barcelona . spain - European Association for the Study of the Liver

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