barcelona . spain - European Association for the Study of the Liver
barcelona . spain - European Association for the Study of the Liver
barcelona . spain - European Association for the Study of the Liver
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BARCELONA . SPAIN<br />
88 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 89<br />
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012<br />
<strong>the</strong> global damage and disturbing cell repair mechanisms. The specific organ damage inflicted by EtOH<br />
depends on <strong>the</strong> final balance between damaging and local defensive host mechanisms.<br />
As it occurs in o<strong>the</strong>r organs, ALD is a dose-dependent disease where total lifetime and duration <strong>of</strong> alcohol<br />
consumption is highly relevant. But this process is also modulated by genetic and personal predisposing<br />
factors with organ-specific susceptibility. The systemic noxious effect <strong>of</strong> EtOH is modulated according to <strong>the</strong><br />
characteristics <strong>of</strong> <strong>the</strong> involved cells. Thus, excitable cells such as neurons and cardiac or skeletal myocytes<br />
mainly suffer <strong>of</strong> disruption in transduction signalling systems at <strong>the</strong> level <strong>of</strong> <strong>the</strong> cytosolic membrane<br />
(receptors, channels) and organelles (mitochondria, sarcoplasmic reticulum, sarcomere). O<strong>the</strong>rwise, nonexcitable<br />
cells will receive <strong>the</strong> effect <strong>of</strong> metabolic, oxidative, inflammatory, hormonal and immune damage<br />
generated by ALD.<br />
In general, progression <strong>of</strong> alcohol-mediated tissue<br />
damage starts with non-detectable or transitory effect,<br />
followed by subclinical dysfunction without structural<br />
damage and progressing to subclinical dysfunction with<br />
structural damage. Afterwards, clinical effects appear<br />
with reversible structural damage and, finally progress<br />
to advanced clinical effects with irreversible structural<br />
damage.<br />
Relationship between ALD and systemic damage<br />
has been largely discussed. It was previously said<br />
that <strong>the</strong> presence <strong>of</strong> ALD spared <strong>the</strong> development <strong>of</strong><br />
cardiomyopathy (CMP). However, a clear relationship<br />
between <strong>the</strong> presence and degree <strong>of</strong> hepatic and cardiac<br />
damage by EtOH has been recently corroborated. Dilated<br />
CMP is also dose-dependent. Diastolic dysfunction<br />
appears at lifetime ethanol consumption > 5 Kg/Kg in<br />
one-third <strong>of</strong> subjects, and systolic dysfunction develops<br />
in 13% <strong>of</strong> subjects with lifetime ethanol consumption ><br />
9 Kg/Kg. If ethanol consumption is maintained, subjects<br />
develop low-output heart failure, arrhythmias and<br />
sudden death. In addition, ethanol increases <strong>the</strong> effect<br />
<strong>of</strong> o<strong>the</strong>r risk factors in <strong>the</strong> heart such as tobacco and<br />
cocaine.<br />
Similarly, skeletal myopathy is present in more than half <strong>of</strong> patients with liver cirrosis. It starts at subclinical<br />
level in lifetime consumption <strong>of</strong> 10Kg/Kg, and usually is clinically apparent with limb muscle weakness and<br />
atrophy in lifetime ethanol consumption >20Kg/Kg.<br />
Ethanol decreases bone density. In fact, one third <strong>of</strong> alcohol misusers develop osteoporosis in a dosedependent<br />
effect that starts at 20g/day ethanol consumption. There is an additional effect <strong>of</strong> liver disease,<br />
malnutrition and Vitamin D deficiency.<br />
Ethanol increases <strong>the</strong> risk <strong>of</strong> neurological damage In a dose-dependent manner. Hemorrhagic stroke<br />
appears at daily ethanol consumption > 60g/day (RR 2.18). Alcoholic-induced brain impairment leading to<br />
alcoholic dementia is present in 70% <strong>of</strong> alcohol misusers consuming >4 Kg/Kg. Cerebellum degeneration<br />
may be detected in 30% alcohol misusers. Wernicke’s Korsakow encephalopathy, Marchiafava-Bignami<br />
disease, central pontine myelinolysis and pellagra develops in chronic alcoholics with malnutrition, thyamin<br />
or o<strong>the</strong>r vitamin deficiencies and ionic disturbances. Peripheral and autonomic neuropathies develop in<br />
daily ethanol consumptions higher than 40g in women and 60 g. in men, being 20% clinically apparent and<br />
70% subclinical, only detected by EMG Studies.<br />
