J Clin Pathol: first published as 10.1136/jcp.37.7.721 on 1 July 1984. Downloaded from J Clin Pathol 1984;37:721-733 Review article Alcohol induced liver disease KA FLEMING, JO'D McGEE From the University of Oxford, Nuffield Department ofPathology, John Radcliffe Hospital, Oxford OX3 9DU, England SUMMARY Alcohol induces a variety of changes in the liver: fatty change, hepatitis, fibrosis, and cirrhosis. The histopathological appearances of these conditions are discussed, with special atten- tion to differential diagnosis. Many forms of alcoholic liver disease are associated with Mallory body formation and fibrosis. Mallory bodies are formed, at least in part, from intermediate filaments. Associated changes in intermediate filament organisation in alcoholic liver disease also occur. Their significance in the pathogenesis of hepatocyte death may be related to abnormalities in messenger RNA function. The mechanisms underlying hepatic fibrogenesis are also discussed. Although alcohol has many effects on the liver, all formed after some period of alcohol abstinence, except cirrhosis are potentially reversible on cessa- alcohol related changes may not be seen. Accord- tion of alcohol ingestion. Cirrhosis is irreversible ingly, we shall consider the morphological changes and usually ultimately fatal. It is therefore important associated with alcohol abuse under the headings in to determine what factors are responsible for Table 1. development of alcohol induced cirrhosis, especially In the second part, the pathogenesis of alcohol since only 17-30% of all alcoholics become' cirrho- induced liver disease will be discussed, but this will tic.' This is of some urgency now, since there has deal only with the induction of alcoholic hepatitis, been an explosive increase in alcohol consumption fibrosis, and cirrhosis-that is, chronic alcoholic http://jcp.bmj.com/ in the Western World, particularly affecting young liver disease-and not with fatty change, for two people, resulting in a dramatic increase in the inci- reasons. Firstly, the role of ethanol in the dence of alcoholic liver disease and cirrhosis. For pathogenesis of fatty liver is well documented, while example, in New York City, alcoholic cirrhosis is the its role in inducing the other features is much less third commonest cause of death in people aged bet- clear. Secondly, the consensus of available evidence ween 25 and 64.2 Our experience in Oxford shows is that fatty change alone probably has no role in the that 20% of all liver biopsies and 50% of liver biop- production of cirrhosis, which for the reasons out- on October 1, 2021 by guest. Protected copyright. sies performed by a physician with a special interest lined in the first paragraph is the most important in hepatology, show alcoholic liver damage. result of excess alcohol ingestion on the liver. Sev- This review is in two parts. In the first part the eral reviews of ethanol metabolism and its role in pathological features of alcohol induced liver dis- pathogenesis of fatty change have been pub- ease will be described, with emphasis on their diag- lished.' -3 nostic, prognostic, or pathogenic importance. Although the usual convention is to divide these fea- Pathology of alcohol induced liver disease tures into three broad categories-namely, fatty change, alcoholic hepatitis with or without fibrosis, Alcohol induces a number of changes in the liver and cirrhosis-this division may be artificial for (Table 1). No one feature is diagnostic, but some are three reasons. Firstly, these categories may well rep- relatively specific. For example, Mallory bodies are resent a continuum of disease. Secondly, at any present in hepatocytes in 94-100% of cases of given time, one or any combination may be present alcoholic hepatitis and cirrhosis. They are also seen, in the same liver. Thirdly, if a liver biopsy is per- however, in 66-100% of cases of Wilson's disease, 17-48% of cases of primary biliary cirrhosis, 11- Accepted for publication 29 March 1984 84% of cases of Indian childhood cirrhosis,4 and 721 J Clin Pathol: first published as 10.1136/jcp.37.7.721 on 1 July 1984. Downloaded from 722 Fleming, McGee Table I Pathological changes in alcohol induced liver association with other more specific changes often disease leads to a correct diagnosis of alcoholic liver disease. Lesion Specificity* FATTY CHANGE (Fig. 1) Fatty liver Fatty change Fatty change in hepatocytes is not a diagnostic fea- Fatty cysts ture of alcohol induced liver disease. It occurs in many other conditions, including obesity, diabetes MegamitochondriaLipogranuloma + Hepatocyte swelling + mellitus, drugs such as steroids and methotrexate, Alcoholic hepatitis + congestive cardiac failure, alimentary disorders, Fibrosis Pericellular + abetalipoproteinaemia, and Kwashiorkor.6 How- Periportal ever, it invariably appears after excessive alcohol Lipoganuloma ingestion, usually being visible within three to seven Central sclerosing hyaline necrosis + Pericentral venous + days.' On cessation of drinking, fatty change may Cirrhosis disappear within a few days, but in severe cases it Micronodular Macronodular