British Journal of Addiction 75(1980) 19-26. 0007-0890/80/00580019$02.00© 1980 Society for the Study of Addiction to Alcohol and other Drugs.

Alcoholic Liver Disease: What the PractisingClinician Needs to Know

Michael Davis, M.D., M.R.C.P.Consultant Physician, Liver Unit, King's College Hospital and Medical School, DenmarkHill, London SE5 9RS

It is now well-established that the incidence and mortality from cirrhosis of theliver in different populations bear a close relationship to the average quantity ofalcohol drunk [1], and in Great Britain there has been a steady and parallelincrease in the two which has become especially marked over the last decade.The reasons for this rise in alcohol consumption is not clear, but a number offactors are probably important. These include changes in social attitudes todrinking, especially amongst women, a wider availability of alcoholic beveragesin supermarkets and a fall in the cost of alcohol in relation to disposable income.

However, while cirrhosis is the marker of alcoholic liver injury most com-monly used in population surveys, it represents only the most advanced end ofthe spectrum of alcohol induced liver pathology. Recognition of hepatic damageat an earlier stage is vitally important, because if the patient can be persuaded tostop drinking, liver architecture and function will in most cases revert to normal.

Pattems of Alcoholic Liver InjuryFatty infiltration of the liver is the earliest lesion which can be detected, and arisesas a result of interference by alcohol with hepatic triglyceride metabolism [2].The changes can occur after a few days' heavy drinking, but disappear afteralcohol is discontinued. Histologically, large fat vacuoles are seen within the liverinitially in the centrilobular area, but involving the entire liver lobule inadvanced cases. In some cases hepatic fibrosis accompanies fatty infiltration andoccasionally may be severe, but can always be distinguished from cirrhosis by thepresence of an intact liver lobule.

Clinically, patients with a fatty liver may be quite asymptomatic, althoughill-defined right hypochondrial pain and vague malaise can be present, and veryrarely a cholestatic jaundice may complicate the condition. Hepatomegaly isalmost invariable, but splenomegaly does not occur in uncomplicated fatty liver.

Uncomplicated fatty liver is generally considered to be a benign conditionwhich does not progress to cirrhosis. However, fatty infiltration is frequently seenin association with more advanced alcoholic liver pathology.

Alcoholic hepatitis is characterized by patchy necrosis of hepatocytes with in-flammatory cell infiltration distributed throughout the liver lobule andcosinophilic intracellular inclusions, known as alcoholic hyaline, are generallydetectable in a proportion of liver cells [3]. These are thought to represent alcohol

20 Davis

denatured hepatocyte components [2], although similar inclusions can be foundin other hepatic disorders, including Wilson's disease and primary biliary cir-rhosis. A severe variant of alcoholic hepatitis is characterized by a predominantlycentrilobular distribution of necrosis and is termed sclerosing central hyaline nec-rosis [4]. Severe alcoholic hepatitis often develops after a bout of particularlyheavy drinking superimposed on a high basal consumption.

The severity of clinical illness can vary greatly [3], and some patients havefew if any symptoms, whilst severely affected cases develop anorexia, malaise,abdominal pain and jaundice, and may become encephalopathic. The severity ofthe histological liver lesion may be out of proportion to the clinical symptoms [5].Hepatomegaly is usually found on clinical examination but the spleen is often notpalpable. Patients with sclerosing central hyaline necrosis often show features ofportal hypertension due to hepatic venous congestion, and the presence of ascitesand oesophageal varices can make the condition difficult to differentiate fromsevere decompensated cirrhosis. Patients can present with a predominantlycholestatic jaundice and the differentiation from extra hepatic biliary obstructionto save the patient an unnecessary and often fatal laparatomy [6] is discussedbelow.

The mortality from severe acute alcoholic hepatitis is high [7, 8, 9] and aprolongation of the prothrombin time which precludes liver biopsy usually indi-cates a bad prognosis [7]. The prognostic and diagnostic value of other liverfunction tests is discussed later. While some patients progress rapidly to cirrhosis,recovery to normal liver function can occur, but the clinical illness is frequentlyprolonged and punctuated by sepsis, encephalopathy and gastrointestinal bleed-ing. An initial deterioration in the clinical state not infrequently occurs in the firstweek or two after admission to hospital. Treatment is largely supportive andalthough corticosteroids have been tried [10-13], their value is unproven, exceptperhaps in severe cases complicated by hepatic encephalopathy [14-15]. There isno doubt that alcoholic hepatitis is a potentially pre-cirrhotic lesion [16] andparticularly at risk are those patients who have few, if any symptoms, and whowith continued drinking progress insidiously to cirrhosis.

