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

BARCELONA . SPAIN
34 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 35
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
Whether the type of alcoholic drink consumed, e.g. wine as opposed to beer or hard liquor, impacts the risk
of ALD is still controversial, however, consensus among scientists exists that it is the content of pure alcohol
that likely outweighs all other constituents in different drinks that may potentially modulate the biological
effects of alcohol. Patterns of drinking vary substantially among patients with ALD and may influence the
risk of ALD. There are conflicting data on this issue, but several recent studies comparing daily vs. binge
drinkers showed that the former had a higher risk of cirrhosis (4). However, it is worrisome that countries
with a high prevalence of binge-drinking, such as the UK, reveal a marked increase of cirrhosis mortality per
year of 3.4 in 1957-61 to 14.1/100.000 in 1997-2001 which may rather reflect a rising incidence of harmful
drinking predicting long-term alcohol abuse (5).
GENETIC VARIANTS ASSOCIATED WITH ALD
In the search for genetic risk factors for ALD tremendous work has been afforded, however, most investigated
genetic variants were not confirmed in independent case control studies. If commonly accepted quality
criteria for candidate gene case control studies are applied, only few studies bear a certain degree of
scrutiny, as many of them are hampered by one or several limitations as outlined in table 1.
An unequivocal risk factor for fibrosis progression in ALD is obesity, with numerous studies demonstrating
that overweight is the most important single risk factor of cirrhosis and necroinflammation in heavy drinkers
(6). The synergy between obesity and heavy alcohol intake presumably reflects similar mechanisms of
disease for both ALD and non-alcoholic fatty liver disease, such as increased oxidative stress via induction
of CYP450 2E1, upregulated secretion of proinflammatory cytokines from adipose tissue, and an expanded
mass of adipose tissue secreting profibrogenic factors such as noradrenaline, angiotensin II and leptin in
combination with low levels of adiponectin.
Numerous case-control, cross-sectional, and cohort studies have unequivocally shown that co-existence of
alcohol misuse and chronic hepatitis C virus infection significantly increases the risk of developing cirrhosis
(7). Together, these data show that individuals with chronic hepatitis C who drink more than 40g per day
increase their risk of developing cirrhosis approximately 4-fold.
HOST GENETICS AND RISK OF ALD
Three lines of evidence suggest an at least partial genetic background of the ALD phenotype: 1. Women
are more susceptible for ALD when exposed to similar amounts of alcohol; 2. Hispanics are more prone to
developing ALD than Blacks and Whites; 3. Twin studies demonstrate that monozygotic twins have a higher
prevalence of alcoholic cirrhosis than dizygotic twins.
Gender-specific susceptibility towards alcohol has been recognized for long. Studies in humans have
demonstrated that women are more susceptible towards the hepatotoxic effects of alcohol, and develop
ALD more quickly with equal amounts of daily alcohol consumption than men (8). The pathophysiology
behind this increased sensitivity to alcohol is not yet fully understood but could be – among other factors
– related to hormonal differences such as estrogens and their synergistic impact on oxidative stress and
inflammation. Gender-related metabolic differences also exist, and women drinking equal amounts of
alcohol reveal higher blood ethanol levels than men due to higher gastric alcohol dehydrogenase levels
resulting in a faster first-pass metabolism of alcohol in men, or to a lower volume of distribution for alcohol
in women compared to men.
Different ethnic groups reveal notable differences in the prevalence of ALD and associated mortality.
However, such seemingly ethnic differences in rates of alcoholic cirrhosis and ALD could also be related to
the amount and type of alcohol consumed, dietary traditions, differences in socioeconomic status, access
to medical care, and/or differences in attitudes towards a healthy life style.
The identification of the genetic background of iron overload by detection of mutations within the
hemochromatosis (HFE) gene gave rise to the hypothesis whether their presence may also affect iron
storage in alcohol abusers. However, genetic case control studies with adequate matching of cases and
controls for age, sex, and alcohol consumption detected no increased prevalence of HFE mutations in
alcoholics with liver disease including cirrhosis (9).
While genetic variation of the ADH, ALDH and GABA system have been consistently found associated with
alcohol dependence, this risk is not further conveyed to developing ALD. In fact, only two candidate gene
polymorphisms reveal sufficient data to consider them highly suspicious as genetic risk factors for ALD.