ALCOHOLIC LIVER DISEASE/CIRRHOSIS

ALCOHOLIC LIVER DISEASE/CIRRHOSIS

Although cirrhosis is the major end point for excessive alcohol intake and liver damage, there is a sequence leading up to this consisting of fatty liver, alcoholic hepatitis, hepatic fibrosis and cirrhosis in that order (1).

1. FATTY LIVER

This condition is common in most western societies and alcohol excess is a significant cause. It was, until recent decades, seen as the major cause but it is now evident that excess fat in the liver, in affluent societies is often caused by factors other than alcohol.

2. THE NON ALCOHOLIC STEATO-HEPATITIS SYNDROME (NASH)

The ICD 10AM Code is K76.0. To understand the changes in the liver

produced by alcohol, it is necessary to be aware of its metabolic

consequences. Oral intake of alcohol is followed by its oxidation firstly by

alcohol dehydrogenases in the gastric mucosa and then in the liver by

another alcohol dehydrogenase and to a lesser extent by cytochrome P450

enzymes. Most of these enzyme systems have genetic variants which may

explain some of the variation in susceptibility. The acetaldehyde produced

by the above is then oxidized to acetate which is metabolized generally but

free fatty acids may be produced in large intake situations with diminished ȕ

oxidation of fatty acid and increased synthesis of them and their conversion

to triglycerides. Lactate may be produced by reduction of acetate with

consequent hyperuricamia and gout. The accumulation of triglycerides

within the liver cells is the major feature of fatty liver. Manifested clinically by a large firm liver with possible moderate elevation of transaminases (AST>ALT), serum alkaline phosphatase and GGTP but no changes in bilirubin or protein levels. The condition may occur within weeks of high intake and resolve equally rapidly on abstinence. If it continues then inflammatory changes may appear and later on fibrotic change – alcoholic hepatitis.

3. ALCOHOLIC HEPATITIS

This, often seen in conjunction with fatty liver, is characterised histologically by liver cell necrosis and neutrophil infiltrate. Clinically there is hepatomegaly, sometimes massive, and often tender, possible splenomegaly, stigmata of chronic liver disease and abnormal liver function tests and biochemical changes even of gross degree and hepatic encephalopathy or bleeding and a fatal outcome in extreme cases. The ICD 10AM Code is K70.1.

There is great variation in susceptibility to alcohol at least in part due to enzyme variation; Chinese and Japanese are poor oxidisers of acetaldehyde and so are intolerant of small amounts of alcohol readily taken by other races. Women have less alcohol dehydrogenase in their gastric mucosa and the rate of alcohol oxidation varies three fold among individuals. As alcohol is water soluble, body size also plays a part. Although not so in all species, nutritional state and intake play no role in the development of alcoholic liver disease in humans. Probably as a result of these factors, only about 10-15%

of alcoholics develop cirrhosis.

4. ALCOHOLIC CIRRHOSIS

In the majority of societies this is the most frequent form of cirrhosis

with an ICD 10AM Code of K70.3. Its prevalence largely mirrors the per

capita consumption of alcohol in the community but its frequency in death

certificates follows changes in alcohol consumption by about a decade. It is

predominantly a male disorder by a ratio of 2:1 even 10:1 and a significant

cause of death; in western Europe the mortality of cirrhosis (17.8/10

),

predominantly alcoholic, exceeds that from motor vehicle accidents

(12.3/10

). WHO data indicate that the countries with the highest per capita

alcohol intake – France, Luxemburg, Spain, Austria and Germany tend to

have the highest cirrhosis death rates too but the association is not precise;

Sweden, Denmark, Portugal and Italy tend to have higher mortality rates than their intake predicts (2).

