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