Ethanol frequently produces protein and caloric type <strong>of</strong> malnutrition and vitamin deficiencies. In fact ethanol<br />
consumption is <strong>the</strong> most important cause <strong>of</strong> malnutrition in Western Countries. Its effect has a multifactorial<br />
etiology (malabsorption, metabolic disturbances) and mainly involves high-dose ethanol consumers (>20<br />
Kg OH/Kg). This is associated with ALD and o<strong>the</strong>r systemic diseases. Malnutrition clearly increases EtOH<br />
damaging effect. There<strong>for</strong>e, malnutrition should be evaluated and corrected to decrease EtOH –induced<br />
tissue damage.<br />
ALD produces dramatic changes in redox state, episodes <strong>of</strong> oxidative stress and generates damaging<br />
products such as ROS, acetaldehyde, acetate and fatty acid ethyl es<strong>the</strong>rs. These aldehydes can rapidly<br />
<strong>for</strong>m covalent protein adducts that alter lipid and protein structure and play a role in derangements <strong>of</strong><br />
hepatic, cardiac, brain and muscle function. In addition, increased levels <strong>of</strong> circulating endotoxins and proinflammatory<br />
cytokines decrease cellular defensive mechanism and induce infections and auto-inflammation.<br />
Kuppfer cells generate TNF-α and promote signalling pathways such a stress-activated-mitogen-proteinkinase<br />
(MAPK) cascade that mediates in systemic cell injury. Resistin is a intra-hepatic cytokine with proinflammatory<br />
actions in hepatic stellate cells, but also with o<strong>the</strong>r significant systemic effects. Insulin-like<br />
growth factor (IGF) resistance is mainly generated in ALD but producing cardiac and brain damage. Since<br />
EtOH affects immune cell functions though dendritic cell dysfunction, Kupffer cells play a key role in this<br />
process. ALD activates pro-apoptotic mechanisms with systemic noxious effects, increasing cell loss and<br />
inhibiting <strong>the</strong> possibility <strong>of</strong> tissue proliferation or repair. Also, disturbances in transcriptional mechanisms<br />
and DNA damage are frequent cause <strong>of</strong> this systemic effect <strong>of</strong> ALD. Tissue regeneration is affected by<br />
excessive alcohol, with low rate <strong>of</strong> renewal capacity in some tissues.<br />
There are common genetic predisposition conditions in ALD such is ALDH2 deficiency, that also supposes<br />
a major risk to develop CMP. In ALD, <strong>the</strong> RAS system increases fibrogenesis through angiotensin II<br />
production. Similarly, in <strong>the</strong> heart <strong>the</strong> “DD” genotype <strong>of</strong> ACE increases <strong>the</strong> risk to develop alcoholic CMP.<br />
Gender differences make women more susceptible to ALD than men, similarly to that happen <strong>for</strong> heart,<br />
muscle and nervous system damage. The presence <strong>of</strong> caloric and protein malnutrition increases <strong>the</strong> risk<br />
<strong>of</strong> EtOH-induced tissue damage.<br />
To summarize, in presence <strong>of</strong> ALD we should consider <strong>the</strong> possible development <strong>of</strong> alcohol-mediated<br />
systemic organ damage, mainly neurologic, cardiovascular and nutritional. Its development depends on<br />
<strong>the</strong> quantity and duration <strong>of</strong> alcohol consumption in each individual, but is modulated by genetic, metabolic<br />
and local tissue factors, with clear organ specificity. Since most pathogenic factors that mediate ALD also<br />
influence in widespread organ damage, ALD should be considered a systemic disease. There is direct<br />
relationship between <strong>the</strong> liver and systemic damage. The greater <strong>the</strong> liver damage <strong>the</strong> greater <strong>the</strong> systemic<br />
damage expected.<br />
There<strong>for</strong>e, to improve global health <strong>of</strong> <strong>the</strong> subject with ALD a multidisciplinary management approach is<br />
necessary to be established.<br />
CONCLUSION<br />
ALD does not involve just <strong>the</strong> liver, but is a real systemic disease.<br />
As screening to evaluate systemic organ damage in ALD, we suggest to per<strong>for</strong>m:<br />
• Heart:<br />
• Muscle:<br />
• Peripheral nerve:<br />
• Brain:<br />
• Nutrition:<br />
• Immunity:<br />
• Bone:<br />
Chest X-ray, ECG, Echosonography<br />
Strength, CK, EMG, Muscle biopsy<br />
Reflex, EMG, Muscle / Nerve biopsy<br />
Brain CT or MR, Cognitive tests<br />
Antropometric, analytic protein /vitamin pr<strong>of</strong>ile<br />
Ig, lymphocyte subsets, Immunocomplexes<br />
X-ray, Densitometry