Cirrhosis due to alcohol is classically micronodular in pattern with bands offibrosis linking adjacent portal tracts and centrilobular areas to produce nodulesof lobular size or smaller. However, with progression of the disease, the cirrhosisbecomes macronodular due to liver cell hyperplasia with regeneration nodules,and the end result may be difficult to defferentiate from cirrhosis due to othercauses. The presence of a marked fatty infiltration or superimposed alcoholichepatitis may aid the diagnosis and an additional histological feature often seen isthat of iron overload due presumably to the large quantities of iron present inmany alcoholic beverages. This occurs more frequently in men than women [9],who may be protected by menstrual iron loss.

Clinically, the liver is often firm and enlarged, although it may be shrunkenand impalpable in advanced cases. Palpable splenomegaly occurs frequently, butits absence does not exclude cirrhosis. Signs of chronic liver disease, with spidernaevi, palmar erythema, loss of body hair, testicular atrophy and gynaecomastiain men are generally but not always seen, and Dupuytren's contracture is said tooccur particularly commonly with cirrhosis due to alcohol. It is important to note

Alcoholic Liver Disease 21

that jaundice is not a feature of hepatic cirrhosis even when it is advanced.Barium swallow will reveal oesophageal varices if they are present.

Presentation may be with any of the complications of cirrhosis, with bleedingfrom oesophageal varices, ascites or encephalopathy. A sudden deterioration in apreviously stable cirrhotic patient may be the result of a superimposed alcoholichepatitis and here the prognosis is gloomy, or the development of hepatocellularcarcinoma. This malignancy is especially prone to develop in cirrhotic males overthe age of 55, for it has been estimated that one in five will develop this complica-tion [9].

Screening for Alcohol Abuse and Diagnosis of Liver DiseaseA high index of suspicion should be maintained for all patients who present withnon-specific abdominal pains and general malaise, and symptoms of early morn-ing nausea and retching often reflect an alcoholic gastritis caused by excessivedrinking the night before. Abdominal palpation for hepatomegaly andsplenomegaly should be routinely performed in such patients and extrahepaticsigns of chronic liver disease looked for. Often it is necessary to interview apatient's relatives, although this may be unrewarding. Men frequently drink inpublic houses rather than at home, and their wives may be unaware of how muchthey drink while conversely women may tipple steadily through the day withoutbecoming drunk or evoking suspicion in other members of the family. Estimationof blood and urinary alcohol content can be helpful, particularly if values arehigh in the morning, or if the patient claims not to be drinking. Recognition of analcoholic aetiology in a patient presenting with hepatomegaly and ascites cansave a patient from a potentially fatal laparotomy for suspected carcinomatosis,an event still seen all too often.

Various laboratory tests may be helpful in screening for alcohol abuse. It isnow well-established that chronic alcohol abuse may lead to toxic effects on thebone marrow. Although anaemia is uncommon in British alcoholics, red cellmacrocytosis is found in up to 85 per cent, and appears to be due to alcohol-induced impairment of dietary folate utilization, since in most cases body folatestores are normal [17]. In some patients, however, anaemia due to a true folatedeficiency is present, consequent on a poor dietary intake. It is of interest that thelatter complication is found more commonly amongst spirit than beer drinkers,for beer contains significant quantities of folic acid.

Markedly elevated serum levels of gamma glutamyl transpeptidase (GGT)characteristically are seen in heavy drinkers [18]. Although this is a hepaticenzyme, and a very sensitive indicator of liver injury, high values can occur withnormal liver function due to stimulation of its activity by alcohol [19].

An abnormally high ratio of the amino acids aN-aminobutyric acid : leucine isfound in drinkers imbibing in excess of 2 g/kg/day of alcohol (equivalent toapproximately half a bottle of spirits for a 70 kg man) [20]. The degree of abnor-mality correlates with the extent of alcohol abuse, although interpretation of thistest, which is outside the scope of most routine laboratories, is complicated if thepatient has cirrhosis [21].

