate has been found to be<br />
effective in the prevention <strong>of</strong> goiter in lambs when the ewes are on a heavy diet <strong>of</strong> kale. For<br />
individual animals, weekly application <strong>of</strong> tincture <strong>of</strong> iodine (4 mL cattle, 2 mL pig and sheep) to<br />
the inside <strong>of</strong> the flank is also an effective preventive. The iodine can also be administered as an<br />
injection in poppy seed oil (containing 40% bound iodine): 1 mL given IM 7-9 weeks before<br />
lambing is sufficient to prevent severe goiter and neonatal mortality in the lambs. Control <strong>of</strong> goiter<br />
can be achieved for up to 2 years. The gestation period is also reduced to normal. A similar<br />
injection 3-5 weeks before lambing is less efficient.<br />
A device to release iodine slowly into the forestomachs, while still retaining its position there,<br />
has given good results in preventing congenital goiter in lambs when fed to ewes during late<br />
pregnancy.<br />
REFERENCES<br />
(1)Korber, R. al. (1985) Mh Vet. Med., 40,220.<br />
(2)Hetzel, B. S. & Mano, M. T. (1989) J. Nutr.,119, 145.<br />
IRON DEFICIENCY<br />
Synopsis<br />
Etiology. Dietary deficiency <strong>of</strong> iron<br />
Epidemiology. Young animals on milk diet; most commonly nursing piglets which have not<br />
received supplemental iron. Housed nursing lambs. Occurs in veal calves fed milk with limited<br />
quantities <strong>of</strong> iron. Continued blood loss due to hemorrhage (lice, blood sucking helminths).<br />
Subclinical iron deficiency occurs in calves and foals <strong>of</strong> doubtful significance. May be more<br />
susceptible to infectious diseases.<br />
Signs. Pale white skin <strong>of</strong> well grown nursing piglets, dyspnea, pallor <strong>of</strong> mucosae, sudden death<br />
may occur. Stillbirths if sows iron deficient. Secondary infectious diseases.<br />
Clinical pathology. Subnormal levels <strong>of</strong> hemoglobin <strong>of</strong> serum iron, microcytic hypochromic<br />
anemia.<br />
Lesions. Pallor, thin watery blood, anasarca, dilated heart, enlarged liver.<br />
Diagnostic confirmation. Low serum hemoglobin and serum iron with microcytic hypochromic<br />
anemia. Response to iron therapy.<br />
Differential diagnosis. Other causes <strong>of</strong> anemia (p. 414).<br />
Treatment. Parenteral and oral iron salts.<br />
Control. Insure adequate iron intake. Parenteral iron dextran to nursing piglets and lambs.<br />
ETIOLOGY<br />
Iron deficiency is usually primary and most likely to occur in newborn animals whose sole source<br />
<strong>of</strong> iron is the milk <strong>of</strong> the dam, milk being a poor source <strong>of</strong> iron. Deposits <strong>of</strong> iron in the liver <strong>of</strong> the<br />
newborn are insufficient to maintain normal hemopoiesis for more than 2-3 weeks, and are<br />
particularly low in piglets.<br />
EPIDEMIOLOGY<br />
Iron-deficiency states are not common in farm animals except in the very young confined to a
milk diet.<br />
Iron deficiency anemia occurs in nursing piglets for three reasons:<br />
1.They do not have access to soil, which is a main source <strong>of</strong> iron for young farm animals<br />
2.They grow rapidly and their absolute requirements for iron are high<br />
3.Milk is a poor source <strong>of</strong> iron.<br />
The administration <strong>of</strong> iron dextran to the piglets at a few days <strong>of</strong> age is preventive and is a<br />
routine health management strategy in modern swine production. If they do not receive<br />
supplemental iron dextran, clinical<br />
1506<br />
disease occurs usually when the piglets are 3-6 weeks old. The losses that occur include those due<br />
to mortality, which may be high in untreated pigs and to failure to thrive. Under modern swine<br />
production systems piglets do not have access to sufficient dietary iron until they are weaned to a<br />
dry diet containing supplemental iron. Thus, the need for parenteral iron dextran at a few days <strong>of</strong><br />
age.<br />
Iron deficiency anemia occurs in nursing lambs that are housed and do not have access to<br />
soil, do not consume much feed other than their dam's milk for the first 7-10 days <strong>of</strong> life, and grow<br />
at 0.4 kg per day (1). The parenteral administration <strong>of</strong> iron dextran at 24 hours <strong>of</strong> age prevents the<br />
anemia (1).<br />
Continued blood loss <strong>by</strong> hemorrhage in any animal may result in subclinical anemia and iron<br />
deficiency. Cattle heavily infested with sucking lice may develop serious and even fatal anemia.<br />
The chronic form is characterized <strong>by</strong> a non-regenerative anemia with subnormal levels <strong>of</strong> serum<br />
iron, and treatment with iron is necessary for an optimal response. Horses carrying heavy burdens<br />
<strong>of</strong> bloodsucking strongylid worms <strong>of</strong>ten have subnormal hemoglobin levels and respond to<br />
treatment with iron. On occasions veal calves, and possibly young lambs and kids, may also suffer<br />
from an iron deficiency.<br />
Good quality veal is traditionally pale in color and is produced <strong>by</strong> feeding calves an all-liquid<br />
milk replacer diet with a low concentration <strong>of</strong> available iron (2, 3). The pallor <strong>of</strong> veal is due<br />
largely to low concentrations <strong>of</strong> myoglobin and other iron-containing compounds in muscle. Milk<br />
replacers containing only 10 mg iron/kg DM results in marked anemia and reduced growth<br />
performance (3). Feeding milk replacers with 50 mg iron/kg DM is considered, physiologically,<br />
the optimum amount <strong>of</strong> iron for veal calves but may be too high for acceptable carcass yield in<br />
some countries (3). A severe iron defi¬ciency with reduced growth rate in veal calves may be<br />
associated with a higher incidence <strong>of</strong> infectious disease because <strong>of</strong> an unpaired immune system (4).<br />
The objective in veal calf management is to walk the narrow line between the maximum<br />
production <strong>of</strong> white meat and a degree <strong>of</strong> anemia insufficient to interfere with maximum<br />
production.<br />
Subclinical iron-deficiency anemia also occurs in newborn calves and kids but there is debate<br />
as to wheteher the condition has practical significance. In newborn calves affected with a<br />
nor-mochromic, normocytic, and poikilo-cytic anemia the levels <strong>of</strong> serum iron are not<br />
significantly different from normal calves (5). It has been proposed that severe poikilocytosis in<br />
calves is associated with abnormalities <strong>of</strong> hemoglobin com¬position and protein 4.2 in the<br />
erythro-cyte membrane, and iron deficiency is the cause <strong>of</strong> moderate poikilocytosis in calves (6).<br />
Clinicopathological anemia, without clinical signs, is most likely to occur when calves are born<br />
with low hemoglobin and hematocrit levels, a relatively common occurrence in twins. It is
possible that suboptimal growth may occur during the period <strong>of</strong> physiological anemia in early<br />
postnatal life. There is some evidence for this in calves in which hemoglobin levels <strong>of</strong> 11 g/dL at<br />
birth fall to about 8 g/dL between the 30th and 70th days and only begin to rise when the calves<br />
start to eat roughage. The daily intake <strong>of</strong> iron from milk is 2-4mg in calves, and their daily<br />
requirement during the first 4 months <strong>of</strong> life is <strong>of</strong> the order <strong>of</strong> 50 mg, so that iron supplementation<br />
<strong>of</strong> the diet is advisable if the calves are fed entirely on milk. Even when hay and gram are fed to<br />
calves and lambs in addition to milk, there is a marked growth response to the administration <strong>of</strong><br />
iron-dextran preparations at the rate <strong>of</strong> 5.5 mg/kg BW. The dietary iron requirement for<br />
fast-growing lambs is between 40 and 70 mg/kg BW, and growth rate is suboptimal on diets <strong>of</strong><br />
less than 25 mg/kg BW.<br />
Low serum iron concentration and low serum ferritin have been observed in hospitalized<br />
young foals (7). Hemoglobin concentrations and packed cell volume decrease in foals from values<br />
at birth, which are similar to those for adult horses, to mean values during the first weeks and<br />
months <strong>of</strong> life below those reported in adults. Serum iron concentration, total iron-binding<br />
capacity, and packed cell volume decreased during the foal's first 24 hours <strong>of</strong> life (8). Based on the<br />
studies <strong>of</strong> foals from birth to 1 year <strong>of</strong> age, the potential for iron deficiency developing under 5<br />
weeks <strong>of</strong> age is possible because 65% <strong>of</strong> foals had minimum ferritin concentrations =45 ng/mL,<br />
and 81% <strong>of</strong> foals had these minimum values recorded between 2 and 4 weeks.<br />
Competition horses are frequently given iron supplementation to treat anemia and to<br />
improve performance despite the fact that neither application has any scientific basis (7). In<br />
contrast, iron overload and toxicity have occurred in competition horses (9, 10). Some studies<br />
have shown high total plasma iron in British 3-day event team horses prior to transport (77µM)<br />
compared to normal levels <strong>of</strong> 24 µM. Immediately after travelling for 3 days on the road, the<br />
plasma levels had declined to 29 µM (11). The iron-binding antioxidant activity, an indicator <strong>of</strong><br />
transfernn saturation, had also declined, suggesting greater saturation <strong>of</strong> available transfernn in the<br />
plasma or a decreased capacity to sequester iron. The saturation <strong>of</strong> mechanisms to sequester iron,<br />
such as may occur with excessive supplementation, may predispose the horses to iron-catalyzed<br />
oxidant injury (11). The total iron intake exceeded the normal recommendation <strong>of</strong> between 550<br />
and 600 mg/day. <strong>An</strong>emia (or a low packed cell volume) is not synonymous with iron deficiency<br />
but is frequently associated with disease processes. Poor performance in an iron-deficient animal<br />
is more likely due to a reduction in the activity <strong>of</strong> metabolically active iron-containing enzymes<br />
rather than a reduction in oxygen transport. In addition, iron deficiency is unlikely to occur in<br />
healthy horses.<br />
Calcium carbonate added to the diet <strong>of</strong> weaned and finishing pigs may cause a conditioned<br />
iron deficiency and a moderate anemia but this effect is not apparent in mature pigs. Manganese<br />
may exert a similar antagonistic effect.<br />
PATHOGENESIS<br />
More than half the iron in the animal body is found as a constituent <strong>of</strong> hemoglobin. A relatively<br />
small amount is found in myoglobin and in certain enzymes which play a part in oxygen<br />
utilization.<br />
Piglets at birth have hemoglobin levels <strong>of</strong> about 90-110g/L. A physiological fall to 40-50 g/dL<br />
occurs in all pigs, the lowest levels occurring at about the 8th--10th day <strong>of</strong> life. Levels <strong>of</strong> iron in<br />
the liver at birtli are unusually low in this species and cannot be increased appreciably <strong>by</strong>
supplementary feeding <strong>of</strong> the sow during pregnancy. The IM injection <strong>of</strong> iron-dextran preparations<br />
to sows during late pregnancy docs elevate the hemoglobin levels <strong>of</strong> the piglets during the first<br />
1507<br />
few weeks <strong>of</strong> life but not sufficiently to prevent anemia in them. Piglets with access to iron show a<br />
gradual return to normal hemoglobin levels starting at about the 10th day <strong>of</strong> life, but in pigs denied<br />
this access the hemoglobin levels continue to fall.<br />
One <strong>of</strong> the important factors in the high incidence <strong>of</strong> anemia in piglets is the rapidity with<br />
which they grow in early postnatal life. Piglets normally reach four to five times their birth weight<br />
at the end <strong>of</strong> 3 weeks, and eight times their birth weight at the end <strong>of</strong> 8 weeks. The daily<br />
requirement <strong>of</strong> iron during the first few weeks <strong>of</strong> life is <strong>of</strong> the order <strong>of</strong> 15 mg. The average intake<br />
in the milk from the sow is about 1 mg/day and the concentration in sow's milk cannot be elevated<br />
<strong>by</strong> feeding additional iron during pregnancy or lactation. Apart from the specific effect on<br />
hemoglobin levels, iron-deficient piglets consume less creep feed, and after the first 3 weeks <strong>of</strong><br />
life make considerably slower weight gains than supplemented piglets. Although specific<br />
pathogen-free pigs show a less marked response to the administration <strong>of</strong> iron than pigs reared in<br />
the normal manner, it is obvious that they need supplementary iron to prevent the development <strong>of</strong><br />
anemia. Iron-deficient piglets appear to be more susceptible to diarrhea at about 2 weeks <strong>of</strong> age<br />
than are piglets that have received iron. A marked impairment <strong>of</strong> gastric secretion <strong>of</strong> acid and<br />
chloride and atrophic gastritis occurs in iron-deprived piglets. Villous atrophy <strong>of</strong> the small<br />
intestine and changes in the gastrointestinal flora also occur in iron-deficient piglets which may<br />
contribute to the increased susceptibility to diarrhea.<br />
Severe iron deficiency in veal calves is characterized <strong>by</strong> impaired growth and reduced feed<br />
intake and utilization. The growth rate is reduced only when hemoglobin concentrations fall below<br />
70g/L (12). The reduced growth rate may be due to reduction in the half-life <strong>of</strong> growth hormone.<br />
CLINICAL FINDINGS<br />
The highest incidence <strong>of</strong> iron deficiency anemia in piglets occurs at about 3 weeks <strong>of</strong> age, but it<br />
can occur up to 10 weeks <strong>of</strong> age.<br />
Affected pigs may be well grown and in good condition, but the growth rate <strong>of</strong> anemic pigs is<br />
significantly lower than that <strong>of</strong> normal pigs and feed intake is reduced. A mild diarrhea may occur<br />
but the feces are usually normal in color. Dyspnea, lethargy, and a marked increase in amplitude<br />
<strong>of</strong> the apex beat <strong>of</strong> the heart can be felt after exercise. The skin and mucosae are pale and may<br />
appear yellow in white pigs. Edema <strong>of</strong> the head and forequarters, giving the animal a fat,<br />
puffed-up appearance may be present. A lean, white hairy look is probably more common. Death<br />
usually occurs suddenly, or affected animals may survive in a thin, unthrifty condition. A high<br />
incidence <strong>of</strong> infectious diseases, especially enteric infection with Escherichia coli, is associated<br />
with the anemia, and streptococcal pericarditis is a well-recognized complication. Under<br />
experimental conditions, similar signs occur in calves and there is, in addition, an apparent<br />
atrophy <strong>of</strong> the lingual papillae. A high incidence <strong>of</strong> stillbirths is recorded in the litters <strong>of</strong> sows<br />
suffering from iron-deficiency anemia.<br />
CLINICAL PATHOLOGY<br />
In normal piglets there is a postnatal fall <strong>of</strong> hemoglobin levels to about 8g/L and sometimes to as<br />
low as 4-5g/L during the first 10 days <strong>of</strong> life. In iron-deficient pigs there is a secondary fall to<br />
20-40g/L during the 3rd week. The hemoglobin level at which clinical signs appear in pigs is<br />
about 40g/L (13). Erythrocyte counts also fall from a normal <strong>of</strong> 5-8 × 10 12 /L down to 3-4 ×10 12 /L
and may be a better index <strong>of</strong> iron status than hemoglobin levels. Iron-deficiency anemia in piglets<br />
is a microcytic hypochromic anemia. In chronic blood loss anemia in cattle infested with sucking<br />
lice, there is a non-regenerative anemia and a decrease in serum iron levels. Serum levels <strong>of</strong> iron<br />
considered to be normal in sheep and cattle are 100-200 µg/dL (17.9-35.8 (µmol/L). In newborn<br />
calves, the levels are 170 µg/dL (30.4µmol/L) at birth and 67µg/dL (12.0µmol/L) at 50 days <strong>of</strong> age.<br />
Serum ferntin concentration is an index for monitoring prelatent iron deficiency <strong>of</strong> calves (14).<br />
The borderline <strong>of</strong> iron-deficiency anemia <strong>of</strong> veal calves at 16-20 weeks <strong>of</strong> age has been defined<br />
as a hemoglobin concentration <strong>of</strong> 9g/L and a saturation <strong>of</strong> total iron binding capacity <strong>of</strong> 10% (15).<br />
NECROPSY FINDINGS<br />
The carcass is characterized <strong>by</strong> pallor, watery blood, and moderate anasarca. The heart is always<br />
dilated, sometimes extremely so. The cardiac dimensions in severely anemic neonatal pigs<br />
indicate that dilatation and hypertrophy occur consistently. The liver in all cases is enlarged, and<br />
has a mottled tan-yellow appearance. Histological examination <strong>of</strong> the bone marrow reveals<br />
maturation asynchrony <strong>of</strong> the erythroid line and a lack <strong>of</strong> hemosiderin stores. Other microscopic<br />
changes described include periacinar hepatocellular changes typical <strong>of</strong> hypoxia and decreased<br />
numbers <strong>of</strong> parietal cells in the gastric mucosa.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
•Toxicology - 50 g liver (ASSAY (Fe))(Note that serum ferritin from surviving littermates is a<br />
better indicator <strong>of</strong>iron status)<br />
•Histology - liver, heart, bone marrow,stomach (LM).<br />
DIFFERENTIAL DIAGNOSIS<br />
Confirmation <strong>of</strong> the diagnosis will depend upon hemoglobin determinations and curative and<br />
preventive trials with administered iron. The possibility that anemia in piglets may be <strong>caused</strong> <strong>by</strong><br />
copper deficiency should not be overlooked especially if the response to administered iron is poor.<br />
Isoimmunization hemolytic anemia can be differentiated <strong>by</strong> the presence <strong>of</strong> jaundice and<br />
hemoglobinuria, and the disease occurs in much younger pigs. Eperythrozoonosis occurs in pigs<br />
<strong>of</strong> all ages and the protozoan parasites can be detected in the erythrocytes.<br />
TREATMENT<br />
The recommendations for the prevention <strong>of</strong> the disease are set out below and can be followed<br />
when treating clinically affected animals. Horses with poor racing performance <strong>of</strong>ten have<br />
suboptimal blood levels <strong>of</strong> hemoglobin and a blood loss anemia due to parasitism, and respond<br />
well to treatment with iron. Treatment is usually parentcral and consists <strong>of</strong> organic iron<br />
preparations such as iron-dextran, iron-sorbitol-citric acid complex, iron saccharate or gluconate.<br />
These must be given exactly as prescribed <strong>by</strong> the manufacturer as some are quite irritant, causing<br />
large sloughs when injected IM. The dose rate is 0.5-1 g elemental iron in one injection per week.<br />
When given IV, or even IM, some horses show idiosyncratic reactions and literally drop dead.<br />
Vitamin B12 (cyanocobalamin) is <strong>of</strong>ten used in the same injection at a dose rate <strong>of</strong> 5000 µg<br />
1508<br />
per week in a single dose. Other additives, especially folic acid and choline, are also used but with<br />
little justification. Oral treatment with iron sulfate or gluconate at a dose rate <strong>of</strong> 2-4 g daily for 2<br />
weeks is as effective and much cheaper, but lacks the style <strong>of</strong> the parenteral injection. It has the<br />
disadvantage <strong>of</strong> being unpalatable and is best dispensed in liquid form to be mixed with molasses<br />
and poured onto dry feed.<br />
CONTROL
Preventive measures must be directed at the neonatal piglets because treatment <strong>of</strong> the sows before<br />
or after farrowing is generally ineffective, although some results are obtained if the iron<br />
preparations are fed at least 2 weeks before farrowing. Ferric choline citrate appears to have some<br />
special merit in this field. Allowing the nursing piglets access to pasture or dirt yards, or<br />
periodically placing sods in indoor pens, <strong>of</strong>fer adequate protection. Where indoor housing on<br />
impervious floors is necessary, iron should be provided at the rate <strong>of</strong> 15 mg/day until weaning<br />
either <strong>by</strong> oral dosing with iron salts <strong>of</strong> a commercial grade or <strong>by</strong> the IM injection <strong>of</strong> organic iron<br />
preparations. These methods are satisfactory, but the results are not usually as good as when<br />
piglets are raised outdoors. However, indoor housing is practiced in many areas to avoid exposure<br />
to parasitic infestation and some bacterial diseases, especially erysipelas. If sods are put into pens<br />
care must be taken to insure that these diseases are not introduced.<br />
Dietary supplementation<br />
Sows<br />
Feeding sows a diet supplemented with 2000 mg iron/kg DM <strong>of</strong> diet will satisfactorily prevent<br />
iron-deficiency anemia in the piglets. The piglets will ingest about 20g <strong>of</strong> sows feces per day,<br />
which will contain sufficient iron and obviate the need for IM injection <strong>of</strong> iron-dextran. The<br />
piglets grow and thrive as well as those receiving the iron-dextran.<br />
Veal calves<br />
Milk replacers for veal calves may contain up to 40 mg/kg DM <strong>of</strong> iron for the first 2 months, but<br />
commonly only 10-15 mg/kg DM for the finishing period. The best indicator <strong>of</strong> the onset <strong>of</strong><br />
anemia in calves on vealer diets is loss <strong>of</strong> appetite, which is a more sensitive indicator than<br />
biochemical measurement.<br />
Heifer calf herd replacements<br />
The National Research Council recommends that milk replacers fed to herd replacements or dairy<br />
beef contain 100 mg/kg <strong>of</strong> DM, with an upper limit <strong>of</strong> 1000 mg/kg DM (13). The preruminant calf<br />
can tolerate between 2000 and 5000 ppm DM iron in milk replacer (13).<br />
Oral dosing<br />
Daily dosing with 4 mL <strong>of</strong> 1.8% solution <strong>of</strong> ferrous sulfate is adequate. Iron pyrophosphatc may<br />
also be used (300 mg/day for 7 days). To overcome the necessity for daily dosing, several other<br />
methods <strong>of</strong> administering iron have been recommended. A single oral treatment with iron-dextran<br />
or iron-galactan has been recommended, provided an excellent creep feed is available, but the<br />
method seems unnecessarily expensive. With this oral treatment it is essential that the iron be<br />
given within 12 hours <strong>of</strong> birth because absorption has to occur through the perforate neonatal<br />
intestinal mucosa; later administration is not followed <strong>by</strong> absorption. Reduced iron (British<br />
Veterinary Codex) can be administered in large doses because it does not cause irritation <strong>of</strong> the<br />
alimentary mucosa. A single dose <strong>of</strong> 0.5-1g once weekly is sufficient to prevent anemia.<br />
Alternatively, the painting <strong>of</strong> a solution <strong>of</strong> ferrous sulfate on the sow's udder has been<br />
recommended (450g ferrous sulfate, 75g copper sulfate, 450g sugar, 2L water - applied daily) but<br />
has the disadvantage <strong>of</strong> being sticky and <strong>of</strong> accumulating litter. Pigs raised on steel gratings can<br />
derive enough iron from them to avoid the need for other supplementation. Excessive oral dosing<br />
with soluble iron salts may cause enteritis, diarrhea, and some deaths in pigs. High intakes <strong>of</strong><br />
ferric hydroxide cause diarrhea, loss <strong>of</strong> weight, and low milk production in cattle. The presence <strong>of</strong><br />
diarrhea in a herd prevents absorption <strong>of</strong> orally administered iron, and treatment <strong>by</strong> injection is<br />
recommended in this circumstance.
Intramuscular injection <strong>of</strong> iron preparations<br />
Suitable preparations must be used and are usually injected IM in piglets on one-occasion only,<br />
between the 3rd and 7th day <strong>of</strong> life. Iron-extran, fumarate, and glutamate are most commonly used.<br />
A dose <strong>of</strong> 200 mg <strong>of</strong> a rapidly absorbed and readily utihzablc form <strong>of</strong> iron within the first few<br />
days <strong>of</strong> life will result in greater body weights at 4 weeks <strong>of</strong> age than piglets given only 100 mg<br />
(16). Multiple injections give better hemoglobin levels but have not been shown to improve<br />
weight gain and, thus, a second injection at 2-3 weeks <strong>of</strong> age may not be economical. A total dose<br />
<strong>of</strong> 200 mg is usually recommended as being required to avoid clinically manifest iron-deficiency<br />
anemia, but in order to avoid any chance <strong>of</strong> a subclinical deficiency the feed should contain<br />
additional iron at the level <strong>of</strong> 240 mg/kg. A new preparation (Heptomcr) contains 200mg/mL <strong>of</strong><br />
iron, permitting a full dose in one injection. Contrasting information is that one injection <strong>of</strong> 100<br />
mg <strong>of</strong> iron is adequate for ba<strong>by</strong> pigs. Acute poisoning and rapid death occurs in piglets given<br />
iron-dextran compounds parenterally if the piglets were born from sows which were deficient in<br />
vitamin E and selenium during gestation. This is discussed under iron-dextran poisoning. In<br />
normal piglets the iron-dextran com¬pounds are safe and are usually not toxic even on repeated<br />
injection. These preparations are ideal for treatment because <strong>of</strong> the rapid response they elicit and<br />
the absence <strong>of</strong> permanent discoloration <strong>of</strong> tissues after their use if given during the first month <strong>of</strong><br />
life. A combination <strong>of</strong> sodium selenite and iron-dextran has been given to piglets at 3 days <strong>of</strong> age<br />
and is superior to treatment with iron alone when the piglets are deficient in selenium.<br />
Iron deficiency anemia in housed lambs is preventable <strong>by</strong> the IM injection <strong>of</strong> 300 mg iron<br />
dextran at 24 hours <strong>of</strong> age (1). At 12 and 24 days after treatment, the liematological values in the<br />
treated group were significantly different than the unsupplemented group, and at weaning the<br />
treated lambs were 1.0 kg heavier than untreated lambs (1).<br />
Comparable doses <strong>of</strong> parenteral iron-dextran compounds have been used for the treatment <strong>of</strong><br />
iron-deficiency or iron-loss anemias in other species, but accurate doses have not been established<br />
and the use <strong>of</strong> these preparations in cattle and horses is expensive. In addition, iron-dextran<br />
preparations given IM to horses may cause death within a few minutes after administration. The<br />
most inexpensive method <strong>of</strong> supplying iron is to use ferrous sulfate orally at a dose <strong>of</strong> 2-4 g daily<br />
for 2 weeks to adult cattle and horses with iron-deficiency anemia.<br />
Iron injection <strong>of</strong> beef calves in the first week alter birth will result in an<br />
1509<br />
increase in packed cell volume (PVC), hemoglobin (Hb), mean corpuscular volume (MCV), and<br />
mean corpuscular hemoglobin (MCH) which persists for 12 weeks. However, weight gains during<br />
the first 18 weeks <strong>of</strong> life were not affected.<br />
REFERENCES<br />
(1)Green, L. E. et al. (1997) Vet. Rec, 140,219.<br />
(2)Limit, F. & BlumJ. W. (1994)J. Vet.Med, A. 41, 237.<br />
(3)Limit, F. & Blum.J. W. (1994)/ Vet.Med., A. 41, 333.<br />
(4)Gygax, M. ct al. (1993) /. Vet. Med. A.,40. 345.<br />
(5)McGillivray, S. R. el al. (1985) Can.].Comp. Med.. 49, 286.<br />
(6)Okabe.J. et al. (1996) J. Vet. Med. Sci., 58,629.<br />
(7)Smith, J. E. et al. (1986)/ Am. Vet. Med.Assoc, 188, 285.<br />
(8)Harvey, J. W. et al. (1987) Am.). Vet.Res., 48, 1348.<br />
(9)Edens, 1. M. et al. (1993) Equine Vet.J..25, 81
(10)LavoieJ. P. & Teuscher, E. (1993) EquineVet. J.. 25, 552.<br />
(11)Mills, V. C. & Marlin, D.J. (1996) Vet.Ret., 139. 215.<br />
(12)Ceppi, A. et al. (1994) <strong>An</strong>n. Nutr. Metal,.,38, 281.<br />
(13)Jenkins, K.J. & Hidiroglou, M. (1988) J.Dairy Sci., 70, 2349.<br />
(14)Mivata, Y. et al. (1984) J. Dairy Set. 61,1256.<br />
(15)Wekhnun, D.DeB, et al. (1988) Vet.Ret.. 123, 505.<br />
(16)Daykm, M. M. et al. (1982) Vet. Rec, 110. 535.<br />
SODIUM CHLORIDE DEFICIENCY<br />
A dietary deficiency <strong>of</strong> sodium is most likely to occur:<br />
•During lactation, as a consequence <strong>of</strong> losses <strong>of</strong> the element in the milk, in rapidly growing young<br />
animals fed on low-sodium, cereal-based diets<br />
•Under very hot environmental conditions where large losses <strong>of</strong> water and sodium occur in the<br />
sweat and where the grass forage and the seeds may be low in sodium<br />
•In animals engaged in heavy or intense physical work and in animals grazing pastures on sandy<br />
soils heavily fertilized with potash, which depresses forage sodium levels (1).<br />
Naturally occurring salt deficiency causing illness in grazing animals is uncommon except<br />
under certain circumstances. The most commonly cited occurrences are on alpine pastures and<br />
heavily fertilized pasture leys. Pasture should contain at least 0.15g/100g dry matter (DM) and<br />
clinical signs are evident after about 1 month on pasture containing 0.1 g/100g DM. Under<br />
experimental conditions, lactating cows give less milk until the chloride deficiency is<br />
compensated. After a period <strong>of</strong> up to 12 months there is considerable deterioration in the animal's<br />
health and anorexia, a haggard appearance, lusterless eyes, rough coat and a rapid decline in body<br />
weight occur. high-producing animals are most severely affected and some may collapse and die.<br />
The oral administration <strong>of</strong> sodium chloride is both preventive and rapidly curative. Experimental<br />
sodium depletion in horses for up to 27 days has no deleterious effect on general health.<br />
In dairy cattle on a sodium-deficient diet there is polyuria, polydipsia, salt hunger, pica,<br />
including licking dirt . and each other's coats, drinking urine, loss <strong>of</strong> appetite and weight, and a fall<br />
in milk production (2). Urination is frequent and the urine has a lower than normal specific gravity<br />
and the urine concentrations <strong>of</strong> sodium and chloride are decreased and the potassium increased.<br />
The salivary concentration <strong>of</strong> sodium is markedly decreased, the potassium is increased and the<br />
salivary sodium:potassium ratio is decreased. The concentration <strong>of</strong> serum sodium and chloride are<br />
also decreased, but the measurement <strong>of</strong> urinary or salivary sodium concentration is a more<br />
sensitive index <strong>of</strong> sodium intake than plasma sodium concentration (2). Of these, it is urinary<br />
sodium which is depressed first and is therefore the preferred indicator in cattle (3) and horses (4).<br />
The polyuria associated with severe sodium depletion may be an antidiuretic hormone<br />
insensitivity due to lack <strong>of</strong> an effective countercurrent mechanism and hyperaldosteronism (2).<br />
Experimental restriction <strong>of</strong> chloride in the diet <strong>of</strong> dairy cows in early lactation results in a<br />
depraved appetite, lethargy, reduced feed intake, reduced milk production, scant feces, gradual<br />
emaciation, and severe hypochloremia and secondary hypokalemic metabolic alkalosis (5).<br />
Lethargy, weakness, and unsteadiness occur after about 6 weeks on the chloride-deficient diet (6).<br />
Bradycardia is also common. The concentration <strong>of</strong> chloride in cerebrospinal fluid is usually<br />
maintained near normal while the scrum concentrations decline (7). The experimental induction <strong>of</strong><br />
a severe, total body chloride deficit <strong>by</strong> the provision <strong>of</strong> a low-chloride diet and the daily removal<br />
<strong>of</strong> abomasal contents results in similar clinical findings to those described above and lesions <strong>of</strong>
nephrocalcinosis (8).<br />
The diagnosis <strong>of</strong> salt deficiency is dependent on the clinical findings, analysis <strong>of</strong> the feed and<br />
water supplies, serum levels <strong>of</strong> sodium and chlorine, and determination <strong>of</strong> the levels <strong>of</strong> sodium in<br />
the saliva, urine and feces <strong>of</strong> deficient animals (9). The concentration <strong>of</strong> sodium in saliva is a<br />
sensitive indicator <strong>of</strong> sodium deficiency. In cattle receiving an adequate supply <strong>of</strong> sodium and<br />
chlorine, the sodium levels in saliva vary from 140 to 150 mmol/L, in deficient cattle the levels<br />
may be as low as 70-100 mmol/L (9). The levels <strong>of</strong> sodium in the urine are low, with a reciprocal<br />
rise in potassium (4). The serum sodium levels are less reliable, but licking begins when the level<br />
falls to 137 mmol/L and signs are intense at 135 mmol/L.<br />
Experimentally induced sodium deficiency in young pigs causes anorexia, reduced water<br />
intake and reduced weight gains (10).<br />
The provision <strong>of</strong> salt in the diet at a level <strong>of</strong> 0.5% is considered to be fully adequate for all farm<br />
animal species. Under practical conditions, salt mixes usually contain added iodine and cobalt. In<br />
some situations the salt mixes are provided on an ad libitum basis rather than adding them to the<br />
diet. However, voluntary consumption is not entirely reliable. The daily amount consumed <strong>by</strong><br />
animals having unrestricted access to salt can be highly variable and <strong>of</strong>ten wasteful. Two factors<br />
influencing voluntary salt intake include the physical form <strong>of</strong> the salt and the salt content <strong>of</strong> the<br />
water and feed supplies. Some cattle consume much more loose than block salt, though the lower<br />
intakes <strong>of</strong> block salt may be adequate. Also, animals dependent on high saline water for drinking<br />
consume significantly less salt than when drinking non-saline water. Voluntary salt consumption is<br />
generally high in cows on low-sodium pastures, which are low inherently or as a result <strong>of</strong> heavy<br />
potash fertilization. Lactating gilts may require 0.7% salt in their diets (11) and energy efficiency<br />
in feedlot cattle may be improved <strong>by</strong> feeding high<br />
1510<br />
levels (5% <strong>of</strong> diet) <strong>of</strong> salt in the diet <strong>of</strong> finishing steers (12).<br />
REVIEW LITERATURE<br />
Aitkcn, F. C. (1976) Sodium and potassium in nutrition <strong>of</strong> mammals. Commw. Bur. <strong>An</strong>im.<br />
Nutr. Techn. Commun., 26. Michel], A. R. (1985) Sodium in health and disease: a comparative<br />
review with emphasis on herbivores. Vet. Rec, 116, 653 657.<br />
REFERENCES<br />
(1)Underwood, E.J. (1981) The Mineral Nutrition <strong>of</strong> Livestock, 2nd edn. Farnham Royal,<br />
Commonwealth AgriculturaI3ureaux.<br />
(2)Whitloik, R. H. etal. (1975) Cornell Vet..65, 512.<br />
(3)Launer, P. & Storm, R. (1979) Mh. Vet.Med., 34, 364.<br />
(4) Meyer, H. & Ahlswede, L. (1979) Zentralbl. Veterinarmed., 26A, 212.<br />
(5)Fettman, M. J. et al. (1984)/. Dairy So.,61, 2321.<br />
(6)Fettman, M.J. etal. (1984)J. Am. Vet.Med. Assoc, 185, 167.<br />
(7)Fettman, M.J. et al. (1984) Am. J. Vet.Res., 45, 403.<br />
(8)Blackmon, D. M. et al. (1984) Am.J. Vet.Res., 45, 1638.<br />
(9)Murphy, G. M. & Gartner. R. J. W.(1974) Aust. Vet.J., 50, 280.<br />
(10) Yusken.J. W. & Reber, E. F. (1957)<br />
(11)Trans. 111. Acad. Sci., 50, 118. (1 1) Friend. D. W. & Wolynetz, M. S. (1981)<br />
(12)Can. J.<strong>An</strong>im. So., 61, 429. (12) Croom, W. J. et al. (1982) Can.). <strong>An</strong>im. Sci., 62, 217.<br />
MAGNESIUM DEFICIENCY
A nutritional deficiency <strong>of</strong> magnesium plays a role in causing lactation tetany in cows and<br />
hypomagnesemic tetany <strong>of</strong> calves, and these diseases are dealt with in Chapter 28 on metabolic<br />
diseases. In both diseases, there are complicating factors that may affect the absorption and<br />
metabolism <strong>of</strong> the clement.<br />
Magnesium is an essential constituent <strong>of</strong> rations for recently weaned pigs (1). Experimentally<br />
induced deficiency causes weakness <strong>of</strong> the pasterns, particularly in the forelegs, causing backward<br />
bowing <strong>of</strong> the legs, sickled hocks, approximation <strong>of</strong> the knees and hocks, arching <strong>of</strong> the back,<br />
hyperirritability, muscle tremor, reluctance to stand, continual shifting <strong>of</strong> weight from limb to limb,<br />
and eventually tetany and death. A reduction in growth rate, feed consumption and conversion,<br />
and levels <strong>of</strong> magnesium in the serum also occur. The requirement <strong>of</strong> magnesium for pigs weaned<br />
at 3-9 weeks <strong>of</strong> age is 400-500 mg/kg <strong>of</strong> the total ration.<br />
REFERENCE<br />
(1) Mayo, R. H. et al. (1959) J. <strong>An</strong>im. Sci., 18, 264.<br />
ZINC DEFICIENCY (PARAKERATOSIS)<br />
Synopsis<br />
Etiology. Dietary deficiency <strong>of</strong> zinc and factors which interfere with zinc<br />
utilization.<br />
Epidemiology. Growing pigs, cattle and sheep. Excess <strong>of</strong> calcium favors disease in pigs.<br />
Signs.<br />
Pigs: Loss <strong>of</strong> body weight gain.<br />
Symmetrical, crusty skin lesions (parakeratosis) over dorsum and ears, tail;become thick and<br />
fissured. No pruritus.<br />
Ruminants: Alopecia, over muzzle, ears,tail-head, hindlegs, flank and neck. Stiff gait and<br />
swelling over coronets. Loss <strong>of</strong> wool and thickened skin is sheep.Infertility in rams.Poor growth in<br />
goats and skin lesions.<br />
Clinical pathology. Serum zinc levels lower than normal.<br />
Lesions. Parakeratosis.<br />