5. RISK FACTORS The major ones to be considered are:

• Alcohol intake, daily intake, duration, age, total lifetime consumption, type of drink

• Sex

• Heredity

• Smoking

• Coffee intake

• Nutritional factors

• Coexistence with other liver disease, Hepatitis B, Hepatitis C

• Race

• Socio-economic factors 5.1 Alcohol intake

Within the individual the correlation between alcohol intake and liver disease is much closer. Lelbach investigated this and did liver biopsies on 265 alcoholics and claimed to have obtained accurate data on lifetime alcohol consumption (3). He found a remarkably close correlation between alcohol consumption and the likelihood of cirrhosis (P<0.001) in the 39 cirrhotics in the group in whom the average ‘cirrhogenic’ consumption was 180g/day for 25 years. The data from this relatively small study indicate that the alcohol intake, measured as grams/kg body weight /day x years, closely mirrors the percentage probability of cirrhosis in males. In a case control study from Canada (4) the RR for biopsy verified cirrhosis in men consuming 40-59 grams of alcohol /day was 1.83 (.76-4.42) compared to those taking <40g/day and for men consuming >80g/day it was 100 (31.6- 315.9) (4).

5.2 Sex

Women were more vulnerable; for those consuming 20-59g/day the RR

was 2.53 (1.0-6.4) compared with those taking <20g/day and rose to 12.21

(3.54-42.14) for those taking more than 60g/day. The mean daily alcohol

consumption in female cirrhotics was 29.7g/day; in males 98.2g/day. The

patients were from six hospitals in Toronto seen over a year and the controls

were from a variety of local industries and they had blood liver enzyme levels estimated and a detailed history taken. Comparisons were done with controls regardless of enzyme levels or history of liver disease and also with these excluded for comparison. In general duration of drinking was irrelevant, the significant risk factors were age, daily consumption (P<0.0001 in males and P<0.015 in females) and total lifetime consumption (P<0.0001 in M, P<0.01 in F in either sex). Further evidence of the sensitivity of females to alcohol was in the estimated lifetime consumption of absolute alcohol, 163kg (range 0-2317kg) compared with males 499kg (range 0-2581kg). It is of interest that the male consumption ranged up to 2581kg or 2 ½ tonnes of absolute alcohol! The figures are consonant with those of Lelbach above. On his data a 75kg male drinking 98.2g alcohol daily, the mean of the Toronto male cirrhotics, for 30 years would have a 98.2/75x30=40% probability of cirrhosis. The data are also consonant with the only data of substance on ‘cirrogenic’ level of alcohol use. Pequignot and his group have concluded that 80-160g daily is potentially cirrhogenic with a high risk at level of 160g daily or above. They have also found a risk of cirrhosis in women begins at levels as low as 20g/day (5, 6).

5.3 Heredity

The only study originates in an enormous database, those 15924 twin pairs of white males born between 1917 and 1927 who served in the US Armed Forces. An extremely complex analysis was done, given major genetic variations in drug handling (7). Concordance rates for alcoholism, alcoholic psychosis and alcoholic cirrhosis were greater in monogygotic than in dizgotic twin pairs providing “evidence in favour of genetic pre- disposition to organ specific complications of alcoholism”. Most of the observed twin concordance of alcoholic cirrhosis was not a direct consequence of concordance for alcoholism, suggesting that apart from the actual intake of alcohol there is a genetic factor in the pre-disposition to developing cirrhosis.

5.4 Coffee

A strange finding of a protective effect of coffee drinking was found in a

study of 128934 adults enrolled in a Kaiser Permanente Medical Care

Program in California. The adjusted RR for hospitalization (0.2) and for

death (0.7) from alcoholic cirrhosis for drinkers of • 4 cups of coffee per day

showed a highly significant risk gradient inversely proportional to coffee

intake. Tea was ineffective. No effect was seen on hospitalization for non-

alcoholic cirrhosis (8). The beneficial factor is obscure; while most attention

has focused on the caffeine content of coffee, there are 600 chemicals in a roast coffee bean. The finding appears real being present in many subsets studied.