Biochemical liver function tests are of little value in predicting the extent of

22 . Davis

histological liver injury [5, 22]. Abnormalities in serum alkaline phosphatase aregenerally present, but these are generally not striking and may be no moreabnormal in a patient with cirrhosis than one with fatty liver. The finding of alow level of serum albumin is a useful pointer to cirrhosis. Serum transaminaselevels are rarely significantly above normal [5, 23], and even in the presence ofsevere alcoholic hepatitis values of these markers of hepatocellular injury arecharacteristically disproportionately low in relation to the degree of necrosis asassessed histologically. Indeed, this finding can be useful in the differential diag-nosis from acute viral hepatitis. It has been reported that serum levels of gluta-mate dehydrogenase are more useful than the transaminases in detecting alcohol-induced hepatocellular necrosis [23], and potentially this test could be of greatvalue in screening for alcoholic hepatitis in asymptomatic individuals. However,this requires further investigation. Currently, the only way of establishing thediagnosis is by liver biopsy, and this should be carried out, if levels of clottingfactors permit, on all patients with abnormal liver function tests, with the excep-tion of those with isolated elevations of GGT.

Hyperbilirubinaemia is not characteristic of alcoholic liver disease, except invery rare cases of fatty liver and patients with severe acute alcoholic hepatitis. Asignificant proportion of the latter group can present with a predominantlycholestatic lesion, with high levels of bilirubin and alkaline phosphatase, andclinically discrimination from extrahepatic biliary obstruction can be impossible.An exploratory laparotomy can be fatal for a patient with acute alcoholichepatitis and differentiation of the two causes is essential. Ultrasound examina-tion of the liver for dilated intrahepatic bile ducts due to biliary obstruction is avaluable non-invasive technique [24] and patients with acute alcoholic hepatitiswithout underlying cirrhosis show a characteristic patten on hepatic scintiscan-ning [25]. In this condition, the liver fails to take up ^'Tecnetium sulphocolloid,while there is markedly increased uptake by the spleen and bone marrow. Con-versely, uptake of selenomethionine is normal, and this disparity in imaging withthe two isotopes which involves the entire liver is almost pathognomonic of acutealcoholic hepatitis. In contrast, with hepatocellular carcinoma, which as previ-ously mentioned can develop in up to 20 per cent of males with cirrhosis, thetumour will be seen as a filling defect on the ^^Tecnetium sulphocolloid scan, withnormal uptake by selenomethionine in a variable proportion of cases. Signs of acirrhotic liver on hepatic scintiscanning are a small liver, with diminished uptakein the right lobe and some increase in the left, together with increased splenicuptake.

Measurement of serum levels of alpha fetoprotein by radioimmunoassay ishelpful in excluding hepatocellular carcinoma, for abnormally high concentrationsofthis tumour marker are found in almost 100 per cent of European patients withthis malignancy when it arises in a cirrhotic liver [26]. Regular screening ofpatients at risk (especially males over the age of 55) can be helpful in the earlydetection of this complication.

Alcohol and the Liver - Common MisconceptionsA strong 'head' for alcohol indicates a strong liverA popular misconception amongst heavy drinkers is that if they do not get drunk.

Alcoholic Liver Disease 23

or feel ill after heavy drinking, alcohol is producing no physical harm. In fact,development of alcoholic liver disease is directly related to the quantity and dura-tion of drinking [27], although the amounts necessary to produce this can varybetween individuals (see below). There is no evidence that the capacity to 'holdone's liquor' bears any relationship to the effect that drinking will have on theliver. As mentioned earlier, significant degrees of liver damage with alcoholichepatitis can occur with few if any symptoms, and progression to cirrhosis canoccur insidiously without the patient noticing anything wrong.

Another popular misconception is that provided an individual is not physi-cally dependent on alcohol and can 'take it or leave it', drinking is safe. Sociallyincapacitated alcoholics of the 'Skid-Row' variety are the exception rather thanthe rule in patients with alcoholic liver disease, and many will be continuing tohold down highly responsible jobs. Our findings show that a high proportionhave low scores on dependency questionnaires, their excessive alcohol intake hav-ing evolved from heavy social drinking.