Diagnostic confirmation. Histology <strong>of</strong> skin lesions and serum zinc levels.<br />
Differential diagnosis list:<br />
•Sarcoptic mange in cattle and pigs<br />
•Exudative epidermitis in piglets.<br />
Treatment. Add zinc to diet.<br />
Control. Supplement zinc in diet.<br />
ETIOLOGY<br />
Swine<br />
A zinc deficiency in young, growing swine can cause parakeratosis, but it is not due to a simple<br />
zinc deficiency. The availability <strong>of</strong> zinc in the diet is adversely affected <strong>by</strong> the presence <strong>of</strong> phytic<br />
acid, a constituent <strong>of</strong> plant protein sources such as soybean meal (1). Much <strong>of</strong> the zinc in plant<br />
protein is in the bound form and unavailable to the monogastric animal such as the pig (2). The<br />
use <strong>of</strong> meat meal or meat scraps in the diet will prevent the disease because <strong>of</strong> the high availability<br />
<strong>of</strong> the zinc. <strong>An</strong>other unique feature <strong>of</strong> the etiology <strong>of</strong> parakeratosis in swine is that an excess <strong>of</strong><br />
dietary calcium (0.5-1.5%) can favor the development <strong>of</strong> the disease, and the addition <strong>of</strong> zinc to<br />
such diets at levels much higher (0.02% zinc carbonate or 100 mg/kg zinc) than those normally<br />
required <strong>by</strong> growing swine prevents the occurrence <strong>of</strong> the disease. The level <strong>of</strong> copper in the diet
may also be <strong>of</strong> some significance, increasing copper levels decreasing the requirement for zinc. A<br />
concurrent enteric infection with diarrhea exacerbates the damage done <strong>by</strong> a zinc deficiency in<br />
pigs.<br />
Ruminants<br />
A primary zinc deficiency due to low dietary zinc in ruminants is rare but does occur (3). Many<br />
factors influence the availability <strong>of</strong> zinc from soils, including the degree <strong>of</strong> compaction <strong>of</strong> the soil,<br />
and the nitrogen and phosphorus concentration. The risk <strong>of</strong> zinc deficiency increases when soil pH<br />
rises above 6.5 and as fertilization with nitrogen and phosphorus increases. Some legumes contain<br />
less zinc than grasses grown on the same soil, and zinc concentration decreases with aging <strong>of</strong> the<br />
plant. Several factors may deleteriously affect the availability <strong>of</strong> zinc to ruminants and cause a<br />
secondary zinc-deficiency. These include the consumption <strong>of</strong> immature grass, which affects<br />
digestibility, the feeding <strong>of</strong> late-cut hay, which may be poorly digestible, and the presence <strong>of</strong><br />
excessive dietary sulfur. The contamination <strong>of</strong> silage with soil at harvesting can also affect the<br />
digestibility <strong>of</strong> zinc (3).<br />
EPIDEMIOLOGY<br />
Swine<br />
Parakeratosis in swine was first recorded in North America in rapidly growing pigs, particularly<br />
those fed on diets containing growth promoters. The disease occurs most commonly during the<br />
period <strong>of</strong> rapid growth, after weaning and between 7 and 10 weeks <strong>of</strong> age. From 20-80% <strong>of</strong> pigs in<br />
affected herds may have lesions, and the main economic loss is due to a decrease in growth rate.<br />
In general, the incidence is greater in pigs fed in dry lot on self-feeders <strong>of</strong> dry feed than in pigs<br />
with access to some pasture, which is preventive and curative.<br />
A low level <strong>of</strong> dietary zinc intake during pregnancy and lactation <strong>of</strong> gilts can result in skin<br />
lesions, stressful parturition and an increased incidence <strong>of</strong> intrapartum mortality <strong>of</strong> piglets and<br />
deleterious effects on neonatal growth (4).<br />
It has been suggested that parakeratosis occurs because very rapidly growing pigs outstrip their<br />
biosynthesis <strong>of</strong> essential fatty acids, and when the diet is high in calcium the digestibility <strong>of</strong> fat in<br />
the diet is reduced at the same time. The net effect in rapidly growing pigs could<br />
1511<br />
be a relative deficiency <strong>of</strong> essential fatty acids.<br />
Ruminants<br />
There are naturally occurring cases in cattle, sheep, and goats. The disease is well-recognized in<br />
Europe, especially in calves. It is common in some families <strong>of</strong> cattle and an inherited increased<br />
dietary requirement for zinc is suspected. The inherited disease occurs in Friesian and Black pied<br />
cattle and is known as lethal trait A46 (5). Signs <strong>of</strong> deficiency appear at 4-8 weeks <strong>of</strong> age. The<br />
main defect is an almost complete inability to absorb zinc from the intestine; zinc administration is<br />
curative.<br />
The disease in cattle has been produced experimentally on diets low in zinc, and naturally<br />
occurring cases have responded to supplementation <strong>of</strong> the diet with zinc (3). Calves remain<br />
healthy on experimental diets containing 40 mg/kg zinc, but parakeratosis has occurred in cattle<br />
grazing pastures with a zinc content <strong>of</strong> 20-80 mg/kg (normal 93 mg/kg) and a calcium content <strong>of</strong><br />
0.6%. There is also an apparently improved response in cattle to zinc administration if copper is<br />
given simultaneously. Parakeratosis has also been produced experimentally in goats and sheep.<br />
Outbreaks <strong>of</strong> the disease have occurred in Sudanese Desert ewes and their lambs fed on a
zinc-deficient diet <strong>of</strong> Rhodes grass containing less than 10 mg/kg <strong>of</strong> zinc. The disease has also<br />
been diagnosed in mature sheep and goats and the cause <strong>of</strong> the deficiency could not be<br />
determined. A marginal zinc deficiency, characterized <strong>by</strong> subnormal growth and fertility and low<br />
concentration <strong>of</strong> zinc in serum, but without other clinical signs, can occur in sheep grazing<br />
pastures containing less than 10 mg/kg zinc (6).<br />
PATHOGENESIS<br />
The pathogenesis <strong>of</strong> zinc deficiency is not well-understood. Zinc is a component <strong>of</strong> the enzyme<br />
carbonic anhydrase, which is located in the red blood cells and parietal cells <strong>of</strong> the stomach, and is<br />
related to the transport <strong>of</strong> respiratory carbon dioxide and the secretion <strong>of</strong> hydrochloric acid <strong>by</strong> the<br />
gastric mucosa. Zinc is also associated with RNA function and related to insulin, glucagon, and<br />
other hormones. It also has a role in keratinization, calcification, wound healing, and somatic and<br />
sexual development. Because it has a critical role in nucleic acid and protein metabolism a<br />
deficiency may adversely affect the cell-mediated immune system.<br />
A zinc deficiency results in a decreased feed intake in all species (6) and is probably the reason<br />
for the depression <strong>of</strong> growth rate in growing animals and body weight in mature animals. Failure<br />
<strong>of</strong> keratimzation resulting in parakeratosis, loss and failure <strong>of</strong> growth <strong>of</strong> wool and hair, and lesions<br />
<strong>of</strong> the coronary bands probably reflect the importance <strong>of</strong> zinc in protein synthesis. There are<br />
lesions <strong>of</strong> the arteriolar walls <strong>of</strong> the dermis. The bones <strong>of</strong> zinc-deficient ruminants reveal<br />
abnormal <strong>mineral</strong>ization and reduction <strong>of</strong> zinc concentration in bones. Retarded tcsticular<br />
development occurs in ram lambs, and complete cessation <strong>of</strong> spermatogenesis suggests<br />
impairment <strong>of</strong> protein synthesis.<br />
CLINICAL FINDINGS<br />
Pigs<br />
A reduced rate and efficiency <strong>of</strong> body weight gain is characteristic. Circumscribed areas <strong>of</strong><br />
erythema appear in the skm on the ventral abdomen and inside the thigh. These areas develop into<br />
papules 3-5 mm in diameter, which are soon covered with scales followed <strong>by</strong> thick crusts. These<br />
crusts arc most visible in areas about the limb joints, ears and tail, and are distributed<br />
symmetrically in all cases. The crusts develop fissures and cracks, become quite thick (5-7 mm)<br />
and easily detached from the skin. They are crumbly and not flaky or scaly. No greasiness is<br />
present except in the depths <strong>of</strong> fissures. Little scratching or rubbing occurs. Diarrhea <strong>of</strong> moderate<br />
degree is common. Secondary subcutaneous abscesses occur frequently, but in uncomplicated<br />
cases the skin lesions disappear spontaneously in 10-45 days if the ration is corrected.<br />
Ruminants<br />
In the naturally occurring disease in cattle, in severe cases, parakeratosis and alopecia may affect<br />
about 40% <strong>of</strong> the skin area. The lesions are most marked on the muzzle, vulva, anus, tail-head,<br />
ears, backs <strong>of</strong> the hindlegs, kneefolds, flank, and neck. Most animals are below average body<br />
condition and are stunted in growth. After treatment with zinc, improvement is apparent in 1 week<br />
and complete in 3 weeks. Experimentally produced cases exhibit the following signs:<br />
•Poor growth<br />
•A stiff gait<br />
•Swelling <strong>of</strong> the coronets, hocks, and knees<br />
•S<strong>of</strong>t swelling containing fluid on the anterior aspect <strong>of</strong> the hind fetlocks<br />
•Alopecia<br />
•Wrinkling <strong>of</strong> the skin <strong>of</strong> the legs, scrotum and on the neck and head, especially around the
nostrils<br />
•Hemorrhages around the teeth<br />
•Ulcers on the dental pad.<br />
The experimental disease in cattle is manifested <strong>by</strong> parakeratotic skin, mainly on the hindlimbs<br />
and udder, and similar lesions on teats, which tend to become eroded during milking. The fetlocks<br />
and pasterns are covered with scab<strong>by</strong> scales. There is exudation first with matting <strong>of</strong> hair, then<br />
drying and cracking. The skin becomes thickened and inelastic. Histologically, there is<br />
parakeratosis. Clinical signs develop about 2 weeks after calves and lambs go onto a deficient diet<br />
so that there is no evidence <strong>of</strong> storage <strong>of</strong> zinc in tissues in these animals. In goats, hair growth,<br />
testicular size, and spermatogenesis are reduced, and growth rate is less than normal. Return to a<br />
normal diet does not necessarily reverse these-signs and the case fatality rate is high. There is a<br />
marked delay in wound healing.<br />
Sheep<br />
The natural disease in sheep is characterized <strong>by</strong> loss <strong>of</strong> wool and the development <strong>of</strong> thick,<br />
wrinkled skin. Wool-eating also occurs in sheep and may be one <strong>of</strong> the earliest signs noticed in<br />
lambs after being on a zinc-deficient diet for 4 weeks. Induced cases in lambs have exhibited<br />
reduced growth rate, salivation, swollen hocks, wrinkled skin, and open skin lesions around the<br />
ho<strong>of</strong> and eyes. The experimental disease in goats is similar to that in lambs.<br />
One <strong>of</strong> the most striking effects <strong>of</strong> zinc deficiency in ram lambs is impaired testicular growth<br />
and complete cessation <strong>of</strong> spermatogenesis. Diets containing 2.44 mg/kg dry matter (DM) <strong>caused</strong><br />
poor growth, impaired testicular growth, cessation <strong>of</strong> spermatogenesis, and other signs <strong>of</strong> zinc<br />
deficiency within 20-24 weeks. A diet containing 17.4 mg/kg DM <strong>of</strong> zinc is adequate for growth,<br />
but a content <strong>of</strong> 32.4 mg/kg DM is necessary for normal testicular development and<br />
spermatogenesis. On severely deficient experimental diets, other clinical signs in young rams are:<br />
1512<br />
•Drooling copious amounts <strong>of</strong> saliva when ruminating<br />
•Parakeratosis around eyes, on nose,feet and scrotum<br />
•Shedding <strong>of</strong> the hooves<br />
•dystrophy and shedding <strong>of</strong> wool,which showed severe staining<br />
•development <strong>of</strong> a pungent odor.<br />
In naturally occurring cases in rams the animals stood with their backs arched and feet close<br />
together.<br />
A marginal zinc deficiency in ewes may be characterized <strong>by</strong> only a reduction in feed intake and<br />
a slightly reduced body weight, and no other external signs <strong>of</strong> disease. This is important because,<br />
in grazing ruminants, the lack <strong>of</strong> external signs indicates that zinc deficiency could easily pass<br />
undetected.<br />
Infertility in ewes<br />
Infertility in ewes and a dietary deficiency <strong>of</strong> zinc have not been <strong>of</strong>ficially linked, but a<br />
zinc-responsive infertility has been described in ewes. Again, attention is drawn to the need for<br />
response trials when soil and pasture levels <strong>of</strong> an element are marginal.<br />
<strong>An</strong> experimental zinc deficiency in pregnant ewes results in a decrease in the birth weight <strong>of</strong><br />
the lambs and a reduced concentration <strong>of</strong> zinc in the tissues <strong>of</strong> the lambs; these effects are due to<br />
the reduced feed intake characteristic <strong>of</strong> zinc deficiency (6). The zinc content <strong>of</strong> the diet did not<br />
significantly influence the ability <strong>of</strong> the ewes to become pregnant or maintain pregnancy. The
combination <strong>of</strong> i pregnancy and zinc deficiency in the ewe leads to highly efficient utilization <strong>of</strong><br />
ingested zinc, and the developing fetus will accumulate about 35% <strong>of</strong> the total dietary intake <strong>of</strong><br />
zinc <strong>of</strong> the ewe during the last trimester <strong>of</strong> pregnancy. The disease is correctable <strong>by</strong> the<br />
supplementary feeding <strong>of</strong> zinc.<br />
Goats<br />
Experimentally induced zinc deficiency in goats results in poor growth, low food intake, testicular<br />
hypoplasia, rough dull coat with loss <strong>of</strong> hair, and the accumularion <strong>of</strong> hard, dry, keratinized skin<br />
on the hindlimb scrotum, head and neck. Onthe lower limbs the scabs fissure, crack, and produce<br />
some exudate. In naturally occurring cases in pygmy goats there was extensive alopecia, a<br />
kyphotic stance, extensive areas <strong>of</strong> parakeratosis, abnormal ho<strong>of</strong> growth and flaky, painful<br />
coronary bands. A zinc-responsive alopecia and hyperkeratosis in <strong>An</strong>gora goats has been described.<br />
Affected animals had recurrent pruritus, hyperemia, exfoliation, fleece loss over the hindquarters,<br />
face and ears, and a decline in reproductive performance.<br />
Immediately before parturition in cows there is a precipitate fall in plasma zinc concentration,<br />
which returns to normal slowly after calving. The depression <strong>of</strong> zinc levels is greater in cows that<br />
experience dystocia. This has led to the hypothesis that dystocia in beef heifers may be <strong>caused</strong> in<br />
some circumstances <strong>by</strong> a nutritional deficiency <strong>of</strong> zinc and that preparturient supplementation <strong>of</strong><br />
the diet with zinc may reduce the occurrence <strong>of</strong> difficult births. This phenomenon does not appear<br />
to occur in sheep. The level <strong>of</strong> serum zinc increased in cattle during the season <strong>of</strong> facial eczema<br />
when sporidesmin intoxication causes depiction <strong>of</strong> liver zinc (7).<br />
CLINICAL PATHOLOGY<br />
Skin scraping<br />
Laboratory examination <strong>of</strong> skin scrapings yields negative results, but skin biopsy will confirm the<br />
diagnosis <strong>of</strong> parakeratosis.<br />
Zinc in serum and hair<br />
Serum zinc levels may have good diagnostic value. Normal levels are 80- 120 µg/dL<br />
(12.2-18.2µmol/L) in sheep and cattle. Calves and lambs on deficient diets may have levels as low<br />
as 18µg/dL (3.0 µmol/L). Normal serum zinc levels in sheep are above 78 µg/dL (12 µmol/L), and<br />
values below 39 µg/dL (6 µmol/L) or less arc considered as evidence ot deficiency (6). There is a<br />
general relationship between the zinc content <strong>of</strong> the hair and the level <strong>of</strong> zinc in the diet, but the<br />
analysis <strong>of</strong> hair is not considered to be a sufficiently accurate indicator <strong>of</strong> an animal's zinc status.<br />
In experimental disease in piglets there is a reduction in serum levels <strong>of</strong> zinc, calcium and alkaline<br />
phosphatase, and it is suggested that the disease could be detected <strong>by</strong> measuring the serum<br />
alkaline phosphate and serum zinc levels. Levels <strong>of</strong> zinc in the blood are very labile and simple<br />
estimations <strong>of</strong> it alone arc-likely to be misleading. For example, other intercurrent diseases<br />
commonly depress serum calcium and copper levels.In addition, zinc levels in plasma fall<br />
precipitately at parturition in cows; they are also depressed <strong>by</strong> hyperthermal stress. After 1 week<br />
on a highly deficient diet serum zinc levels fall to about 50% <strong>of</strong> normal, or pretreatment levels.<br />
NECROPSY FINDINGS<br />
Necropsy examinations are not usually performed, but histological examination <strong>of</strong> skin biopsy<br />
sections reveals a marked increase in thickness <strong>of</strong> all the elements <strong>of</strong> the epidermis. Tissue levels<br />
<strong>of</strong> zinc differ between deficient and normal animals but the differences are statistical rather than<br />
diagnostic.<br />
DIFFERENTIAL DIAGNOSIS
Sarcoptic mange may resemble parakeratosis, but is accompanied <strong>by</strong> much itching and rubbing.<br />
The parasites may be found in skin scrapings. Treatment with appropriate parasiticides relieves the<br />
condition.<br />
Exudative epidermitis is quite similar in appearance, but occurs chiefly in unweaned pigs. The<br />
lesions have a greasy character that is quite different from the dry, crumbly lesions <strong>of</strong><br />
parakeratosis. The mortality rate is higher.<br />
TREATMENT<br />
In outbreaks <strong>of</strong> parakeratosis in swine, zinc should be added to diet immediately at the rate <strong>of</strong> 50<br />
mg/kg DM (200 mg <strong>of</strong> zinc sulfate or carbonate per kg <strong>of</strong> feed). The calcium level <strong>of</strong> the diet<br />
should be maintained at between 0.65 and 0.75%. The injection <strong>of</strong> zinc at a rate <strong>of</strong> 2-4 mg/kg BW<br />
daily for 10 days is also effective. Zinc oxide suspended in olive oil and given IM at a dose <strong>of</strong> 200<br />
mg <strong>of</strong> zinc for adult sheep and 50 mg <strong>of</strong> zinc for lambs will result in a clinical cure within 2<br />
months. The oral administration <strong>of</strong> zinc at the rate <strong>of</strong> 250 mg zinc sulfate daily for 4 weeks<br />
resulted in a clinical cure <strong>of</strong> zinc deficiency in goats in 12-14 weeks.<br />
CONTROL<br />
Swine<br />
The calcium content <strong>of</strong> diets for growing pigs should be restricted to 0.5-0.6%. However, rations<br />
containing as little as 0.5% calcium and with normal zinc content (30 mg/kg DM) may produce<br />
the disease. Supplementation with zinc (to 50 mg/kg DM) as sulfate or carbonate has been found<br />
to be highly effective as a preventive and there appears to be a wide<br />
1513<br />
margin <strong>of</strong> safety in its use, diets containing 1000mg/kg DM added zinc having no apparent toxic<br />
effect. The standard recommendation is to add 200 g <strong>of</strong> zinc carbonate or sulfate to each tonne <strong>of</strong><br />
feed. Weight gains in affected groups arc appreciably increased <strong>by</strong> the addition <strong>of</strong> zinc to the diet.<br />
The addition <strong>of</strong> oils containing unsaturated fatty acids is also an effective preventive. Access to<br />
green pasture, reduction in food intake, and the deletion <strong>of</strong> growth stimulants from rations will<br />
lessen the incidence <strong>of</strong> the disease but arc not usually practicable.<br />
Ruminants<br />
For cattle, the feeding <strong>of</strong> zinc sulfate (2-4 g daily) is recommended as an emergency measure<br />
followed <strong>by</strong> the application <strong>of</strong> a zinc-containing fertilizer. As an alternative to dietary<br />
supplementation for ruminants, an intraruminal pellet has been demonstrated in sheep. It was<br />
effective for 7 weeks only and would not be satisfactory for long-term use. The creation <strong>of</strong><br />
subcutaneous depots <strong>of</strong> zinc <strong>by</strong> the injection <strong>of</strong> zinc oxide or zinc metal dust has been<br />
demonstrated. The zinc dust <strong>of</strong>fered a greater delayed effect.<br />
REVIEW LITERATURE<br />
Lamand, M. (1984) Zinc deficiency in<br />
ruminants. Irish Vet.)., 38, 40-47. Luccke, R. W. (1984) Domestic animals in theelucidation <strong>of</strong><br />
zinc's role in nutrition. Fed.<br />
Proc, 43, 2823-2828.<br />
REFERENCES<br />
(1)Luecke, R. W. (1984) Fed. Proc, 43, 2823.<br />
(2)Forbes. R. M. (1984) Fed. Proc, 43, 2835.<br />
(3)Lamand, M. (1984) Irish Vel.J., 38, 40.<br />
(4)Kalinowski.J. & Chavez, E. R. (1986) Can. J.<strong>An</strong>im. Sci., 66,201, 217.
(5)Machen, M. el al. (1996)/. Vet. Diagn. Invest., 2, 219.<br />
(6)Underwood, E.J. (1981) The Mineral Nutrition <strong>of</strong> Livestock, 2nd edn. Farnham Royal,<br />
Commonwealth Agricultural Bureaux.<br />
(7)Dewes, H. F. & Lowe, M. D. (1987) NZ Vet.J., 35, 16.<br />
MANGANESE DEFICIENCY<br />
A dietary deficiency <strong>of</strong> manganese may cause infertility and skeletal deformities both congenitally<br />
and after birth.<br />
ETIOLOGY<br />
A primary deficiency occurs endemically in some areas because <strong>of</strong> a geological defiency in the<br />
local rock formations (1). Apart from a primary dietary deficiency <strong>of</strong> manganese, the existence <strong>of</strong><br />
factors depressing the availability <strong>of</strong> ingested manganese is suspected. <strong>An</strong> excess <strong>of</strong> calcium<br />
and/or phosphorus in the diet is known to increase the requirements <strong>of</strong> manganese in the diet <strong>of</strong><br />
calves (5), and is considered to reduce the availability <strong>of</strong> dietary manganese to cattle<br />
generally.Congential chondrodystrophy in calves has been associated with a manganese deficiency<br />
(2), and an outbreak <strong>of</strong> congenital skeletal defects in Holstein calves due to manganese deficiency<br />
has been reported (3).<br />
EPIDEMIOLOGY<br />
Soils containing less than 3 mg/kg <strong>of</strong> manganese are unlikely to be able to support normal fertility<br />
in cattle. In areas where manganese-responsive infertility occurs, soils on farms with infertility<br />
problems have contained less than 3 mg/kg <strong>of</strong> manganese, whereas soils on neighboring farms<br />
with no infertility problems have had levels <strong>of</strong> more than 9 mg/kg. A secondary soil deficiency is<br />
thought to occur and one <strong>of</strong> the factors suspected <strong>of</strong> reducing the availability <strong>of</strong> manganese in the<br />
soil to plants is high alkalinity. Thus, heavy liming is associated with manganese-responsive<br />
infertility. There are three main soil types on which the disease occurs:<br />
•Soils low in manganese have low out put even when pH is less than 5.5<br />
•Sandy soils where availability starts to fall<br />
•Heavy soils where availability starts to fall at pH <strong>of</strong> 7.0.<br />
Many other factors are suggested as reducing the availability <strong>of</strong> soil manganese but the<br />
evidence is not conclusive. For example, heavy liming <strong>of</strong> soils to neutralize sulfur dioxide<br />
emissions from a neighboring smelter is thought to have reduced the manganese intake <strong>of</strong> grazing<br />
animals.<br />
Herbage on low manganese soils, or on marginal soils where availability is decreased (possibly<br />
even soils with normal manganese content), is low in manganese. A number <strong>of</strong> figures are given<br />
for critical levels. It is suggested that pasture containing less than 80 mg/kg <strong>of</strong> manganese is<br />
incapable <strong>of</strong> supporting normal bovine fertility, and that herbage containing less than 50 mg/kg is<br />
<strong>of</strong>ten associated with infertility and anestrus. The Agricultural Research Council feels that,<br />
although definite figures are not available, levels <strong>of</strong> 40 mg/kg dry matter (DM) in the diet should<br />
be adequate. Other authors state that rations containing less than 20 mg/kg DM may cause<br />
anestrus and reduction in conception rates in cows and the production <strong>of</strong> poor quality semen <strong>by</strong><br />
bulls. Most pasture contains 50-100 mg/kg DM. Skeletal deformities in calves occur when the<br />
deficiency is much greater than the above for example, a diet containing more than 200 mg/kg<br />
DM is considered to be sufficient to prevent them.<br />
Rations fed to pigs usually contain more than 20 mg/kg DM <strong>of</strong> manganese, and deficiency is<br />
unlikely unless there is interference with manganese metabolism <strong>by</strong> other substances.
There are important variations in the manganese content <strong>of</strong> seeds, an important matter in<br />
poultry nutrition (1). Maize and barley have the lowest content. Wheat or oats have three to five<br />
times as much, and bran and pollard are the richest natural sources with 10-20 times the content <strong>of</strong><br />
maize or wheat. Cows' milk is exceptionally low in manganese.<br />
PATHOGENESIS<br />
Manganese plays an active role in bone matrix formation, and in the synthesis <strong>of</strong> chondroitin<br />
sulfate, responsible for maintaining the rigidity <strong>of</strong> connective tissue. In manganese deficiency<br />
these are affected deleteriously and skeletal abnormalities result. Only 1% <strong>of</strong> manganese is<br />
absorbed from the diet and the liver removes most <strong>of</strong> it, leaving very low blood levels <strong>of</strong> the<br />
element (2).<br />
CLINICAL FINDINGS<br />
In cattle, the common syndromes are infertility, calves with congenital limb deformities and calves<br />
with manifest poor growth, dry coat, and loss <strong>of</strong> coat color. The deformities include knuckling<br />
over at the fetlocks, enlarged joints and, possibly, twisting <strong>of</strong> the legs. The bones <strong>of</strong> affected lambs<br />
are shorter and weaker than normal and there are signs <strong>of</strong> joint pain, hopping gait, and reluctance<br />
to move.<br />
A severe congenital chondrodystrophy in Charolais calves occurred on one farm (2). The limbs<br />
were shortened and the joints enlarged. The pregnant cows were fed on apple pulp and corn silage<br />
both <strong>of</strong> which were low in manganese.<br />
1514<br />
<strong>An</strong> outbreak <strong>of</strong> congenital skeletal malformations in Holstein calves was characterized<br />
clinically <strong>by</strong> small birth weights (average 15 kg). Abnormalities included joint laxity, doming <strong>of</strong><br />
the foreheads, superior brachynathia, and a dwarflike appearance due to the short long bones. The<br />
features <strong>of</strong> the head were similar to those <strong>of</strong> the wildebeest. The majority <strong>of</strong> affected calves were<br />
dyspneic at birth, and snorting and grunting respratory sounds were common. Affected calves<br />
failed to thrive and most were culled due to poor performance.<br />
A manganese-responsive infertility has been described in ewes and is well known in cattle. In<br />
cattle it is manifested <strong>by</strong> slowness to exhibit estrus, and failure to conceive, <strong>of</strong>ten accompanied <strong>by</strong><br />
subnormal size <strong>of</strong> one or both ovaries. Subestrus and weak estrus have also been observed.<br />
Functional infertility' was once thought to occur in cattle on diets with calcium to phosphorus<br />
ratios outside the range <strong>of</strong> 1:2 to 2:1. This was not upheld on investigation but may have been<br />
correct if high calcium to phosphorus intakesdirectly reduced manganese (or copper or iodine)<br />
availability in diets marginally deficient in one or other <strong>of</strong> these elements.<br />
In pigs,experimental diets low in manganese cause reduction in skeletal growth, muscle<br />
weakness, obesity, irregular, diminished or absent estrus, agalactia, and resorption <strong>of</strong> fetuses or the<br />
birth <strong>of</strong> stillborn pigs. Leg weakness, bowing <strong>of</strong> the front legs, and shortening <strong>of</strong> bones also occur.<br />
CLINICAL PATHOLOGY<br />
Theblood<strong>of</strong>normalcattlecontains18-19 µg/dL (3.3-3.5 µmol/L) <strong>of</strong> manganese, although<br />
considerably lower levels are sometimes quoted.The livers <strong>of</strong> normalcattlecontain12 mg/kg(0.21<br />
mmol/kg) <strong>of</strong> manganese anddownto 8mg/kg(0.15 mmol/kg)innewborn calves, which also have a<br />
lower content in hair.Themanganesecontent<strong>of</strong>hairvaries with intake.The normal level is<br />
about12mg/kg(0.21 mmol/kg)and infertility is observed in association with levels<strong>of</strong>lessthan8<br />
mg/kg(0.15 mmol/kg). In normal cows,the manganese content <strong>of</strong> hair falls during pregnancy from<br />
normal levels <strong>of</strong> 12 mg/kg (0.21 mmol/kg)in the first month <strong>of</strong> pregnancy to 4.5 mg/kg (0.08
mmol/kg) at calving.All<strong>of</strong> these figures require much more critical evaluation than they have had,<br />
before they can be used as diagnostic tests.<br />
Although tissue manganese levels in normal animals have been described as being between 2<br />
and 4 mg/kg (0.04 and 0.07 mmol/kg), in most tissue (1) there appears to be more variation<br />
between tissues than this. However, tissue levels <strong>of</strong> manganese do not appear to be depressed in<br />
deficient animals, except for ovaries in which levels <strong>of</strong> 0.6 mg/kg (0.01 mmol/kg) and 0.85 mg/kg<br />
(0.02 mmol/kg) are recorded in contrast to a normal level <strong>of</strong> 2 mg/kg (0.04 mmol/kg).<br />
There is then no simple, single diagnostic test permitting detection <strong>of</strong> manganese deficiency in<br />
animals. Reproductive functions, male and female, are most sensitive to manganese deficiency<br />
and are affected before possible biochemical criteria, e.g. blood and bone alkaline phosphatase,<br />
and liver arginase levels, are significantly changed. The only certain way <strong>of</strong> detecting moderate<br />
deficiency states is <strong>by</strong> measuring response to supplementation. Clinical findings in response to<br />
treatment which may provide contributory evidence <strong>of</strong> manganese deficiency are set out below.<br />
NECROPSY FINDINGS<br />
In congenital chondrodystrophy in calves, the limbs are shortened and all the joints are enlarged.<br />
Histologically, there is poor cartilage maturation with excessive amounts <strong>of</strong> rarefied cartilage<br />
matrix. There are degenerative changes in the chondrocytes and severe reduction in the<br />
mucopolysaccharide content <strong>of</strong> all body hyaline cartilage (2, 3).<br />
TREATMENT AND CONTROL<br />
Young cattle have shown a general response in fertility to 2 g MnSO4 daily, but the general<br />
recommendation is daily supplementation with 4 g manganese sulfate providing 980 mg elemental<br />
manganese. This level <strong>of</strong> feeding is estimated to raise the dietary intake <strong>by</strong> 75 mg/kg DM<br />
(estimated on a daily intake <strong>of</strong> 12 kg DM <strong>by</strong> a 450 kg cow). In some herds a full response was<br />
obtained only after doubling this rate <strong>of</strong> feeding. Although the feeding <strong>of</strong> 15 g <strong>of</strong> manganese<br />
sulfate daily is reported to cause no signs <strong>of</strong> toxicity, manganese is known to interfere with the<br />
utilization <strong>of</strong> cobalt and zinc in ruminants. Very large levels <strong>of</strong> intake to calves can reduce growth<br />
rate and hemoglobin levels. The recommended procedure is to feed the supplement for 9 weeks<br />
commencing 3 weeks before the first service.<br />
Excessive supplementation, up to 5000 mg/kg, <strong>of</strong> the diet with manganese for periods <strong>of</strong> up to 3<br />
months appeared to cause only a reduction in appetite and weight gain.<br />
For pigs, the recommended dietary intakes are 24-57 mg manganese per 45 kg BW. Expressed<br />
as a proportion <strong>of</strong> food intake the recommended dietary level is 40 mg/kg DM in feed.<br />
REFERENCES<br />
(1)Underwood, E.J. (1981) The Mineral Nutrition <strong>of</strong> Livestock, 2nd edn. Famhain Royal,<br />
Commonwealth Agricultural Bureaux.<br />
(2)Valero, G. et al. (1990) NZ Vet.]., 38, 161.<br />
(3)Stalcy, G. P. et al. (1994)/ South African Vet. Assoc., 65, 73.<br />
POTASSIUM DEFICIENCY<br />
Naturally occurring dietary deficiency <strong>of</strong> potassium is thought to be rare. However, calves fed on<br />
roughage grown on soils deficient in potassium, or in which the availability <strong>of</strong> potassium is<br />
reduced, may develop a clinical syndrome <strong>of</strong> poor growth, anemia, and diarrhea. Supplementation<br />
<strong>of</strong> the diet with potassium salts appears to be curative. A similar syndrome has been produced<br />
experimentally in pigs (1) that manifested poor appetite, emaciation, rough coat, incoordination,<br />
and marked cardiac impairment as indicated <strong>by</strong> electrocardiographs examination. The optimum
level <strong>of</strong> potassium in the diet <strong>of</strong> young, growing pigs is about 0.26%, and in ruminants 0.5% (i.e.<br />
65 mg/kg BW) (2). Electrocardiographic changes have also been observed in cattle on<br />
potassium-deficient diets and these are probably related to the degeneration <strong>of</strong> Purkinje fibers <strong>of</strong><br />
the myocardium which occurs on such diets. Similar changes have been recorded on diets<br />
deficient in magnesium or vitamin E.<br />
<strong>An</strong> intake <strong>of</strong> potassium above requirement is more likely to occur than a deficiency and,<br />
although very large doses <strong>of</strong> potassium are toxic, ruminants are capable <strong>of</strong> metabolizing intakes<br />
likely to be encountered under natural conditions (3). It seems probable, however, that potassium<br />
interferes with the absorption <strong>of</strong> magnesium and heavy applications <strong>of</strong> potash fertilizers to grass<br />
pastures may contribute to the development<br />
1515<br />
<strong>of</strong> the hypomagnesemia <strong>of</strong> lactation tetany.<br />
Hypokalemia in cattle may occur secondary to anorexia, diarrhea, upper gastrointestinal<br />
obstruction, right-side displacement and torsion <strong>of</strong> the abomasum, and impaction <strong>of</strong> the abomasum.<br />
In most cases, the hypokalemia is not severe enough to cause weakness and recumbency.<br />
Hypokalemia resulting in severe weakness and recumbency has occurred in dairy cattle treated<br />
with is<strong>of</strong>lupredone acetate for ketosis (4). Serum potassium levels were below 2.3 mEq/L. Cows<br />
ranged in age from 2 to 7 years, all had a history <strong>of</strong> moderate to severe ketosis and had calved<br />
within the previous 30 days. Most had been treated with insulin, glucose IV, and propylene glycol<br />
orally. Affected cows were recumbent, pr<strong>of</strong>oundly weak, appeared flaccid, and lay in sternal or<br />
lateral recumbency. They were unable to support the weight <strong>of</strong> their heads <strong>of</strong>f the ground and they<br />
were commonly held in their flanks. <strong>An</strong>orexia was common. Cardiac arrhythmias were detectable<br />
on auscultation, and atrial fibrillation was confirmed on elcctrocardiography. Treatment included<br />
IV and oral administration <strong>of</strong> potassium chloride and fluid therapy, but the response was<br />
ineffective. Most affected cattle died or were euthanized. At necropsy,muscle necrosis was present<br />
in the pelvic limbs, and histological examination <strong>of</strong> non-weight bearing muscle revealed<br />
multifocal myonecrosis with macrophage infiltration and my<strong>of</strong>iber vacuolation, which is<br />
characteristic <strong>of</strong> hypokalemic myopathy in man and dogs. It is important to note that myopathy<br />
was also present in muscles not subject to ischemia or recumbency.<br />
Potassium excretion <strong>by</strong> the kidneys is via secretion <strong>by</strong> the distal tubular cells. Aldosterone or<br />
other steroids with <strong>mineral</strong>ocorticoid activity enhance distal tubular secretion <strong>of</strong> potassium <strong>by</strong><br />
increasing permeability <strong>of</strong> the tubular luminal membranes to potassium and increasing losses <strong>of</strong><br />
potassium in the urine. Glucocorticoids are <strong>of</strong>ten used to treat ketosis; the most commonly used<br />
are dexamethasone and is<strong>of</strong>lupredone acetate. Dexamethasone has little <strong>mineral</strong>ocorticoid activity<br />
compared to prednisone and prednisolone, which are related chemically to is<strong>of</strong>lupredone. It is<br />
recommended for the treatment <strong>of</strong> ketosis in dairy cattle at a single dose <strong>of</strong> 10-20 mg IM, and<br />
repeated if necessary, 12-24 hours later. Field observatons indicate that repeated doses <strong>of</strong><br />
is<strong>of</strong>lupredone acetate decreases plasma concentrations <strong>of</strong> potassium <strong>by</strong> 70-80%, which suggests a<br />
strong <strong>mineral</strong>ocorticoid activity. It is recommended that is<strong>of</strong>lupredone be used judiciously and<br />
animals be monitored for plasma potassium and any evidence <strong>of</strong> weakness and recumbency.<br />
Treatment with oral potassium choride may be required, but may be ineffective.<br />
REFERENCES<br />
(1)CoxJ. L. et al. (1966)J. <strong>An</strong>im. Sci., 25, 203.<br />
(2)Telle, P. P. et al. (1964)J Aium. Sci., 23, 59.