5.5 Cigarette Smoking

The Kaiser Permanente study also looked at smoking with important results. The adjusted RR for hospitalization (3.0) or death (3.3) for alcoholic cirrhosis in smokers was significant (P<0.05) with no significant elevation for non-alcoholic cirrhosis (8). However, smoking is strongly associated with drinking and untangling the association is a formidable task yet to be undertaken.

5.6 Nutritional Status

In the mid twentieth century much attention was given to nutritional factors in liver disease but it is now generally agreed that, apart from gross examples of malnutrition as seen in the East, nutritional status has little relevance. However it is not clear that the subject has been adequately studied in recent decades.

5.7 Socio-economic Status

Disentangling the complex interaction of heredity, childhood and adult environment, education, income and race, and the problems of cause and effect make this difficult. The Kaiser Permanente study found race was not a factor but by definition enrollees could afford to insure themselves.

Similarly, the RR of alcoholic cirrhosis was only 0.2 (0.1-0.5) in white college graduates. Similarly currently being married was protective, RR 0.4 (table 2 of this paper almost certainly incorporates a typographical reversal of figures).

6. CO-EXISTENCE OF OTHER LIVER DISEASES

There is strong evidence that the co-existence of alcohol use/abuse and

Hepatitis B and C hastens the onset of cirrhosis even in small amounts (See

chapters on Hepatitis B and C).

7. SUMMARY

Alcoholic cirrhosis is an important cause of morbidity and mortality in the western world. While it is axiomatic that its cause is excessive use of alcohol, through mechanisms not yet fully elucidated, its course and development are subject to modifications by a wide variety of agents. Given that the major determinants are the daily intake and total life-time intake, with females more sensitive, it is clear that there are genetic factors at work, not only in the proclivity to abuse alcohol but in the sensitivity of the liver to assault by alcohol.

For obscure reasons coffee clearly is protective and smoking is probably a positive risk factor. While prohibition has its diminishing band of enthusiasts on a population wide basis, exortations to avoid alcohol excess are probably fruitless. The consumption of alcohol in the community is log- normally distributed and to reduce the frequency of heavy use it is necessary to move the distribution curve to the left which can only be done by reducing the standard deviation of the mean alcohol intake in the community by encouraging those who drink little to drink more or by reducing the total community consumption of which price manipulation is one important factor.

References

1. Sherlock S, Dooley J. Alcohol and the liver. In : Sherlock S, Dooley J. Diseases of the liver and biliary system. 10th ed. (Blackwell Science, Oxford, 1997).

2. Salaspuro M. Epidemiological aspects of alcoholic liver disease, ethanol metabolism and pathogenesis of alcoholic liver injury. In : Bucher J, Benhawou JP, McIntyre N, Rizeto M, Rodes M eds. Oxford Textbook of Hepatology 2

ed. ( OUP,Oxford, 1999), pp.1157- 78.

3. Lelbach WK. Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse.

Ann. N. Y. Acad. Sci. 252,85-105 (1975).

4. Coates RA, Halliday ML, Rankin JG, Feinman SV, Fisher MM. Risk of fatty infiltration or cirrhosis of the liver in relation to ethanol consumption : a case control study. Clin.

Invest .Med. 9,26-32 (1986).

5. Pequignot G, Tuyns AL, Berta JL. Ascitic cirrhosis in relation to alcohol consumption.

Int. J. Epidemiol. 7(2),113-20 (1978).

6. Tuyns AJ, Pequignot G. Greater risk of ascitic cirrhosis in females in relation to alcohol consumption. Int. J. Epidemiol. 13,53-7 (1984).

7. Hrubec Z, Omenn GS. Evidence of genetic predisposition to alcoholic cirrhosis and psychosis : twin concordance for alcoholism and its end points by zygosity among male veterans. Alcohol Clin. Exp. Res. 5,207-215 (1981).

8. Klatsky KL, Armstrong MA. Alcohol, smoking, coffee and cirrhosis. Am. J. Epidemiol.

136,1248-57 (1992).