takes four to six weeks to clear.8 Accordingly, it is Mixed unusual not to see some fatty change in a biopsy Miscellaneous Cholestasis from an alcoholic unless a reliable history of pro- a -antiy in granules longed alcohol abstinence is obtained. In established iaemos'ierosis alcoholic cirrhosis, Chronic active hepatitis however, fatty change may be Hepatocellular cancer absent. Thus the presence of fatty change, even in minimal amounts, should suggest the diagnosis, if + = yes, - = no. only for exclusion. Fatty change typically occurs focally in the cen- 1-5% of cases of non-alcoholic cirrhosis.5 In con- trilobular zone, but in severe cases it can affect vir- trast, fatty change is not specific for alcoholic liver tually the whole liver lobule, mimicking Kwashior- disease, being found in a multitude of other diseases kor. Usually the cytoplasm is almost totally replaced (see below). Although it may appear that non- by a single vacuole, with displacement of the nucleus specific changes are unimportant, their presence in to the periphery of the hepatocyte producing "large I _qW _w v p 4.4 http://jcp.bmj.com/ N "P... q .-t 9/ 't. * Fig. 1 Fatty change C,b* and fat cysts. _r show both Hepatocytes on October 1, 2021 by guest. Protected copyright. S'6 large and small droplet * fatty change. nb: .jv *t .w ii Ib:,i t*- A -* mmw:~lt.f:'r 4f 3.wf.:.. ^k I 'P J Clin Pathol: first published as 10.1136/jcp.37.7.721 on 1 July 1984. Downloaded from Alcohol induced liver disease 723 droplet" fatty change. Occasionally the fat is in the form of many small cytoplasmic vacuoles with no nuclear displacement ("small droplet" fatty change), mimicking the appearances seen in tet- racycline toxicity and fatty liver of pregnancy. It has been suggested that the "small droplet" change reflects recent rapid accumulation or mobilisation of lipid.9 FAT CYSTS (Fig. 1) These are not infrequent and consist of small lipid filled spaces in the liver lobule, apparently formed by the rupture of contiguous fat filled hepatocytes. They are apparently of no importance, except perhaps indicating severity of fatty change. LIPOGRANULOMA These are small foci of mononuclear cells surround- ing a central extracellular fat filled space. The cells present can vary from a small collection of eosinophil polymorphs and mononuclear cells, to well formed epithelioid granulomata with mul- tinucleate giant cells, although this latter type is Fig. 2 Megamitochondria. Swollen hepatocytes contain rather uncommon. Lipogranulomata are normally megamitochondria in cytoplasm (arrows). found in a centrilobular location but can occur any- where, including portal tracts. They are reported to per high power field) is said to indicate heavy occur in 30-50% of cases of alcohol induced liver alcohol ingestion within the last 30 days.'2 They are disease.'0 In our experience in the UK, however, the occasionally found in morphologically normal livers incidence of lipogranulomata is much lower. and in non-alcohol induced disorders, but with much Although the recent convention has been to lower frequency.'3 Although they are not of any regard fatty change and its sequelae (for example, known prognostic significance, the presence of large lipogranuloma) as totally reversible and of no long numbers of megamitochondria is highly suggestive http://jcp.bmj.com/ term significance, results of baboon experiments of recent heavy alcohol consumption. have suggested that fatty change may progress to cirrhosis without a detectable intervening stage of HEPATOCYTE SWELLING (Fig. 3) alcoholic hepatitis. In addition, lipogranulomata can Hepatocyte swelling is a characteristic and well occasionally apparently coalesce and be associated documented feature of alcoholic liver disease.'4 Its with surrounding fibrosis." The significance of these presence and significance, however, is not always findings is unknown, but will be discussed in more realised by the non-specialist. It involves hepato- on October 1, 2021 by guest. Protected copyright. detail later (see section on fibrosis and cytes mainly in the centrilobular region and affects pathogenesis). many hepatocytes, but to varying extents. The hepatocyte may be massively swollen, often being MEGAMITOCHONDRIA (Fig. 2) three times normal size. The cytoplasm does not Megamitochondria are not infrequently found in show the changes of cloudy swelling, hydropic or alcohol induced liver disease. They are similar in fatty change, but clumps either into fine eosinophilic size and eosinophilia to red blood cells, but their granules or into a fine web like pattern. These cells presence in hepatocytes and their perfect symmetry also often contain typical Mallory bodies or finer allows their positive identification. Some authors structures of Mallory body type which react with claim that they are more readily detected in tri- antibodies to Mallory bodies.'5 This resembles the chrome stains (as red cytoplasmic globules), but in ballooning degeneration of viral hepatitis, but there our experience haematoxylin and eosin staining is are rarely any acidophil bodies or other features of adequate for their detection.