(3)Ward, G. M. (1966) J. Dairy Sri., 49, 268.<br />
(4)Sielman, E. S. et al. (1997) J. Am. Vet. Med. Assoc., 210, 240.<br />
SELENIUM AND/OR VITAMIN E DEFICIENCIES<br />
Several diseases <strong>of</strong> farm animals are <strong>caused</strong> <strong>by</strong>, or associated with, a deficiency <strong>of</strong> either selenium<br />
or vitamin E alone or in combination, usually in association with predisposing factors such as<br />
dietary polyunsaturated fatty acids, unaccustomed exercise, and rapid growth in young animals.<br />
These are summarized in Table 29.5. All <strong>of</strong> these diseases are described under one heading<br />
because both selenium and vitamin E are important in the etiology, treatment and control <strong>of</strong> the<br />
major diseases <strong>caused</strong> <strong>by</strong> their <strong>deficiencies</strong>.<br />
They are also known as selenium-vitamin E-responsive diseases because, with some exceptions,<br />
they can be prevented <strong>by</strong> adequate supplementation <strong>of</strong> the diet with both <strong>nutrients</strong>.<br />
The term 'selenium-responsive disease' has created some confusion relative to the<br />
selenium-deficiency diseases. In some regions <strong>of</strong> the world, particularly New Zealand, and in parts<br />
<strong>of</strong> Australia and North America, diseases such as ill-thrift in sheep and cattle, and poor<br />
reproductive performance respond beneficially to selenium administration. While these usually<br />
occur in selenium-deficient regions, they may not be due solely to selenium deficiency. Thus,<br />
there are some reasonably well-defined selenium deficiency diseases, and some ill-defined<br />
'selenium-responsive' diseases.<br />
Synopsis<br />
Etiology. Dietary <strong>deficiencies</strong> <strong>of</strong> selenium and vitamin E, and conditioning factors like dietary<br />
polyunsaturated fatty acids.<br />
Epidemiology<br />
•Enzootic muscular dystrophy occurs in young growing calves, lambs, goat kids,and foals born<br />
to dams in selenium-deficient areas and unsupplemented.Occurs worldwide and common in<br />
Australasia, United Kingdom, Great Plains <strong>of</strong> North America where soils are deficient in selenium.<br />
Vitamin E deficiency in animals fed poor quality forage and diets high in polyunsaturated fatty<br />
acids. Outbreaks <strong>of</strong> muscular dystrophy precipitated <strong>by</strong> exercise.<br />
•Mulberry heart disease in finishing pigs.<br />
•Selenium-responsive diseases occur in Australasia and are not obvious clinically but respond to<br />
selenium supplementation. Selenium and vitamin E deficiency may be involved in reproductive<br />
performance, retained placenta in cattle, resistance to infectious disease like bovine mastitis.<br />
Controversial.<br />
Signs. Muscular dystrophy characterized <strong>by</strong> groups <strong>of</strong> animals with stiffness, weakness,<br />
Table 29.5 <strong>Diseases</strong> considered to be <strong>caused</strong> <strong>by</strong> or associated with a deficiency <strong>of</strong> either selenium<br />
or vitamin E or both (including 'selenium-responsive' diseases)<br />
Cattle Horse Swine<br />
Nutritional<br />
(enzootic)<br />
muscular<br />
dystrophy<br />
Retained fetal<br />
Nutritional<br />
muscular<br />
dystrophy<br />
Mulberry heart<br />
disease Hepatosis<br />
dietetica<br />
Exudative<br />
diathesis Iron<br />
hypersensitivity<br />
Sheep<br />
Nutritional (enzootic) muscular<br />
dystrorrropf<br />
Reproductive inefficiency<br />
Bone marrow abnormalities<br />
'selenium responsive'
membranes<br />
Resistance to<br />
mastitis<br />
Nutritional<br />
muscular<br />
dystrophy<br />
<strong>An</strong>emia<br />
1516<br />
recumbency, severe in myocardial form.Mulberry heart disease characterized <strong>by</strong> outbreaks <strong>of</strong><br />
sudden death in finishing pigs.<br />
Clinical pathology. Increased plasma levels <strong>of</strong> creatine kinase. Low serum levels <strong>of</strong> selenium and<br />
vitamin E. Glutathione peroxidase activity.<br />
Lesions. Bilaterally symmetrical pale skeletal muscle, pale streaks in myocardial muscle. Hyaline<br />
degeneration <strong>of</strong> affected muscle.<br />
Diagnostic confirmation. Low selenium and vitamin E in diet and tissues, increased creatine<br />
kinase and muscle degeneration.<br />
Differential diagnosis list:<br />
Acute muscular dystrophy in calves and yearlings:<br />
•Haemophilus somnus septicemia (p. 895)<br />
•Pneumonia (p. 443).<br />
Subacute enzootic muscular dystrophy:<br />
•Musculoskeletal diseases-plyarthritis, traumatic or infectious myopathies (blackleg),<br />
osteodystrophy, and fractures <strong>of</strong> long bones (Chapter 13)<br />
•<strong>Diseases</strong> <strong>of</strong> the nervous system-spinal cord compression (p. 543), Haemophilus somnus<br />
meningoencephalitis (pp. 528, 895), and myelitis (p. 546), organophosphatic insecticide poisoning<br />
(p. 1615)<br />
•<strong>Diseases</strong> <strong>of</strong> the digestive tract-arbohydrate engorgement resulting in lactic acidosis, shock,<br />
dehydration, and weakness (p. 284).<br />
•Muscular dystrophy in lambs and kids-zootic ataxia and swayback (p. 1495)<br />
•Muscular dystrophy in foals-raumatic injury to the musculoskeletal system and polyarthritis<br />
(Chapter 13); meningitis (pp. 538, 708); traumatic injury to the spinal cord.<br />
Treatment. Vitamin E and selenium parenterally.<br />
Control. Selenium and vitamin E supplementation <strong>of</strong> diet, strategic oral and/or parenteral vitamin<br />
E and selenium to pregnant dams or young animals on pasture.<br />
ETIOLOGY<br />
The selenium- and vitamin E-responsive or deficiency diseases <strong>of</strong> farm animals are <strong>caused</strong> <strong>by</strong><br />
diets deficient in selenium and/or vitamin E, with or without the presence <strong>of</strong> conditioning factors<br />
such as an excessive quantity <strong>of</strong> polyunsaturated fatty acids in the diet. Almost all <strong>of</strong> the diseases<br />
that occur naturally have been reproduced experimentally using diets deficient in selenium and/or<br />
vitamin E. Conversely, the lesions can usually be prevented with selenium and vitamin E<br />
supplementation. In certain instances, as for example in hand-fed dairy calves, the incorporation <strong>of</strong><br />
excessive quantities <strong>of</strong> polyunsaturated fatty acids was a major factor in the experimental disease<br />
and this led to the conclusion that certain myopathic agents were necessary to produce the lesion,<br />
which is no longer tenable. The presence <strong>of</strong> polyunsaturated fatty acids in the diet may cause a<br />
conditioned vitamin E deficiency because the vitamin acts as an antioxidant. In the case <strong>of</strong><br />
naturally occurring muscular dystrophy in calves, lambs and foals on pasture, the myopathic agent,
if any, is unknown and selenium is protective. However, selenium is not protective against the<br />
muscular dystrophy associated with the feeding <strong>of</strong> cod liver oil to calves.<br />
Selenium is an essential nutrient for animals, and diseases due to selenium inadequacy in<br />
livestock are <strong>of</strong> worldwide distribution (1). Selenium is a biochemical component <strong>of</strong> the enzyme<br />
glutathione peroxidase (GSH-PX). The activity <strong>of</strong> the enzyme in erythrocytes is positively related<br />
to the blood concentration <strong>of</strong> selenium in cattle, sheep, horses and swine, and is a useful aid for<br />
the diagnosis <strong>of</strong> selenium deficiency and to determine the selenium status <strong>of</strong> the tissues <strong>of</strong> these<br />
animals. The enzyme from the erythrocytes <strong>of</strong> both cattle and sheep contains 4 g atoms <strong>of</strong><br />
selenium per mol <strong>of</strong> enzyme (1). Selenium is also a component <strong>of</strong> thyroid gland hormones.<br />
Plasma GSH-PX protects cellular membranes and lipid-containing organelles from<br />
peroxidative damage <strong>by</strong> inhibition and destruction <strong>of</strong> endogenous peroxides, acting in conjunction<br />
with vitamin E to maintain integrity <strong>of</strong> these membranes (1). Hydrogen peroxide and lipid<br />
peroxides are capable <strong>of</strong> causing irreversible denaturation <strong>of</strong> essential cellular proteins, which<br />
leads to degeneration and necrosis. GSH-PX catalyzes the breakdown <strong>of</strong> hydrogen peroxide and<br />
certain organic hydroperoxides produced <strong>by</strong> glutathione during the process <strong>of</strong> redox cycling. This<br />
dependence <strong>of</strong> GSH-PX activity on the presence <strong>of</strong> selenium <strong>of</strong>fers an explanation for the<br />
interrelationship <strong>of</strong> selenium, vitamin E, and sulfur-containing amino acids in animals. The<br />
sulfur-containing amino acids maybe precursors <strong>of</strong> glutathione, which in turn acts as a substrate<br />
for GSH-PX and maintains sulfhydryl groups in the cell. Selenium is also a component <strong>of</strong> several<br />
other proteins such as selenoprotein <strong>of</strong> muscle, selen<strong>of</strong>lagellin, Se-transport proteins, and the<br />
bacterial enzymes, formate dehydrogenase and glycine reductase. Selenium also facilitates<br />
significant changes in the metabolism <strong>of</strong> many drugs and xenobiotics. For example, selenium<br />
functions to counteract the toxicity <strong>of</strong> several metals such as arsenic, cadmium, mercury, copper,<br />
silver, and lead.<br />
Vitamin E is an antioxidant that prevents oxidative damage to sensitive membrane lipids <strong>by</strong><br />
decreasing hydroperoxide formation (1). The vitamin has a central role in protection <strong>of</strong> cellular<br />
membranes from lipoperoxidation, especially membranes rich in unsaturated lipids, such as<br />
mitochondria, endoplasmic reticulum, and plasma membranes.<br />
<strong>An</strong> important interrelationship exists between selenium, vitamin E, and the sulfur-containing<br />
amino acids in preventing some <strong>of</strong> the nutritional diseases <strong>caused</strong> <strong>by</strong> their deficiency. If vitamin E<br />
prevents fatty acid hydroperoxide formation, and the sulfur amino acids (as precursors <strong>of</strong> GSH-PX)<br />
and selenium are involved in peroxide destruction, these <strong>nutrients</strong> would produce a similar<br />
biochemical result, that is, lowering <strong>of</strong> the concentration <strong>of</strong> peroxides or peroxide-induced<br />
products in the tissues (1). Protection against oxidative damage to susceptible non-membrane<br />
proteins <strong>by</strong> dietary selenium, but not <strong>by</strong> vitamin E, might explain why some nutritional diseases<br />
respond to selenium but not to vitamin E. On the other hand, certain tissues or subcellular<br />
components may not be adequately protected from oxidant damage because they are inherently<br />
low in GSH-PX even with adequate dietary selenium. Damage to such tissues would be expected<br />
to be aggravated <strong>by</strong> diets high in unsaturated fatty acids and to respond adequately to vitamin E<br />
but not to selenium. The variations in GSH-PX activity between certain tissues, such as liver, heart,<br />
skeletal and myocardial muscles, would explain the variations in the severity <strong>of</strong> lesions between<br />
species.
There are both selenium-dependent GSH-PX and non-selenium-dependent GSH-PX activities<br />
in the tissues and blood. The non-selenium-dependent enzyme does not contain selenium and does<br />
not react with hydrogen peroxide but shows activity toward organic<br />
1517<br />
hydroperoxide substrates. The spleen, cardiac muscle, erythrocytes, brain, thymus, adipose tissue,<br />
and striated muscles <strong>of</strong> calves contain only the selenium-dependent enzyme. The liver, lungs,<br />
adrenal glands, testes, and kidney contain both enzymes. Hepatic tissue contains the highest level<br />
<strong>of</strong> non-selenium-dependent enzyme.<br />
EPIDEMIOLOGY<br />
Enzootic nutritional muscular dystrophy (NMD)<br />
Occurrence<br />
This muscular dystrophy occurs in all farm animal species, but most commonly in young, rapidly<br />
growing calves, lambs, goat kids, and foals born from dams that have been fed for long<br />
periods,usually during the winter months, on diets low in selenium and vitamin E (2). It is an<br />
important cause <strong>of</strong> mortality in goat kids from birth to about 3 months <strong>of</strong> age(3). Goat kids may<br />
require more selenium than lambs or calves, which may explain the higher incidence <strong>of</strong> the<br />
disease in kids.The disease in kids may also be associated with low α-tocopherol levels and<br />
normal selenium status (4).<br />
NMD in horses occurs most commonly in foals to about 7 months <strong>of</strong> age (5). In reported cases,<br />
the concentration <strong>of</strong> selenium in the blood <strong>of</strong> the mares was subnormal, the concentrations <strong>of</strong><br />
selenium and vitamin E in the feedstuffs were subnormal, the level <strong>of</strong> unsaturated fatty acids in<br />
the feed was high and vitamin E and selenium supplementation prevented the disease. The disease<br />
is not well-recognized in adult horses, but sporadic cases <strong>of</strong> dystrophic myodegeneration are<br />
recorded in horses from 5 to 10 years <strong>of</strong> age (5). Some baseline data for selenium and vitamin E<br />
concentration in horses from breeding farms is available (6).<br />
The disease also occurs in grain-fed yearling cattle. Stressors such as being turned outdoors<br />
after winter housing, walking long distances, the jostling and movement associated with<br />
vaccination and dehorning procedures and the like are <strong>of</strong>ten precipitating factors. The disease has<br />
occurred in steers and bulls 12-18 months <strong>of</strong> age under feedlot conditions. There may even be<br />
laboratory evidence <strong>of</strong> subclinical myopathy in normal animals in a group from which an index<br />
case occurred. Outbreaks <strong>of</strong> severe and fatal NMD have occurred in heifers at the time <strong>of</strong><br />
parturition which were previously on a diet deficient in both selenium and vitamin E. The disease<br />
may also occur sporadically in adult horses that are deficient in selenium.<br />
There are two major syndromes:<br />
•<strong>An</strong> acute form - myocardial dystrophy, which occurs most commonly in young calves and lambs,<br />
and occasionally foals<br />
•A subacute form - skeletal muscular dystrophy, which occurs in older calves and yearling cattle.<br />
The two forms are not mutually exclusive.<br />
Geographical distribution<br />
NMD occurs in most countries <strong>of</strong> the world but is common in the United Kingdom, the United<br />
States, Scandinavia, Europe, Canada, Australia, and New Zealand. In North America, it is<br />
common in the northeast and northwest and uncommon on the relatively high selenium soils <strong>of</strong> the<br />
Great Plains, where selenium toxicity has occurred. It is one <strong>of</strong> most common deficiency diseases<br />
<strong>of</strong> farm livestock in the United States (7). Soils, and therefore the pastures they earn vary widely
in their selenium content, depending largely on their geological origin. In general, soils derived<br />
from rocks <strong>of</strong> recent origin, e.g. the granitic and pumice sands <strong>of</strong> New Zealand, are notably<br />
deficient in selenium. Soils derived from igneous rocks are likely to be low in selenium.<br />
Sedimentary rocks, which are the principal parent material <strong>of</strong> agricultural soils, are richer in<br />
selenium. Forage crops, cereal grains and corn grown in these areas are usually low in selenium<br />
content (below 0.1 mg/kg dry matter (DM)), compared to the concentration in crops (above 0.1<br />
mg/kg DM) grown in areas where the available soil selenium is much higher and usually adequate.<br />
The disease occurs in pigs, usually in association with other more serious diseases, such as<br />
mulberry heart disease and hepatosis dietetica.<br />
Selenium in soil and animals<br />
In the United States, the States <strong>of</strong> the Pacific northwest and <strong>of</strong> the northeastern and southeastern<br />
seaboard are generally low in selenium (2). In Canada, western prairie grains generally contain<br />
relatively high levels <strong>of</strong> selenium, whereas in the eastern provinces, soils and feedstuffs usually<br />
have low selenium concentrations. Most soils in the Atlantic provinces <strong>of</strong> Canada are acidic and,<br />
consequently, the forages are deficient in selenium. Most forage samples contain less than 0.10<br />
mg/kg DM <strong>of</strong> selenium, and enzootic nutritional muscular dystrophy is common throughout the<br />
region.<br />
Surveys in the United Kingdom found that the selenium status may be low in sheep and cattle<br />
fed locally produced feedstuffs without any <strong>mineral</strong> supplementation. In some surveys, up to 50%<br />
<strong>of</strong> farms are low in selenium, which places a large number <strong>of</strong> animals at risk. There are also<br />
differences in the selenium concentrations <strong>of</strong> different feeds grown in the same area. For example,<br />
in some areas 75% <strong>of</strong> cattle fed primarily corn silage, or 50% <strong>of</strong> the cattle fed sedge hay, might be<br />
receiving diets inadequate in selenium.<br />
There may be wide variations in the serum selenium concentrations and glutathione peroxidase<br />
activities in cattle grazing forages <strong>of</strong> various selenium concentrations within the same<br />
geographical area. The selenium status <strong>of</strong> beef cows can vary between geographical areas within a<br />
region <strong>of</strong> a country, which is likely due to variations in selenium concentration <strong>of</strong> the soil and<br />
plants in these areas (8). Beef herds from areas with adequate soil levels <strong>of</strong> selenium, herds<br />
provided with supplemental feed on pasture, and herds in which pregnancy diagnosis was done,<br />
had higher average herd blood selenium values than other herds (8).<br />
Several factors influence the availability <strong>of</strong> soil selenium to plants.<br />
•Soil pH - alkalinity encourages selenium absorption <strong>by</strong> plants and the presence <strong>of</strong> a high level <strong>of</strong><br />
sulfur,which competes for absorption sites with selenium in both plants and animals,are two<br />
factors reducing availability<br />
•Variation between plants in their ability to absorb selenium; ‘selector' and ‘converter'plants are<br />
listed under the heading <strong>of</strong> selenium poisoning;legumes take up much less selenium than do<br />
grasses<br />
•Seasonal conditions also influence the selenium content <strong>of</strong> pasture, the content being lowest in<br />
the spring and when rainfall is heavy. Blood selenium in dairy cows in the United States were<br />
lower during the summer and fall than during the winter and spring (9).<br />
1518<br />
In this way a marginally deficient soil may produce a grossly deficient pasture if it is heavily<br />
fertilized with superphosphate, thus increasing its sulfate content, if the rainfall is heavy and the<br />
sward is lush and dominated <strong>by</strong> clover as it is likely to be in the spring months.
Environmental sulfur from various anthropogenic activities has been suspected to be a<br />
significant factor in contributing to several health problems in livestock (10). Livestock producers<br />
near natural sour gas desulfurization plants have reported that sulfur emissions are responsible for<br />
an increased occurrence <strong>of</strong> nutritional muscular dystrophy, weak calves, and retarded growth.<br />
Experimentally, a moderate increase in dietary sulfur does not impair selenium and copper status,<br />
or cause related disease in cattle (10).<br />
Vitamin E<br />
Vitamin E deficiency occurs most commonly when animals are fed inferior quality hay or straw or<br />
root crops. Cereal grains, green pasture, and well-cured fresh hay contain adequate amounts <strong>of</strong> the<br />
vitamin.<br />
α-Tocopherol levels are high in green grasses and clovers, but there are wide variations in the<br />
concentrations from one area to another. The serum tocopherol levels are higher in calves born<br />
from cows fed grass silage than in those born from cows fed the same grass as hay. Many factors<br />
influence the tocopherol content <strong>of</strong> pasture and hence the animals' intake. The level <strong>of</strong> tocopherol<br />
in pasture declines <strong>by</strong> up to 90% as it matures. Levels as low as 0.7 mg/kg DM have been reported<br />
in dry summer pastures grazed <strong>by</strong> sheep. The α-tocopherol content <strong>of</strong> rye-grass and clover pasture<br />
ranges from 22 to 350 and 90 to 210 mg/kg DM, respectively. After harvesting and storage, the<br />
tocopherol content <strong>of</strong> pasture and other crops may fall further, sometimes to zero. Preservation <strong>of</strong><br />
grain with propionic acid does not prevent the decline. Thus, the dietary intake <strong>of</strong> α-tocopherol <strong>by</strong><br />
cattle and sheep may be expected to vary widely and lead to wide variations in tissue levels. The<br />
plasma vitamin E status <strong>of</strong> horses is highest from May to August in Canada when fresh grass is<br />
being grazed and lowest when the horses are being fed harvested or stored feed during the same<br />
period (11). Plasma vitamin E levels in dairy cows in the United States were higher during the<br />
summer and fall than during the winter and spring (9).<br />
Outbreaks <strong>of</strong> NMD may occur in yearling cattle fed on high-moisture grain treated with<br />
propionic acid as a method <strong>of</strong> inexpensive storage and protection from fungal growth. There is a<br />
marked drop in the vitamin E content <strong>of</strong> acid-treated grain, and an increase in the levels <strong>of</strong><br />
peroxides <strong>of</strong> fat, which is consistent with a loss <strong>of</strong> naturally occurring antioxidants such as the<br />
tocopherols (secondary vitamin E deficiency). In these situations, the levels <strong>of</strong> selenium in the<br />
feed were below 0.05 mg/kg DM, which is inadequate and emphasizes the interdependence <strong>of</strong><br />
selenium and vitamin E. The tocopherol content <strong>of</strong> moist grain (barley and maize) stored for 6<br />
months, with or without propionic acid, falls to extremely low levels compared to conventionally<br />
stored grain in which the tocopherol levels usually persist over the same length <strong>of</strong> time.<br />
Selenium-deficient barley treated with sodium hydroxide to deplete it <strong>of</strong> vitamin E can be used to<br />
induce NMD when fed to yearling cattle. The disease may occur in sucking lambs with low<br />
plasma α-tocopherol levels and an adequate selenium status, which indicates that the sparing<br />
effect <strong>of</strong> each nutrient may not occur over the broad spectrum <strong>of</strong> clinical <strong>deficiencies</strong>.<br />
Polyunsaturated fatty acids (PUFAs) in diet<br />
Diets rich in PUFA such as cod liver oil,other fish oils, fishmeal used as a protein<br />
concentrate, lard, linseed oil, soybean and corn oils have been implicated in the production <strong>of</strong><br />
NMD, particularly in calves fed milk replacers containing these ingredients. The disease can be<br />
reproduced experimentally in young ruminant cattle 6-9 months <strong>of</strong> age, <strong>by</strong> feeding a diet low in<br />
vitamin E and selenium, and adding a linolenic acid. There are widespread<br />
lesions <strong>of</strong> myodegeneration <strong>of</strong> skeletal and myocardial muscles (12). Fresh spring grass containing
a sufficient concentration <strong>of</strong> linolenic acid to equal the amount necessary to produce NMD in<br />
calves may explain the occurrence <strong>of</strong> the naturally occurring disease in the spring months. The<br />
oxidation during rancidification <strong>of</strong> the oils causes destruction <strong>of</strong> the vitamin ,thus increasing the<br />
dietary requirements (a conditioned vitamin E deficiency), and the presence <strong>of</strong> myopathic agents<br />
in the oils may also contribute to the occurrence <strong>of</strong> the disease. A secondary vitamin E deficiency<br />
occurs when NMD develops on rations containing vitamin E in amounts ordinarily considered to<br />
be adequate, but the disease is prevented <strong>by</strong> further supplementation with the vitamin. The lack <strong>of</strong><br />
specificity <strong>of</strong> vitamin E in the prevention <strong>of</strong> muscular dystrophy in some circumstances is<br />
indicated <strong>by</strong> its failure, and <strong>by</strong> the efficiency <strong>of</strong> selenium, as a preventive agent in lambs on lush<br />
legume pasture.<br />
Other myopathic agents in diet<br />
Not all <strong>of</strong> the myopathic agents that maybe important in the development <strong>of</strong> NMD in farm animals<br />
have been identified. Unsaturated fatty acids in fish and vegetable oils may be myopathic agents in<br />
some outbreaks <strong>of</strong> NMD <strong>of</strong> calves and lambs. Lupinosis-associated myopathy in sheep is a<br />
substantial skeletal muscle myopathy encountered in weaner sheep grazing lupin stubbles infected<br />
with the fungus Phomopsis spp. (13). Affected sheep have a stiff gait, walk reluctantly, stand with<br />
their back humped and their feet under the body.and have difficulty getting to their feet.<br />
Unaccustomed exercise<br />
Historically, NMD occurred most commonly in rapidly growing, well-nourished beef calves 2-4<br />
months <strong>of</strong> age, shortly following unaccustomed exercise. This was commonplace in countries<br />
where calves were born and raised indoors until about 6-8 weeks <strong>of</strong> age when they were turned<br />
out onto new pasture in the spring <strong>of</strong> the year. This has been a standard practice in small beef<br />
herds in the United Kingdom, Europe, and North America. A similar situation applies for ewes<br />
that lambed indoors and the lambs were let out to pasture from 1 to 3 weeks <strong>of</strong> age. Thus,<br />
unaccustomed activity in calves and lambs running and frolicking following their turnout onto<br />
pasture is an important risk factor but is not necessarily a prerequisite for the disease. In lambs, the<br />
vigorous exertion associated with running and sucking may account for the peracute form <strong>of</strong><br />
myocardial dystrophy in young lambs on deficient pastures and from deficient ewes. In older<br />
lambs up to 3 months <strong>of</strong> age, outbreaks <strong>of</strong> acute NMD and stifflamb disease may be associated<br />
with the driving <strong>of</strong> flocks long distances. A similar<br />
1519<br />
situation applies for calves that are moved long distances from calving grounds and early spring<br />
pastures to lush summer pastures. The wandering and bellowing that occurs in beef calves weaned<br />
at 6-8 months <strong>of</strong> age may precipitate outbreaks <strong>of</strong> subacute NMD. Degenerative myopathy <strong>of</strong><br />
yearling cattle (feedlot cattle, housed yearling bulls and heifer replacements) is now being<br />
recognized with increased frequency (14). The disease resembles subacute NMD <strong>of</strong> calves, and in<br />
the United Kingdom is <strong>of</strong>ten seen when yearlings are turned outdoors in the spring <strong>of</strong> the year<br />
after being housed during the winter and fed a poor quality hay or straw or propionic acid-treated<br />
grain. Unaccustomed exercise is a common precipitating factor. However, the disease has<br />
occurred in housed yearling bulls with no history <strong>of</strong> stress or unaccustomed exercise but whose<br />
diet was deficient in selenium and vitamin E.<br />
In horses subjected to exercise there is an increase in erythrocyte malondialdehyde, a product <strong>of</strong><br />
peroxidation, but selenium supplementation has no beneficial effect. There is inconclusive<br />
evidence that a selenium-vitamin E deficiency causes NMD in adult horses. There is no evidence
that paralytic myoglobinuria and the 'tying-up' syndrome are due to a deficiency <strong>of</strong> selenium and<br />
vitamin E.<br />
Congenital nutritional muscular dystrophy<br />
Congenital NMD is rare in farm animals. Isolated cases have been reported but not<br />
well-documented. Similarly, NMD can occur in calves and lambs only a few days <strong>of</strong> age but<br />
rarely. Selenium readily crosses the bovine placenta and fetal selenium is always higher than the<br />
maternal status (15). There is no evidence that the weak-calf syndrome is associated with selenium<br />
deficiency (16). Long-term parenteral supplementation with neither selenium alone nor in<br />
combination with vitamin E had any effect on the incidence <strong>of</strong> the weak-calf syndrome.<br />
In pigs, NMD has been produced experimentally on vitamin E - and selenium-deficient rations<br />
but is usually only a part <strong>of</strong> the more serious complex <strong>of</strong> mulberry heart disease and hepatosis<br />
dietetica.<br />
Vitamin E-Selenium Deficiency (VESD) syndrome<br />
Mulberry heart disease, hepatosis dietetica, exudative diathesis and nutritional myopathy,<br />
also known as the VESD syndrome (vitamin E and selenium deficiency), occurs naturally in<br />
rapidly growing pigs, usually during the postweaning period (3 weeks to 4 months), particularly<br />
during the finishing period. It is usually associated with diets deficient in both selenium and<br />
vitamin E and those that may contain a high concentration <strong>of</strong> unsaturated fatty acids. Such diets<br />
include those containing mixtures <strong>of</strong> soybean, high-moisture corn, and the cereal grains grown on<br />
soils with low levels <strong>of</strong> selenium. The feeding <strong>of</strong> a basal ration <strong>of</strong> cull peas, low in selenium and<br />
vitamin E, to growing pigs can cause the typical syndrome, and low tissue levels <strong>of</strong> selenium are<br />
present in pigs with spontaneously occurring hepatosis dietetica. However, there are reports <strong>of</strong><br />
naturally occurring cases <strong>of</strong> mulberry' heart disease <strong>of</strong> swine in Scandinavia in which the tissue<br />
levels <strong>of</strong> selenium and vitamin E are within normal ranges compared to normal pigs (17). In<br />
Ireland, in spite <strong>of</strong> supplementation <strong>of</strong> pig rations with vitamin E and selenium at levels higher<br />
than that necessary to prevent experimental disease, spontaneous mulberry heart disease may still<br />
occur (18). Affected pigs have lower tissue vitamin E levels than control pigs, which suggests an<br />
alteration in а-tocopherol metabolism unrelated to dietary selenium and PUFA contents.<br />
Natural occurrence <strong>of</strong> the disease complex in swine is not uncommonly associated with diets<br />
containing 50% coconut meal, fish-liver oil emulsion, fish scraps with a high content <strong>of</strong><br />
unsaturated fatty acids, or flaxseed, which produces yellow and brown discoloration <strong>of</strong> fat<br />
preventable <strong>by</strong> the incorporation <strong>of</strong> adequate amounts <strong>of</strong> а-tocopherol or a suitable antioxidant.<br />
The quality <strong>of</strong> the dietary fat does not necessarily influence blood vitamin E levels, but the<br />
presence <strong>of</strong> oxidized fat reduces the resistance <strong>of</strong> the red blood cells against peroxidation. The<br />
higher requirement for vitamin E <strong>by</strong> pigs fed oxidized fat may be due to the low vitamin E content<br />
in such fat.<br />
Mulberry heart disease<br />
This is the most common form <strong>of</strong> selenium and vitamin E deficiency <strong>of</strong> swine. It occurs most<br />
commonly in rapidly growing feeder pigs (60-90 kg) in excellent condition being fed on a<br />
high-energy diet low in vitamin E and selenium. The diets most commonly incriminated are<br />
soybean, corn, and barley. The а-tocopherol content <strong>of</strong> corn is usually low and it is virtually<br />
absent from solvent-extracted soybean meal. Both are low in selenium. The use <strong>of</strong> high-moisture<br />
corn may further exacerbate the tocopherol deficiency. The level <strong>of</strong> PUFAs in the diet was thought<br />
to be an important etiological factor but this is now not considered to be a necessary prerequisite.
Outbreaks <strong>of</strong> the disease may occur in which 25% <strong>of</strong> susceptible pigs are affected, and the case<br />
mortality rate is about 90%. The disease has occurred in young piglets and in adult sows.<br />
Hepatosis dietetica<br />
Hepatosis dietetica appears to be less common than mulberry heart disease but the<br />
epidemiological characteristics are similar. It affects young growing pigs up to 3-4 months <strong>of</strong> age.<br />
NMD in swine usually occurs in cases <strong>of</strong> mulberry heart disease and hepatosis dietetica but it has<br />
occurred alone in gilts (11-12 months <strong>of</strong> age) 48 hours after farrowing. The gilts had been fed on a<br />
diet <strong>of</strong> barley and lupin seed which contained only 0.03 mg/kg <strong>of</strong> selenium.<br />
Selenium-responsive unthriftiness<br />
In New Zealand, a variety <strong>of</strong> diseases have been known as selenium-responsive diseases (19),<br />
because they respond beneficially to the strategic administration <strong>of</strong> selenium. These include<br />
ill-thrift in lambs and calves on pasture, ewe infertility, and diarrhea in older calves and<br />
lactating ewes. The pathogenesis <strong>of</strong> these selenium-responsive diseases is not known but it would<br />
appear that the selenium deficiency is only marginal. Most investigations into selenium-responsive<br />
diseases have occurred in selenium-deficient areas in which diseases such as NMD <strong>of</strong> calves and<br />
lambs occur (19). The evidence that selenium deficiency in breeding ewes can result in a decline<br />
in reproductive performance has not been substantiated experimentally. Reproductive performance<br />
was not affected in ewes on a selenium-depleted diet. A recent report indicated that<br />
selenium-responsive infertility in ewes may be present when the whole blood levels <strong>of</strong> selenium<br />
are below 10 ng/mL (12.7 nmol/L) (19).<br />
Selenium-responsive unthriftiness in sheep has received considerable attention in New Zealand<br />
where the response to selenium administration<br />
1520<br />
has been most dramatic compared to Australia where the syndrome has also been recognized but<br />
where the response is much smaller. The oral administration <strong>of</strong> selenium to lambs in these areas<br />
results in greater body weight gains from weaning to 1 year <strong>of</strong> age compared to lambs not<br />
receiving selenium supplementation (19). The mean fleece weight <strong>of</strong> selenium-treated lambs is<br />
also greater.<br />
The diagnosis <strong>of</strong> selenium-responsive unthriftiness depends on analyses <strong>of</strong> the soil, pasture and<br />
animal tissues for selenium, and response trials to selenium supplementation. A deficiency state<br />
might be encountered when the selenium content <strong>of</strong> the soil is below 0.45 mg/kg, the pasture<br />
content below 0.02 mg/kg DM, the liver content below 21ug/kg (0.27 µmol/kg) (WW) and wool<br />
concentrations below 50-60µg/kg (0.63-0.76 µmol/kg). For the blood in selenium-responsive<br />
unthriftiness <strong>of</strong> sheep the following criteria are suggested (19):<br />
•Mean blood selenium<br />
•Selenium status (ug/dL)<br />
Deficient = 1.0<br />
•Doubtful 1.1-1.9<br />
•Normal~2.0.<br />
The GSH-PX activity is a good index <strong>of</strong> the selenium status <strong>of</strong> sheep with a<br />
selenium-responsive disease. If measured on a regular basis, it can provide an indication <strong>of</strong> the<br />
selenium status <strong>of</strong> grazing sheep in individual flocks. Single measurements <strong>of</strong> GSH-PX activity<br />
may fail to detect recent changes in grazing area, differences in pasture species and pasture<br />
composition, and alterations in the physiological state <strong>of</strong> the animals.