Drinking no more than one's friends is safeAlthough a number of studies have shown a statistically significant relationshipbetween quantity and duration of alcohol consumption and the development ofalcoholic liver disease, individual susceptibility can vary widely. Undoubtedlysome individuals can drink heavily and for prolonged periods of time withoutdeveloping hepatic damage, but others can develop severe changes having drunkrelatively little. There is evidence that some women may be especially susceptibleto the hepatotoxic effects of alcohol [9] with a worse prognosis than men if theycontinue to drink. Because of these wide individual variations in susceptibility, itis not at present possible to recommend 'safe' quantities of alcohol which can bedrunk without risk of harm to the liver. A recent report [28] suggested an upperlimit of the equivalent of 80 g alcohol daily, but for some this limit should prob-ably be lower.

The reasons for differing individual susceptibility to alcoholic liver damageare not fully understood, but there is some evidence that genetic factors areinvolved which predispose susceptible individuals to mount a damagingimmunological attack against alcohol-altered liver cells. Studies have shown anincreased frequency of certain HLA (tissue typing) antigens in patients withalcoholic cirrhosis [29], and it is of interest that these particular tissue types arealso found in association with a number of immunologically mediated disorders[30]. However, for alcoholic liver disease tissue typing is not yet discriminatoryenough to be of predictive value in the clinical situation.

Spirits and cheap liquor are more harmful than beerLiver damage can develop if any alcoholic beverage is drunk to excess, andalthough it is easier to consume large quantities of alcohol in a relatively smallvolume of spirits, advanced hepatic damage can develop in beer drinkers.Patients should be reminded that one pint of beer contains the same quantity ofalcohol as a double measure of spirits.

It has been suggested that higher alcohol congeners in spirits such as brandy.

24 Davis

and toxic impurities such as acetaldehyde in cheap liquor may be important inproducing hepatic damage. However, the concentrations of these are minute inrelation to the ethanol content, and for acetaldehyde the amounts present in the'dirtiest' liquors are many times lower than the quantities produced by ethanolmetabolism in the liver. Thus, although potentiation of liver damage by thesecompounds cannot be excluded, it is ethanol which plays the primary role inpathogenesis.

An adequate diet protects against alcoholic liver injuryThis concept was derived largely from studies of malnourished 'Skid-Row'alcoholics in the United States whose condition improved after admission to hos-pital with reinstitution of a nutritious diet. While it is possible that malnutritionand alcohol-induced malutilization of nutrients may contribute to liver damage,many patients with severe hepatic pathology have a more than adequate dietaryintake. Furthermore, Lieber and his colleagues [31] have been able to reproducein experimental studies the entire spectrum of alcoholic liver pathology, includingcirrhosis, in baboons fed alcohol together with a diet rich in protein, calories andvitamins. This again reinforces the primary importance of alcohol intake, asopposed to other environmental factors, in the pathogenesis of alcoholic liverinjury.

ManagementThe main therapeutic aim in patients with alcholic liver disease must be to per-suade them to stop drinking, or at least drastically to cut down their alcoholintake. The latter course is probably acceptable in a heavy social drinker withsimple fatty infiltration of the liver, but if the patient has alcoholic hepatitis orcirrhosis, the goal must be abstinence. A number of studies [9, 32, 33] haveclearly demonstrated that progression to cirrhosis can be prevented, and survivalimproved, if the patient stops drinking. Rare cases, and particularly women, mayprogress from alcoholic hepatitis to cirrhosis despite abstinence [9, 16], but theoutlook is so gloomy if they continue to drink that every effort must be made topersuade them to stop. Thus, in one study [9], only 30 per cent of women withalcoholic hepatitis or cirrhosis who survied their first hospital admission but whocontinued to drink were alive five years later, compared with 72 per cent of men.

The best way of establishing and maintaining abstinence is not known, andfor further progress to be made in this area more needs to be known of the factorspredisposing to alcohol abuse in these patients. It is possible, although not yetproven, that the heavy social drinker will respond to simple advice and educationabout the physical harm inflicted, and the health benefits of abstinence. Others,with high degrees of dependence or underlying psychiatric problems, will requiremore specialized and intensive support from a psychiatrist or psychologist, andvoluntary organizations such as Alcoholics Anonymous can provide invaluableback-up in such cases. Much could be achieved by a greater interaction betweenphysicians and psychiatrists, so that physicians were made more aware of thefactors underlying alcohol abuse, and psychiatrists alerted to the possibility ofdamage to the liver and other organs in their patients.

Alcoholic Liver Disease 25

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