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

BARCELONA . SPAIN
122 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 123
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
Chronic alcohol consumption in hepatitis C not only stimulates fibrogenesis but also hepatocarcinogenesis
demonstrated by a number of studies. In the study by Tagger and co-workers from Italy (12) alcohol of
more than 80 grams per day increased the risk for HCC significantly by a factor of 7.3 when compared to
less than 40 grams. In hepatitis C patients this risk increased to 126. It also should be noted that hepatitis
C patients with less than 40 grams ethanol per day showed an increased risk for HCC with an odds ratio of
26 as compared to non-alcohol consumers. Additional results were obtained from Hassan and co-workers
from the US (13). In this study, it has been shown that those patients with hepatitis C who consume alcohol
had a relative risk of 54 as compare to 19 in those who abstained from alcohol.
IN SUMMARY
1. Fibrogenesis is dose independent and starts already at small alcohol doses (below 30 g/day).
There is no safe alcohol dose in patients with HCV infection. It has to be emphasized that
patients with overweight and obesity as well as diabetics are especially on risk.
2. HCV patients with excessive alcohol abuse have a 2 to 3 fold increased risk to develop a
severe liver disease compared with HCV patients without any alcohol history.
3. It is still unclear how long a patient has to be alcohol abstinent until a negative effect of
alcohol disappears.
4. Alcoholics with a HCV infection are easier to motivate for abstinence as compared to
alcoholics without HCV infection.
Effect of alcohol on the response to HCV therapy
Alcoholics have a poorer response rate to interferon therapy. The question appears whether this is an
inhibitory effect of alcohol or non-compliance. It has to be emphasized that there was an increased rate of
non-compliance in 726 patients with alcohol consumption during the last 10 months of therapy. When noncompliance
was considered respond rates between patients with and without alcohol consumption where
found to be comparable (14). Therefore, it has been concluded that compliance in alcoholics is probably the
major cause for a poor response to HCV therapy.
Possible mechanisms of the synergism of alcohol and HCV
Various mechanisms of alcohol-HCV-interaction have been discussed:
1. Stimulation of HCV replication by alcohol
2. Increased occurrence of quasispecies
3. Increased apoptosis
4. Immunosuppression by ethanol
5. Additional Oxidative stress due to ethanol (Induction of cytochrome P-4502E1)
6. Stimulation of hepatic steatosis by ethanol
HEPATITIS B AND ALCOHOL
In contrast to hepatitis C, the data for the interaction of ethanol with hepatitis B is limited. Unquestionable
alcohol accelerates carcinogenesis in patients with hepatitis B infection. In a Japanese study it has been
shown that patients with hepatitis B infection develop HCC proximately ten years earlier than those patients
who did not drink at all. This occurred already at an alcohol dose less than 24 grams per day and did further
increase with advancing alcohol doses (15).
ALCOHOL AND NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
Although it has been reported in epidemiologic studies that small amounts of alcohol may improve peripheral
insulin resistance which in many cases occurs in NAFLD (16), it also has been shown that additional alcohol
intake deteriorate NAFLD at various states of the disease in animals (2) as well as in humans (17-20).
In the Northern Italy Dionysos-Study it has been shown that alcohol consumption of more than 60 grams
per day increased fatty liver diagnosed by ultrasound by 46 % as compared to 16 % in control Individuals.
Individuals with a body mass index of more than 25 kg per m2 have a further increase in steatosis to more
than 70 % and if both overweight and alcohol consumption comes together fatty liver occurred in more than
90 % (17).
Hepatic fibrosis also increases with alcohol consumption. A French study showed that daily alcohol intake
of more than 100 grams showed almost a double increased risk for cirrhosis of the liver in patients with
a body mass index of 29 as compared to those with 21 (Fig.5)(18,19). It has been shown recently by a
retrospective epidemiologic study that even social drinking in patients with NASH resulted in a significant
increased risk for HCC (Fig6) (20).
Animal studies have clearly demonstrated that ethanol administration deteriorates fatty liver disease induced
by high fat diets and may also enhance the generation of carcinogenic DNA lesions (2,21)
HEREDITARY HAEMOCHROMATOSIS (HH) AND ALCOHOL
According to the data from the National Health and Nutrition Examination Survey (NHANES 1) iron overload
is a negative prognostic factor for the development of liver disease (3). More than two drinks per day had a
hazard ratio of 4.1 for liver disease, while two drinks per day plus a transferin saturation of more than 40 %
had a hazard ratio of 6.9. This is not surprising as hepatic iron is toxic. Alcohol increases reactive oxygen
species by producing H 2
O 2
which may lead to increased iron absorption and iron release due to a decrease
in hepcidin. This may also lead to an increased iron accumulation in the liver with increased toxicity (Fig.7).
Thus, individuals with HH should avoid alcohol consumption.
ALCOHOL AND DRUG INTERACTION
Toxicity of various drugs may be increased by concomitant alcohol consumption. This is especially wellknown
for methotrexate. Chronic methotrexate administration in higher dosis may result in stellate cell
activation leading to centrizonal fibrosis which is further enhanced by alcohol consumption, since alcohol by
itself leads to an activation of stellate cells. As a result central portal fibrosis occurs (Fig.8).
In addition alcohol induces cytochrome P450 2E. Beside the fact that CYP2E1 is responsible for ethanol
metabolism, it is also responsible for the metabolism of various drugs, procarcinogens and xenobiotics (4)
(Fig.9). In this context two drugs are special importance, namely paracetamol (acetaminophen) (4) and
isoniazide (22). An induction of CYP2E1 by alcohol results in an enhanced metabolism of paracetamol with
an increased generation of highly toxic intermediates which are usually detoxified by glutathione to become
non-toxic. Since alcohol decreases hepatic glutathione levels, this detoxification pathway cannot occur and
highly toxic intermediates bind to hepatocytes and induce severe hepatic injuries (Fig.10).
Another interaction occurs with isoniazide, a tuberculostatic drug (22). This is also of importance since
alcoholics have an increased risk for tuberculosis. Isoniazide toxicity depends on two factors: 1. The speed
of isoniazide acetylation. 2. The speed of the metabolism of the intermediate acetylhydrazine by CYP2E1
(Fig.11). If isoniazide is acetylated adequately, acetylisoniazide, acetyl hydrazin and finally the detoxification
product diacetylhydrazin occurs. However, in a slow metabolizer the intermediate acetylhydazine
accumulates and may be further metabolized by CYP2E1. CYP2E1 is polymorph coding for a rapid or a slow
metabolizing protein. If the individual is a rapid CYP2E1 metabolizer and a slow acetylizer, hepatotoxins
may occur and may injure the liver (Fig.12). Other drugs, chemicals and carcinogens interactions with
alcohol are shown in table 2.
Finally, it should be pointed out that vitamin A and beta carotene taking in access may lead to hepatic fibrosis
and cirrhosis. Additional alcohol stimulates the development of hepatic cirrhosis by CYP2E1 mediated
increase in the metabolism of retinol and retinoic acid (5). As retinoic acid decreases 1. an increase in
the expression of the AP1 gene occurs leading to hyperproliferation, a procarcinogenic state (23) and 2.
Various apoptotic intermediates are generated damaging the liver (24) (Fig.13). Thus, vitamin A and alcohol
should not be taken together.