Subclinical selenium insufficiency<br />
Subclinical insufficiencies <strong>of</strong> selenium in grazing ruminants are widespread over large areas <strong>of</strong><br />
southern Australia (20). The plasma concentrations <strong>of</strong> affected sheep flocks are low, there are no<br />
obvious clinical signs <strong>of</strong> insufficiency in the ewes, and there are significant responses in wool<br />
production and fiber diameter to selenium supplementation. The incidence <strong>of</strong> estrus and fertility is<br />
not affected <strong>by</strong> selenium supplementation (21). Liveweights at birth, in mid-lactation and at<br />
weaning were increased in lambs born to selenium-supplemented and crossbred ewes, and in<br />
lambs born as singletons (22).<br />
Clean fleece weight at 10 months <strong>of</strong> age was increased <strong>by</strong> 9.5% and fiber diameter <strong>by</strong> 0.3um in<br />
lambs born to ewes that had received supplementary selenium. Differences in fleece weight and<br />
liveweight were not detected at 22 months, suggesting that subclinical selenium insufficiency in<br />
early life did not permanently impair productivity if selenium status subsequently increased.<br />
Selenium is a component <strong>of</strong> type-I iodothyronine deiodinase, which catalyzes the extrathyroidal<br />
conversion <strong>of</strong> thyroxine (T4) to the more active triiodothyronine (T3). Sheep grazing pastures low<br />
in selenium frequently have higher circulating T4 and lower circulating T3 concentrations than<br />
sheep receiving selenium supplementations.<br />
When ewes grazing pastures low in selenium were supplemented thiocyanate (to cause iodine<br />
insufficiency), iodide and selenium, there was no evidence <strong>of</strong> clinical <strong>deficiencies</strong> (23). Growth<br />
rates <strong>of</strong> lambs were not affected <strong>by</strong> thiocyanate <strong>of</strong> their dams during midpregnancy, but plasma T3<br />
and T4 concentrations were depressed in ewes receiving thiocyanate. The iodide supplementation<br />
increased thyroid hormone concentrations in ewes, but depressed plasma T3 concentrations in<br />
lambs. Supplementation <strong>of</strong> sheep grazing pastures low in selenium with both selenium and thyroid<br />
hormones improved wool characteristics, liveweight gain, and blood selenium, but there was no<br />
evidence <strong>of</strong> an interaction between the selenium and the hormones (24). Thus it seems unlikely<br />
that the decline in the quantity <strong>of</strong> T3 produced, or <strong>of</strong> T4 utilized for T3 production, in<br />
selenium-deficient sheep is responsible for the observed differences in the productivity <strong>of</strong><br />
selenium-deficient and supplemented sheep. The thyroids have a major role in regulating<br />
thermogenesis, and lambs born to ewes supplemented with iodide tend to have higher rectal<br />
temperatures during cold stress (25). The thermoregulatory ability <strong>of</strong> the perinatal lamb is not<br />
adversely affected <strong>by</strong> subclinical selenium deficiency.<br />
Reproductive performance<br />
The published information on the effects <strong>of</strong> vitamin E and selenium deficiency or <strong>of</strong> dietary<br />
supplementation with one or the other or both on reproductive performance in farm animals are<br />
conflicting and controversial. Reproductive performance is complex and dependent on the<br />
interaction <strong>of</strong> many factors. Reproductive inefficiency is likewise complex, and it is difficult to<br />
isolate one factor like a deficiency <strong>of</strong> vitamin E or selenium as a cause <strong>of</strong> reproductive<br />
inefficiency. Conversely, it is difficult to prove that supplementation with these <strong>nutrients</strong> will<br />
insure optimum reproductive performance.<br />
Sheep<br />
The evidence about the effect <strong>of</strong> selenium and vitamin E deficiency on reproductive performance<br />
in sheep is conflicting. Observations in the 1960s concluded that selenium deficiency <strong>caused</strong><br />
embryonic deaths 20-30 days after fertilization in ewes. But supplementation <strong>of</strong> ewes, low or<br />
marginal in selenium status, with selenium did not improve reproductive performance.<br />
Experimental studies using selenium-deficient diets in ewes have been unable to find any adverse
effect <strong>of</strong> selenium depletion on ewe conception rates, embryonic mortality or numbers <strong>of</strong> lambs<br />
born. The parenteral administration <strong>of</strong> selenium to pregnant ewes between 15 and 35 days after<br />
mating resulted in a reduced embryonic survival rate and is not recommended during the first<br />
month <strong>of</strong> pregnancy (26).<br />
Cattle<br />
The importance <strong>of</strong> selenium and vitamin E for the maintenance <strong>of</strong> optimum reproductive<br />
performance is not clear. The IM injection <strong>of</strong> dairy cattle with selenium and vitamin E 3 weeks<br />
prepartum did not have any effect on average days to first estrus or first service, average days to<br />
conception, services per conception, or number <strong>of</strong> uterine infusions required. The prepartum IM<br />
injection <strong>of</strong> vitamin E and selenium 3 weeks prepartum increased the percentage <strong>of</strong> cows pregnant<br />
to first service, reduced the number <strong>of</strong> services per conception, decreased the incidence <strong>of</strong> retained<br />
placenta, and reduced the interval from calving to conception (27). In a randomized field trial in a<br />
large dairy herd in the United States, oral supplementation <strong>of</strong> pregnant first-calf dairy heifers with<br />
selenium using a commercially available sustained-release intraruminal selenium bolus, increased<br />
blood selenium concentrations in treated animals at 30 days after treatment until after calving (28).<br />
However, based on data analyzed midlactation and late lactation, there were no differences<br />
between<br />
1521<br />
treated and control groups in somatic cell count, days not pregnant, total milk production, or times<br />
bred. The use <strong>of</strong> an intra-ruminal pellet <strong>of</strong> selenium at two different levels in dairy herds in New<br />
Zealand was evaluated in yearling heifers (29). The recommended dose was effective in elevating<br />
whole blood GSH-FX activity and selenium concentrations to over 10 times those <strong>of</strong> control<br />
animals. Milk production was increased and there was a trend to decreased somatic cell counts.<br />
There were no differences in calving-first-service or calving-conception intervals, or in the<br />
percentage <strong>of</strong> animals pregnant to first or all services. In other observations, following the<br />
treatment <strong>of</strong> dairy cows with oral selenium pellets there was an improvement in first service<br />
conception rate and significantly higher blood levels <strong>of</strong> GSH-PX. The inconsistent results<br />
obtained following the use <strong>of</strong> selenium and vitamin E in pregnant cows may be related to the<br />
selenium status <strong>of</strong> the animals; in some herds the blood levels are marginal and in others the levels<br />
are within the normal range.<br />
Retained fetal placenta<br />
A high incidence (more than 10%) <strong>of</strong> retained fetal membranes has been associated with marginal<br />
levels <strong>of</strong> plasma selenium compared with herds without a problem. In some cases, the incidence<br />
could be reduced to below 10% <strong>by</strong> the injection <strong>of</strong> pregnant cattle with selenium and vitamin E<br />
about 3 weeks prepartum, while in other studies similar prepartum injections neither reduced the<br />
incidence nor improved reproductive performance. A single injection <strong>of</strong> selenium 3 weeks<br />
prepartum can reduce the number <strong>of</strong> days postpartum required for the uterus to reach minimum<br />
size and to reduce the incidence <strong>of</strong> metritis and cystic ovaries during the early postpartum period.<br />
The parenteral administration <strong>of</strong> a single injection <strong>of</strong> 3000 mg vitamin E prepartum to dairy cows<br />
<strong>of</strong> all ages decreased the incidence <strong>of</strong> retained placenta and metritis to 6.4% and 3.9%,<br />
respectively, in the treated group, compared to 12.5% and 8.8%, in the control group (30). The<br />
injection, 20 days prepartum, <strong>of</strong> 50 mg <strong>of</strong> selenium and 680 IU <strong>of</strong> vitamin E reduced the incidence<br />
<strong>of</strong> retained fetal membranes in one series, but did not in another series. The plasma selenium<br />
concentration at parturition ranged from 0.02 to 0.05 ppm in control cows in winch there was an
incidence <strong>of</strong> 51% retained membranes, and from 0.08 to 0.1 ppm in treated cows in which the<br />
incidence was reduced to 9%. A dietary level <strong>of</strong> 0.1 mg/kg DM selenium is recommended to<br />
minimize the incidence <strong>of</strong> the problem. The complex nature <strong>of</strong> the etiology <strong>of</strong> retained fetal<br />
membranes also requires a well-designed experimental trial to account for all <strong>of</strong> the possible<br />
factors involved.<br />
Resistance to infectious disease<br />
Many studies have examined the role <strong>of</strong> selenium and vitamin E resistance to infectious disease<br />
(31). Most <strong>of</strong> the evidence is based on in vitro studies <strong>of</strong> the effects <strong>of</strong> <strong>deficiencies</strong> <strong>of</strong> selenium or<br />
vitamin E or supplementation with the <strong>nutrients</strong> on leukocyte responses to mitogens, or on the<br />
antibody responses <strong>of</strong> animals to a variety <strong>of</strong> pathogens. The status <strong>of</strong> selenium and vitamin E in<br />
an animal can alter; antibody response, phagocytes function, lymphocyte response, and resistance<br />
to infectious disease (31). In general, a deficiency <strong>of</strong> selenium results in immunosuppression, and<br />
supplementation with low doses <strong>of</strong> selenium augments immunological functions. A deficiency <strong>of</strong><br />
selenium has been shown to inhibit:<br />
• Resistance to microbial and viral infections<br />
• Neutrophil function<br />
• <strong>An</strong>tibody production<br />
• Proliferation <strong>of</strong> T and B lymphocytes in response to mitogens<br />
•Cytodestruction <strong>of</strong> T lymphocytes and natural killer lymphocytes (32).<br />
Vitamin E and selenium have interactive effects on lymphocyte responses to experimental<br />
antigens (33).<br />
Neutrophil function<br />
Selenium deficiency can affect the function <strong>of</strong> polymorphonuclear neutrophils (PMNs), which are<br />
associated with physiological changes in GSH-PX levels. In calves on an experimental<br />
selenium-deficient diet, the oxygen consumption and the activities <strong>of</strong> GSH-PX are lower than<br />
normal in neutrophils. The feeding <strong>of</strong> 80-120 mg <strong>of</strong> selenium/kg <strong>of</strong> <strong>mineral</strong> mixture provided ad<br />
libitum is an effective method <strong>of</strong> increasing blood selenium in a group <strong>of</strong> cattle and optimizing the<br />
humoral antibody response experimentally. It is suggested that blood selenium levels over 100<br />
(Jg/L are necessary to maintain optimum immunocompetence in growing beef cattle (34). In<br />
selenium-deficient goats, the production <strong>of</strong> leukotriene B4, a product <strong>of</strong> neutrophil arachidonic<br />
acid lipoxygenation and a potent chemotactic and chemokinetic stimulus for neutrophils, is<br />
decreased, resulting in dysfunction <strong>of</strong> the neutrophils. A deficiency <strong>of</strong> selenium in pregnant sows<br />
impairs neutrophil function, and vitamin E deficiency impairs function <strong>of</strong> both neutrophils and<br />
lymphocytes, which may result in increased susceptibility <strong>of</strong> their piglets to infectious diseases<br />
(35). It is suggested that selenium supplementation be maintained at 0.3 mg/kg <strong>of</strong> the diet.<br />
Immune response<br />
The effects <strong>of</strong> selenium deficiency and supplementation on the immune response <strong>of</strong> cattle to<br />
experimental infection with the infectious bovine rhinotracheitis virus, and sheep to<br />
parainfluenza-3 virus indicate that a deficiency can affect the humoral response and<br />
supplementation enhances the response. Pigs fed a vitamin E and selenium-deficient diet develop<br />
an impaired cell-mediated immunity as measured <strong>by</strong> lymphocyte response to mitogenic<br />
stimulations. Supplementation <strong>of</strong> the diets <strong>of</strong> young swine with selenium at levels above those<br />
required for normal growth has increased the humoral response, but not in sows. The wide<br />
variations in antibody responses that occur in these experiments indicate that there is a complex
elationship between the selenium status <strong>of</strong> the host, humoral immune responses, and protective<br />
immunity. The concept <strong>of</strong> using selenium supplementation to enhance antibody responses in sheep<br />
to vaccines is probably unfounded.<br />
Vitamin E can stimulate the immune defense mechanisms in laboratory animals and cattle,<br />
experimentally (36). In most cases, the immunostimulatory effects <strong>of</strong> additional vitamin E are<br />
associated with supplementation in excess <strong>of</strong> levels required for normal growth. The parenteral<br />
administration to calves <strong>of</strong> 1400 mg <strong>of</strong> vitamin E weekly increases their serum vitamin E<br />
concentrations and lymphocyte stimulation indices. Similarly in growing pigs, a serum vitamin E<br />
concentration above 3 mg/L was necessary to achieve a significant response <strong>of</strong> the lymphocytes to<br />
stimulation with mitogens.<br />
1522<br />
General resistance<br />
These changes may render selenium-deficient animals more susceptible to infectious disease, but<br />
there is no available evidence to indicate that naturally occurring selenium and vitamin E<br />
<strong>deficiencies</strong> are associated with an increase in the incidence or severity <strong>of</strong> infectious diseases.<br />
Neutrophils from selenium-deficient animals lose some ability to phagocytose certain organisms,<br />
but how relevant this observation is in naturally occurring infections is unclear. Field studies <strong>of</strong><br />
the incidence and occurrence <strong>of</strong> pneumonia in housed calves found that selenium status was not a<br />
risk factor.<br />
Neonatal morbidity and mortality<br />
Based on some preliminary observations <strong>of</strong> the selenium content <strong>of</strong> hair samples <strong>of</strong> young calves,<br />
higher selenium levels in newborn calves may have some protective effect against morbidity due<br />
to neonatal disease. Similarly, neonatal piglets with high blood levels <strong>of</strong> GSH-PX activity may be<br />
more resistant to infectious diseases or other causes <strong>of</strong> neonatal mortality. Administration <strong>of</strong><br />
vitamin E and selenium to dairy cows in late pregnancy resulted in the production <strong>of</strong> increased<br />
quantities <strong>of</strong> colostrum and the calves have increased quantities <strong>of</strong> GSH-PX at birth and 28 days<br />
<strong>of</strong> age, but the improved selenium status did not provide any improvement in passive immunity or<br />
growth (37). Supplementing selenium to beef cows grazing selenium-deficient pastures with a salt<br />
<strong>mineral</strong> mix containing 120 mg selenium/kg <strong>of</strong> mix increased the selenium status <strong>of</strong> the cows and<br />
increased the serum IgG concentration, or enhanced transfer <strong>of</strong> IgG from serum to colostrum and<br />
increased the selenium status <strong>of</strong> the calves (38). The parenteral administration <strong>of</strong> 0.1 mg Se and 1<br />
mg ot vitamin E/kg BW at midgestation did not affect the production <strong>of</strong> systemic or colostrai<br />
antibodies. Supplementation <strong>of</strong> dairy cows at dry-<strong>of</strong>f with selenium at 3 mg/d as selenite via an<br />
intrarurninal bolus resulted in sufficient transfer <strong>of</strong> selenium to meet a target concentration <strong>of</strong><br />
more than 2.2 p.g <strong>of</strong> selenium/g <strong>of</strong> liver DM in newborn calves (39).<br />
Mastitis in dairy cattle<br />
There is some evidence that a dietary deficiency <strong>of</strong> vitamin E may be associated with an<br />
increased incidence <strong>of</strong> mastitis in dairy cattle (40). <strong>An</strong> increased incidence <strong>of</strong> mastitis during the<br />
early stages <strong>of</strong> lactation coincides with the lowest plasma concentration <strong>of</strong> vitamin E.<br />
Supplementation <strong>of</strong> the diet <strong>of</strong> dairy cows beginning 4 weeks before and continuing for up to 8<br />
weeks after parturition with vitamin E at 3000 IU/cow/d combined with an injection <strong>of</strong> 5000 IU, 1<br />
week before parturition, prevented the suppression <strong>of</strong> blood neutrophil and macrophage function<br />
during the early postpartum period compared to controls (40). The vitamin E prevented the<br />
suppression <strong>of</strong> blood neutrophils during the postpartum period (41). Cows in both the treated and
control groups were fed diets containing selenium at 0.3 ppm <strong>of</strong> total dry matter. When selenium<br />
status in dairy cows is marginal, plasma concentrations <strong>of</strong> a-tocopherol should be at least 3 µg/mL<br />
(42). Cows receiving a dietary supplement <strong>of</strong> about 1000 IU/d <strong>of</strong> vitamin E had 30% less clinical<br />
mastitis than did cows receiving a supplement <strong>of</strong> 100 lU/d <strong>of</strong> vitamin E (42). The reduction was<br />
88% when cows were fed 4000 IU/d <strong>of</strong> vitamin E during the last 14 days <strong>of</strong> the dry period (42).<br />
The selenium status <strong>of</strong> dairy cows may also have an effect on the prevalence <strong>of</strong> mastitis and<br />
mammary gland health (43, 44). Dairy herds with low somatic cell counts had significantly higher<br />
mean blood GSH-PX and higher whole blood concentrations <strong>of</strong> selenium than in herds with high<br />
somatic cell counts (44). The prevalence <strong>of</strong> infection due to Streptococcus agalactiac and<br />
Staphylococcus aureus was higher in herds with the high somatic cell counts compared to those<br />
with the low somatic cell counts. This suggests that phagocytic function in the mammary gland<br />
may be decreased <strong>by</strong> a marginal selenium deficiency. In a survey <strong>of</strong> cattle in herds in Switzerland,<br />
those with chronic mastitis had lower serum levels <strong>of</strong> selenium than healthy control herds (45).<br />
Experimental coliform mastitis in cattle is much more severe in selenium-deficient animals than<br />
selenium-adequate animals (46). The severity was in part due to the increased concentrations <strong>of</strong><br />
eicosanoids.<br />
Milk neutrophils from cows fed a selenium-deficient diet have significantly reduced capacity to<br />
kill ingested Escherichia coli and Staph. aureus, compared to cells from cows fed a<br />
selenium-supplemented diet (47). However, other experimental results are not as convincing.<br />
Blood abnormalities<br />
In young cattle from areas where NMD is endemic, and particularly at the end <strong>of</strong> winter housing,<br />
the erythrocytes have an increased susceptibility to hemolysis following exposure to hypotonic<br />
saline. During clinical and subclinical white muscle disease in calves, there is a significant<br />
increase in both the osmotic and the peroxidative hemolysis <strong>of</strong> the erythrocytes. This defect is<br />
thought to be the result <strong>of</strong> alterations in the integrity <strong>of</strong> cell membranes <strong>of</strong> which tocopherols are<br />
an essential component. Abnormalities <strong>of</strong> the bone marrow associated with vitamin E deficiency<br />
in sheep have been described, and abnormal hematological responses have been described in<br />
young growing pigs on an experimental selenium and vitamin E deficient diet. Vitamin E<br />
deficiency in sheep results in increased hemolytic susceptibility <strong>of</strong> erythrocytes, which may<br />
provide a basis for a single functional test for vitamin E deficiency in sheep (48).<br />
<strong>An</strong>emia characterized <strong>by</strong> a decreased packed cell volume, decreased hemoglobin concentration,<br />
and Heinz body formation has been observed in cattle grazing on grass grown on peaty muck soils<br />
in the Florida everglades. Selenium supplementation corrected the anemia, prevented Heinz body<br />
formation, increased the body weight <strong>of</strong> cows and calves, and elevated blood selenium.<br />
Equine degenerative myeloencephalopathy<br />
Equine degenerative myeloencephalopathy, which may have an inherited basis (49), has been<br />
associated with a vitamin E deficiency. The vitamin E status is low in some affected horses and<br />
supplementation with the vitamin was associated with a marked reduction in the incidence <strong>of</strong> the<br />
disease. However, scrum vitamin E and blood GSH-PX activities determined in horses with<br />
histologically confirmed diagnosis <strong>of</strong> the disease compared to age-matched controls failed to<br />
reveal any differences, and the findings did not support a possible role for vitamin E deficiency as<br />
a cause (50). Foals sired <strong>by</strong> a stallion with degenerative myeloencephalopathy and with<br />
neurological deficits consistent with the disease during their first year <strong>of</strong> life had lower plasma<br />
levels <strong>of</strong> a-tocopherol when the levels were determined serially beginning at 6
1523<br />
weeks to 10 months <strong>of</strong> age than age-matched controls (51). Absorption tests with vitamin E<br />
revealed that the lower a-tocopherol levels were not due to an absorption defect (51). The protocol<br />
for the oral vitamin E absorption test has been reported (52).<br />
Equine motor neuron disease<br />
This a neurodegenerative disease <strong>of</strong> the somatic lower motor neurons resulting in a syndrome <strong>of</strong><br />
diffuse neuromuscular disease in the adult horse (53). Case-control studies found the mean plasma<br />
vitamin E concentrations in affected horses were lower than that <strong>of</strong> control horses. Adult horses<br />
are affected with the risk peaking at 16 years <strong>of</strong> age. In addition to the role <strong>of</strong> vitamin E depletion,<br />
other individual and farm-level factors, contribute to the risk <strong>of</strong> developing the disease.<br />
Generalized steatitis<br />
Steatitis in farm animals and other species may be associated with vitamin E and/or selenium<br />
deficiency. Most cases in horses have involved nursing or recently weaned foals. Generalized<br />
steatitis in the foal has been described as either generalized cachexia due to steatitis alone, or as a<br />
primary myopathy or myositis with steatitis <strong>of</strong> secondary importance. The terms used have<br />
included steatitis, generalized steatitis, fat necrosis, yellow fat disease, polymyositis, and muscular<br />
dystrophy. The relationships between steatitis and vitamin E and selenium deficiency in the horse<br />
are not clear and there may be none. Many more clinical cases must be examined in detail before a<br />
cause-effect relationship can be considered.<br />
PATHOGENESIS<br />
Dietary selenium, sulfur-containing amino acids and vitamin E act synergistically to protect<br />
tissues from oxidative damage (1). GSH-PX, which is selenium-dependent, functions <strong>by</strong><br />
detoxifying lipid peroxides and reducing them to nontoxic hydroxy fatty acids. Vitamin E prevents<br />
fatty acid hydroperoxide formation. High levels <strong>of</strong> PUFAs in the diet increase the requirements for<br />
vitamin E and, with an inadequate level <strong>of</strong> selenium in the diet, tissue oxidation occurs, resulting<br />
in degeneration and necrosis <strong>of</strong> cells. Vitamin E protects cellular membranes from<br />
lipoperoxidation, especially membranes rich in unsaturated lipids, such as mitochondric,<br />
endoplasmic reticulum, and plasma membranes. Thus dietary PUFA are not a prerequisite for the<br />
disease. Diets low in selenium and/or vitamin E do not provide sufficient protection against the<br />
'physiological' lipoperoxidation that occurs normally at the cellular level.<br />
The relative importance <strong>of</strong> selenium, vitamin E and sulfur-containing amino acids in providing<br />
protection in each <strong>of</strong> the known diseases <strong>caused</strong> <strong>by</strong> their deficiency is not clearly understood.<br />
Selenium has a sparing effect on vitamin E and is an efficient prophylactic against muscular<br />
dystrophy <strong>of</strong> calves and lambs at pasture, but does not prevent muscular dystrophyin calves fed on<br />
a diet containing cod liver oil. The current understanding <strong>of</strong> the biochemical function <strong>of</strong> selenium<br />
and its relation to vitamin E and the mechanisms <strong>of</strong> action <strong>of</strong> selenium and vitamin E in protection<br />
<strong>of</strong> biological membranes has been reviewed (54).<br />
Nutritional muscular dystrophy<br />
A simplified integrated concept <strong>of</strong> the pathogenesis <strong>of</strong> the NMD would be as follows. Diets<br />
deficient in selenium and/or vitamin E permit widespread tissue lipoperoxidation leading to<br />
hyalineh degeneration and calcification <strong>of</strong> muscle fibers. One <strong>of</strong> the earliest changes in<br />
experimental selenium deficiency in lambs is the abnormal retention <strong>of</strong> calcium in muscle fibers<br />
undergoing dystrophy, and selenium supplementation prevents the retention <strong>of</strong> calcium.<br />
Unaccustomed exercise can accelerate the oxidative process and precipitate clinical disease.
Muscle degeneration allows the release <strong>of</strong> enzymes, such as lactate dehydrogenase, aldolase and<br />
creatine phosphokinase, the last <strong>of</strong> which is <strong>of</strong> paramount importance in diagnosis. Degeneration<br />
<strong>of</strong> skeletal muscle is rapidly and successively followed <strong>by</strong> invasion <strong>of</strong> phagocytes and<br />
regeneration. In myocardial muscle, replacement fibrosis is the rule.<br />
In calves, lambs, and foals the major muscles involved are skeletal, myocardial, and<br />
diaphragmatic. The myocardial and diaphragmatic forms <strong>of</strong> the disease occur most commonly in<br />
young calves, lambs and foals, resulting in acute heart failure, respiratory distress and rapid death,<br />
<strong>of</strong>ten in spite <strong>of</strong> treatment. The skeletal form <strong>of</strong> the disease occurs more commonly in older calves,<br />
yearling cattle and older foals, and results in weakness and recumbency, is usually less severe and<br />
responds to treatment. The biceps femoris muscle is particularly susceptible in calves, and muscle<br />
biopsy is a reliable diagnostic aid.<br />
In foals with NMD there is a higher proportion <strong>of</strong> type IIC fibers and a lower proportion <strong>of</strong> type<br />
I and IIA fibers than in healthy foals. The type IIC fibers are found in fetal muscle and are<br />
undifferentiated and still under development. During the recovery period, fibers <strong>of</strong> types IIA and<br />
IIB increase and the proportion <strong>of</strong> type IIC fibers decreases. A normal fiber type composition is<br />
present in most surviving foals 1-2 months after the onset <strong>of</strong> the disease.<br />
Acute NMD results in the liberation <strong>of</strong> myoglobin into the blood, which results in<br />
myoglobinuria. This is more common in horses, older calves and yearling cattle, than in young<br />
calves whose muscles have a lower concentration <strong>of</strong> myoglobin. Hence, the tendency to<br />
myoglobinuria will vary depending on the species and age <strong>of</strong> animal involved.<br />
Subclinical selenium insufficiency<br />
Selenium deficiency affects thyroid hormone metabolism and may explain the cause <strong>of</strong> ill-thrift.<br />
The conversion <strong>of</strong> the iodine-containing hormone, thyroxine (T4) to the more potent<br />
triiodothyronine (T3) is impaired in animals with low selenium status and<br />
iodothyroninedeiodinase is a selenoprotein which mediates this conversion (54).<br />
VESD syndrome and others<br />
The pathogenesis <strong>of</strong> mulberry heart disease, hepatosis dietetica, exudative diathesis, and muscular<br />
dystrophy <strong>of</strong> swine is not yet clear. Vitamin E and selenium are necessary to prevent widespread<br />
degeneration and necrosis <strong>of</strong> tissues, especially liver, heart, skeletal muscle, and blood vessels.<br />
Selenium and vitamin E deficiency in swine results in massive hepatic necrosis (hepatosis<br />
dietetica), degenerative myopathy <strong>of</strong> cardiac and skeletal muscles, edema, microangiopathy, and<br />
yellowish discoloration <strong>of</strong> adipose tissue. Myocardial and hepatic calcium concentrations are<br />
increased in pigs with mulberry heart disease (55). In addition, there may be esophagogastnc<br />
ulceration, but it is uncertain whether or not this lesion is <strong>caused</strong> <strong>by</strong> a selenium and/or vitamin E<br />
deficiency. <strong>An</strong>emia has also occurred and has been attributed to a block in bone marrow<br />
maturation, resulting in inadequate erythropoiesis, hemolysis<br />
1524<br />
or both. However, there is no firm evidence that anemia is a feature <strong>of</strong> selenium and vitamin E<br />
deficiency in swine. The entire spectrum <strong>of</strong> lesions has been reproduced experimentally in swine<br />
with natural or purified diets deficient in selenium and vitamin E, or in which an antagonist was<br />
added to inactivate vitamin E or selenium. However, in some studies, the selenium content <strong>of</strong><br />
tissues <strong>of</strong> pigs that died from mulberry heart disease was similar to that <strong>of</strong> control pigs without the<br />
disease.<br />
The extensive tissue destruction in pigs may account for the sudden death nature <strong>of</strong> the complex
(mulberry heart disease and hepatosis dietetica) and the muscle stiffness that occurs in some<br />
feeder pigs and sows <strong>of</strong> farrowing time with muscular dystrophy. The tissue degeneration is<br />
associated with marked increases in serum enzymes related to the tissue involved. <strong>An</strong> indirect<br />
correlation between vitamin E intake and peroxide hemolysis in pigs on a deficient diet sugests<br />
that lipoperoxidation is the ultimate biochemical defect in swine and that vitamin E and selenium<br />
are protective.<br />
CLINICAL FINDINGS<br />
Acute enzootic muscular dystrophy<br />
Affected animals may collapse and die suddenly after exercise without any other premonitory<br />
signs. The excitement associated with the hand-feeding <strong>of</strong> dairy calves may precipitate peracute<br />
death. In calves under dose observation, a sudden onset <strong>of</strong> dullness and severe respiratory distress,<br />
accompanied <strong>by</strong> a frothy or blood-stained nasal discharge, may be observed in some cases.<br />
Affected calves, lambs, and foals are usually in lateral recumbency and may be unable to assume<br />
sternal recumbency even when assisted. When picked up and assisted to stand, they feel and<br />
appear limp. However, their neurological reflexes are normal. Their eyesight and mental attitude<br />
are normal and they are usually thirsty and can swallow unless the tongue is affected. The heart<br />
rate is usually increased up to 150-200/min and <strong>of</strong>ten with arrhythmia, the respiratory rate is<br />
increased up to 60-72/min and loud breath sounds are audible over the entire lung fields. The<br />
temperature is usually normal or slightly elevated. Affected animals commonly die 6-12 hours<br />
after the onset <strong>of</strong> signs in spite <strong>of</strong> therapy. Outbreaks <strong>of</strong> the disease occur in calves and lambs in<br />
which up to 15% <strong>of</strong> susceptible animals may develop the acuteform, and the case fatality<br />
approaches100%.<br />
Subacute enzootic muscular dystrophy<br />
This is the most common form in rapidly growing calves, 'white muscle disease', and in young<br />
lambs, 'stiff-Iamb disease'.Affected animals may be found in sternal recumbency and unable to<br />
stand but some make an attempt to stand. If they are standing, the obvious signs are stiffness,<br />
trembling <strong>of</strong> the limbs, weakness and, in most cases, an inability to stand for more than a few<br />
minutes. The gait in calves is accompanied <strong>by</strong> rotating movements <strong>of</strong> the hocks, and in lambs a<br />
stiff, goose-stepping gait. Muscle tremor is evident if the animal is forced to stand for more than a<br />
few minutes. On palpation the dorsolumbar, gluteal, and shoulder muscle masses may be<br />
symmetrically enlarged and firmer than normal (although this may be difficult to detect). Most<br />
affected animals retain their appetite and will suck if held up to the dam or eat if hand-fed. Major<br />
involvement <strong>of</strong> the diaphragm and intercostal muscles causes dyspnea with labored and<br />
abdominal-type respiration. The temperature is usually in the normal range but there may be a<br />
transient fever (41℃, 105℃) due to the effects <strong>of</strong> myoglobmemia and pain. The heart rate may be<br />
elevated, but there are usually no rhythmic irregularities. Following treatment, affected animals<br />
usually respond in a few days, and within 3-5 days they are able to stand and walk unassisted.<br />
In some cases, the upper borders <strong>of</strong> the scapulae protrude above the vertebral column and are<br />
widely separated from the thorax. This has been called the 'flying scapula' and has occurred in<br />
outbreaks in heifers from 18 to 24 months <strong>of</strong> age within a few days after being turned out in the<br />
spring following loose-housing throughout the winter (56, 57). The abnormality is due to bilateral<br />
rupture <strong>of</strong> the serratus ventralis muscles (58) and has been reported in a red deer (59).<br />
Occasionally, the toes are spread and there is relaxation <strong>of</strong> carpal and metacarpal joints or<br />
knuckling at the fetlocks and standing on tip-toe, inability to raise the head, difficulty in
swallowing, inability to use the tongue, and relaxation <strong>of</strong> abdominal muscles. Choking may occur<br />
when the animal attempt to drink. In 'paralytic myoglobinuria' <strong>of</strong> yearling cattle, there is usually a<br />
history <strong>of</strong> recent turning out on pasture following winter housing. Clinical signs occur within 1<br />
week and consist <strong>of</strong> stiffness, recumbency, myoglobinuria, hyperpnea, and dyspnea. Severe cases<br />
may die within a few days and some are found dead without premonitory signs. In rare cases,<br />
lethargy, anorexia, diarrhea, and weakness are the first clinical abnormalities recognized, followed<br />
<strong>by</strong> recumbency and myoglobinuria.<br />
Subcapsular liver rupture in lambs has been associated with vitamin E deficiency in lambs<br />
usually under 4 weeks <strong>of</strong> age (60). Affected lambs collapse suddenly, become limp, and die within<br />
a few minutes or several hours after the onset <strong>of</strong> weakness.<br />
In foals, muscular dystrophy occurs most commonly during the first few months <strong>of</strong> life and is<br />
common in the first week. The usual clinical findings are failure to suck, recumbency, difficulty in<br />
rising, and unsteadiness and trembling when forced to stand. The temperature is usually normal<br />
but commonly there is polypnea and tachycardia.<br />
In adult horses with muscular dystrophy, a stiff gait, myoglobinuria, depression, inability to<br />
eat, holding the head down low, and edema <strong>of</strong> the head and neck are common. The horse may be<br />
presented initially with clinical signs <strong>of</strong> colic.<br />
In pigs, muscular dystrophy is not commonly recognized clinically because it is part <strong>of</strong> the<br />
more serious disease complex <strong>of</strong> mulberry heart disease and hepatosis dietetica. However, in<br />
outbreaks <strong>of</strong> this complex, sucking piglets, feeder pigs, and sows after farrowing may exhibit an<br />
uncoordinated, staggering gait suggestive <strong>of</strong> muscular dystrophy.<br />
Subclinical nutritional muscular dystrophy occurs in apparently normal animals in herds at<br />
the time clinical cases are present. The serum levels <strong>of</strong> creatine phosphokinase levels may be<br />
elevated in susceptible animals for several days before the onset <strong>of</strong> clinical signs; following<br />
treatment with vitamin E and selenium the level <strong>of</strong> serum enzymes returns to normal. Grossly<br />
abnormal electrocardiograms occur in some animals and may be detectable before clinical signs<br />
are evident.<br />
Mulberry heart disease<br />
In mulberry heart disease, affected animals are commonly found dead without premonitory<br />
1525<br />
signs. More than one pig may be found dead. When seen alive, animals show severe dyspnea,<br />
cyanosis and recumbency, and forced walking can cause immediate death. In some outbreaks,<br />
about 25% <strong>of</strong> pigs will show a slight inappetence and inactivity, these are probably in the<br />
subclinical stages <strong>of</strong> the disease.The stress <strong>of</strong> movement, inclement weather or transportation will<br />
precipitate further acute deaths. The temperature is usually normal, the heart rate rapid,and<br />
irregularities maybe detectable. The feces are usually normal.<br />
Hepatosis dietetica<br />
In hepatosis dietetica, most pigs are found dead. In occasional cases, before death there will be<br />
dyspnea, severe depression, vomiting, staggering, diarrhea and a state <strong>of</strong> collapse. Some pigs are<br />
icteric. Outbreaks also occur similar to the pattern in mulberry heart disease. Muscular dystrophy<br />
is almost a consistent necropsy finding in both mulberry heart disease and hepatosis dietetica but<br />
is usually not recognized clinically because <strong>of</strong> the seriousness <strong>of</strong> the two latter diseases. Clinical<br />
muscular dystrophy has been described in gilts at 11 months <strong>of</strong> age. About 48 hours after<br />
farrowing, there was muscular weakness, muscular tremors, and shaking. This was followed <strong>by</strong>
collapse, dyspnea, and cyanosis. There were no liver or heart lesions. In experimental selenium<br />
and vitamin E deficiency in young growing pigs, a subtle stiffness occurs along with a significant<br />
increase in the creatinine phosphatase (CPK) and serum glutamicoxaloacetic transaminase (SGOT)<br />
values.<br />
CLINICAL PATHOLOGY<br />
Myopathy<br />
Plasma creatine kinase (CK)<br />
This is the most commonly used laboratory aid in the diagnosis <strong>of</strong> NMD. The enzyme is highly<br />
specific for cardiac and skeletal muscle and is released into the blood following unaccustomed<br />
exercise and myodegeneration. In cattle and sheep, its half-life is 2-4 hours and plasma levels<br />
characteristically decline quickly unless there is continued myodegeneration, but remain a good<br />
guide to the previous occurrence <strong>of</strong> muscle damage for a period <strong>of</strong> about 3 days. The normal<br />
plasma levels <strong>of</strong> CK (IU/L) are: sheep 52 +/- 10; cattle 26 +/- 5; horses 58 +/-6; and pigs 226 +/-<br />
43. In cattle and sheep with NMD, the CK levels will be increased usually above 1000 IU/L,<br />
commonly increased to 5000-10000 IU/L and not uncommonly even higher. Following turnout <strong>of</strong><br />
housed cattle onto pasture the CK levels will increase up to 5000 IU/L within a few days. The CK<br />
levels will usually return to normal levels within a few days following successful treatment.<br />
Persistent high levels suggest that muscle degeneration is still progressive or has occurred within<br />
the last 2 days. Measurement <strong>of</strong> plasma CK activity could be used to monitor recovery <strong>of</strong> animals<br />
treated for nutritional myopathy (61).<br />
Aspartate aminotransferase<br />
Aspartate aminotransferase (AST) activity is also an indicator <strong>of</strong> muscle damage, but is not as<br />
reliable as the CK because increased AST levels may also indicate liver damage. The AST activity<br />
remains elevated for 3-10 days because <strong>of</strong> a much longer half-life than CK. In acute cases, levels<br />
<strong>of</strong> 300-900 IU/L in calves and 2000-3000 IU/L in lambs have been observed. In normal animals <strong>of</strong><br />
these species, serum levels are usually less than 100 IU/L.<br />
The magnitude <strong>of</strong> the increase in AST and CK is directly proportional to the extent <strong>of</strong> muscle<br />
damage. Both are elevated initially; an elevated AST and declining CK would suggest that muscle<br />
degeneration is no longer active. The levels <strong>of</strong> both enzymes will be increased slightly in animals<br />
that have just been turned out and subjected to unaccustomed exercise, horses in training, and in<br />
animals with ischemic necrosis <strong>of</strong> muscle due to recumbency <strong>caused</strong> <strong>by</strong> diseases other than<br />
muscular dystrophy. However, in acute muscular dystrophy, the levels are usually markedly<br />
elevated.<br />
Selenium status<br />
Although information on the critical levels <strong>of</strong> selenium in soil and plants is accumulating<br />
gradually, the estimations are difficult and expensive. Most field diagnoses are made on the basis<br />
<strong>of</strong> clinicopathological findings, the response to treatment and control procedures using selenium.<br />
The existence <strong>of</strong> NMD is accepted as presumptive evidence <strong>of</strong> selenium deficiency, which can<br />
now be confirmed <strong>by</strong> analyses <strong>of</strong> GHS-PX and the concentrations <strong>of</strong> selenium in soil, feed<br />
samples, and animal tissues. Tentative critical levels <strong>of</strong> the element are as follows:<br />
•Forages and grains - A content <strong>of</strong> 0.1 mg/kg DM is considered adequate<br />
•Soil - Soils containing less than 0.5 mg/kg are likely to yield crops inadequate in selenium<br />
concentration (2)<br />
•<strong>An</strong>imal tissues, blood, and milk -
The concentration <strong>of</strong> selenium in various tissues are reliable indicators <strong>of</strong> the selenium status <strong>of</strong><br />
the animal.There is a positive correlation between the selenium content <strong>of</strong> feed and the selenium<br />
content <strong>of</strong> the tissues and blood <strong>of</strong> animals ingesting that feed and the values fluctuate with the<br />
dietary intake <strong>of</strong> the element (2).<br />
Kidney cortex and liver<br />
Normal liver selenium concentrations range from 1.2 to 2.0 µg/g DM, regardless <strong>of</strong> species or age<br />
(62). Levels <strong>of</strong> 3.5-5.3 mg/g (67-101 nmol/g) DM in the kidney cortex and 0.90-1.75 µg/g (11-22<br />
nmol/g) DM in the liver <strong>of</strong> cattle are indicative <strong>of</strong> adequate selenium. Levels <strong>of</strong> 0.6-1.4 µg/g (8-18<br />
nmol/g) in the kidney cortex and 0.07-0.60 µg/g (0.9-8 nmol/g) in the liver represent a deficient<br />
state.<br />
The selenium content <strong>of</strong> bovine fetal liver samples collected at an abattoir contained<br />
0.77(µg/mL WW. and 0.13 µg/mL WW, from dairy breeds and beef breeds <strong>of</strong> cattle, respectively<br />
(63). Mean liver selenium levels from aborted bovine fetuses with myocardial lesions were<br />
5.5 .µmol/kg, 6.5 µmol/kg in fetuses without myocardial lesions and 7.5 µmol/kg in fetuses from<br />
the abattoir, which suggests that selenium deficiency may be the cause <strong>of</strong> abortion (64).<br />
Blood and milk<br />
Blood and milk levels <strong>of</strong> selenium are used as indicators <strong>of</strong> selenium status in cattle and the effect<br />
<strong>of</strong> dietary supplementation (65). Serum selenium values increase gradually with age from starting<br />
ranges for neonates <strong>of</strong> 50-80 ng/L for calves and sheep, and 70-90 for foals and pigs (62).<br />
Expected or normal values for adults are in the ranges <strong>of</strong> 70-100 for cattle, 120-150 for sheep,<br />
130-160 for horses, and 180-220 for swine.<br />
Dams <strong>of</strong> affected calves have had levels <strong>of</strong> 1.7ng/ml (2.2 nmol/L) (blood) and 4.9 ng/mL(6.2<br />
nmol/L) (milk); their<br />
1526<br />
calves have blood levels <strong>of</strong> 5 8 ng/mL (6.3-10.1 nmol/L). Normal selenium-supplemented cows<br />
have 19-48 ng/mL (24.1-60.8 nmol/L) in blood and 10-20 ng/mL (12.7-25.3 nmol/L) in milk, and<br />
their calves have blood levels <strong>of</strong> 33-61 ng/mL (41.8-77.2 nmol/L). Mean selenium concentrations<br />
in the blood <strong>of</strong> normal mares have been 26-27 ng/mL (32.9-34.2 nmol/L). In Thoroughbred horses,<br />
selenium concentrations in serum range from 39.5 to 118.5mg/mL (50-150 µmol/L) and there arc<br />
significant differences between various stables <strong>of</strong> horses.<br />
Bulk tank milk<br />
The bulk tank milk selenium levels are closely related to the mean herd blood and milk levels and<br />
have the potential to be a low-cost, non-invasive means <strong>of</strong> evaluating herd selenium levels in order<br />
to determine selenium deficiency in the dairy herd (66).<br />
Glutathione peroxidase<br />
There is a direct relationship between the GSH-PX activity <strong>of</strong> the blood and the selenium levels <strong>of</strong><br />
the blood and tissues <strong>of</strong> cattle, sheep, horses, and pigs (1). The normal selenium status <strong>of</strong> cattle is<br />
represented <strong>by</strong> whole blood selenium concentration <strong>of</strong> 100 ng/mL (126.6 nmol/L) and blood<br />
GSH-PX activity <strong>of</strong> approximately 30 mU/mg hemoglobin (67). There is a high positive<br />
relationship (r = 0.87-0.958) between blood GSH-PX activity and blood selenium concentrations<br />
in cattle (67). Blood selenium levels less than 50 ng/mL are considered as selenium-deficient,<br />
while levels between 50 and 100 ng/mL (126.6 nmol/L) are marginal, and greater than 100 ng/mL<br />
are adequate (1). Comparable whole blood levels <strong>of</strong> GSH-PX are deficient if less than 30 mU/mg<br />
hemoglobin, marginal if 30-60 mU/mg, and adequate if greater than 60 mU/mg hemoglobin (1).
There is some evidence <strong>of</strong> variation in GSH-PX activities between breeds <strong>of</strong> sheep; levels may<br />
also decrease with increasing age. Low levels in some breeds <strong>of</strong> sheep may also be a reflection <strong>of</strong><br />
adaptation to low selenium intake because <strong>of</strong> low levels <strong>of</strong> selenium in the soil and forages.<br />
The GSH-PX activity is a sensitive indicator <strong>of</strong> the level <strong>of</strong> dietary selenium intake and the<br />
response to the oral or parenteral administration <strong>of</strong> selenium (1, 2). Because selenium is<br />
incorporated into erythrocyte GSH-PX only during erythropoiesis, an increase in enzyme activity<br />
<strong>of</strong> the blood will not occur for 4-6 weeks following administration <strong>of</strong> selenium (1). Plasma<br />
GSH-PX will rise more quickly and will continue to increase curvihnearly with increasing dietary<br />
selenium levels because it is not dependent on incorporation <strong>of</strong> the selenium into the erythrocytes.<br />
The liver and selenium concentration and scrum GSH-PX activity may respond to changes in<br />
dietary selenium more rapidly than either whole blood selenium or erythrocyte GSH-PX activity.<br />
The response in GSH-PX activity may depend upon the selenium status <strong>of</strong> the animals at the time<br />
when selenium is administered. Larger increases in the enzyme activity occur in<br />
selenium-deficient animals. The GSH-PX activity in foals reflects the amount <strong>of</strong> selenium given to<br />
the mare during pregnancy.<br />
The sandwich ELISA is a simplified method for the estimation <strong>of</strong> GSH-PX activity and<br />
selenium concentration in bovine blood, and can be used for rapid screening <strong>of</strong> the selenium status<br />
<strong>of</strong> a large number <strong>of</strong> cattle (68).<br />
The GSH-PX activity can be determined rapidly using a spot test which is semiquantitative and<br />
can place a group <strong>of</strong> samples from the same herd or flock into one <strong>of</strong> three blood selenium<br />
categories: deficient, low marginal, and marginal adequate (69). A commercial testing kit known<br />
as the Ransel Kit is now available (70). Because <strong>of</strong> the instability <strong>of</strong> GSH-PX plasma, GSH-PX<br />
activity in sheep, cattle, and pigs should be measured in fresh plasma or stored at -20℃ (-4 ℉ ) .<br />
For absolute measurements, it is suggested that swine plasma GSH-PX activity be measured<br />
immediately after separation from the blood cells, or be assayed within 24 hours under specified<br />
laboratory conditions (71).<br />
Vitamin E status<br />
Vitamin E occurs in nature as a mixture <strong>of</strong> tocopherols in varying proportions. They vary widely<br />
in their biological activity so that chemical determination <strong>of</strong> total tocopherols is <strong>of</strong> much less<br />
value than biological assay. Tocopherol levels in blood and liver provide good information on the<br />
vitamin E status <strong>of</strong> the animal. However, because <strong>of</strong> the difficulty <strong>of</strong> the laboratory assays <strong>of</strong><br />
tocopherols, they are not commonly done and insufficient reliable data available. <strong>An</strong>alysis <strong>of</strong> liver<br />
from clinically normal animals on pasture reveal a mean a-tocopherol level <strong>of</strong> 20 mg/kg WW for<br />
cattle and 6 mg/kg WW for sheep. The corresponding ranges were 6.0-53 WW mg/kg for cattle<br />
and 1.8-17 mg/kg WW in sheep. The critical level below which signs <strong>of</strong> deficiency may be<br />
expected are 5 mg/kg WW for cattle and 2 mg/kg WW for sheep. Tocopherol levels in the serum<br />
<strong>of</strong> less than 2 mg/L in cattle and sheep are considered to be critical levels below which deficiency<br />
diseases may occur. However, if the diet contains adequate quantities <strong>of</strong> selenium, but not an<br />
excessive quantity <strong>of</strong> PUFAs, animals may thrive on low levels <strong>of</strong> serum tocopherols. In growing<br />
pigs, the serum vitamin E levels are between 2 and 3 mg/L (72). In summary, there are insufficient<br />
reliable data available on the vitamin E status on animals with NMD to be <strong>of</strong> diagnostic value.<br />
The mean plasma vitamin E levels in clinically normal horses <strong>of</strong> various ages and breeds were<br />
2.8 µg/mL (73). The optimal method for storing equine blood prior to a-tocopherol analysis is in<br />
an upright position in the refrigerator for up to 72 hours (74). If a longer period is needed, the
serum or plasma should be separated, blanketed with nitrogen gas, and frozen in the smallest<br />
possible vial; the a-tocopherol in these samples will be stable at 16 for at least 3 months.<br />
A summary <strong>of</strong> the GSH-PX activity, tocopherol and selenium levels in blood and body tissues<br />
<strong>of</strong> animals deficient in selenium appears m Table 29.6. Normal values are also tabulated for<br />
comparison (75). Both the abnormal and normal .values should be considered as guidelines for<br />
diagnosis because <strong>of</strong> the wide variations in levels between groups <strong>of</strong> animals. The level <strong>of</strong> dietary<br />
selenium may fluctuate considerably, which may account for variations in GSH-PX.<br />
Swine<br />
<strong>An</strong> increase in the activity <strong>of</strong> several plasma enzymes occurs in selenium and vitamin E<br />
<strong>deficiencies</strong> <strong>of</strong> swine. The measurement <strong>of</strong> AST, CPK, lactic acid dehydrogenase and isucitrate<br />
dehydrogenase can be used to detect the onset <strong>of</strong> degeneration <strong>of</strong> skeletal and myocardial muscles<br />
and liver. However, these are not commonly used for diagnostic purposes because <strong>of</strong> the acuteness<br />
<strong>of</strong> the illness.<br />
The determination <strong>of</strong> the levels <strong>of</strong> selenium in feed supplies,tissues,and<br />
1527<br />
Table 29.6 Glutathione peroxidase (GSH-PX) activity and selenium levels in blood and body<br />
tissues <strong>of</strong> animals deficient in selenium<br />
species<br />
Catter<br />
sheep<br />
pigs<br />
Clinical state or<br />
degree <strong>of</strong> deficienc<br />
Normal or adequte<br />
marginal<br />
deficient<br />
normal or adequte<br />
marginal<br />
deficient<br />
adequte<br />
deficient<br />
Erythrocyte gsh-px<br />
activity µmol/min at<br />
37. ℃ /g hemoglobin<br />
19.0-36.0<br />
10.0-19.0<br />
0.2-10.0<br />
60-180<br />
8-30<br />
2-7<br />
100-200<br />
400-1500 nmol/L. These values must be interpreted along with the concentration <strong>of</strong> PUFAs in the<br />
diet.<br />
There is a close relationship between blood vitamin E and resistance <strong>of</strong> erythrocytes against<br />
lipid peroxidation. The supplementation <strong>of</strong> the diet <strong>of</strong> pigs with vitamin E will increase both the<br />
serum levels <strong>of</strong> vitamin E and the resistance <strong>of</strong> the erythrocytes to lipid peroxidation (72).<br />
NECROPSY FINDINGS<br />
The microscopic appearance <strong>of</strong> the muscle lesions is quite constant, but the distribution <strong>of</strong> affected<br />
muscles varies widely in different animals. Affected groups <strong>of</strong> skeletal muscle are bilaterally<br />
symmetrical and contain localized white or graying areas <strong>of</strong> degeneration. These areas may be in<br />
streaks, involving a large group <strong>of</strong> muscle fibers that run through the center <strong>of</strong> the apparently<br />
normal muscle or as a peripheral boundary around a core <strong>of</strong> normal muscle. In the diaphragm, the<br />
distribution <strong>of</strong> damaged bundles gives the tissue a radially striated appearance. The affected<br />
muscle is friable and edematous and may be <strong>mineral</strong>ized. Secondary pneumonia <strong>of</strong>ten occurs in<br />
cases where the muscles <strong>of</strong> the throat and chest are affected. In cases with myocardial involvement,<br />
white areas <strong>of</strong> degeneration are visible, particularly under the endocardium <strong>of</strong> the left ventricle in<br />
calves and <strong>of</strong> both ventricles in lambs. The lesions may extend to involve the inter-ventricular<br />
septum and papillary muscles and have a gritty character consistent with <strong>mineral</strong>ization.<br />
Pulmonary congestion and edema is common.<br />
Histologically, the muscle lesions are non-inflammatory.Hyaline degeneration is followed <strong>by</strong><br />
coagulation necrosis and variable degrees <strong>of</strong> <strong>mineral</strong>ization.<br />
A generalized steatitis has been described in newborn foals less than 2 months <strong>of</strong> age. The<br />
microscopic appearance <strong>of</strong> this yellow-brown fat consists <strong>of</strong> necrotic fat infiltrated <strong>by</strong> neutrophils,<br />
macrophages, and giant cells. Supplemental vitamin E is believed to protect against this condition.<br />
In mulberry heart disease the carcass is in good condition. All body cavities contain excessive<br />
amounts <strong>of</strong> fluid and shreds <strong>of</strong> fibrin. In the peritoneal cavity, the fibrin is <strong>of</strong>ten in the form <strong>of</strong> a<br />
lacy net covering all the viscera. The liver is enlarged, mottled, and has a characteristic nutmeg<br />
appearance on the cut surface. The lungs are edematous and excessive fluid in the pleural cavities<br />
is accompanied <strong>by</strong> collapse <strong>of</strong> the ventral lung field. The pericardia! sac is filled with gelatinous<br />
fluid interlaced with bands <strong>of</strong> fibrin. Beneath the epicardium and endocardium are multiple<br />
hemorrhages <strong>of</strong> various sizes. Usually, this hemorrhage is more severe on the right side <strong>of</strong> the<br />
heart. Histologically, the characteristic lesion is widespread myocardial congestion, hemorrhage,<br />
and my<strong>of</strong>iber degeneration. Multiple fibrinous microthrombi are within the myocardial capillaries<br />
and, occasionally, degenerative changes are visible in walls <strong>of</strong> small arterioles in many organs,<br />
including the heart. Malacia <strong>of</strong> cerebral white matter, or more rarely the molecular layer <strong>of</strong> the<br />
cerebellum, may occur and is attributable to microvascular damage. It should be stressed that, in<br />
some cases, the disease course is so rapid that morphologic changes are not discernible in the<br />
myocardial cells. Since it can be extremely difficult to distinguish mulberry heart disease from<br />
Strep, suis septicemia histologically, it is prudent to also attempt bacteriologic culture when<br />
attempting to confirm the diagnosis.<br />
In hepatosis dietetica the liver is swollen and has a mottled to mosaic-like appearance throughout<br />
its lobes. Typically, the disease course is so rapid that jaundice does not develop. Histologically,<br />
there is a distinct lobular distribution <strong>of</strong> hemorrhage, degeneration, and necrosis. In NMD <strong>of</strong><br />
swine the lesions are <strong>of</strong>ten only visible at the microscopic level and consist <strong>of</strong> areas <strong>of</strong> bilaterally<br />
distributed areas <strong>of</strong> muscular degeneration. The changes include hyalinization, loss <strong>of</strong> striations,
and fragmentation <strong>of</strong> my<strong>of</strong>ibers. A mild degree <strong>of</strong> NMD may accompany some cases <strong>of</strong> hepatosis<br />
dietetica.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
•Toxicology - 50 g liver (ASSAY (Se) (Vit E))<br />
•Histology-formalin-fixedskeletal muscle (multiple sites), heart (both left<br />
1528<br />
and right ventricular walls), brain (including cerebral hemisphere) (LM) Bacteriology (for<br />
mulberry heart disease only)-heart, liver, swab from pericardia sac (CULT).<br />
DIFFERENTIAL DIAGNOSIS<br />
Nutritional muscular dystrophy<br />
NMD is most common in young rapidly growing animals fed a selenium-vitamin E deficient<br />
ration or whose dams were on a deficient, unsupplemented ration throughout the winter months.<br />
Characteristically, the disease is sudden in onset, and several animals are affected initially or<br />
within a few days, particularly following unaccustomed exercise. In the acute form, generalized<br />
weakness and a state <strong>of</strong> collapse are common. In the subacute form, the major clinical findings are<br />
stiffness in walking, long periods <strong>of</strong> recumbency or total recumbency, inability to stand, a normal<br />
mental attitude and appetite, and no abnormal neurological findings to account for the recumbency.<br />
The CP levels are markedly elevated.<br />
Calves and yearlings<br />
Acute enzootic muscular dystrophy in calves with myocardial involvement must be<br />
differentiated from other diseases causing generalized weakness, toxemia and shock. These<br />
include:<br />
•Septicemias-Haemophilus septicemia resulting in weakness, recumbency, and fever<br />
•Pneumonia-Pneumonic pasteurellosis causing dyspnea, toxemia, fever, and weakness,. .<br />
Subacute enzootic muscular dystrophy in which skeletal muscle lesions predominate must be<br />
differentiated from other diseases <strong>of</strong> young calves and yearlings characterized clinically <strong>by</strong> paresis<br />
and paralysis. The subacute form is more common in yearlings and young cattle, and is<br />
characterized <strong>by</strong> recumbency with other body systems being relatively within normal ranges. The<br />
other diseases include:<br />
•Musculoskeletal diseases - Polyarthritis, traumatic or infectious myopathies (blackleg),<br />
osteodystrophy and fractures <strong>of</strong> long bones<br />
•<strong>Diseases</strong> <strong>of</strong> the nervous system-Spinal cord compression, Haemophilus meningoencephalitis<br />
and myelitis, organophosphatic insecticide poisoning<br />
•<strong>Diseases</strong> <strong>of</strong> the digestive tract-Carbohydrate engorgement resulting in lactic acidosis, shock,<br />
dehydration, and weakness.<br />
Lambs and kids<br />
In lambs with 'stiff-lamb' disease there is stiffness and a stilted gait, affected animals prefer<br />
recumbency, they are bright and alert, and will suck the ewe if assisted. The serum levels <strong>of</strong> CPK<br />
and SGOT are also markedly elevated. Differentiation may be necessary from enzootic ataxia and<br />
sway-back, but in these two diseases stiffness is not characteristic but rather weakness and paresis.<br />
Foals<br />
In foals, NMD must be differentiated from acute diseases <strong>of</strong> the musculoskeletal and nervous<br />
system causing abnormal gait, weakness and recumbency. They include:<br />
•Traumatic injury to the musculoskeletal system
•Polyarthritis . .<br />
•Meningitis<br />
•Traumatic injury to the spinal cord.<br />
Mulberry heart disease<br />
Mulberry heart disease must be differentiated from other common causes <strong>of</strong> sudden death in pigs<br />
in which the diagnosis is made at necropsy and include:<br />
•Acute septicemias due to salmonellosis, erysipelas, pasteurellosis, and anthrax<br />
•Porcine stress syndrome<br />
•Gut edema<br />
•Intestinal volvulus, heat exhaustion, suffocation during transportation.<br />
TREATMENT<br />
Because <strong>of</strong> the overlapping functions <strong>of</strong> selenium and vitamin E, and because it is not always<br />
possible to know the relative etiological importance <strong>of</strong> one nutrient or the other in causing some <strong>of</strong><br />
the acute conditions already described, it is recommended that a combined mixture <strong>of</strong> selenium<br />
and α-tocopherol be used in treatment. α-Tocopherol is the most potent form <strong>of</strong> the tocopherols<br />
and is available in a number <strong>of</strong> pharmaceutical forms, which also vary in their biological activity.<br />
It has become necessary to express the unitage <strong>of</strong> vitamin E in terms <strong>of</strong> international units <strong>of</strong><br />
biological activity. (1 IU:1 mg synthetic racemic α-tocopherol acetate. Natural D-α-tocopherol<br />
acetate 1 mg: 1 IU and natural D-α-tocopherol mg:0.92 IU).<br />
Nutritional muscular dystrophy<br />
For treatment <strong>of</strong> NMD in calves, lambs, and foals a mixture containing 3 mg<br />
selenium (as sodium or potassium selenite) and 150IU/mL <strong>of</strong> DL-α-tocopherol acetate, given IM<br />
at 2 mL/45 kg BW is recommended. One treatment is usually sufficient. <strong>An</strong>imals with severe<br />
myocardial involvement will usually not respond to treatment, and the case mortality rate is about<br />
90%. However, all incontact animals in the herd (calves, lambs, and foals) should be treated<br />
prophylactically with the same dose <strong>of</strong> selenium and vitamin E. They should be handled carefully<br />
during treatment to avoid precipitating acute muscular dystrophy. <strong>An</strong>imals with subacute skeletal<br />
muscular dystrophy will usually begin to improve <strong>by</strong> 3 days following treatment and may be able<br />
to stand and walk unassisted within a week.<br />
Mulberry heart disease<br />
In outbreaks <strong>of</strong> mulberry heart disease, hepatosis dietetica, and related selenium and vitamin E<br />
deficiency diseases in pigs, all clinically affected pigs and all pigs at risk should be treated<br />
individually with a combination <strong>of</strong> selenium and vitamin E parenterally.<br />
CONTROL<br />
The control and prevention <strong>of</strong> the major diseases <strong>caused</strong> <strong>by</strong> selenium and vitamin E <strong>deficiencies</strong><br />
can generally be accomplished <strong>by</strong> the provision <strong>of</strong> both <strong>nutrients</strong> to susceptible animals fed on<br />
deficient rations. The following points are relevant and applicable to most situations:<br />
•Provide selenium and vitamin E<br />
•Maternal transfer to newborn<br />
•Selenium potentially toxic<br />
•Selenium in milk supplies<br />
•Dietary requirement <strong>of</strong> selenium<br />
•High sulfate diets<br />
•Gluthathione peroxidase activity
•Different methods <strong>of</strong> supplementation.<br />
Provide selenium and vitamin E<br />
While selenium alone is protective against a greater spectrum <strong>of</strong> diseases than is vitamin E, there<br />
are situations in which vitamin E is more protective. Both selenium and vitamin E should be<br />
provided when the diets are deficient in both <strong>nutrients</strong>, but this may not apply in every situation.<br />
NMD can occur in ruminants with vitamin E deficiency and an adequate selenium status (76).<br />
Most <strong>of</strong> the emphasis has been on selenium supplementation at the<br />
1529<br />
expense <strong>of</strong> vitamin E, which is more expensive and less stable. Most injectable vitamin E and<br />
selenium preparations are adequate in selenium but insufficient in vitamin E.<br />
Maternal transfer to newborn<br />
<strong>Diseases</strong> <strong>caused</strong> <strong>by</strong> selenium deficiency are preventable <strong>by</strong> the administration <strong>of</strong> selenium to the<br />
dam during pregnancy or directly to the young growing animal. Selenium is transported across the<br />
placenta and provides protection for the neonate. Oral supplementation <strong>of</strong> beef cattle with<br />
selenium will provide sufficient to maintain blood levels in the dam and for adequate transfer to<br />
the fetus, ; which can sequester selenium when the levels are low in the dam. The colostrum <strong>of</strong><br />
selenium-supplemented cattle also contains an adequate amount <strong>of</strong> selenium to prevent severe<br />
selenium-deficiency diseases (39). However, <strong>by</strong> 7 days after parturition, the levels in milk may be<br />
inadequate to maintain adequate serum levels in calves. The strategic administration <strong>of</strong> selenium<br />
and vitamin E before the expected occurrence <strong>of</strong> the disease is also a reliable method <strong>of</strong><br />
preventing the disease.<br />
Selenium potentially toxic<br />
Selenium is toxic, and any treatment and control program using it must be carefully monitored.<br />
Selenium injected into or fed to animals concentrates in liver, skeletal muscle, kidney and other<br />
tissues, and withdrawal periods before slaughter must be allowed. There is some concern that<br />
selenium may be a carcinogen for man. The only tissues that appear likely to consistently<br />
accumulate more than 3-4 mg/kg <strong>of</strong> selenium are the kidney and liver, and these are very unlikely<br />
to constitute more than a very small part <strong>of</strong> the human diet. There have been no reports <strong>of</strong><br />
untoward effects <strong>of</strong> selenium on human health when it has been used at nutritional levels in<br />
food-producing animals. The incorporation <strong>of</strong> selenium into commercially prepared feeds for<br />
some classes <strong>of</strong> cattle and swine has been approved in some countries.<br />
Selenium in milk supplies<br />
The use <strong>of</strong> selenium in the diet <strong>of</strong> lactating dairy cows has <strong>caused</strong> concern about possible<br />
adulteration <strong>of</strong> milk supplies. However, the addition <strong>of</strong> selenium to the diets <strong>of</strong> lactating dairy<br />
cows at levels that are protective against the deficiency diseases does not result in levels in the<br />
milk that are hazardous for human consumption. The feeding <strong>of</strong> excessive quantities <strong>of</strong> selenium<br />
to dairy cattle would cause toxicity before levels became toxic for man.<br />
Dietary requirement <strong>of</strong> selenium<br />
The dietary requirement <strong>of</strong> selenium for both ruminants and non-ruminants is 0.1 mg/kg DM <strong>of</strong><br />
the element in the diet. There may be nutritionally important differences in the selenium status<br />
between the same feeds grown in different regions and between different feeds within a region.<br />
Even within a region featuring high selenium concentrations, some feeds may contain levels <strong>of</strong><br />
selenium below the 0.1 mg/kg minimum requirement for livestock. Thus a selenium analysis <strong>of</strong><br />
feeds appears necessary in order to supplement livestock appropriately. Some geographical areas
are known to be deficient in selenium and the feeds grown in these areas must be supplemented<br />
with selenium and vitamin E on a continuous basis.<br />
High sulfate diets<br />
Avoidance <strong>of</strong> high sulfate diets is desirable, but provision <strong>of</strong> adequate selenium overcomes the<br />
sulfate effect.<br />
Glutathione peroxidase activity<br />
Whole blood GSH-PX activity is a reliable and useful index for monitoring the selenium status <strong>of</strong><br />
cattle and sheep, perhaps not as reliable in pigs, and not a good indicator in the horse.<br />
Different methods <strong>of</strong> supplementation<br />
The prevention <strong>of</strong> the major diseases <strong>caused</strong> <strong>by</strong> selenium and vitamin E <strong>deficiencies</strong> can be<br />
achieved <strong>by</strong> different methods, including:<br />
•Dietary supplementation in the feed or water supplies<br />
•Individual parenteral injections<br />
•Oral administration<br />
•Pasture top-dressing.<br />
The method used will depend on the circumstances <strong>of</strong> the farm, ease <strong>of</strong> administration, cost, the<br />
labor available, severity <strong>of</strong> the deficiency that exists, and whether or not the animals are being<br />
dosed regularly for other diseases such as parasitism. The subcutaneous injection <strong>of</strong> barium<br />
selenate, the administration <strong>of</strong> an intraruminal pellet, and the addition <strong>of</strong> selenium to the water<br />
supply were compared in cattle; each method was effective for periods ranging from 4 to 12<br />
months.<br />
Dietary supplementation<br />
The inclusion <strong>of</strong> selenium and vitamin E in the feed supplies or salt and <strong>mineral</strong> mixes has been<br />
generally successful in preventing the major diseases <strong>caused</strong> <strong>by</strong> <strong>deficiencies</strong> <strong>of</strong> these two <strong>nutrients</strong>.<br />
Muscular dystrophy<br />
Under most conditions, NMD <strong>of</strong> calves and lambs can be prevented <strong>by</strong> providing selenium and<br />
vitamin E in the diets <strong>of</strong> the cow or ewe during pregnancy at 0.1 mg/kg DM <strong>of</strong> actual selenium,<br />
and (a-tocopherol at 1 g/d/cow and 75 mg/d/ewe. If possible, the supplementation should be<br />
continued during lactation to provide a continuous source <strong>of</strong> selenium to the calves and lambs.<br />
Under some conditions the level <strong>of</strong> 0.1 mg/kg DM may be inadequate. In some circumstances the<br />
optimal selenium concentration in the feed is considerably higher than 0.1 mg/kg DM, and levels<br />
up to 1.0 mg/kg DM in the feed result in increases in GSH-PX activity which may be beneficial;<br />
however, the cost-effectiveness has not been determined. Pregnant ewes being fed on alfalfa hay<br />
may require selenium at a level <strong>of</strong> up to 0.2 mg/kg DM to prevent white muscle disease in their<br />
lambs. Young growing cattle, particularly beef cattle likely to receive hay and straw deficient in<br />
selenium and those which are fed high-moisture grain, should receive a supplement <strong>of</strong> selenium at<br />
the rate <strong>of</strong> 0.1 mg/kg DM and a-tocophero] at 150 mg/d/head. If selenium-supplemented<br />
concentrates are used as part <strong>of</strong> a feeding program for dairy cows, it is not necessary to provide<br />
additional selenium <strong>by</strong> parenteral injection.<br />
Lambs are born with a low serum level <strong>of</strong> vitamin E but the concentration increases rapidly<br />
after the ingestion <strong>of</strong> colostrum (77). Supplementation <strong>of</strong> pregnant ewes with a-tocopherol, either<br />
as a single IM dose (500 mg 2 weeks before lambing) or orally (150 mg daily during 3-4 weeks<br />
before lambing) results in a<br />
1530
marked increase in the levels <strong>of</strong> the vitamin in the serum and colostrum. The vitamin E<br />
concentration in colostrum was 5-11 times higher than in milk 1 week after lambing.<br />
Vitamin E supplementation <strong>of</strong> the feed <strong>of</strong> weaner sheep <strong>by</strong> oral drench or feed additive is<br />
effective in increasing plasma α-tocopherol concentrations. This is the most practical method for<br />
housed sheep and prevents subclinica] myopathy (78). The IM oily injection was slow to increase<br />
plasma levels <strong>of</strong> tocopherols and did not prevent myopathy in grazing experiments. Vitamin E<br />
supplements have no beneficial effects on wool quality or quantity in grazing sheep, and unless<br />
certain flocks are susceptible to vitamin E deficiency myopathy it is not recommended.<br />
Salt-<strong>mineral</strong> mixture<br />
NMD can be prevented in unweaned beef calves and lambs <strong>by</strong> the inclusion <strong>of</strong> selenium (14.8<br />
mg/kg) and vitamin E (2700 IU/kg) in the <strong>mineral</strong> supplement provided ad libitum to the pregnant<br />
cows and ewes on a selenium-deficient ration during the latter two-thirds <strong>of</strong> gestation and for the<br />
first month <strong>of</strong> lactation. Under most conditions this will provide selenium at 0.1 mg/kg DM in the<br />
diet.<br />
The provision <strong>of</strong> sodium selenite in a salt-<strong>mineral</strong> mixture to provide 90 mg <strong>of</strong> selenium/kg<br />
salt-<strong>mineral</strong> mixture on a year-round basis, even under range conditions, increased GSH-PX<br />
activity levels into normal ranges in beef cows for 3 months when fed to extremely deficient<br />
animals. Calves <strong>of</strong> these cows had increased weaning weights and decreased incidence <strong>of</strong><br />
infectious diseases, but the trial was uncontrolled. The provision <strong>of</strong> 30 mg selenium/kg<br />
salt-<strong>mineral</strong> mixture was insufficient to raise the GSH-PX activity levels to normal ranges. Peak<br />
blood selenium levels were achieved in wearied beef calves supplemented with 80 and 160 mg<br />
selenium/kg in free-choice salt-<strong>mineral</strong> mixtures for a period <strong>of</strong> 108 days. In some jurisdictions, it<br />
may be necessary for the veterinarian to prescribe a supplement containing higher levels than<br />
those permitted <strong>by</strong> legislation. A level <strong>of</strong> 25 mg/kg selenium <strong>of</strong> a salt-<strong>mineral</strong> mixture provided ad<br />
libitum for sheep will result in sufficient levels <strong>of</strong> selenium in the dam's blood and milk to prevent<br />
selenium deficiency diseases. Each ewe must consume from 8 to 12 g <strong>of</strong> the salt-<strong>mineral</strong> mixture<br />
per day.<br />
Daily cattle<br />
The legal commercial selenium supplementation <strong>of</strong> complete rations for dairy cattle in the United<br />
States has recently been increased from 0.1 to 0.3 mg/kg DM <strong>of</strong> complete feed (79). At this rate, a<br />
lactating cow consuming 20 kg <strong>of</strong> DM/d would consume about 6 mg supplemental selenium in<br />
addition to that naturally present in the feedstuffs. Current recommendations indicate that<br />
selenium intake for lactating and gestating dairy cattle should range from 5 to 7 mg/d for adequate<br />
concentrations in serum or plasma which would range from 70 to 100 ng <strong>of</strong> selenium/ml., serum<br />
(80). Such supplementation should result in improved selenium status <strong>of</strong> the newborn, improved<br />
concentration <strong>of</strong> selenium in colostrum, and improved health <strong>of</strong> the calves. The effects <strong>of</strong><br />
selenium supplementation in dairy cattle on reproductive performance is equivocal. Some studies<br />
over a period <strong>of</strong> two lactations revealed no effect on reproductive performance (79), while others<br />
report an improvement in dairy cattle in a district considered to be marginally deficient in<br />
selenium. Intakes <strong>of</strong> inorganic selenium as sodium selenite in amounts <strong>of</strong> 50 mg/d for 90 days or<br />
100 mg/d for 28 days <strong>by</strong> adult dairy cows (10-30 times the nutritional requirement) did not cause<br />
any health problems (81). The toxic dose for cattle ranges from 0.25 to 0.5 mg/kg BW.<br />
Milk replacers for dairy calves should contain a suitable antioxidant and be supplemented with<br />
300 IU/kg DM <strong>of</strong> a-tocopherol acetate at the rate <strong>of</strong> 0.1 mg/kg DM <strong>of</strong> the milk replacer.
Swine<br />
In growing swine, both selenium and vitamin E at 30 IU/kg DM <strong>of</strong> feed are necessary for the<br />
prevention <strong>of</strong> the diseases <strong>caused</strong> <strong>by</strong> diets deficient in vitamin E and selenium. Supplementation<br />
<strong>of</strong> the diet <strong>of</strong> the sow will result in an adequate transfer to the piglets. Satisfactory protection <strong>of</strong><br />
the diseases <strong>of</strong> swine <strong>caused</strong> <strong>by</strong> vitamin E selenium deficiency depends on the correct balance<br />
between selenium, α-tocopherol, PUFAs in the diet, and the presence <strong>of</strong> a suitable antioxidant to<br />
conserve the a-tocopherol.<br />
Selenium dose<br />
The generally recommended dose <strong>of</strong> selenium is 0.1 mg/kg BW SC. The GSH-PX activity will<br />
increase to peak levels at about 30 days following the administration <strong>of</strong> the selenium. The SC<br />
administration <strong>of</strong> selenium at 0.10 or 0.15 mg/kg BW, as sodium selenate, will increase and<br />
maintain the blood selenium and GSH-PX activity in dairy cattle for up to 6 months following<br />
injection. A single SC or oral dose <strong>of</strong> 5 mg <strong>of</strong> selenium at strategic intervals to prevent or treat<br />
selenium deficiency in weaned lambs will increase the selenium residues in the meat, but not at<br />
levels considered hazardous to the public.<br />
Individual injections<br />
Injections <strong>of</strong> selenium and vitamin E have been used successfully for prevention, particularly in<br />
circumstances where the diet cannot be easily supplemented. Following IM injections <strong>of</strong> sodium<br />
selenite into calves, lambs and piglets, the selenium concentration <strong>of</strong> the tissues, particularly the<br />
liver, increases and then declines to reach preinjection levels in 23 days in calves, and 14 days in<br />
lambs and piglets. Adequate sources <strong>of</strong> vitamin E also must be provided. Injectable preparations<br />
<strong>of</strong> selenium and vitamin E are usually adequate in selenium and deficient in vitamin E and it may<br />
not be possible to correct a marginal deficiency <strong>of</strong> vitamin E in pregnant beef cattle, for example,<br />
<strong>by</strong> IM injection <strong>of</strong> a selenium and vitamin E preparation which contains an inadequate<br />
concentration <strong>of</strong> vitamin E (82). The current label dose <strong>of</strong> injectable selenium, 0.055 mg<br />
selenium/kg BW, which is therapeutically adequate for NMD, is not sufficient for long-term<br />
selenium supplementation <strong>of</strong> cattle on a selenium-deficient diet (83). Copper and selenium<br />
supplementation <strong>by</strong> parenteral administration can be combined when both <strong>deficiencies</strong> are present<br />
(84).<br />
Subcutaneous injection<br />
A slow-release preparation <strong>of</strong> barium selenate for SC injection is now available for use in cattle<br />
and sheep (69). A SC injection <strong>of</strong> 1 mg selenium/kg BW to ewes 3 weeks before breeding<br />
elevated the selenium level in milk during lactation, and increased the selenium concentration and<br />
GSH-PX in the blood <strong>of</strong> the lambs during the period when they are at<br />
1531<br />
greatest risk from selenium-deficiency diseases (85). At a dose <strong>of</strong> 1 mg selenium/kg BW to<br />
pregnant ewes, the GSH-PX activity is increased and maintained at adequate levels for up to 5<br />
months. There is adequate transfer <strong>of</strong> selenium to the lambs, providing protetion for up to 12<br />
weeks <strong>of</strong> age, which covers the period when lambs are at greatest risk. A dose <strong>of</strong> 1.2 mg<br />
selenium/kg BW provided adequate selenium status for as long as two consecutive lambing<br />
seasons. Barium selenate at 1 mg selenium/kg BW SC provides protection in young sheep for at<br />
least 3 months and is not associated with risk <strong>of</strong> selenium toxicity or unacceptable residues <strong>of</strong><br />
selenium in tissues other than the site <strong>of</strong> injection (69). A dose <strong>of</strong> 1 mg selenium/kg BW (barium<br />
selenate) to cattle SC increased the GSH-PX activity within 4 weeks and was maintained at high
levels for up to 5 months.<br />
The SC injection <strong>of</strong> barium selenate <strong>of</strong> pregnant sows at 0.5-1.0 mg selenium/kg BW resulted in<br />
a significant difference in GSH-PX activity in the piglets from treated sows compared to untreated<br />
controls. The SC injection <strong>of</strong> barium selenate .it 2.5 mg selenium/kg BW into pigs weighing 20 kg<br />
also maintained blood levels <strong>of</strong> selenium and GSH-PX activity during the most rapid growing<br />
period. The relative safety <strong>of</strong> barium selenate is due to its slow rate <strong>of</strong> release from the site <strong>of</strong><br />
injection. By comparison, when selenium is administered as a soluble salt, such as sodium<br />
selenate, acute toxicity may occur at doses <strong>of</strong> 0.45 mg selenium/kg BW. Treatment with barium<br />
selenate increases the concentration <strong>of</strong> selenium in blood, liver and muscle, and persists for at<br />
least 4 months. One disadvantage <strong>of</strong> barium selenate is that a large residue persists at the site <strong>of</strong><br />
injection for long periods. The use <strong>of</strong> sodium selenate also increases tissue and blood<br />
concentrations <strong>of</strong> selenium, but they begin to decline <strong>by</strong> 23 days. The bovine liver rapidly<br />
removes approximately 40% <strong>of</strong> injected selenium salts (soluble) from the systemic plasma, binds<br />
it to a plasma component, and within 1 hour <strong>of</strong> injection releases it back into circulation.<br />
NMD in the neonate<br />
If the risk <strong>of</strong> NMD is high in the first few weeks <strong>of</strong> life for any <strong>of</strong> the species, selenium can be<br />
given to the dam; if it is later, at say 2-3 months <strong>of</strong> age, it is administered to the lamb or calf. The<br />
recommended dose rates <strong>of</strong> repeated injections at monthly intervals are: 1 mg <strong>of</strong> selenium to<br />
lambs, 5 mg to ewes, 10 mg to calves, and 30 mg to adult cattle. The injections are administered<br />
about 1 month before the anticipated danger period. In calves on a selenium-deficient pasture a<br />
dose <strong>of</strong> 0.1 selenium mg/kg BW every 2 months or 0.2 selenium mg/kg BW every 4 months may<br />
be necessary. Comparable dose rates <strong>of</strong> the various compounds in use are: 1 mg selenium is<br />
equivalent to 2.2 mg anhydrous sodium selenate, 2.4 mg anhydrous sodium selenate, or 4.7 mg<br />
hydrated sodium selenate. These doses may be repeated without danger at monthly intervals. A<br />
mixture <strong>of</strong> selenium and vitamin E can also be used as a preventive at half the dose recommended<br />
under the heading <strong>of</strong> treatment above. It can be administered to the young or to the dam and<br />
repeated at 2-4 week intervals.<br />
The prevention <strong>of</strong> NMD and lupinosis-associated myopathy in weaner sheep at 6-12 months <strong>of</strong><br />
age in Western Australia can be achieved <strong>by</strong> the SC injection <strong>of</strong> selenomethionine (0.1 mg<br />
selenium/kg BW) and α-tocopherol acetate (2000 iU per sheep) (13). The SC treatment was highly<br />
effective in preventing lupinosis-associated myopathy, and also produced the highest vitamin E<br />
concentrations in plasma and liver. The supplemental vitamin E was more efficacious than<br />
supplemental selenium. <strong>An</strong> oral dose <strong>of</strong> vitamin E was the least effective method <strong>of</strong> increasing<br />
concentrations in liver.<br />
Weak-calf syndrome<br />
The parenteral injection <strong>of</strong> selenium and iodine to pregnant cattle in Ireland did not significantly<br />
reduce the incidence <strong>of</strong> the weak-calf syndrome, which is <strong>of</strong>ten attributed to a selenium deficiency<br />
(16).<br />
Swine<br />
The injection <strong>of</strong> selenium 0.06 mg/kg BW into piglets under 1 week <strong>of</strong> age, repeated at weaning<br />
time and into the sow 3 weeks before farrowing will be effective. The minimum lethal dose <strong>of</strong><br />
selenium for piglets is 0.9 mg/kg BW, which provides a reasonably wide range <strong>of</strong> safety. A high<br />
concentration <strong>of</strong> selenium in the diet <strong>of</strong> pregnant sows in the last half <strong>of</strong> gestation has been<br />
associated with hemorrhagic lesions on the claws <strong>of</strong> newborn piglets (86).
Horses<br />
Little information is available on the need <strong>of</strong> horses for selenium but the optimum intake is 6<br />
mg/week or 2.4ug/kg BW daily. The oral supplementation <strong>of</strong> 1 mg selenium/d increases blood<br />
selenium concentrations above levels associated with myodegeneration in horses and foals. To<br />
insure nutritional adequacy, and to have an adequate safety margin, adult Standardbred horses<br />
should receive 600-1800 mg DL-a-tocopherol daily in their feed. The parenteral administration <strong>of</strong><br />
vitamin E and selenium to mares in late pregnancy, and to their foals beginning at birth, will<br />
increase blood selenium to adequate levels. In selenium-deficient areas or when mares are fed<br />
selenium-deficient hay, the prepartum injections <strong>of</strong> selenium and vitamin E are indicated followed<br />
<strong>by</strong> intermittent injection <strong>of</strong> the foals, or supplementation <strong>of</strong> the diet with selenium at 0.1 mg/kg<br />
DM.<br />
Intra-ruminal selenium pellets<br />
Sheep<br />
Intra-ruminal selenium pellets, similar to those used in cobalt deficiency, have produced<br />
satisfactory blood levels <strong>of</strong> selenium for up to 4 years in ewes at pasture (69). A satisfactory pellet<br />
is composed <strong>of</strong> 0.5 g elemental selenium and finely divided metallic iron. The technique is<br />
efficient, but not completely, due to wide variations between animals in the absorption rate <strong>of</strong> the<br />
selenium. The average delivery <strong>of</strong> selenium is 1 mg/d and there is no danger <strong>of</strong> toxicity. In sheep<br />
grazing selenium-deficient pastures, the ruminal pellets increase the selenium status and weight<br />
gains compared to controls. About 15% <strong>of</strong> treated sheep reject the pellets within 12 months and in<br />
varying degrees the pellets acquire deposits <strong>of</strong> calcium phosphate. Sheep fed pellets recovered<br />
from sheep have low selenium levels, which suggests a low release <strong>of</strong> selenium from pellets that<br />
have been in the rumen <strong>of</strong> other sheep for several months. The peak levels <strong>of</strong> selenium occur 3<br />
months after administration; there is a rapid decline in activity between 5 and 13 months.<br />
Sustained-released boluses containing sodium selenate, cobalt sulfate, potassium iodide,<br />
manganese sulfate, zinc oxide and sulfate, and vitamins A, D and<br />
1532<br />
E have also been formulated to provide long-term maintenance <strong>of</strong> selenium (87).<br />
Cattle<br />
A selenium pellet containing 10% selenium and 90% iron grit is available for cattle and will<br />
maintain plasma selenium and GSH-PX activity above the critical level for up to 2 years (88).<br />
When given to beef cows in the last 3 months <strong>of</strong> pregnancy, the selenium levels in milk are higher<br />
than in controls, and the selenium status <strong>of</strong> the calves was sufficient to prevent NMD. The use <strong>of</strong><br />
these pellets at two, three and four times the recommended dose in growing cattle weighing<br />
300-350 kg did not cause toxicosis, and the selenium levels in the tissues at slaughter were not a<br />
risk for humans (89).<br />
Use <strong>of</strong> the intra-ruminal selenium pellets in dairy cattle in New Zealand resulted in improved<br />
growth and milk production in herds where the selenium status was below the adequate range, but<br />
there was no effect on udder health and reproductive performance (29).<br />
A sustained-release intra-reticular bolus is an osmotic pump designed to release 3 mg selenium<br />
into the reticulorumen (88). It is intended to provide selenium supplementation for 120 days in<br />
grown heifers and pregnant beef cattle.<br />
Oral selenium and anthelmintics<br />
Oral dosing using sodium selenate is sometimes combined with the administration <strong>of</strong>
anthelmintics and vaccinations. The dose should approximate 0.044 mg/kg BW. A routine<br />
program in a severely deficient area comprises three doses <strong>of</strong> 5 mg <strong>of</strong> selenium (11 mg sodium<br />
selenate) each to ewes, one before mating, one at mid-pregnancy, and one 3 weeks before lambing,<br />
and four doses to the lambs. The first dose to lambs (<strong>of</strong> 1 mg) is given at docking and the others (2<br />
mg each) at weaning and then at 3-month intervals. A 100-day controlled release anthelmintic<br />
capsule containing 13.9 mg <strong>of</strong> selenium will protect lambs from selenium deficiency for at least<br />
180 days (90).<br />
Both selenium and cobalt can be incorporated into an anthelmintic program. The levels <strong>of</strong><br />
GSH-PX activity may be monitored on a regular basis following the drenching with selenium and<br />
provide a good indication <strong>of</strong> selenium availability and selenium status <strong>of</strong> grazing sheep.<br />
Selenium toxicity and residues<br />
Selenium intoxication can occur follow ng the administration <strong>of</strong> toxic amounts <strong>of</strong> a selenium salt.<br />
The use <strong>of</strong> selenium selenate instead <strong>of</strong> sodium selenate and giving a dose <strong>of</strong> five times the<br />
intended dose resulted in a high mortality within several hours after administration (91). <strong>An</strong>imals<br />
deficient in selenium are more susceptible to selenium toxicosis than those that are<br />
selenium-adequate. The pharmacokineaics <strong>of</strong> selenium toxicity in sheep given selenium selenate<br />
parenterally has been examined. When oral preparations <strong>of</strong> selenium and monensin are given<br />
concurrently as part <strong>of</strong> a routine dietary management practice, there is greater risk <strong>of</strong> selenium<br />
intoxication than if the selenium is given alone (92). Administration <strong>of</strong> monensin sodium at a<br />
constant, safe dosage enhanced the toxicity <strong>of</strong> selenium as demonstrated <strong>by</strong> increased severity <strong>of</strong><br />
the signs <strong>of</strong> intoxication, fatalities, tissue selenium concentrations and intensified gross,<br />
histopathological, and biochemical changes (93). There is some concern about selenium<br />
supplementation <strong>of</strong> beef cattle being a potential source <strong>of</strong> contamination for near<strong>by</strong> aquatic<br />
systems, but there is no evidence that this has occurred (94).<br />
Pasture top-dressing<br />
The application <strong>of</strong> sodium selenate as a top-dressing to pasture is now practiced and permitted in<br />
some countries (95). Top-dressing at the approved rate <strong>of</strong> 10 g selenium/hectare is effective for 12<br />
months and has a toxicity margin <strong>of</strong> safety <strong>of</strong> about 20 times. Sodium selenate is now used in<br />
preference to sodium selenate because only about one-fifth is required to raise the pasture level <strong>of</strong><br />
selenium to the same concentrations provided <strong>by</strong> sodium selenate. Top-dressing severely deficient<br />
pumice soils in New Zealand prevented deficiency for at least 12 months, sheep were protected<br />
against white muscle in lambs, and reproduction performance and weight gains were improved. It<br />
is recommended that sodium selenate be applied annually to all selenium-deficient soils at the rate<br />
<strong>of</strong> 10 g selenium/hectare added to the superphosphate fertilizer, or as prills <strong>of</strong> sodium selenate<br />
alone. Top-dressing is an economical alternative to individual animal dosing, particularly in<br />
severely deficient areas with a high stocking rate. At the approved rate no adverse effects are<br />
anticipated in human or animal health or on the environment.<br />
REVIEW LITERATURE<br />
Gerl<strong>of</strong>f, B.J. (1992) Effect <strong>of</strong> selenium<br />
supplementation on dairy cattle. J. <strong>An</strong>im. Sci., 70, 3934-3940.<br />
Macphereon, A. (1994) Selenium, vitamin E and biological oxidation. In: Recent Advances in<br />
<strong>An</strong>imal Nutrition. Eds. Garnsworthy, P. C. & Cole, D.J. A. Nottingham: Nottingham Press,<br />
pp.3-30.
REFERENCES<br />
(1)Roller, L. D. & Exon.J. H. (1986) Can. j. Vet. Res., 50, 297.<br />
(2)National Academy <strong>of</strong> Science (1983) Selenium in Nutrition. Washington, DC: National<br />
Research Council.<br />
(3)Rammcll, C. G. et al. (1989) NZ Vei.J., 37, 4.<br />
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DIETARY DEFICIENCY OF PHOSPHORUS. CALCIUM AND VITAMIN D AND<br />
IMBALANCE OF THE CALCIUM:PHOSPHORUS RATIO<br />
A dietary deficiency or disturbancein the metabolism <strong>of</strong> calcium, phosphorus or vitamin D,<br />
including imbalance <strong>of</strong> the calcium:phosphorus ratio, is the principal cause <strong>of</strong> the<br />
osteodystrophies. The interrelation <strong>of</strong> these various factors is <strong>of</strong>ten very difficult to define and<br />
because the end result in all these <strong>deficiencies</strong> is so similar the precise etiologicasl agent is <strong>of</strong>ten<br />
difficult determine in any given circumstance.<br />
In an attempt to simplify this situation the diseases in this section have been dealt with in the<br />
following order:<br />
•Calcium deficiency (hypocalcicosis)<br />
•Primary-an absolute deficiency in the diet<br />
•Secondary-when the deficiency is conditioned <strong>by</strong> some other factor, principally an excess intake<br />
<strong>of</strong> phosphorus<br />
•Phosphorus deficiency (hypophosphatosis)<br />
•Primary-an absolute deficiency in the diet<br />
•Secondary-when the deficiency is conditioned <strong>by</strong> some other factor; although in general terms an<br />
excessive intake <strong>of</strong> calcium could be such a factor, specific instances <strong>of</strong> this situation are lacking<br />
•Vitamin D deficiency(hypovitaminosis-D)<br />
•Primary-an absolute deficiency intake <strong>of</strong> the vitamin<br />
•Secondary-when the deficiency is conditioned <strong>by</strong> other factors <strong>of</strong> which excess carotene intake is<br />
the best known.<br />
In different countries with varying climates, soil types, and methods <strong>of</strong> husbandly, these<br />
individual <strong>deficiencies</strong> are <strong>of</strong> varying importance. For instance in South Africa, northern Australia,<br />
and North America the most common <strong>of</strong> the above <strong>deficiencies</strong> is that <strong>of</strong> phosphorus; vitamin D<br />
deficiency is uncommon. In Great Britain, Europe, and parts <strong>of</strong> North America, a deficiency <strong>of</strong><br />
vitamin D can also be <strong>of</strong> major importance. <strong>An</strong>imals are housed indoors for much <strong>of</strong> the year, they<br />
are exposed to little ultraviolet irradiation, and their forage may contain little vitamin D. Under<br />
such conditions the absolute and relative amounts <strong>of</strong> calcium and phosphorus in the diet need to be<br />
greater than in other areas if vitamin D deficiency is to be avoided. In New Zealand, where much<br />
lush pasture and cereal grazing is used for feed,the vitamin D status is<br />
1534
educed not only <strong>by</strong> poor solar irradiation <strong>of</strong> the animal and plant sterols, but in addition an<br />
anti-vitamin D factor is present in the diet possibly in the form <strong>of</strong> carotene.<br />
Now that the gross errors <strong>of</strong> managment with respect to calcium and phosphorus and vitamin D<br />
are largely avoided, more interest is devoted to the marginal errors; in these, diagnosis is not<br />
nearly so easy and the deficiency can be evident only at particular times <strong>of</strong> the year. The conduct<br />
<strong>of</strong> a response trial in which part <strong>of</strong> the herd is treated is difficult unless they are hand-fed daily;<br />
there are no suitable reticular retention pellets or long-term injections <strong>of</strong> calcium or phosphorus<br />
because the daily requirement is so high. Two methods suggest themselves:<br />
1.<strong>An</strong>alysis <strong>of</strong> ash content <strong>of</strong> samples <strong>of</strong> spongy bone from the tuber coxae<br />
2.The metabolic pr<strong>of</strong>ile method.<br />
The latter program may have some value as a monitoring and diagnostic weapon in the fields <strong>of</strong><br />
metabolic disease, nutritional deficiency, and nutritional excesses.<br />
ABSORPTION AND METABOLISM OF CALCIUM AND PHOSPHORUS<br />
In ruminants, dietary calcium is absorbed <strong>by</strong> the small intestine according to body needs. Whereas<br />
young animals with high growth requirements absorb and retain calcium in direct relation to<br />
intake over a wide range <strong>of</strong> intakes, adult male animals, irrespective <strong>of</strong> intake, absorb only enough<br />
calcium to replace that lost <strong>by</strong> excretion into urine and intestine, retaining none <strong>of</strong> it. Calcium<br />
absorption is increased in adult animals during periods <strong>of</strong> high demand, such as pregnancy and<br />
lactation, or after a period <strong>of</strong> calcium deficiency, but a substantial loss <strong>of</strong> body stores <strong>of</strong> calcium<br />
appears to be necessary before this increase occurs. The dietary factors influencing the efficiency<br />
<strong>of</strong> absorption <strong>of</strong> calcium include the nature <strong>of</strong> the diet, the absolute and relative amounts <strong>of</strong><br />
calcium and phosphorus present in the diet and the presence <strong>of</strong> interfering substances. Calcium <strong>of</strong><br />
milk is virtually all available for absorption, but calcium <strong>of</strong> forage-containing diets has an<br />
availability <strong>of</strong> only about 50%. The addition <strong>of</strong> grain to an all-forage diet markedly improves the<br />
availability <strong>of</strong> the calcium.<br />
Phosphorus is absorbed <strong>by</strong> young animals from both milk and forage-containing diets with a<br />
high availability (80-100%), but the availability is much lower (50-60%) in adult animals. Horses<br />
fed diets containing adequate amounts <strong>of</strong> calcium and phosphorus absorb 50-65% <strong>of</strong> the calcium,<br />
and slightly less than 50% <strong>of</strong> the phosphorus present in a variety <strong>of</strong> feedstuffs. In grains, 50-65%<br />
<strong>of</strong> the phosphorus is in the phytate form which is utilizable <strong>by</strong> ruminants, but not as efficiently <strong>by</strong><br />
non-ruminants like the horse and pig. <strong>An</strong> average availability <strong>of</strong> 70% has been assumed for<br />
phosphorus in early weaning diets for young pigs, and a value <strong>of</strong> 50% in practical cereal-based<br />
feeds as supplied to growing pigs, sows, and boars.<br />
The metabolism <strong>of</strong> calcium and phosphorus is influenced <strong>by</strong> the parathyroid hormone calcitonin<br />
and vitamin D. Parathyroid hormone is secreted in response to hypocalcemia and stimulates the<br />
conversion <strong>of</strong> 25-dihydroxycholecalciferol to 1,25-dihydroxycholecalciferol (1,25-DHCC).<br />
Parathyroid hormone and 1,25-DHCC together stimulate bone resorption, and 1,25-DHCC alone<br />
stimulates intestinal absorption <strong>of</strong> calcium. Calcium enters the blood from bone and intestine, and<br />
when the serum calcium level increases above normal, parathyroid hormone is inhibited and<br />
calcitonin secretion stimulated. The increased calcitonin concentration blocks bone resorption and<br />
the decreased parathroid hormone concentration depresses calcium absorption.<br />
CALCIUM DEFICIENCY<br />
Calcium deficiency may be primary or secondary, but in both cases the end result is an<br />
osteodystrophy, the specific disease depending largely on the species and age <strong>of</strong> the animals
affected.<br />
Synopsis<br />
Etiology. Primary dietary deficiency <strong>of</strong> calcium uncommon. Secondary calcium deficiency due to<br />
marginal calcium intake and high phosphorus intake.<br />
Epidemiology. Sporadic. Not common if diets adequate.<br />
Signs. Poor growth and dentition. Tetany may occur in lactating ewes. Inappetence, stiffness,<br />
fracture <strong>of</strong> long bones. Specific diseases include: rickets, osteomalacia, and osteodystrophia<br />
fibrosa.<br />
Clinical pathology. Serum calcium and phosphorus. Radiography.<br />
Lesions. Osteoporosis; low ash content <strong>of</strong> bone.<br />
Diagnostic confirmation. Histology <strong>of</strong> bone and bone ash analyses.<br />
Differential diagnosis list. See differential diagnosis <strong>of</strong> each specific disease.<br />
Treatment. Calcium salts parenterally and orally.<br />
Control. Adequate calcium and phosphorus levels in diet.<br />
ETIOLOGY<br />
A primary deficiency due to a lack <strong>of</strong> calcium in the diet is uncommon, although a secondary<br />
deficiency due to a marginal calcium intake aggravated <strong>by</strong> a high phosphorus intake is not<br />
uncommon. In ponies, such a diet depresses intestinal absorption and retention <strong>of</strong> calcium in the<br />
body, and the resorption <strong>of</strong> calcium from bones is increased. The effects <strong>of</strong> reduced calcium intake<br />
and parathyroidectomy are understandably additive in pigs, but parathyroid insufficiency seems an<br />
unlikely natural phenomenon.<br />
EPIDEMIOLOGY<br />
Calcium deficiency is a sporadic disease occurring in particular groups <strong>of</strong> animals rather than in<br />
geographically limited areas. Although death does not usually occur there may be considerable<br />
loss <strong>of</strong> function and disabling lesions <strong>of</strong> bones or joints.<br />
Horses in training, cattle being fitted for shows, and valuable stud sheep are <strong>of</strong>ten fed artificial<br />
diets containing cereal or grass hays which contain little calcium, and grains which have a high<br />
content <strong>of</strong> phosphorus. The secondary calcium deficiency that occurs in these circumstances is<br />
<strong>of</strong>ten accompanied <strong>by</strong> a vitamin D deficiency because <strong>of</strong> the tendency to keep animals confined<br />
indoors. Pigs are <strong>of</strong>ten fed heavy concentrate rations with insufficient calcium supplement. Dairy<br />
cattle may occasionally be fed similarly unbalanced diets, the effects <strong>of</strong> which are exaggerated <strong>by</strong><br />
high milk production.<br />
There are no well-established records <strong>of</strong> calcium deficiency in grazing sheep or cattle, but there<br />
are records <strong>of</strong> low calcium intake in feedlots accompanied <strong>by</strong> clinical osteodystrophy. There is<br />
also a well-recognized field occurrence <strong>of</strong> calcium deficiency in young sheep in southeast<br />
Australia. Outbreaks can affect many sheep and are usually seen in winter and spring, following<br />
exercise or temporary starvation. In most outbreaks the charac-<br />
1535<br />
teristic osteoporosis results from a long-term deprivation <strong>of</strong> food due to poor pasture growth.<br />
Occasional outbreaks occur on green oats used for grazing. The calcium intake in some cases is as<br />
low as 3-5 g /week in contrast to the requirement <strong>of</strong> 3-5 g/day.<br />
High protein intake and rapid growth have been suggested as contributory factors in the<br />
development <strong>of</strong> skeletal problems in young horses. However, a concentration <strong>of</strong> dietary protein <strong>of</strong><br />
20%, which is significantly above the NRC recommended level <strong>of</strong> 14% , is neither helpful nor
harmful to growing horses. The high protein intake did not affect the rate <strong>of</strong> growth, height, and<br />
circumference <strong>of</strong> cannon bones compared with horses receiving the lower 14% diet. The high<br />
protein diet did not result in hypercalciuria and did not affect calcium absorption or calcium<br />
retention.<br />
In females there is likely to be a cycle <strong>of</strong> changes in calcium balance, a negative balance<br />
occurring in late pregnancy and early lactation, and a positive balance in late lactation and early<br />
pregnancy and when lactation has ceased. The negative balance in late pregnancy is in spite <strong>of</strong> a<br />
naturally occurring increased absorption <strong>of</strong> calcium from the intestine at that time, at least in ewes.<br />
PATHOGENESIS<br />
The main physiological functions <strong>of</strong> calcium are the formation <strong>of</strong> bone and milk, participation in<br />
the clotting <strong>of</strong> blood, and the maintenance <strong>of</strong> neuromuscular excitability. In the development <strong>of</strong><br />
osteodystrophies, dental defects, and tetany the role <strong>of</strong> calcium is well understood but the relation<br />
between deficiency <strong>of</strong> the element and lack <strong>of</strong> appetite, poor growth, loss <strong>of</strong> condition, infertility,<br />
and reduced milk flow is not readily apparent. The disinclination <strong>of</strong> the animals to move about and<br />
graze, and poor dental development may contribute to these effects.<br />
Experimentally, feeding young lambs a diet low in calcium and phosphorus for 12 weeks results<br />
in s<strong>of</strong>t and pliable ribs with thickening <strong>of</strong> the costochondral junctions, reduction in feed intake <strong>by</strong><br />
about 34%, significant changes in plasma calcium and phosphorus concentrations, and changes in<br />
dry matter digestibility (1). Feeding repletion diets results in complete re<strong>mineral</strong>ization <strong>of</strong> rib<br />
bones, but only partial re<strong>mineral</strong>ization <strong>of</strong> the metatarsal bones.<br />
Nutritional factors other than calcium, phosphorus, and vitamin D may be<br />
important in the production <strong>of</strong> ostcodystrophies, which also occur in copper deficiency, fluorosis,<br />
and chronic lead poisoning. Vitamin A is also essential for the development <strong>of</strong> bones, particularly<br />
those <strong>of</strong> the cranium.<br />
CLINICAL FINDINGS<br />
The clinical findings, apart from the specific syndromes described later, are less marked in adults<br />
than in young animals, in which there is decreased rate or cessation <strong>of</strong> growth and dental<br />
maldevelopment. The latter is characterized <strong>by</strong> deformity <strong>of</strong> the gums, poor development <strong>of</strong> the<br />
incisors, failure <strong>of</strong> permanent teeth to erupt for periods <strong>of</strong> up to 27 months, and abnormal wear <strong>of</strong><br />
the permanent teeth due to defective development <strong>of</strong> dentine and enamel, occurring principally in<br />
sheep.<br />
A calcium deficiency may occur in lactating ewes and sucking lambs whose metabolic<br />
requirements for calcium are higher than in dry and pregnant sheep. There is a pr<strong>of</strong>ound fall in<br />
serum calcium. Tetany and hyperirritability do not usually accompany hypocalcemia in these<br />
circumstances, probably because it develops slowly. However, exercise and fasting <strong>of</strong>ten<br />
precipitate tetanic seizures and parturient paresis in such sheep. This is typical <strong>of</strong> the disease as it<br />
occurs in young sheep in southeast Australia. Attention is drawn to the presence <strong>of</strong> the disease <strong>by</strong><br />
the occurrence <strong>of</strong> tetany, convulsions, and paresis but the important signs are ill-thrift and failure<br />
to respond to anthelmintics. Serum calcium levels will be as low as 5.6 mg/dL (1.4mmol/L). There<br />
is lameness, but fractures are not common even though the bones are s<strong>of</strong>t. A simple method for<br />
assessing this s<strong>of</strong>tness is compression <strong>of</strong> the frontal bones <strong>of</strong> the skull with the thumbs. In affected<br />
sheep the bones can be felt to fluctuate.<br />
Pigs fed on heavy concentrate rations may develop a hypocalcemic tetany, which responds to<br />
treatment with calcium salts. Tetany may also occur in young growing cattle in the same
circumstances.<br />
Inappetence, stiffness, tendency <strong>of</strong> bones to fracture, disinclination to stand, difficult parturition,<br />
reduced milk flow, loss <strong>of</strong> condition, and reduced fertility are all non-specific signs recorded in<br />
adults.<br />
SPECIFIC SYNDROMES<br />
Primary calcium deficiency<br />
No specific syndromes are recorded.<br />
Secondary calcium deficiency<br />
Rickets, osteomalacia, osteodystrophia fibrosa <strong>of</strong> the horse and pig, and degenerative arthropathy<br />
<strong>of</strong> cattle arc the common syndromes in which secondary calcium deficiency is one <strong>of</strong> the specific<br />
causative factors. In sheep, rickets is seldom recognized, but there are marked dental abnormalities.<br />
Rickets has been produced experimentally in lambs <strong>by</strong> feeding a diet low in calcium.<br />
CLINICAL PATHOLOGY<br />
Because <strong>of</strong> the effect <strong>of</strong> the other factors listed above on body constituents, examination <strong>of</strong><br />
specimens from living animals may give little indication <strong>of</strong> the primary cause <strong>of</strong> the disturbance.<br />
For example, hypocalcemia need not indicate a low dietary intake <strong>of</strong> calcium. Data on serum<br />
calcium and phosphorus, and plasma phosphatase levels, radiographical examination <strong>of</strong> bones, and<br />
balance studies <strong>of</strong> calcium and phosphorus retention are all <strong>of</strong> value in determining the presence<br />
<strong>of</strong> osteodystrophic disease, but determination <strong>of</strong> the initial causative factor will still depend on<br />
analysis <strong>of</strong> feedstuffs and comparison with known standard requirements. The levels <strong>of</strong> serum<br />
calcium may be within the normal range in most cases (2). However, in spite <strong>of</strong> evidence to the<br />
contrary it seems that calcium deficiency is followed, at least in sheep, <strong>by</strong> a marked fall in serum<br />
calcium levels to as low as 3.5 mg/dL (0.87 mmol/L). In an uncomplicated nutritional deficiency<br />
<strong>of</strong> calcium in sheep, there is only a slight reduction in the radiopacity <strong>of</strong> bone, in contrast to sheep<br />
with a low phosphorus and vitamin D status which show marked osteoporosis. The response to<br />
dietary supplementation with calcium is also <strong>of</strong> diagnostic value.<br />
NECROPSY FINDINGS<br />
True primary calcium deficiency is extremely rare but when it does occur, severe osteoporosis and<br />
parathyroid gland hypertrophy are the significant findings. The cortical bone is thinned and the<br />
metaphyseal trabeculae appear reduced in size and number. The ash content <strong>of</strong> the bone is low<br />
because the bone is resorbed before it is properly <strong>mineral</strong>ized.<br />
1536<br />
Calcium deficiency secondary to other nutritional factors is common and typically induces the<br />
form <strong>of</strong> osteodystrophy known as osteodystrophia fibrosa (sec subsequent description). In most<br />
instances, the confirmation <strong>of</strong> a diagnosis <strong>of</strong> hypocalcinosis at necropsy inclucies an analysis <strong>of</strong><br />
the diet for calcium, phosphorus, and vitamin D content.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
•Toxicologylong bone (ASSAY (ash)); feed (ASSAY (Ca) (P) (Vit D))<br />
•Histology formalin-fixed section <strong>of</strong> long bone (including metaphysis), parathyroid (LM).<br />
DIFFERENTIAL DIAGNOSIS<br />
A diagnosis <strong>of</strong> calcium deficiency depends upon pro<strong>of</strong> that the diet is, either absolutely or<br />
relatively, insufficient in calcium, that the lesions and signs observed are characteristic, and that<br />
the provision <strong>of</strong> calcium in the diet alleviates the condition. The diseases that may be confused<br />
with calcium deficiency are described under the diagnosis <strong>of</strong> each <strong>of</strong> the specific disease entities
described below.<br />
The close similarity between the dental defects in severe calcium deficiency <strong>of</strong> sheep and those<br />
occurring in chronic fluorosis may necessitate quantitative estimates <strong>of</strong> fluorine in the teeth or<br />
bone to determine the cause.<br />
TREATMENT<br />
The response to treatment is rapid, and the preparations and doses recommended below are<br />
effective as treatment. Parenteral injections <strong>of</strong> calcium salts arc-advisable when tetany is present.<br />
When animals have been exposed to dietary depletion <strong>of</strong> calcium and phosphorus over a period <strong>of</strong><br />
time, it is necessary to supplement the diet with calcium and phosphorus during dietary <strong>mineral</strong><br />
repletion (1).<br />
CONTROL<br />
The provision <strong>of</strong> adequate calcium in the diet, the reduction <strong>of</strong> phosphorus intake where it is<br />
excessive, and the provision <strong>of</strong> adequate vitamin D are the essentials <strong>of</strong> both treatment and<br />
prevention. Some examples <strong>of</strong> estimated minimum daily requirements for calcium, phosphorus<br />
and vitamin D are set out in Table 29.7. These are estimated minimum requirements and may need<br />
to be increased <strong>by</strong> a safety factor <strong>of</strong> 10% to allow for variation in individual animal requirements,<br />
the biological availability <strong>of</strong> <strong>nutrients</strong> in the feedstuffs, and the effect which total amount <strong>of</strong>. feed<br />
intake has on absolute intake <strong>of</strong> <strong>mineral</strong>s. For example, the use <strong>of</strong> a complete swine ration on a<br />
restricted basis may require that the concentration <strong>of</strong> both calcium and phosphorus be increased in<br />
order for that ration to deliver the actual total quantity <strong>of</strong> calcium and phosphorus necessary to<br />
meet a particular requirement for growth, pregnancy or lactation. The information in Table 29.7 is<br />
presented merely as a guideTable 29.7 Some examples <strong>of</strong> estimated daily requirements <strong>of</strong> calcium,<br />
phosphorus and vitamin D<br />
Species, kg body weight<br />
and function<br />
Calcium Phosphorus Vitamin D
DAIRY CATTLE<br />
Growing heifers (large breeds)<br />
159<br />
300<br />
400<br />
Growing heifers (small breeds)<br />
100<br />
200<br />
300<br />
Growing bulls (large breeds)<br />
300<br />
400<br />
500<br />
Maintenance <strong>of</strong> mature lactating cows<br />
400<br />
500<br />
600<br />
Maintenance and pregnancy<br />
400<br />
500<br />
600<br />
Milk production<br />
BEEF CATTLE<br />
Dry mature pregnant cows<br />
Cows nursing calves<br />
Bulls, growth and maintenance<br />
Growing heifers (200 kg live-weight<br />
gaining 0.8 kg/day)<br />
Growing steers (200 kg live-weight<br />
gaining 0.8 kg/day)<br />
SWINE<br />
Growing swine (10-100 kg live-weight)<br />
Breeding swine (gilts, sows, boars)<br />
SHEEP<br />
(g/animal)<br />
15<br />
24<br />
26<br />
9<br />
15<br />
19<br />
27<br />
30<br />
30<br />
17<br />
20<br />
22<br />
23<br />
29<br />
34<br />
Add 2-3 g<br />
calcium and<br />
1.7-2.4 g<br />
phosphortfs to the<br />
maintenance<br />
requirements for<br />
each kg <strong>of</strong> milk<br />
produced<br />
(% <strong>of</strong> ration)<br />
0.16<br />
0.30<br />
0.26<br />
0.33<br />
0.36<br />
0.65<br />
0.75<br />
300 iu/kg dry matter intake<br />
12<br />
18<br />
20<br />
7<br />
11<br />
14<br />
20<br />
23<br />
23<br />
13<br />
15<br />
17<br />
18<br />
22<br />
26<br />
300 iu/kg dry matter intake<br />
0.160<br />
0.25<br />
0.20<br />
0.26<br />
0.28<br />
0.50 200 iu/kg ration<br />
0.50 275 /kg ration
Ewes<br />
Maintenance<br />
Pregnant(early)<br />
Pregnant(late)<br />
Lactating<br />
Rams(40-120kg live-weight)<br />
Lambs<br />
Early weaned(10-30kg live-weight)<br />
Finishing(30-55kg live-weight)<br />
HORSES<br />
Mature horses (400-600 kg live-weight)<br />
Mares (400-600 kg live-weight)<br />
Last 90 days pregnancy<br />
Peak <strong>of</strong> lactation<br />
Growing horses (400kg mature weight)<br />
3 months old<br />
6 months old<br />
12 months old<br />
Growing horses (500kg mature weight)<br />
3 months old<br />
6 months old<br />
12 months old<br />
0.30<br />
0.27<br />
0.24<br />
0.52<br />
0.35<br />
0.40<br />
0.30<br />
0.30<br />
0.38<br />
0.50<br />
0.68<br />
0.68<br />
0.45<br />
0.69<br />
0.82<br />
0.43<br />
0.28 250-300 iu/kg dry<br />
matter intake<br />
0.25 200 iu/kg dry matter<br />
intake<br />
0.23 200 iu/kg dry matter<br />
intake<br />
0.37 150 iu/kg dry matter<br />
intake<br />
0.19<br />
0.27<br />
0.20<br />
0.20 6-8 iu/kg body weight<br />
0.30<br />
0.40<br />
0.43<br />
0.48<br />
0.30<br />
0.44<br />
0.51<br />
0.28<br />
1537<br />
line. When investigating a nutritional problem <strong>of</strong> formulating rations, it is recommended that the<br />
most recently available publications on the nutrient requirements <strong>of</strong> domestic animals be consulted.<br />
Ground limestone is most commonly used to supplement the calcium in the ration, but should<br />
be prepared from calcite and not from dolomite. Variations in availability <strong>of</strong> the calcium in this<br />
product occur with variations in particle size, a finely ground preparation being superior in this<br />
respect. Bone meal and dicalcium phosphate are more expensive and the additional phosphorus<br />
may be a disadvantage if the calcium: phosphorus ratio is very wide. Alfalfa, clover, and molasses<br />
are also good sources <strong>of</strong> calcium but vary in their content. The optimum calcium:phosphorus ratio<br />
is within the range <strong>of</strong> 2:1 to 1:1. In cattle, absorption <strong>of</strong> both elements is better at the 2:1 ratio. For<br />
optimum protection against the development <strong>of</strong> urolithiasis in sheep a ratio <strong>of</strong> 2 2.5 calcium to 1<br />
phosphorus is recommended.<br />
The dustiness <strong>of</strong> powdered limestone can be overcome <strong>by</strong> dampening the feed or adding the<br />
powder mixed in molasses. Addition to salt or a <strong>mineral</strong> mixture is subject to the usual<br />
disadvantage that not all animals partake <strong>of</strong> it readily when it is provided free-choice, but this<br />
method <strong>of</strong> supplementation is <strong>of</strong>ten necessary in pastured animals. High-producing dairy cows<br />
should receive the <strong>mineral</strong> mixture in their ration as well as having access to it in boxes or in<br />
blocks.
REFERENCES<br />
(1)Temouth J H & Scvilla, C. C. (1990) ,Aust J Agnic. Res., 41, 413.<br />
(2)Heaney, D. P. et al (1985) Can.J. <strong>An</strong>im. Sci., 65, 163.<br />
PHOSPHORUS DEFICIENCY<br />
Phosphorus deficiency is usually primary and is characterized <strong>by</strong> pica, poor growth, infertility and,<br />
in the later stages, osteo-dystrophy. Hypophosphatemia m dairy cattle is also associated with<br />
increased fragility <strong>of</strong> red blood cells and postparturient hemoglobinuria.<br />
Synopsis<br />
Etiology. Usually a primary deficiency in diet; may be conditioned <strong>by</strong> vitamin D deficiency.<br />
Epidemiology. Primary phosphorus deficiency occurs worldwide. Soils and crops commonly<br />
deficient in phosphorus.Primary deficiency may occur in lactating dairy cattle in early lactation.<br />
Occurs under range conditions in beef cattle and sheep.In swine not supplemented with sufficient<br />
phosphorus.<br />
Signs. Young animals grow slowly; develop rickets. Adults develop osteomalacia,unthriftiness,<br />
weight loss, reduced feed consumption, reluctance to move, leggy appearance, fractures, impaired<br />
fertility.Recumbency in high-producing cows on marginally phosphorus-deficient diet.<br />
Clinical pathology. Serum phosphorus.Phosphorus content <strong>of</strong> diet.<br />
Lesions. Rickets and osteomalacia; lack <strong>of</strong> <strong>mineral</strong>ization <strong>of</strong> bones.<br />
Diagnostic confirmation. Histology <strong>of</strong> bone lesions; bone ash analyses.<br />
Differential diagnosis. Those diseases resembling rickets and osteomalacia.<br />
Treatment. Phosphates parenterally and orally and vitamin D.<br />
Control. Supplement diets with adequate phosphorus, calcium and vitamin D.<br />
ETIOLOGY<br />
Phosphorus deficiency is usually primary under field conditions but may be exacerbated <strong>by</strong> a<br />
deficiency <strong>of</strong> vitamin D and possibly <strong>by</strong> an excess <strong>of</strong> calcium.<br />
EPIDEMIOLOGY<br />
Geographical occurrence<br />
In contrast to calcium deficiency, a dietary deficiency <strong>of</strong> phosphorus is widespread under natural<br />
conditions. It has a distinct geographical distribution depending largely upon the phosphorus<br />
content <strong>of</strong> the parent rock from which the soils <strong>of</strong> the area are derived, but also upon the influence<br />
<strong>of</strong> other factors, such as excessive calcium, aluminum or iron, which reduce the availability <strong>of</strong><br />
phosphorus to plants. Large areas <strong>of</strong> grazing land in many countries are <strong>of</strong> little value for livestock<br />
production without phosphorus supplementation. In New Zealand, for example, where fertilization<br />
<strong>of</strong> pasture with superphosphate has been practiced for many years, phosphorus deficiency may<br />
still occur in dairy herds because <strong>of</strong> inadequate maintenance <strong>of</strong> application over several years (1).<br />
There is evidence also that the quality <strong>of</strong> the superphosphate declined over a period <strong>of</strong> several<br />
years. Soil reserves <strong>of</strong> phosphorus may also be low because <strong>of</strong> high phosphate retention soils.<br />
<strong>An</strong>imals in affected areas mature slowly and are inefficient breeders, and additional losses due to<br />
botulism and defects and injuries <strong>of</strong> bones may occur. Apart from areas in which frank<br />
phospho¬rus deficiency is seen, it is probable that in many other areas a mild degree <strong>of</strong> deficiency<br />
is a limiting factor in the production <strong>of</strong> meat, milk, and wool.<br />
Heavy leaching <strong>by</strong> rain and constant removal <strong>by</strong> cropping contribute to phosphorus deficiency<br />
in the soil, and the low-phosphorus levels <strong>of</strong> the plant cover may be further diminished <strong>by</strong> drought<br />
conditions. Pastures deficient in phosphorus are classically also deficient in protein.
Cattle<br />
A primary dietary deficiency <strong>of</strong> phosphorus in dairy cattle within the first several weeks <strong>of</strong><br />
lactation can result in postparturient hemoglobinuria (2).In high-producing dairy cows, small<br />
restrictions in dietary phosphorus intake compared with National Research Council<br />
recommendations can result in acute recumbency in early lactation (3).<br />
Under range conditions milking cows are most commonly affected, but under intensive<br />
conditions it is the dry and young stock receiving little supplementation which suffer. The<br />
incidence <strong>of</strong> the disease varies: it is most common in animals at pasture during drought seasons<br />
but can also be a serious problem in housed cattle feel on hay only. The dietary requirements <strong>of</strong><br />
phosphorus are given in Table 29.8. Cattle constantly grazing pasture in the southern hemisphere<br />
appear to require somewhat less phosphorus in their diet (0.20% is probably adequate) than do<br />
higher-producing, partly housed livestock. The dietary requirements <strong>of</strong> phosphorus recommended<br />
<strong>by</strong> the National Research Council for beef cows weighing 450 kg may exceed the basic<br />
requirements (4). Over a period <strong>of</strong> several gestations a daily allowance <strong>of</strong> 12 g <strong>of</strong><br />
phosphorus/day/animal was adequate for beef cows (4,5). Cattle given a phosphorus-deficient diet<br />
did not develop detectable signs <strong>of</strong> phosphorus deficiency until they had been on a severely<br />
deficient diet for 6 months.<br />
Sheep and horses<br />
Sheep and horses at pasture are much less susceptible to the osteodystrophy <strong>of</strong> phos¬phorus<br />
deficiency than are cattle and their failure to thrive on phosphorus-deficient<br />
1538<br />
Table 29.8 Approximate levels <strong>of</strong> phosphorus in soil and pasture (quoted as phosphate radical) at<br />
which phosphorus deficiency occurs in cattle<br />
Levels at which deficiency Levels at which<br />
does not occur<br />
deficiency does not occur<br />
Soil<br />
0.005%<br />
0.002%<br />
Pasture<br />
0.3%<br />
0.2%-osteophagia<br />
Secondary phosphorus deficiency<br />
This is <strong>of</strong> minor importance compared with the primary condition. A deficiency <strong>of</strong> vitamin D is<br />
not necessary for the development <strong>of</strong> osteodystrophy, although with suboptimal phosphate intakes<br />
deficiency <strong>of</strong> this vitamin becomes critical. Excessive intake <strong>of</strong> calcium does not result in<br />
secondary phosphorus deficiency, although it may cause a reduction in weight gains, due probably<br />
to interference with digestion, and may contribute to the development <strong>of</strong> phosphorus deficiency<br />
when the intake is marginal. The presence <strong>of</strong> phytic acid in plant tissues, which renders phosphate<br />
unavailable to carnivora, is a major consideration in pigs but <strong>of</strong> only minor importance in<br />
herbivora, except that increasing intakes <strong>of</strong> calcium may reduce the availability <strong>of</strong> phytate<br />
phosphorus even for ruminants. Rock phosphates containing large amounts <strong>of</strong> iron and aluminum<br />
have been shown to be <strong>of</strong> no value to sheep as a source <strong>of</strong> phosphorus. A high intake <strong>of</strong><br />
magnesium, such as that likely to occur when magnesite is fed to prevent lactation tetany, may<br />
cause hypophosphatemia if the phosphorus intake <strong>of</strong> dairy cows is already low.<br />
Hypophosphatemia has been induced in pigs <strong>by</strong> experimental supplementation <strong>of</strong> their diets<br />
with aluminum hydroxide (7). After 3 weeks severe hypophosphatemia, intense hypercalcemia,<br />
decreased growth rate, and a lower concentration <strong>of</strong> 2,3-diphosphoglycerate in the crythrocytes<br />
developed (7).<br />
PATHOGENESIS<br />
Phosphorus is essential for the laying down <strong>of</strong> adequately <strong>mineral</strong>ized bones and teeth, and a<br />
deficiency will result in their abnormal development. Inorganic phosphate, which may be ingested<br />
as such, or liberated from esters during digestion or in intermediary metabolism, is utilized in the<br />
formation <strong>of</strong> proteins and tissue enzymes and is withdrawn from the plasma inorganic phosphate<br />
for this purpose.<br />
Experimentally, female beef cattle fed diets containing =6 g <strong>of</strong> phosphorus/day developed an<br />
insidious and subtle complex syndrome characterized <strong>by</strong> weight loss, rough hair coat, abnormal<br />
stance, and lameness (4). Spontaneous fractures occurred in the vertebrae, pelvis, and ribs. Some<br />
affected bones were severely de<strong>mineral</strong>ized, and the cortical surfaces were porous, chalky white,<br />
s<strong>of</strong>t, and fragile. The osteoid tissue was not properly <strong>mineral</strong>ized.<br />
Experimental acute depletion <strong>of</strong> phosphorus in cattle results in a marked decline in serum<br />
inorganic phosphorus and affected animals display an avid appetite for old bones (8). The signs<br />
include:<br />
•Failure to gain weight and maintain body condition<br />
•Reduced bone weight<br />
•Osteopenia radiographicaily<br />
•Evidence <strong>of</strong> reduced bone formation.<br />
Prolonged phosphorus deficiency was associated with increased plasma concen¬trations <strong>of</strong> total<br />
calcium and 1,25-dihy-droxyvitamin D and reduced plasma concentrations <strong>of</strong> parathyroid<br />
hormone.<br />
Inorganic phosphate also plays an important role in the intermediary metabolism <strong>of</strong><br />
carbohydrate and <strong>of</strong> creatine in the chemical reactions occurring in muscle contraction. This may<br />
be <strong>of</strong> importance in those cows that are recumbent after calving and have hypophosphatemia. The<br />
loss <strong>of</strong> phosphorus in the phospholipids <strong>of</strong> milk due to the onset <strong>of</strong> pr<strong>of</strong>use lactation may be the<br />
crucial factor in the development <strong>of</strong> postparturient hemoglobinuria. <strong>An</strong> increased susceptibility to
loat has been postulated as an effect <strong>of</strong> phosphorus deficiency.<br />
CLINICAL FINDINGS<br />
Primary phosphorus deficiency is common only in cattle. Young animals grow slowly and develop<br />
rickets. In adults there is an initial subclinical stage followed <strong>by</strong> osteomalacia. In cattle <strong>of</strong> all ages<br />
a reduction in voluntary intake <strong>of</strong> feed is a first effect <strong>of</strong> phosphorus deficiency and is the basis <strong>of</strong><br />
most <strong>of</strong> the general systemic signs. Retarded growth, low milk yield, and reduced fertility are the<br />
earliest signs <strong>of</strong> phosphorus deficiency. For example, in severe phosphorus deficiency in range<br />
beef cattle, the calving percentage has been known to drop from 70% to 20%. Although it is<br />
claimed that relative infertility occurs in dairy heifers on daily intakes <strong>of</strong> less than 40 g <strong>of</strong><br />
phosphate, the infertility being accompanied <strong>by</strong> anestrus, subestrus and irregular estrus, and<br />
delayed sexual maturity this has not been borne out <strong>by</strong> other experimental work, which indicates<br />
that fertility is independent <strong>of</strong> the calcium or phosphorus content or the calcium:phosphorus ratio<br />
<strong>of</strong> the diet in cattle. The effects <strong>of</strong> malnutrition on fertility are likely to be general and the<br />
infertility may <strong>of</strong>ten be related to lack <strong>of</strong> total energy intake rather than to specific<br />
deficiency.Thedevelopmentand wear<strong>of</strong><br />
1539<br />
teeth are not greatly affected, in contrast with the severe dental abnormalities that occur in a<br />
nutritional deficiency <strong>of</strong> calcium. However, malocclusion may result from poor <strong>mineral</strong>ization and<br />
resulting weakness <strong>of</strong> the mandible.<br />
In the experimental production <strong>of</strong> phosphorus deficiency in beef cows, several months on a<br />
deficient diet are necessary before clinical signs develop (5). The clinical signs included general<br />
unthrifti-ness, marked body weight loss, reduced feed consumption, reluctance to move, abnormal<br />
stance, bone fractures, and finally impaired reproduction. The detectable signs <strong>of</strong> phosphorus<br />
deficiency developed in the following sequence:<br />
•Loss <strong>of</strong> body weight and condition<br />
•Decreased whole blood phosphorus associated with increased whole blood calcium concentration<br />
•Allotriophagia<br />
•Abnormal stance, locomotion, and recumbency (4).<br />
In a severely deficient area a characteristic conformation develops and introduced cattle revert to<br />
the district type in the next generation. The animals have a leggy appearance with a narrow chest<br />
and small girth, the pelvis is small, and the bones are fine and break easily. The chest is slab-sided<br />
due to weakness <strong>of</strong> the ribs, and the hair coat is rough and staring and lacking in pigment. In areas<br />
<strong>of</strong> severe deficiency the mortality rate may be high due to starvation, especially during periods <strong>of</strong><br />
drought when <strong>deficiencies</strong> <strong>of</strong> phosphorus, protein, and vitamin A are exaggerated. Osteophagia is<br />
common and may be accompanied <strong>by</strong> a high incidence <strong>of</strong> botulism. Cows in late pregnancy <strong>of</strong>ten<br />
become recumbent and, although they continue to eat, are unable to rise. Such animals present a<br />
real problem in drought seasons because many animals in the area may be affected at the same<br />
time. Parentcral injections <strong>of</strong> phosphorus salts are ineffective and the only treatment that may be<br />
<strong>of</strong> benefit is to terminate the pregnancy <strong>by</strong> the administration <strong>of</strong> corticosteroids or <strong>by</strong> cesarean<br />
section.<br />
Acute recumbency in high-producing dairy cows on a marginally phosphorus-deficient diet may<br />
become recumbent in early lactation (3). Affected animals are recumbent and cannot stand. They<br />
may be bright and alert, and their vital signs are within normal range.
Although sheep and horses in phosphorus-deficient areas do not develop clinically apparent<br />
osteodystrophy they are <strong>of</strong>ten <strong>of</strong> poor stature and unthrifty, and may develop perverted appetites.<br />
<strong>An</strong> association between low blood phosphorus and infertility in mares has been suggested but the<br />
evidence is not conclusive. The principal sign in affected sows is posterior paralysis.<br />
CLINICAL PATIIOLOGY<br />
Serum phosphorus<br />
Blood levels <strong>of</strong> phosphorus are not a good indicator <strong>of</strong> the phosphorus status <strong>of</strong> an animal because<br />
they can remain at normal levels for long periods after cattle have been exposed to a serious<br />
deficiency <strong>of</strong> the element. Serum inorganic phosphorus levels are affected <strong>by</strong> such factors as age<br />
<strong>of</strong> animal, milk yield, stage <strong>of</strong> pregnancy, season <strong>of</strong> year, breed, feeding patterns, and dietary<br />
phosphorus. The times <strong>of</strong> sampling in a herd must be standardized to reduce the effect <strong>of</strong> diurnal<br />
variation in serum concentrations <strong>of</strong> inorganic phosphorus. Attention is drawn to the need to use<br />
standard methods <strong>of</strong> collection because <strong>of</strong> the effect that technique can have on phos¬phorus<br />
levels in blood. In cattle, the recommended procedure is to collect blood from the coccygeal vein<br />
and preserve it in buffered trichloracetic acid. Hair does not reflect the status either. However, a<br />
marked hypophosphatemia is a good indicator <strong>of</strong> a severe phosphorus deficiency. The<br />
mild-to-moderate <strong>deficiencies</strong>, which are the most common ones, are usually accompanied <strong>by</strong><br />
normal blood levels <strong>of</strong> phosphorus. Generally, clinical signs occur when blood levels have fallen<br />
from the normal <strong>of</strong> 4-5 mg/dL (1.3-1.7 mmol/L) to 1.5-3.5 mg/dL (0.5-1.2 mmol/L) and a<br />
response to phosphate supplementation in body weight gain can be anticipated in cattle that have<br />
blood inorgarlic phosphorus levels <strong>of</strong> less than 4 mg/dL (1.3 mmol/L). Levels may fall as low as 1<br />
mg/dL (0.3 mmol/L) or less in severe clinical cases. Serum levels <strong>of</strong> calcium are usually<br />
unaffected.<br />
Phosphorus content <strong>of</strong> diet<br />
Estimation <strong>of</strong> the <strong>mineral</strong> content in pasture and drinking water is a valuable aid in diagnosis, but<br />
has major difficulty in representing what the animal has actually<br />
been taking in. A technique has been I devised for determining phosphorus intake <strong>of</strong> sheep <strong>by</strong><br />
estimating the phosphorus content <strong>of</strong> feces. A pool <strong>of</strong> three pellets from each <strong>of</strong> 30 sheep is used<br />
as a sampling technique.<br />
Bone ash concentrations<br />
Determination <strong>of</strong> total bone ash concentrations, and bone calcium and phosphorus concentrations<br />
from sample <strong>of</strong> rib can provide useful diagnostic information and comparison to normal values (9).<br />
There is usually a marked deterioration in the radiopacity <strong>of</strong> the bones. However, the bone<br />
content <strong>of</strong> phosphorus is still considered the most accurate indication <strong>of</strong> phosphorus status.<br />
NECROPSY FINDINGS<br />
The necropsy findings are those <strong>of</strong> the specific diseases, rickets, and osteomala-<br />
DIFFERENTIAL DIAGNOSIS<br />
A diagnosis <strong>of</strong> phosphorus deficiency depends upon evidence that the diet is lacking in<br />
phosphorus, and that the lesions and signs are typical <strong>of</strong> those <strong>caused</strong> <strong>by</strong> phosphorus deficiency<br />
and can be arrested or reverted <strong>by</strong> the administration <strong>of</strong> phosphorus. Differentiation from those<br />
diseases that may resemble rickets and osteomalacia is dealt with under those headings (pp. 1543<br />
and 1545).<br />
TREATMENT<br />
The preparations and doses recom¬mended under control can be satisfactorily used for the
treatment <strong>of</strong> affected animals. In cases where the need for phosphorus is urgent, as in<br />
postparturient hemoglobinuria and in cases <strong>of</strong> parturient paresis complicated <strong>by</strong><br />
hypophosphatemia, the intravenous administration <strong>of</strong> sodium acid phosphate (30 g in 300 mL<br />
distilled water) is recommended.<br />
CONTROL<br />
Phosphorus supplements<br />
Under field conditions the difficulty usually encountered is that <strong>of</strong> providing phosphorus<br />
supplements to large groups <strong>of</strong> cattle running under extensive range conditions. The minimum<br />
daily requirement <strong>of</strong> cattle for phosphorus (as phosphate) is 15 g, and 40-50 g is considered<br />
optimal. The Agricultural Research Council recommendation <strong>of</strong> 22 g phosphorus/day for a 470 kg<br />
cow producing about 7.5 kg milk/day is adequate (10).<br />
1540<br />
Dairy cattle producing 7500 kg milk annually should receive diets containing 0.42% phosphorus<br />
(3).<br />
Bone meal, dicalcium phosphate, disodiurh phosphate and sodium pyrophosphate may be<br />
provided in supplementary feed or <strong>by</strong> allowing free access to their mixtures with salt or more<br />
complicated <strong>mineral</strong> mixtures. The availability <strong>of</strong> the phosphorus in feed supplements varies and<br />
this needs to be taken into consideration when compounding rations. The relative biological values<br />
for young pigs in terms <strong>of</strong> phosphorus are: dicalcium phosphate or rock phosphate 83%, steamed<br />
bone meal 56%, and colloidal clay or s<strong>of</strong>t phosphate 34%. It is suggested that in deficient areas<br />
adult dry cattle and calves up to 150 kg should receive 225 g bone meal per week, growing stock<br />
over 150 kg BW 350 g per week and lactating cows 1 kg weekly, but experience in particular<br />
areas may indicate the need for varying these amounts. The top-dressing <strong>of</strong> pasture with<br />
superphosphate is an adequate method <strong>of</strong> correcting the deficiency and has the advantage <strong>of</strong><br />
increasing the bulk and protein yield <strong>of</strong> the pasture, but is <strong>of</strong>ten impractical under the conditions in<br />
which the disease occurs.<br />
The addition <strong>of</strong> phosphate to drinking water is a much more satisfactory method provided the<br />
chemical can be added <strong>by</strong> an automatic dispenser to water piped into troughs. Adding chemicals to<br />
fixed tanks introduces errors in concentration, excessive stimulation <strong>of</strong> algal growth, and<br />
precipitation in hard waters. Monosodium dihydrogen phosphate (monosodium or thophosphate)<br />
is the favorite additive and is usually added at the rate <strong>of</strong> 10 20 g/20 L <strong>of</strong> water. Superphosphate<br />
may be used instead but is not suitable for dispensers, must be added in larger quantities (50 g/20<br />
L) and may contain excess fluorine. A reasonably effective and practical method favored <strong>by</strong><br />
Australian dairy farmers is the provision <strong>of</strong> a supplement referred to as 'super juice'. Plain<br />
superphosphate at a rate <strong>of</strong> 2.5 kg in 40 L <strong>of</strong> water is mixed and stirred vigorously in a barrel.<br />
When it has settled for a day the 'super juice' is ready for use and is administered <strong>by</strong> skimming <strong>of</strong>f<br />
the supernatant and sprinkling 100 200 mL on the feed <strong>of</strong> each cow.<br />
Toxicity <strong>of</strong> supplements<br />
The use <strong>of</strong> phosphate supplements in the diet is not without hazards. Phosphoricacid is directly<br />
toxic and should not be used, and monosodium phosphate is unpalatable to many animals; the<br />
depression <strong>of</strong> appetite that results may discount the improved feed utilization it provides.<br />
Superphosphate used as fertilizer can cause toxicosis in ruminants (11). Clinical signs in sheep<br />
include teeth grinding, diarrhea, nervous system depression, apparent blindness, stiffness and<br />
ataxia, and high fatality rate (11).
REFER ENCES<br />
(1)Brooks, H. V. et al. (1984) NZ Vet.]., 32,174.<br />
(2)Ogawa, E. et al. (1989) Am. J. Vet. Res.,50, 388.<br />
(3)Gerl<strong>of</strong>f, B.J. & Swenson, E. P. (1996) J.Am. Vet. Med. Assoc, 208, Tib.<br />
(4)Shupe.J. L. et al. (1988) Am.J. Vet. Res.,49, 1629.<br />
(5)Call, J. W. et al. (1986) Am.]. Vet. Res ,41, 475.<br />
(6)Denny, J. E. F. M. (1987) J. South Afr. Vet.Assoc, 58, 85.<br />
(7)Haglin, L. et al. (1988) Ada. Vet. Scund.,29, 91.<br />
(8)Blair-Wcst.J. R. et al. (1992) Am.].PhyswL, 26.1, R656.<br />
(9)Beighle, 1). E. et al. (1994) Am.]. Vet.Res., 55, 85.<br />
(10)Fishwick, G. & Hemingway, R. G. (1989)Br. Vet.J, 145. 141.<br />
(11)East, N. E. (1993) J. Am. Vet. Med. Assoc,20 J, 1176.<br />
VITAMIN D DEFICIENCY<br />
VitaminD deficiencys usually <strong>caused</strong> <strong>by</strong> insufficient solar irradiation<strong>of</strong> animals or their feed and<br />
is manifested <strong>by</strong> poor appetiteand growth, and in advanced cases <strong>by</strong> osteodystrophy.<br />
Synopsis<br />
Etiology. Lack <strong>of</strong> ultravioletsolar irradiation and/or deficiency <strong>of</strong> preformed vitamin D in diet.<br />
Epidemiology. Uncommon because diets are supplemente. Occurs in animals in countries with<br />
relative lack <strong>of</strong> UV irradiation especially in winter months; animals raised indoors for long periods.<br />
May occur in young grazinganimals in winter months. May be antivitamin D factor.<br />
Signs. Reduced productivity; poor weight gain; reduced reproductive performance. Rickets in<br />
young; osteomalacia in adults.<br />
Clinical pathology. Serumcalcium and phosphorus. Plasma vitamin D.<br />
Lesions. Lack <strong>of</strong> <strong>mineral</strong>ization <strong>of</strong> bone.<br />
Diagnostic confirmation. Histology <strong>of</strong> bone<br />
lesions.<br />
Differential diagnosis list. See Rickets and<br />
osteomalacia.<br />
Treatment. Administervitamin D parenterally and oral calcium and phosphates.<br />
Control. Supplement diets with vitamin D.Injections <strong>of</strong> vitamin D when oral supplementation not<br />
possible.<br />
ETIOLOGY<br />
A lack <strong>of</strong> ultraviolet solar irradiation <strong>of</strong> the skin, coupled with a deficiency <strong>of</strong> preformed vitamin<br />
D complex in the diet, leads to a deficiency <strong>of</strong> vitamin D in tissues.<br />
EPIDEMIOLOGY<br />
Although the effects <strong>of</strong> clinically apparent vitamin D deficiency have been largely eliminated <strong>by</strong><br />
improved nutrition, the subclinical effects have received little attention. For example, retarded<br />
growth in young sheep in New Zealand and southern Australia during winter months has been<br />
recognized for many years as responding to vitamin D administration.<br />
However, general realization <strong>of</strong> the importance <strong>of</strong> this subclinical vitamin D deficiency in<br />
limiting productivity <strong>of</strong> livestock has come only in recent years. This is partly due to the<br />
complexity <strong>of</strong> the relations between calcium, phosphorus and the vitamin, and their common<br />
association with protein and other <strong>deficiencies</strong> in the diet. Much work remains to be done before
these individual dietary-essentials can be assessed in their correct economic perspective.<br />
Ultraviolet irradiation<br />
The lack <strong>of</strong> ultraviolet irradiation becomes important as distance from the equator increases and<br />
the sun's rays are filtered and refracted <strong>by</strong> an increasing depth <strong>of</strong> the earth's atmosphere. Cloudy,<br />
overcast skies, smoke-laden atmospheres, and winter months exacerbate the lack <strong>of</strong> irradiation.<br />
The effects <strong>of</strong> poor irradiation are felt first <strong>by</strong> animals with dark skin (particularly swine and some<br />
breeds <strong>of</strong> cattle) or heavy coats (particularly sheep), <strong>by</strong> rapidly growing animals, and <strong>by</strong> those that<br />
are housed indoors for long periods. The concentration <strong>of</strong> plasma vitamin D3 recorded in grazing<br />
sheep varies widely throughout the year. During the winter months in the United Kingdom the<br />
levels<br />
1541<br />
in sheep fall below what is considered optimal, while in the summer months the levels are more<br />
than adequate (1). There is a marked difference in vitamin D status between sheep with a long<br />
fleece and those that have been recently shorn, especially in periods <strong>of</strong> maximum sunlight. The<br />
higher blood levels <strong>of</strong> vitamin D in the latter group are probably due to their greater exposure to<br />
sunlight. Pigs reared under intensive farming conditions and animals being prepared for shows are<br />
small but important susceptible groups.<br />
Dietary vitamin D<br />
The importance <strong>of</strong> dietary sources <strong>of</strong> preformed vitamin D must not be underestimated. Irradiated<br />
plant sterols with anti-rachitic potency occur in the dead leaves <strong>of</strong> growing plants. Variation in the<br />
vitamin D content <strong>of</strong> hay can occur with different methods <strong>of</strong> curing. Exposure to irradiation <strong>by</strong><br />
sunlight for long periods causes a marked increase in anti-rachitic potency <strong>of</strong> the cut fodder,<br />
whereas modern haymaking technique with its emphasis on rapid curing tends to keep vitamin D<br />
levels at a minimum. Grass ensilage also contains very little vitamin D<br />
Based on a survey <strong>of</strong> the concentrations <strong>of</strong> vitamin D in the serum <strong>of</strong> horses m the United<br />
Kingdom, the levels may be low (2). In the absence <strong>of</strong> a dietary supplement containing vitamin D,<br />
the concentration <strong>of</strong> 25-OH D2 and 25-OH D3 are, respectively, a reflection <strong>of</strong> the absorption <strong>of</strong><br />
vitamin D2 from the diet and <strong>of</strong> biosynthesis <strong>of</strong> vitamin D3<br />
Information on the vitamin D requirements <strong>of</strong> housed dairy cattle is incomplete and<br />
contradictor)'. It appears, however, that m some instances natural feedstuffs provide less than<br />
adequate amounts <strong>of</strong> the vitamin for optimum reproductive performance in high-producing cows<br />
(3).<br />
Grazing animals<br />
The grazing <strong>of</strong> animals, especially in winter time, on lush green feed including cereal crops, leads<br />
to a high incidence <strong>of</strong> rickets in the young. <strong>An</strong> antivitamin D factor is suspected because calcium,<br />
phos¬phorus, and vitamin D intakes are usually normal, but the condition can be prevented <strong>by</strong> the<br />
administration <strong>of</strong> calciferol. Carotene, which is present in large quantities in this type <strong>of</strong> feed, has<br />
been shown to have antivitamin D potency but the existence <strong>of</strong> a further rachitogenic substance<br />
seems probable. The rachitogenic potency <strong>of</strong> this green feed varies widely according to the stage<br />
<strong>of</strong> growth and virtually disappears when flowering commences. Experimental overdosing with<br />
vitamin A causes a marked retardation <strong>of</strong> bone growth in calves. Such overdosing can occur when<br />
diets are supplemented with the vitamin, and may produce clinical effects (4).<br />
The importance <strong>of</strong> vitamin D to animals is now well-recognized and supplementation <strong>of</strong> the diet<br />
where necessary is usually performed <strong>by</strong> the livestock owner. Occasional outbreaks <strong>of</strong> vitamin D
deficiency are experienced in intensive systems where animals are housed and in areas where<br />
specific local problems are encountered, e.g. rickets in sheep on green cereal pasture in New<br />
Zealand.<br />
PATHOGENESIS<br />
Vitamin D is a complex <strong>of</strong> substances with anti-rachitogenic activity. The important components<br />
are as follows:<br />
•Vitamin D3 (cholecalciferol) is produced from its precursor 7-dehydro-cholesterol in mammalian<br />
skin and <strong>by</strong> natural irradiation with ultraviolet light<br />
•Vitamin D2 is present in sun-cured hay and is produced <strong>by</strong> ultraviolet irradiation <strong>of</strong> plant sterols.<br />
Calciferol or viosterol is produced commercially <strong>by</strong> theirradiation <strong>of</strong> yeast. Ergosterol is<br />
the :provitamin<br />
•Vitamin D4 and D5 occur naturally in the oils <strong>of</strong> some fish.<br />
Vitamin D produced in the skin or ingested with the diet and absorbed <strong>by</strong> the small intestine is<br />
transported to the liver. In the liver, 25-hydroxycholecalcif-erol is produced, which is then trans<br />
ported to the kidney where at least two additional derivatives are formed <strong>by</strong> 1-Ct-hydroxylase (5).<br />
One is 1,25-dihydroxycholecalciferol (DHCC), and the other is 24,25-DHCC. Under conditions <strong>of</strong><br />
calcium need or calcium deprivation the form predominantly produced <strong>by</strong> the kidney is<br />
1,25-DHCC. At present it seems likely that 1,25-DHCC is the metabolic form <strong>of</strong> vitamin D most<br />
active in eliciting intestinal calcium transport ; and absorption and is at least the closest known<br />
metabolite to the form <strong>of</strong> vitamin D functioning in bone <strong>mineral</strong>ization. The metabolite also<br />
functions in regulat- ing the absorption and metabolism <strong>of</strong> the phosphate ion, and especially its<br />
loss from the kidney. A deficiency <strong>of</strong> the metabolite may occur in animals with renal disease,<br />
resulting in decreased absorption <strong>of</strong> calcium and phosphorus, decreased <strong>mineral</strong>ization <strong>of</strong> bone,<br />
and excessive losses <strong>of</strong> the <strong>mineral</strong>s through the kidney. A deficiency <strong>of</strong> vitamin D per se is<br />
governed in its importance <strong>by</strong> the calcium and phosphorus status <strong>of</strong> the animal.<br />
Because <strong>of</strong> the necessity for the conversion <strong>of</strong> vitamin D to the active metabolites, there is a lag<br />
period <strong>of</strong> 2- 4 days following the administration <strong>of</strong> the vitamin parenterally before a significant<br />
effect on calcium and phosphorus absorption can occur. The use <strong>of</strong> synthetic-analogs <strong>of</strong> the active<br />
metabolites such as 1-α-hydroxycholecalciferol (an analog <strong>of</strong> 1,25-DHCC) can increase the<br />
plasma concentration <strong>of</strong> calcium and phosphorus within 12 hours following administration (6) and<br />
has been recommended for the control <strong>of</strong> parturient paresis in cattle.<br />
Maternal status<br />
Maternal vitamin D status is important m determining neonatal plasma calcium concentration. I<br />
here is a significant correlation between maternal and neonatal calf plasma concentrations <strong>of</strong><br />
25-OH D2, 25-OH D3, 24,25-(OH)2, D2, 24,25-(OH)2, D3 and 25,26-(OH)2 D3. This indicates<br />
that the vitamin D metabolite status <strong>of</strong> the neonate is primarily dependent on the 25-OH D status<br />
<strong>of</strong> the dam (7). The maternal serum concentrations <strong>of</strong> calcium, phosphorus, and magnesium do not<br />
determine concentrations <strong>of</strong> these <strong>mineral</strong>s found in the newborn calf. The ability <strong>of</strong> the placenta<br />
to maintain elevated plasma calcium or phosphorus in the fetus is partially dependent on maternal<br />
1,25-(OH)2, D status. Parenteral cholecalciferol treatment <strong>of</strong> sows before parturition is an<br />
effective method <strong>of</strong> supplementing neonatal piglets with cholecalciferol via the sow's milk and its<br />
metabolite via placenta transport (6).<br />
Calcium:phosphorus ratio
When the calcium:phosphorus ratio is wider than the optimum (1:1 to 2:1), vitamin D<br />
requirements for good calcium and phosphorus retention and bone <strong>mineral</strong>ization are increased. A<br />
minor degree <strong>of</strong> vitamin D deficiency in an environment supplying an imbalance <strong>of</strong> calcium and<br />
phosphorus might well lead to<br />
1542<br />
disease, whereas the same degree <strong>of</strong> vitamin deficiency with a normal calcium and phosphorus<br />
intake could go unsus¬pected. For example, in growing pigs, vitamin D supplementation is not<br />
essential provided calcium and phosphorus intakes are rigidly controlled, but under practical<br />
circumstances this may not be possible.<br />
The minor functions <strong>of</strong> the vitamin include maintenance <strong>of</strong> efficiency <strong>of</strong> food utilization and a<br />
calorigenic action, the metabolic rate being depressed when the vitamin is deficient. These actions<br />
are probably the basis for the reduced growth rate and productivity in vitamin D deficiency. Some<br />
evidence suggests that vitamin D may have a role in the immune system (8). Local production <strong>of</strong><br />
1,25-(OH)2 D <strong>by</strong> monocytes may be important in the immune function, particularly in the<br />
parturient dairy cow.<br />
CLINICAL FINDINGS<br />
The most important effect <strong>of</strong> lack <strong>of</strong> vitamin D in farm animals is reduced productivity. A<br />
decrease in appetite and efficiency <strong>of</strong> food utilization cause poor weight gains in growing stock<br />
and poor productivity in adults. Reproductive efficiency is also reduced and the overall effect on<br />
the animal economy may be severe.<br />
In the late stages lameness, which is most noticeable in the forelegs, is accompanied in young<br />
animals <strong>by</strong> bending <strong>of</strong> the long bones and enlargement <strong>of</strong> the joints. This latter stage <strong>of</strong> clinical<br />
rickets may occur simultaneously with cases <strong>of</strong> osteomalacia in adults. <strong>An</strong> adequate intake <strong>of</strong><br />
vitaminD appears to be necessary for the maintenance <strong>of</strong> fertility in cattle, particularly if the<br />
phosphorus intake is low. In one study in dairy cattle, the first ovulation after parturition was<br />
advanced significantly in vitamin D supplemented cows (3).<br />
CLINICAL PATHOLOGY<br />
Serum calcium and phosphorus<br />
A pronounced hypophosphatemia occurs m the early stages and is followed some months later <strong>by</strong><br />
a fall in serum calcium. Plasma alkaline phosphatase levels are usually elevated. The blood picture<br />
quickly returns to normal with treatment, <strong>of</strong>ten several months before the animal is clinically<br />
normal. Typical figures for beef cattle kept indoors are serum calcium 8.7 mg/dL (10.8 normal),<br />
2.2 mmol/L (2.7 normal); serum inorganic phosphate 4.3 mg/dL (6.3 normal), 1.1 mmol/L (1.6<br />
normal); and alkaline phosphatase 5.7 units (2.75 normal).<br />
Plasma vitamin D<br />
The normal ranges <strong>of</strong> plasma concentrations <strong>of</strong> vitamin D and its metabolites in the farm animal<br />
species are now available (9) and can be used to monitor the response <strong>of</strong> the administration <strong>of</strong><br />
vitamin D parenterally or orally in sheep (10, 11). The serum concentrations <strong>of</strong> vitamin I) in the<br />
horse have been determined (2).<br />
NECROPSY FINDINGS<br />
The pathological changes in young animals arc those <strong>of</strong> rickets, while in older animals there is an<br />
osteomalacia. In all ages a variable amount <strong>of</strong> osteodystrophcia fibrosa may develop, and<br />
distinction <strong>of</strong> the origin <strong>of</strong> these osteodystrophies based on only gross and microscopic<br />
examination is impractical. A review <strong>of</strong> management factors and a nutritional analysis <strong>of</strong> the feed
is essential. The samples for confirmation <strong>of</strong> the diagnosis at necropsy are as per calcium<br />
deficiency.<br />
DIFFERENTIAL DIAGNOSIS<br />
A diagnosis <strong>of</strong> vitamin D deficiency depends upon evidence <strong>of</strong> the probable occurrence <strong>of</strong> the<br />
deficiency and response <strong>of</strong> the animal when vitamin D is provided. Differentiation from clinically<br />
similar syndromes is discussed under the specific osteodystrophies.<br />
TREATMENT<br />
It is usual to administer vitamin D in the dose rates set out under control. Affected animals should<br />
also receive adequate calcium and phosphorus in the diet.<br />
CONTROL<br />
Supplementation<br />
The administration <strong>of</strong> supplementary vitamin D to animals <strong>by</strong> adding it to the diet or <strong>by</strong> injection<br />
is necessary only when exposure to sunlight or the provision <strong>of</strong> a natural ration containing<br />
adequate amounts <strong>of</strong> vitamin D is impractical.<br />
A total daily intake <strong>of</strong> 7-12 IU/kg BW is optimal. Sun-dried hay is a good source, but green<br />
fodders are generally deficient in vitamin D. Fish liver oils arc-high in vitamin D, but are subject<br />
to deterioration on storage, particularly with regard to vitamin A. They have the added<br />
disadvantage <strong>of</strong> losing their vitamin A and 1) content in premixed feed, <strong>of</strong> destroying vitamin E in<br />
these feeds when they become rancid, and <strong>of</strong> seriously reducing the butterfat content <strong>of</strong> milk.<br />
Stable water-soluble vitamin A and D preparations do not suffer from these disadvantages.<br />
Irradiated dry yeast is probably a simpler and cheaper method <strong>of</strong> supplying vitamin D in mixed<br />
grain feeds.<br />
Stable water-soluble preparations <strong>of</strong> vitamin D are now available and are commonly added to<br />
the rations <strong>of</strong> animals being fed concentrate rations. The classes <strong>of</strong> livestock that usually need<br />
dietary supplementation include:<br />
•Calves raised indoors on milk replacers<br />
•Pigs raised indoors on grain rations<br />
•Beef cattle receiving poor quality roughage during the winter months<br />
•Cattle raised indoors for prolonged periods and not receiving sun-cured forage containing<br />
adequate levels <strong>of</strong> vitamin D. These include calves raised as herd replacements, yearling cattle fed<br />
concentrate rations, bulls in artificial insemination centers, and purebred bulls maintained indoors<br />
on farms<br />
•Feedlot lambs fed grain rations during the winter months or under totally covered confinement<br />
•Young growing horses raised indoors or outdoors on rations that may not contain adequate<br />
concentrations <strong>of</strong> calcium and phosphorus. This may be a problem in rapidly growing,<br />
well-muscled horses receiving a high level <strong>of</strong> grain.<br />
Because there is limited storage <strong>of</strong> vitaminD in the body, compared to the storage <strong>of</strong> vitamin A,<br />
it is recommended that daily dietary supplementation be provided when possible for optimum<br />
effect.<br />
Injection<br />
In situations where dietary supplementa¬tion is not possible, the use <strong>of</strong> single IM injections <strong>of</strong><br />
vitamin D2 (calciferol) in oil will protect ruminants for 3-6 months. A dose <strong>of</strong> 1 1 000 units/kg<br />
BW is recommended and should maintain an adequate vitamin D status for 3-6 months.
In mature non-pregnant sheep weighing about 50 kg, a single IM injection <strong>of</strong> 6000 IU/kg body<br />
weight produced concentrations <strong>of</strong> 25-hydroxyvitamin D3 at adequate levels for 3 months (11).<br />
The parenteral administration <strong>of</strong> vitamin D,<br />
1543<br />
results in both higher tissue and plasma levels <strong>of</strong> vitamin D3 than does oral administration, and IV<br />
administration produces higher plasma levels than does the IM injection (12). The timing <strong>of</strong> the<br />
injection should be selected so that the vitamin D status <strong>of</strong> the ewe is adequate at the time <strong>of</strong><br />
lambing (11). The vitamin D3 status <strong>of</strong> lambs can be increased <strong>by</strong> the parenteral administration <strong>of</strong><br />
the vitamin to the pregnant ewe (13). Dosing pregnant ewes with 300000 IU <strong>of</strong> vitamin D3 in a<br />
rapidly available form, approximately 2 months before lambing, provides a safe means <strong>of</strong><br />
increasing the vitamin D status <strong>of</strong> the ewe and the newborn lambs <strong>by</strong> preventing seasonally low<br />
concentrations <strong>of</strong> 25-hydroxyvitamin D3 (14). In adult sheep there is a wide margin <strong>of</strong> safety<br />
between the recommended requirement and the toxic oral dose, which provides ample scope for<br />
safe supplementation if such is desirable (10). In adult sheep given 20 times the recommended<br />
requirements for 16 weeks there was no evidence <strong>of</strong> pathological cification (10). Oral dosing with<br />
30-45 units/kg BW is adequate, provided treatment can be given daily. Massive oral doses can<br />
also be used to give long-term effects, e.g. a single dose <strong>of</strong> 2 million units is an effective<br />
preventive for 2 months in lambs. Excessive doses may cause toxicity, with signs <strong>of</strong> drowsiness,<br />
muscle weakness, fragility <strong>of</strong> bones, and calcification in the walls <strong>of</strong> blood vessels. The latter<br />
finding has been recorded in cattle receiving 10 million units per day and in unthrifty lambs<br />
receiving a single dose <strong>of</strong> 1 million units, although larger doses are tolerated <strong>by</strong> healthy lambs.<br />
REVIEW LITERATURE<br />
Dobson, R. C. & Ward, G. (1974) Vitamin Dphysiology and its importance to dairy cattle:a<br />
review. J. Dairy Sci., 57, 985.<br />
Horst, R. L. & Reinhardt, T. A. (1983) Vitamin D metabolism in ruminants and its relevance<br />
to the periparturient cow.J. Dairy Sci., 66, 661-678.<br />
Wasserman, R. H. (1975) Metabolism, function and clinical aspects <strong>of</strong> vitamin D. Cornell , 65, 3.<br />
REFERENCES<br />
(1)Smith, B. S. W. & Wright, H. (1984) Vet..Rec, 115.537.<br />
(2)Smith, B. S. W. & Wright, H. (1984) Vet.Rec, 115. 579.<br />
(3)Ward, G. et al. (1971)J. Dairy Sci., 54, 204.<br />
(4)Grey, R. M. et al. (1965) Pathol. Vet., 2,446.<br />
(5)Engstrom, G. W. et al. (1987) J. Dairy Sci.,70, 2266.<br />
(6)G<strong>of</strong>f.J. P. (1984) J. Nutr., 114, 163.<br />
(7)G<strong>of</strong>f,J. P. ct al. (1982)J Nutr., 112, 1387.<br />
(8)Reinhardt, T. A. & Hustmyer, F. G.(1987) J. Dairy Sci., 70, 952.<br />
(9)Horst, R. L. et al. (1981) <strong>An</strong>al. Biochem.,116, 189.<br />
(10)Smith, B. S. W. et al. (1985) Res. Vet. Sci.,38, 317.<br />
(11)Smith, B, S. W. & Wright, H. (1985) Res.Vet. Sci., 39, 59.<br />
(12)Hidiroglou, M. et al. (1984) Can.J. <strong>An</strong>im.Sci., 64, 697.<br />
(13)Hidiroglou, M. & Knipfel.J. E. (1984)Can.J. Comp. Med., 48, 78.<br />
(14)Smith, B. S. W. et al. (1987) Vet. Rec,120, 199.<br />
VITAMIN D TOXICITY<br />
Vitamin D toxicity has occurred in cattle (1), horses (2), and swine (3) following the parenteral or
oral administration <strong>of</strong> excessive quantities <strong>of</strong> the vitamin.<br />
n cattle, large parenteral doses <strong>of</strong> vitamin D, 15 17 million IU, results in prolonged<br />
hypercalcemia, hyperphosphatemia, and large increases in plasma concentrations <strong>of</strong> vitamin D,<br />
and its metabolites (1). Clinical signs <strong>of</strong> toxicity occur within 2-3 weeks and include marked<br />
anorexia, loss <strong>of</strong> body weight, dyspnea, tachycardia, loud heart sounds, weakness, recumbency,<br />
torticollis, fever, and a high case fatality rate (1). Pregnant cows 1 month before parturition are<br />
more susceptible than non-pregnant cows.<br />
Accidental vitamin D3 toxicity has occurred in horses fed a grain diet that supplied 12000-13<br />
000 IU/kg BW <strong>of</strong> vitamin D3 daily for 30 days (2), equivalent to about 1 million IU vitamin D,/kg<br />
<strong>of</strong> feed. Clinical findings included anorexia, stiffness, loss <strong>of</strong> body weight, polyuria, and<br />
polydipsia. There was also evidence <strong>of</strong> hyposthenuria, aciduria, s<strong>of</strong>t-tissue <strong>mineral</strong>ization, and<br />
fractures <strong>of</strong> the ribs (2). Calcification <strong>of</strong> the endocardium and the walls <strong>of</strong> large blood vessels are<br />
characteristic.<br />
Severe toxicity in pigs occurs at a daily oral dose <strong>of</strong> 50000-70000 IU/kg BW. Signs include a<br />
sudden onset <strong>of</strong> anorexia, vomiting, diarrhea, dyspnea, apathy, aphonia, emaciation, and death (2).<br />
Clinical signs arc commonly observed within 2 days after consumption <strong>of</strong> the feed containing<br />
excessive vitamin D. At necropsy, hemorrhagic gastritis and mild interstitial pneumonia are<br />
commonly present (3). Arteriosclerosis with calcification <strong>of</strong> the heart base vessels may also be<br />
visible macroscopically in poisoned cattle. Osteoporosis with multiple fractures has been observed<br />
in subacute to chronic hypervitaminosis D in swine. Histologically, there is widespread s<strong>of</strong>t tissue<br />
<strong>mineral</strong>ization, with a predilection for the lung and gastric mucosa, as well as elastinrich tissue,<br />
such as blood vessels. Changes in bone vary with the duration <strong>of</strong> exposure to toxic levels <strong>of</strong> the<br />
vitamin.<br />
Assay <strong>of</strong> the various metabolites <strong>of</strong> vitamin D in tissues is difficult. The diagnosis is therefore<br />
usually confirmed <strong>by</strong> correlating microscopic changes with a history <strong>of</strong> exposure to toxic levels <strong>of</strong><br />
vitamin D.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
•Toxicology - 500 g <strong>of</strong> suspect feed(ASSAY (Vit D))<br />
•Histolog -formalin-fixed lung,stomach/abomasum, proximal aorta,lung, bone (LM).<br />
REFERENCES<br />
(1)Littledike. E. T. & 1 horst, R. L. (1982)J.Dairy Sci., 65. 749.<br />
(2)Harrington, D. D. & Page, E. H. (1983) J.Am. Vet. Med. Assoc, 182, 1358.<br />
(3)Long, G. C. (1984) J. Am. Vet. Med. Assoc,184, 164.<br />
RICKETS<br />
Rickets is a disease <strong>of</strong> young, growing animals characterized <strong>by</strong> defective calcification <strong>of</strong> growing<br />
bone. The essential lesion is a failure <strong>of</strong> provisional calcification with persistence <strong>of</strong> hypertrophic<br />
cartilage, and enlargement <strong>of</strong> the epiphyses <strong>of</strong> long bones and the costochondral junctions<br />
(so-called 'rachitic rosary'). The poorly <strong>mineral</strong>ized bones are subject to pressure distortions.<br />
Synopsis<br />
Etiology. Deficiencies <strong>of</strong> any or combination <strong>of</strong> calcium, phosphorus, and vitamin D.<br />
Epidemiology. Young growing animals. No longer common. In calves on phosphorus-deficient<br />
diets (range or housed). In grazing lambs due to lack <strong>of</strong> solar irradiation. Rare in foals and pigs.<br />
Signs. Stiff gait and lameness, enlargement <strong>of</strong> ends <strong>of</strong> long bones, curvature <strong>of</strong> long bones,<br />
prolonged periods <strong>of</strong> recumbency. Delayed dentition.
Clinical pathology. Elevated alkaline phosphatase; low serum calcium and<br />
1544<br />
phosphorus. Lack <strong>of</strong> density <strong>of</strong> bone radiographically.<br />
Lesions. Abnormal bones and teeth. Bone shafts are s<strong>of</strong>t, epiphyses enlarged. Ratio <strong>of</strong> bone ash to<br />
organic matter is decreased.<br />
Diagnostic confirmation. Histology <strong>of</strong> bone, especially epiphyses.<br />
Differential diagnosis list:<br />
• Epiphysitis<br />
• Congenital and acquired abnormalities<br />
• Infectious synovitis.<br />
Treatment. Vitamin D injections, calcium and phosphate orally.<br />
Control. Supplement deficient diets with calcium, phosphorus, and vitamin D.<br />
ETIOLOGY<br />
Rickets is <strong>caused</strong> <strong>by</strong> an absolute or relative deficiency <strong>of</strong> any or a combination <strong>of</strong> calcium,<br />
phosphorus or vitamin D in young, growing animals. The effects <strong>of</strong> the deficiency are also<br />
exacerbated <strong>by</strong> a rapid growth rate.<br />
<strong>An</strong> inherited form <strong>of</strong> rickets has been described in pigs. It is indistinguishable from rickets<br />
<strong>caused</strong> <strong>by</strong> nutritional inadequacy.<br />
EPIDEMIOLOGY<br />
Clinical rickets is not as important economically as the subclinical stages <strong>of</strong> the various dietary<br />
<strong>deficiencies</strong> that produce it. The provision <strong>of</strong> diets adequate and properly balanced with respect to<br />
calcium, phosphorus, and sufficient exposure to sunlight, are mandatory in good livestock<br />
production. Rickets is no longer a common disease because these requirements are widely<br />
recognized, but the incidence can be high in extreme environments, including purely exploitative<br />
range grazing, intensive feeding in fattening units, and heavy dependence On lush grazing,<br />
especially in winter months.<br />
Rickets is a disease <strong>of</strong> young, rapidly growing animals and occurs naturally under the following<br />
conditions.<br />
Calves<br />
Primary phosphorus deficiency in phosphorus-deficient range areas, and vitamin D deficiency in<br />
calves housed for long periods are the common circumstances. Vitamin D deficiency is the most<br />
common form <strong>of</strong> rickets in cattle raised indoors for prolonged periods in Europe and North<br />
America. Grazing animals may also develop vitamin D deficiency rickets at latitudes where solar<br />
irradiation during winter is insufficient to promote adequate dermal photobiosynthesis <strong>of</strong> vitamin<br />
D3 from 7-dihydrocholesterol. Rickets has occurred in yearling steers in New Zealand wintered on<br />
swede (Brassica napus) crop deficient in phosphorus (1).<br />
In young, rapidly growing cattle raised intensively indoors a combined deficiency <strong>of</strong> calcium,<br />
phosphorus, and vitamin D can result in leg weakness characterized <strong>by</strong> stiffness, reluctance to<br />
move, and retarded growth. In some cases, rupture <strong>of</strong> the Achilles tendon and spontaneous<br />
fracture occur (2). The Achilles tendon may rupture at the insertion <strong>of</strong>, or proximal to, the<br />
calcaneus.<br />
Lambs<br />
Lambs are less susceptible to primary phosphorus deficiency than cattle, but rickets does occur<br />
under the same conditions. Green cereal grazing and, to a lesser extent, pasturing on lush rye-grass
during winter months may cause a high incidence <strong>of</strong> rickets in lambs; this is considered to be a<br />
secondary vitamin D deficiency. <strong>An</strong> outbreak <strong>of</strong> vitamin D deficiency rickets involving 50% <strong>of</strong><br />
lambs aged 6-12 months grazing new grass and rape occurred during the early winter months in<br />
Scotland (3). In the South Island <strong>of</strong> New Zealand, where winter levels <strong>of</strong> solar irradiation are low,<br />
rickets occurs in hoggets grazing green oats, or other green crops, which have been shown to<br />
contain high levels <strong>of</strong> rachitogenic carotenes (1).<br />
Pigs<br />
Rickets in young pigs occurs in intensive fattening units where the effects <strong>of</strong> diet containing<br />
excessive phosphate (high cereal diets) are exacerbated <strong>by</strong> vitamin D and calcium <strong>deficiencies</strong>.<br />
Foals<br />
Rickets is uncommon in foals under natural conditions, although it has been produced<br />
experimentally.<br />
PATHOGENESIS<br />
Dietary <strong>deficiencies</strong> <strong>of</strong> calcium, phosphorus, and vitamin D result in defective <strong>mineral</strong>ization <strong>of</strong><br />
the osteoid and cartilaginous matrix <strong>of</strong> developing bone. There is persistence and continued<br />
growth ot hypertroplnc epiphyseal cartilage, increasing the width <strong>of</strong> the epiphyseal plate. Poorly<br />
calcified spicules <strong>of</strong> diaphyseal bone and epiphyseal cartilage yield to normal stresses, resulting in<br />
bowing <strong>of</strong> long bones and broadening <strong>of</strong> the epiphyses with apparent enlargement <strong>of</strong> the joints.<br />
Rapidly growing animals on an otherwise good diet will be first affected because <strong>of</strong> their higher<br />
requirement <strong>of</strong> the specific <strong>nutrients</strong>.<br />
CLINICAL FINDINGS<br />
The subclinical effects <strong>of</strong> the particular deficiency disease will be apparent in the group <strong>of</strong> animals<br />
affected and have been described in the earlier general section. Clinical rickets is characterized <strong>by</strong>:<br />
• Stiffness in the gait<br />
• Enlargement <strong>of</strong> the limb joints, especially in the forelegs<br />
• Enlargement <strong>of</strong> the costochondral junctions<br />
• Long bones show abnormal curvature, usually forward and outward at the carpus in sheep and<br />
cattle<br />
• Lameness and a tendency to lie down for long periods.<br />
Outbreaks affecting 50% <strong>of</strong> a group <strong>of</strong> lambs have been described (3). Arching <strong>of</strong> the back and<br />
contraction, <strong>of</strong>ten to the point <strong>of</strong> virtual collapse, <strong>of</strong> the pelvis occur and there is an increased<br />
tendency for bones to fracture.<br />
Eruption <strong>of</strong> the teeth is delayed and irregular, and the teeth are poorly calcified with pitting,<br />
grooving, and pigmentation. They are <strong>of</strong>ten badly aligned, and wear rapidly and unevenly. These<br />
dental abnormalities, together with thickening and s<strong>of</strong>tness <strong>of</strong> the jaw bones, may make it<br />
impossible for severely affected calves and lambs to close their mouths. As a consequence the<br />
tongue protrudes, and there is drooling <strong>of</strong> saliva and difficulty in feeding. In less severely affected<br />
animals dental malocclusion may be a significant occurrence. Severe deformity <strong>of</strong> the chest may<br />
result in dyspnea and chronic ruminal tympany. In the final stages, the animal shows<br />
hypersensitivity, tetany, recumbency, and eventually dies <strong>of</strong> inanition.<br />
CLINICAL PATHOLOGY<br />
The plasma alkaline phosphatase is commonly elevated, but serum calcium and phosphorus levels<br />
depend upon the causative factor. If phosphorus or vitamin D <strong>deficiencies</strong> are the cause, the serum<br />
phosphorus level will usually be below
1545<br />
the normal lower limit <strong>of</strong> 3 mg/dL. The serum concentrations <strong>of</strong> 25-hydroxyvitamin D3 and<br />
25-hydroxyvitamin D2 are markedly decreased in vitamin D-deficient rickets compared with the<br />
normal values <strong>of</strong>≈ 5 ng/mL (3). Serum calcium levels will be low only in the final stages. In leg<br />
weakness <strong>of</strong> young, rapidly growing cattle, the serum concentration <strong>of</strong> 25-hydroxyvitamin D may<br />
be nondetectable and the serum levels <strong>of</strong> calcium and inorganic phosphorus may be low (2).<br />
Radiographic examination <strong>of</strong> bones and joints is one <strong>of</strong> the most valuable aids in the<br />
detection <strong>of</strong> rickets. Rachitic bones have a characteristic lack <strong>of</strong> density compared to normal bones.<br />
The ends <strong>of</strong> long bones have a 'woolly' or 'motheaten' appearance and have a concave or flat,<br />
instead <strong>of</strong> the normal convex, contour. Surgical removal <strong>of</strong> a small piece <strong>of</strong> costochondral junction<br />
for histological examination has been used extensively in experimental work and should be<br />
applicable in field diagnosis.<br />
NECROPSY FINDINGS<br />
Apart from general poorness <strong>of</strong> condition, the necropsy findings are restricted to abnormal bones<br />
and teeth.The bone shafts are s<strong>of</strong>ter and larger in diameter,due in part to the subperiosteal<br />
deposition <strong>of</strong> osteoid tissue. The joints are enlarged, and on cutting, the epiphyseal cartilage can<br />
be seen to be thicker than usual. Histological examination <strong>of</strong> the epiphysis is desirable for final<br />
diagnosis. In sheep, the best results are obtained from an examination <strong>of</strong> the distal cartilages <strong>of</strong> the<br />
metacarpal and metatarsal bones.<br />
A valuable diagnostic aid is the ratio <strong>of</strong> ash to organic matter in the bones. Normally the ratio is<br />
three parts <strong>of</strong> ash to two <strong>of</strong> organic matter but in rachitic bone this may be depressed to 1:2, or 1:3<br />
in extreme cases. A reduction below 45% <strong>of</strong> the bone weight as ash also suggests osteodystrophy.<br />
Because <strong>of</strong> the difficulty encountered in repeating the results <strong>of</strong> bone ash determinations, a<br />
standardized method has been devised in which the ash content <strong>of</strong> green bone is determined, using<br />
either the metacarpus or metatarsus, and the ash content related to the age <strong>of</strong> the animal, as<br />
expressed <strong>by</strong> the length <strong>of</strong> the bone. Although normal standards are available only for pigs, the<br />
method suggests itself as being highly suitable for all species.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
• Toxicology - long bone (ASSAY(ash)); 500 g feed (ASSAY (Ca) (P)(Vit D))<br />
•Histology - formalin-fixed long bone (including growth plate) (LM).<br />
DIFFERENTIAL DIAGNOSIS<br />
Rickets occurs in young, rapidly growing animals and is characterized <strong>by</strong> stiffness <strong>of</strong> the gait and<br />
enlargement <strong>of</strong> the distal physes <strong>of</strong> the long bones, particularly noticeable on the metacarpus and<br />
metatarsus as circumscribed painful swellings. A history <strong>of</strong> a dietary deficiency <strong>of</strong> any <strong>of</strong> calcium,<br />
phosphorus, or vitamin D will support the clinical diagnosis. Radiographic evidence <strong>of</strong> widened<br />
and irregular physes suggests rickets. Copper deficiency in young cattle under 1 year <strong>of</strong> age can<br />
also result in clinical, radiographic, and pathological findings similar to rickets. Clinically, there is<br />
an arched back, severe stiffness <strong>of</strong> gait, reluctance to move, and loss <strong>of</strong> weight. There are marked<br />
swellings <strong>of</strong> the distal aspects <strong>of</strong> metacarpus and metatarsus, and radiographically there is a<br />
widened zone <strong>of</strong> cartilage and lipping <strong>of</strong> the medial and lateral areas <strong>of</strong> the physeal plate. Copper<br />
concentration in plasma and liver are low and there is usually dietary evidence <strong>of</strong> copper<br />
deficiency.<br />
Epiphysitis occurs in rapidly growing yearling cattle raised and fed intensively under<br />
confinement. There is severe lameness, swelling <strong>of</strong> the distal physes, and radiographic and
pathological evidence <strong>of</strong> a necrotizing epiphysitis. The etiology is uncertain but thought to be<br />
related to the type <strong>of</strong> housing.<br />
Congenital and acquired abnormalities <strong>of</strong> the bony skeletal system are frequent in newborn<br />
and rapidly growing foals. Rickets occurs, but only occasionally. 'Epiphysitis' in young foals<br />
resembles rickets and is characterized <strong>by</strong> enlargements and abnormalities <strong>of</strong> the distal physes <strong>of</strong><br />
the radius, tibia, third metacarpal and metatarsal bones, and the proximal extremity <strong>of</strong> the<br />
proximal phalanx. There may or may not be deviation <strong>of</strong> the limbs <strong>caused</strong> <strong>by</strong> uneven growth rates<br />
in various growth plates. The suggested causes include improper nutrition, faulty conformation<br />
and ho<strong>of</strong> growth, muscle imbalance, overweight, and compression <strong>of</strong> the growth plate. Recovery<br />
may occur spontaneously or require surgical correction.<br />
Rickets in swine is uncommon and the diagnosis may be difficult. The disease is usually<br />
suspected in young, rapidly growing swine in which there is stiffness in the gait, walking on<br />
tiptoes, enlargements <strong>of</strong> the distal ends <strong>of</strong> long bones, and dietary evidence <strong>of</strong> a marginal<br />
deficiency <strong>of</strong> calcium or phosphorus. The radiographic and pathological findings may suggest a<br />
rickets-like lesion.<br />
Mycoplasmaj synovitis and arthritis clinically resemble rickets <strong>of</strong> pigs. There is a sudden<br />
onset <strong>of</strong> stiffness <strong>of</strong> gait, habitual recumbency, a decrease in feed consumption, and enlargements<br />
<strong>of</strong> the distal aspects <strong>of</strong> the long bones which may or may not be painful, spontaneous recovery<br />
usually occurs in 10-14 days. The locomotor problems in young, growing pigs raised in<br />
confinement and with limited exercise must be considered in the differential diagnosis. In<br />
performance testing stations, up to 20% <strong>of</strong> boars may be affected with leg weakness.<br />
Rickets in lambs must be differentiated from chlamydial and erysipelas arthritis, which are<br />
readily diagnosed at necropsy.<br />
TREATMENT AND CONTROL<br />
Recommendations for the treatment <strong>of</strong> the individual dietary <strong>deficiencies</strong> (calcium, phosphorus,<br />
and vitamin D) are presented under their respective headings. Lesser deformities recover with<br />
suitable treatment but gross deformities usually persist. A general improvement in appetite and<br />
condition occurs quickly, and is accompanied <strong>by</strong> a return to normal blood levels <strong>of</strong> phosphorus<br />
and alkaline phosphatase. The treatment <strong>of</strong> rickets in lambs with vitamin A, vitamin D3, calcium<br />
borogluconate solution containing magnesium and phosphorus parenterally, and supplementation<br />
<strong>of</strong> the diet with bone meal and protein resulted in a dramatic response (3) Recumbent animals<br />
were walking within a few days.<br />
REFERENCES<br />
(1)Thompson, K. G. & Cook, T. G. (1987) NZ Vet.J., 35, 11.<br />
(2)Sturen, M. (1985) Acta Vet. Scand., 26, 169.<br />
(3)Bonniwell, M. A. et al. (1988) Vet. Rec,122, 386.<br />
OSTEOMALACIA<br />
Osteomalacia is a disease <strong>of</strong> mature animals affecting bones in which endochondral ossification<br />
has been completed. The characteristic lesion is osteoporosis and the formation <strong>of</strong> excessive<br />
uncalcified<br />
1546<br />
matrix. Lameness and pathological fractures are the common clinical findings.<br />
Synopsis<br />
Etiology. Absolute or relative deficiency <strong>of</strong> any one or combination <strong>of</strong> calcium, phosphorus, and
vitamin D in adult animals.<br />
Epidemiology. Primarily in cattle and sheep on phosphorus-deficient diets. In feedlot animals due<br />
to excessive phosphorus without complementary calcium and vitamin D.<br />
Signs. Reduced productivity, licking and chewing inanimate objects, stiff gait, moderate non<br />
specific lameness, shifting from leg to leg, crackling sounds while walking, arched back, lying<br />
down for long periods. 'Milk lameness' in high-producing dairy cows on deficient diet<br />
Clinical pathology. Increased alkaline phosphatase, decreased serum phosphorus levels.<br />
Decreased density <strong>of</strong> long bones radiographically.<br />
Lesions. Decreased density <strong>of</strong> bones, erosions <strong>of</strong> articular cartilages.<br />
Diagnostic confirmation. Histology <strong>of</strong> bones.<br />
Differential diagnosis list:<br />
•Chronic fluorosis<br />
•Polysynovitis and arthritis<br />
•Spinal cord compression.<br />
Treatment. As for calcium, phosphorus, and vitamin D deficiency.<br />
Control. Adequate supplementation <strong>of</strong> diet.<br />
ETIOLOGY<br />
In general, the etiology and occurrence <strong>of</strong> osteomalacia are the same as for rickets except that the<br />
predisposing cause is not the increased requirement <strong>of</strong> growth but the drain <strong>of</strong> lactation and<br />
pregnancy.<br />
EPIDEMIOLOGY<br />
Osteomalacia occurs in mature animals under the same conditions and in the same areas as rickets<br />
in young animals, but is recorded less commonly. Its main occurrence is in cattle in areas seriously<br />
deficient in phosphorus. It is also recorded in sheep, again in association with hypophosphatemia.<br />
In pastured animals, osteomalacia is most common in cattle, and sheep raised in the same area are<br />
less severely affected. In feedlot animals, excessive phosphorus intake without complementary<br />
calcium and vitamin D is likely as a cause, especially if the animals are kept indoors. It also occurs<br />
in sows that have recently weaned their pigs after a long lactation period (6-8 weeks) while on a<br />
diet deficient usually in calcium. A marginal deficiency <strong>of</strong> both phosphorus and vitamin D will<br />
exaggerate the condition.<br />
PATHOGENESIS<br />
Increased resorption <strong>of</strong> bone <strong>mineral</strong> to supply the needs <strong>of</strong> pregnancy, lactation, and endogenous<br />
metabolism leads to osteoporosis and weakness and deformity <strong>of</strong> the bones. Large amounts <strong>of</strong><br />
uncalcified osteoid are deposited about the diaphyses. Pathological fractures are commonly<br />
precipitated <strong>by</strong> sudden exercise or handling <strong>of</strong> the animal during transportation.<br />
CLINICAL FINDINGS<br />
Ruminants<br />
In the early stages, the signs are those <strong>of</strong> phosphorus deficiency, including lowered productivity<br />
and fertility and loss <strong>of</strong> condition. Licking and chewing <strong>of</strong> inanimate objects begins at this stage<br />
and may : bring their attendant ills <strong>of</strong> oral, pharyngeal and esophageal obstruction, traumatic<br />
reticuloperitonitis, lead poisoning, and botulism.<br />
The signs specific to osteomalacia are those <strong>of</strong> a painful condition <strong>of</strong> the bones and joints, and<br />
include a stiff gait, moderate lameness <strong>of</strong>ten shifting from leg to leg, crackling sounds while
walking, and an arched back.The hindlegs are most severely affected and thehocks may be rotated<br />
inwards.The animals are disinclined to move, he down for long periods,and are<br />
unwilling togetup.The colloquial names 'pegleg' ,creeps' , 'stiffs', 'cripples' and 'bog-lame' describe<br />
the. syndrome aptly.The names and 'milk-lameness' are commonly applied to the condition when<br />
it occurs in heavily milking 'milkleg' cows. Fractures <strong>of</strong> bones and separation <strong>of</strong> tendon<br />
attachments occur frequently, <strong>of</strong>ten without apparent precipitating stress. In extreme cases,<br />
deformities <strong>of</strong> bones occur, and when the pelvis is affected dystocia may result. Finally, weakness<br />
leadsto permanent ; recumbency and death from starvation.<br />
Swine<br />
Affected sows are usually found recumbent and unable to rise from lateral recumbency or from<br />
the dog-sitting position. The shaft <strong>of</strong> one femur or the neck <strong>of</strong> the femur is commonly fractured.<br />
The fracture usually occurs within a few days following weaning <strong>of</strong> the pigs. The placing <strong>of</strong> the<br />
sow with other adult pigs usually results in some fighting and increased exercise, which<br />
commonly precipitates the pathological fractures.<br />
CLINICAL PATHOLOGY<br />
In general, the findings are the same as those for rickets, including increased scrum alkaline<br />
phosphatase and decreased serum phosphorus levels. Radiographic examination <strong>of</strong> long bones<br />
shows decreased density <strong>of</strong> bone shadow.<br />
NECROPSY FINDINGS<br />
It can be difficult to discern any gross changes as the epiphyses are seldom enlarged and the<br />
altered character <strong>of</strong> cancellous bone may not be macroscopically visible. Cortical bone may be<br />
somewhat thinned and erosions <strong>of</strong> the articular cartilages have been recorded in cattle suffering<br />
from primary phosphorus deficiency. The parathyroid glands maybe enlarged. Histologicially ,<br />
abnormal ostoid covers trabeculae and a degree <strong>of</strong> fibrous tissue proliferation is <strong>of</strong>ten evident.<br />
<strong>An</strong>alysis reveals the bones to be lighter than normal with a low ratio <strong>of</strong> ash to organic matter.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
•Toxicology – long bone (ASSAY (ash)); 500 g feed(ASSAY (Ca) (P) (Vit D))<br />
•Histology - formalin-fixed bone, parathyroid(LM).<br />
DIFFERENTIAL DIAGNOSIS<br />
The occurrence <strong>of</strong> non-specific lameness with pathological fractures in mature animals should<br />
arouse suspicion <strong>of</strong> osteomalacia. There may be additional evidence <strong>of</strong> subnormal productivity<br />
and reproductive performance, and dietary evidence <strong>of</strong> a recent deficiency <strong>of</strong> calcium, phosphorus,<br />
or vitamin D.<br />
A similar osteoporotic disease <strong>of</strong> cattle in Japan has been ascribed to a dietary deficiency <strong>of</strong><br />
magnesium. The cattle are on high-concentrate , low-roughage diets, have high serum calcium<br />
and alkaline phosphatase levels, but a low serum magnesium level. The osteoporosis is observable<br />
at slaughter and clinical signs observed are those <strong>of</strong> intercurrent disease,<br />
1547<br />
especially ketosis, milk fever, and hypomagnesemia. Reproductive and renal disorders occur<br />
concurrently.<br />
In cattle it must be differentiated from chronic fluorosis in mature animals, but the typical<br />
mottling and pitting <strong>of</strong> the teeth and the enlargements on the shafts <strong>of</strong> the long bones are<br />
characteristic. In some areas, e.g. northern Australia, where the water supply is obtained from<br />
deep subartesian wells, the two diseases may occur concurrently. <strong>An</strong>alysis <strong>of</strong> water supplies and
foodstuffs for fluorine may be necessary in doubtful cases.<br />
In sows, osteomalacia with or without pathological fractures must be differentiated from spinal<br />
cord compression due to a vertebral body abscess and chronic arthritis due to erysipelas.<br />
TREATMENT AND CONTROL<br />
Recommendations for the treatment and control <strong>of</strong> the specific nutritional <strong>deficiencies</strong> have been<br />
described under their respective headings. Some weeks will elapse before improvement occurs<br />
and deformities <strong>of</strong> the bones are likely to be permanent.<br />
OSTEODYSTROPHIA FIBROSA<br />
Osteodystrophia fibrosa is similar in its pathogenesis to osteomalacia, but differs in that s<strong>of</strong>t,<br />
cellular, fibrous tissue is laid down as a result <strong>of</strong> the weakness <strong>of</strong> the bones instead <strong>of</strong> the<br />
specialized uncalcified osteoid tissue <strong>of</strong> osteomalacia. It occurs in horses, goats, and swine.<br />
ETIOLOGY<br />
A secondary calcium deficiency due to excessive phosphorus feeding is the common cause in<br />
horses and probably also in pigs. The disease can be readily produced in horses on diets with a<br />
ratio <strong>of</strong> calcium:phosphorus <strong>of</strong> 1 :2.9 or greater, irrespective <strong>of</strong> the totalcalcium intake.<br />
Calcium :phosphoru ratios <strong>of</strong> 1:0.9 to 1:1.4 have been shown to be preventive and curative. With a<br />
very low calcium intake <strong>of</strong> 2-3 g/day and a calcium: phosphorus ratio <strong>of</strong> 1: 13 the disease may<br />
occur within 5 months. With a normal calcium intake <strong>of</strong> 26 g/day and a calcium: phosphorus ratio<br />
<strong>of</strong> 1:5, obvious signs appear ; in about 1 year, but shifting lameness may appear as early as 3<br />
months. The disease is reproducible in pigs on similar diets to those described above and also on<br />
diets low in both calcium and phosphorus. The optimum calcium: phosphorus ratio is 1.2:1 and<br />
the intake for pigs should be within the range<strong>of</strong> 0.6-1.2%<strong>of</strong> the diet.<br />
EPIDEMIOLOGY<br />
Osteodystrophia fibrosa is principally a disease <strong>of</strong> horses and other Equidae, and to a lesser extent<br />
<strong>of</strong> pigs. It has also occurred in goats. Amongst horses, those engaged in heavy city work and in<br />
racing are more likely to be affected because <strong>of</strong> the tendency to maintain these animals on<br />
unbalanced diets. The major occurrence is in horses fed a diet high in phosphorus and low in<br />
calcium. Such diets include cereal hays combined with heavy gram or bran feeding. Legume hays,<br />
because <strong>of</strong> their high calcium content, are preventive.<br />
The disease may reach endemic proportions in army horses moved into new territories, whereas<br />
local horses, more used to the diet, suffer little. Although horses may be affected at any age after<br />
weaning it is the 2-7-year age group that suffer most, probably because they are the group most<br />
likely to be exposed to the rations that predispose to the disease.<br />
A novel occurrence has been recorded <strong>of</strong> an endemic form <strong>of</strong> the disease affecting large<br />
numbers <strong>of</strong> horses at pasture. The dietary intake <strong>of</strong> calcium and phosphorus, and their proportions,<br />
were normal. The occurrence was thought to be due to the continuous ingestion <strong>of</strong> oxalate in<br />
specific grasses: Cenchrus ciharis, Panicum maximum var. trichoglume, Setaria anceps,<br />
Brachiaria mutica and Pennisetum clandestinum.<br />
PATHOGENESIS<br />
Defective <strong>mineral</strong>ization <strong>of</strong> bones follows the imbalance <strong>of</strong> calcium and phosphorus in the diet,<br />
and a fibrous dysplasia occurs. This may be in response to the weakness <strong>of</strong> the bones or it may be<br />
more precisely a response to hyperparathyroidism stimulated <strong>by</strong> the excessive intake <strong>of</strong><br />
phosphorus. The weakness <strong>of</strong> the bones predisposes to fractures and separation <strong>of</strong> muscular and<br />
tendinous attachments. Articular erosions occur commonly and displacement <strong>of</strong> the bone marrow
may cause the development <strong>of</strong> anemia.<br />
CLINICAL FINDINGS<br />
Horse<br />
As in most osteodystrophies, the major losses are probably in the early stages before clinical signs<br />
appear or on diets where the aberration is marginal. In horses, a shifting lameness is characteristic<br />
<strong>of</strong> this stage <strong>of</strong> the disease and arching <strong>of</strong> the back may sometimes occur. The horse is lame, but<br />
only mildly so, and in many cases no physical deformity can be found <strong>by</strong> which the seat <strong>of</strong><br />
lameness can be localized. Such horses <strong>of</strong>ten creak badly in the joints when they walk. These<br />
signs probably result from relaxation <strong>of</strong> tendon and ligaments and appear in different limbs at<br />
different times. Articular erosions may contribute to the lameness. In more advanced cases severe<br />
injuries, including fracture and visible sprains <strong>of</strong> tendons, may occur but these are not specific to<br />
osteodystrophia fibrosa, although their incidence is higher in affected than in normal horses.<br />
Fracture <strong>of</strong> the lumbar vertebrae while racing has been known to occur in affected horses.<br />
The more classical picture <strong>of</strong> the disease has largely disappeared because cases are seldom<br />
permitted to progress to this advanced stage. Local swelling <strong>of</strong> the lower and alveolar margins <strong>of</strong><br />
the mandible is followed <strong>by</strong> s<strong>of</strong>t, symmetrical enlargement <strong>of</strong> the facial bones, which may become<br />
swollen so that they interfere with respiration (1). Initially these bony swellings are firm and<br />
pyramidal and commence just above and anterior to the facial crests.The lesions are bilaterally<br />
symmetrical. Flattening <strong>of</strong> the ribs may be apparent, and fractures and detachment <strong>of</strong> ligaments<br />
occur if the horse is worked. There may be obvious swelling <strong>of</strong> joints and curvature <strong>of</strong> long bones.<br />
Severe emaciation and anemia occur in the final stages.<br />
Swine<br />
In pigs, the lesions and signs are similar to those in the horse and in severe cases pigs may be<br />
unable to rise and walk, show gross distortion <strong>of</strong> limbs, and enlargement <strong>of</strong> joints and the face. In<br />
less severe cases there is lameness, reluctance to rise, pain on standing, and bending <strong>of</strong> the limb<br />
bones, but normal facial bones and joints. With suitable treatment the lameness disappears, but<br />
affected pigs may never attain their full size. The relationship <strong>of</strong> this disease to atrophic rhinitis is<br />
discussed under the latter heading.<br />
CLINICAL PATHOLOGY<br />
There are no significant changes in blood chemistry in horses affected with severe osteodystrophia<br />
fibrosa. However,the<br />
1548<br />
serum calcium level will tend to be lower than normal, the serum inorganic phosphorus higher<br />
than normal, and the alkaline phosphatase activity higher than normal. The levels <strong>of</strong> diagnostic<br />
alkaline phosphatase have not been determined. Affected horses may be unable to return their<br />
serum calcium levels to normal following the infusion <strong>of</strong> a calcium salt. Radiographic<br />
examination reveals increased translucency <strong>of</strong> bones.<br />
NECROPSY FINDINGS<br />
The entire skeleton is abnormal in this severe form <strong>of</strong> metabolic bone disease, but the change is<br />
most notable in the mandibular, maxillary and nasal bones, which may appear thickened and<br />
distorted. The fleshy tissue that replaces normal cancellous bone in these sites is also present in<br />
the metaphyses <strong>of</strong> the long bones. Microscopically, there is proliferation <strong>of</strong> fibrous tissue and<br />
markedly increased osteoclast activity along thinned and abnormally oriented bony trabeculae.<br />
The parathyroid glands are enlarged. It must be remembered that osteodystrophia fibrosa is a
lesion, not a disease. The pathway to this lesion usually involves a dietary unbalance in calcium<br />
and phosphorus, but the kidneys should also be examined to rule out the possibility <strong>of</strong> renal<br />
secondary hyperparathyroidism.<br />
Samples for confirmation <strong>of</strong> diagnosis<br />
•Toxicology -bone(ASSAY(ash));500 g feed (ASSAY (ca) (P) (Vit D))<br />
•Histologyformalin-fixed bone,parathyroid gland, kidney (LM).<br />
DIFFERENTIAL DIAGNOSIS<br />
In the early stages, the diagnosis may be difficult because <strong>of</strong> the common occurrence <strong>of</strong> traumatic<br />
injuries to horses' legs. A high incidence <strong>of</strong> lameness in a group <strong>of</strong> horses warrants examination<br />
<strong>of</strong> the ration and determination <strong>of</strong> their calcium and phosphorus status. <strong>An</strong> identical clinical<br />
picture has been described in a mare with an adenoma <strong>of</strong> the parathyroid gland. Inherited<br />
multiple exostosis has been described in the horse.<br />
In pigs, osteodystrophia can be the result <strong>of</strong> hypovitaminosis A, and experimentally as a result <strong>of</strong><br />
manganese deficiency.<br />
TREATMENT AND CONTROL<br />
A ration adequately balanced with regard to calcium and phosphorus<br />
(calcium:phosphorus should be in the vicinity <strong>of</strong> 1:1 and not wider than 1:1.4) is preventive in<br />
horses and affected animals can only be treated <strong>by</strong> correcting the existing imbalance. Even severe<br />
lesions may disappear in time with proper treatment. Cereal hay may be supplemented with alfalfa<br />
or clover hay, or finely ground limestone (30 g daily) should be fed. Dicalcium phosphate or bone<br />
meal are not as efficient because <strong>of</strong> their additional content <strong>of</strong> phosphorus.<br />
REFERENCE<br />
(1) Clarke, C.J. et al. (1996) Vet. Rec., 138, 568.'BOWIE' OR 'BENTLEG'<br />
This is a disease <strong>of</strong> lambs <strong>of</strong> unknown etiology. There is a characteristic lateral curvature <strong>of</strong> the<br />
long bones <strong>of</strong> the front legs, but the lesions differ from those <strong>of</strong> ricket. It has been observed only<br />
on unimproved range pasture in New Zealand. The cause is unknown, although phosphorus<br />
deficiency has been suggested.<br />
Improvement <strong>of</strong> the pasture <strong>by</strong> top-dressing with superphosphate and sowing-improved grasses<br />
is usually followed <strong>by</strong> disappearance <strong>of</strong> the disease.Only sucking lambs are affected and cases<br />
occur only in the spring at a time when rickets does not occur. Up to 40% <strong>of</strong> a group <strong>of</strong> lambs may<br />
be affected without breed differences in incidence. A similar syndrome has been produced <strong>by</strong> the<br />
feeding <strong>of</strong> wild parsnip (Trachemene glautifolia) and, experimentally, <strong>by</strong> the feeding <strong>of</strong> a diet low<br />
in both calcium and phosphorus.<br />
The disease has also been reported from South Africa where it occurs primarily in ram lambs<br />
and develops from as early as 3 months up to 1 year <strong>of</strong> age (1). There is gradual bending <strong>of</strong> the<br />
forelimbs with hooves turned inwards and the carpal joints turned outwards. <strong>An</strong>imals <strong>of</strong> the South<br />
African Mutton Merino breed had significantly higher plasma phosphorus concentrations than<br />
those <strong>of</strong> the Merino and Dohne Merino breeds. The plasma calcium: phosphorus ratio was lower<br />
in affected lambs and their ewes, and this converse ratio is thought to result in an induced plasma<br />
ionized calcium deficiency leading to improper calcification <strong>of</strong> bone.<br />
Some tenderness <strong>of</strong> the feet and lateral curvature at the knees may be seen as early as 2-3 weeks<br />
<strong>of</strong> age and marked deformity is present at 6-8 weeks with maximum seventy at weaning. The<br />
forelimbs are more commonly affected than the hindlimbs. Medial curvature occurs in rare cases.<br />
The sides <strong>of</strong> the feet become badly worn, and the lateral aspects <strong>of</strong> the lower parts <strong>of</strong> the limbs
may be injured and be accompanied <strong>by</strong> lameness. The lambs grow well at first, but <strong>by</strong> the time <strong>of</strong><br />
weaning, affected lambs are in poor condition because <strong>of</strong> their inability to move about and feed<br />
properly. A rather similar syndrome has been observed in young Saanen bucks, but the condition<br />
showed more tendency to recover spontaneously.<br />
At necropsy in spite <strong>of</strong> the curvature <strong>of</strong> the limbs there is no undue porosis, and although the<br />
epiphyseal cartilages are thickened they are supported <strong>by</strong> dense bone. There may be excessive<br />
synovial fluid in the joints and, in the later stages, there are articular erosions. Increased deposition<br />
<strong>of</strong> osteoid is not observed.<br />
Supplementation <strong>of</strong> the diet with phosphorus or improvement <strong>of</strong> the pasture seems to reduce the<br />
incidence <strong>of</strong> the disease. Dosing with vitamin D or providing <strong>mineral</strong> mixtures containing all trace<br />
elements is ineffective (2).<br />
REFERENCES<br />
(1)van Niekerk, F. E. c-t al. (1989)J South Ajr.Vet. hM. Assoc., 60, 36.<br />
(2)Cunningham, I.J. (1957) NZ I'ei.J.. 5, 103.<br />
DEGENERATIVE JOINT DISEASE<br />
Degenerative arthropathy occurs in cattle <strong>of</strong> all breeds, but reaches its highest incidence as a<br />
sporadic disease <strong>of</strong> young beef bulls. The disease has been identified as hip dysplasia because <strong>of</strong><br />
the pre-existing shallow contour <strong>of</strong> the acetabulum. It is considered to be inherited as a recessive<br />
characteristic and exacerbated <strong>by</strong> rapid weight gain in young animals. The occurrence <strong>of</strong> the<br />
condition in these animals is usually associated with rearing on nurse cows, housing for long<br />
periods, provision <strong>of</strong> a ration high in cereal grains and <strong>by</strong>products (a high phosphorus:calcium<br />
ratio), and possibly with an inherited straight conformation <strong>of</strong> the hindlegs. Although the disease<br />
occurs in all beef breeds there is a strong familial tendency which appears to be directly related to<br />
the rate <strong>of</strong> body weight gain and the straightness<br />
1549<br />
<strong>of</strong> the hindleg. If the potential for rapid weight gain is being realized in animals being force fed,<br />
the rate <strong>of</strong> occurrence appears to be dependent on their breeding, and animals in the same herd that<br />
are allowed to run at pasture under natural conditions are either not affected or are affected at a<br />
much later age. Thus, animals in a susceptible herd may show signs as early as 6 months <strong>of</strong> age if<br />
they are heavily hand-fed and raised on dairy cow foster mothers. In the same herd, signs do not<br />
appear until 1-2 years <strong>of</strong> age if supplementary feeding is not introduced until weaning, and not<br />
until 4 years if there is no significant additional feeding.<br />
Clinically there is a gradual on set <strong>of</strong> lameness in one or both hindlegs. The disease progresses<br />
with the lameness becoming more severe over a period <strong>of</strong> 6-12 months. In some animals there is a<br />
marked sudden change for the worse, usually related to violent muscular movements, as in<br />
breeding or fighting. In severely affected animals the affected limb is virtually useless and, on<br />
movement, distinct crepitus can <strong>of</strong>ten be felt and heard over the affected joints. This can be<br />
accomplished <strong>by</strong> rocking the animal from side to side or having it walk while holding the hands<br />
over the hip joints.<br />
<strong>An</strong> additional method <strong>of</strong> examination is to place the hand in the rectum close to the hip joint,<br />
whilst the animal is moved. Passive movement <strong>of</strong> the limb may also elicit crepitus, or louder<br />
clinking or clicking sounds. The hip joints are always most severely affected, but in advanced<br />
cases there may be moderate involvement <strong>of</strong> the stifles and minimal lesions in other joints.<br />
Affected animals lie down most <strong>of</strong> the time and are reluctant to rise and to walk. The joints are not
swollen, but in advanced cases local atrophy <strong>of</strong> muscles may be so marked that the joints appear to<br />
be enlarged. There is a recorded occurrence in which the lesions were confined mainly to the front<br />
fetlocks.<br />
Radiographic examination may provide confirmatory or diagnostic evidence.<br />
At necropsy the most obvious finding is extensive erosion <strong>of</strong> the articular surfaces, <strong>of</strong>ten<br />
penetrating to the cancellous bone, and disappearance <strong>of</strong> the normal contours <strong>of</strong> the head <strong>of</strong> the<br />
femur or the epiphyses in the stifle joint. The synovial cavity is distended, with an increased<br />
volume <strong>of</strong> brownish, turbid fluid, the joint capsule is much thickened and <strong>of</strong>ten contains calcified<br />
plaques. Multiple, small exostoses are present on the periarticular surfaces. When the stifle is<br />
involved the cartilaginous menisci, particularly the medial one, are very much reduced in size and<br />
may be completely absent. In cattle with severe degenerative changes in the cox<strong>of</strong>emoral joint, an<br />
acetabular osseous bulla may be present at the cranial margin <strong>of</strong> the obturator foramen (1).<br />
Adequate calcium, phosphorus and vitamin D intake, and a correct calcium:phosphorus ratio in<br />
the ration should be insured. Supplementation <strong>of</strong> the ration with copper at the rate <strong>of</strong> 15 mg/kg has<br />
also been recommended for the control <strong>of</strong> a similar disease.<br />
Degenerative joint disease <strong>of</strong> cattle is recorded on an enzootic scale in Chile and is thought to<br />
be due to gross nutritional deficiency. The hip and tarsal joints are the only ones affected and<br />
clinical signs appear when animals are 8-12 months old. There is gross lameness and progressive<br />
emaciation. <strong>An</strong> inherited osteoarthntis is described under that heading. Sporadic cases <strong>of</strong><br />
degenerative arthropathy, with similar signs and lesions, occur in heavy-producing, aged dairy<br />
cows, and are thought to be <strong>caused</strong> <strong>by</strong> long-continued negative calcium balance. Rare cases also<br />
occur in aged beef cows but are thought to be associated with an inherited predisposition. In both<br />
instances the lesions are commonly restricted to the stifle joints.