From: [p--r--n] at [gsb013.cs.ualberta.ca] (Peter Jordan) Newsgroups: alt.drugs,talk.politics.drugs,sci.chem,sci.med,alt.beer Subject: Alcoholic Liver Disease and Cirrhosis Date: 19 Mar 1995 19:50:58 GMT Basic Pathology; Robbins, kumar, Saunders, 1987 Pgs. 584 - 590 : Long-term excessive consumption of alcohol is the single most important cause of liver disease in the United States and much of the Western world. Chronic abuse of alcohol can produce three patterns of change in the liver--fatty liver, alcoholic hepatitis, and cirrhosis. Each one of these may be the sole manifestation of alcoholic liver disease or may coexist with one or both of the other two. [ Snipped ] Acoholic cirrhosis is the most common form of cirrhosis in North America and Europe, and it is also increasing in frequency at an incredible rate (*). In the United States, in the interval from 1950 to 1974, the number of deaths from cirrhosis climbed more than 70%, whereas mortality from many other causes, especially cardiovascular disease, declined. Although at one time this was almost exclusively a male disorder, changing conventions have made it clear that women are equally susceptible. The mortality rate among both male and female nonwhites in urban areas in the United States doubles that of whites. [ Access to health care ? No ref *%&$ ] The morphology will be presented first because it facilitates the consideration of the pathogenesis. MORPHOLOGY. [ Snipped ] The Fatty Liver in the chronic alcoholic does not differ at the outset from that related to other causations, as described on page 17. However, in the alcoholic the liver may be massive, up to 4 to 6 kg, and a soft, yellow, greasy, readily fractured organ. The fatty change is entirely centrilobular, but later on it involves the entire lobule (diffuse). The hepatocytes are virtually transformed into lipocytes with peripherally compressed nuclei. Ocassionally the fat accumulates in small droplets without nuclear displacement, as seen in Reye's syndrome. With excessive fat accumulation the plasma membranes of adjacent hepatocytes rupture to create fatty-cysts (*). There is little or no obvious increase in fibrous tissue at the outset, but subtle sclerotic changes, described later, develop insidiously. UP TO THE TIME OF APPEREANCE OF THESE FIBROSING REACTIONS, THE FATTY CHANGE IS REVERSIBLE IF THERE IS COMPLETE ABSTENSION FROM FURTHER ALCOHOL INTAKE. [ Snipped ] Alcoholic Cirrhosis, the final and irreversible form of alcoholic liver disease, evolves slowly and usually insidiously. At first the liver is still enlarged but the smooth, tawny, fatty surface and transection become micronodular (1 to 3 mm in diameter) (Fig. 17-15). As the fibrosis increases with time, the fat content decreases and the liver becomes browner. In later stages, scattered larger nodules develop, presumably as a consequence of regeneration of liver cells; nodules range in size up to 1 cm in diameter to produce a so-called hobnail appearance. Ultimately the scars become even larger and may in time produce a macronodular cirrhosis resembling the post-necrotic pattern (p. 590). ......... [ Snipped ] * * * PATHOGENESIS. There is now abundant evidence that alcohol or its metabolites are hepatotoxic and indeed toxic to other cells of the body as well (*). The older view that the "empty calories" of alcohol and consequent malnutrition was the major cause of the alcohol-related liver disease is slowly fading. Instead it is now believed that secondary malnutrition, which is inevitably associated with chronic alcoholism, contributes to the organ damage initiated by the toxic effects of alcohol (*). [ I don't quite understand the difference ............................. ] The pathogenesis of alcohol-induced liver injury can be conveniently considered within three contexts: (1) clinical and epidemiological evidence, (2) hepatic metabolism of ethanol, and (3) the mechanism of fibrogenesis. On cllinical and epidemiological grounds, there is an unmistakable association between the level and duration of alcohol consumption and the developement of cirrhosis of the liver. National surveys document a close correlation between per capita alcohol consumption and mortality from cirrhosis. Since susceptibility to alcohol-induced liver injury varies among individuals, it is difficult to define a "safe" upper limit of alcohol consumption. Nevertheless, it is generally accepted that a daily intake in excess of 60 to 80 gm for men and 20 gm for women over a period of 10 to 15 years incurs a high risk of developing cirrhosis. [ I would like to know how they arrived at that conclusion. No ref. either ] It should be pointed out, however, that only 17 to 30% of all alcoholics become cirrhotic. Individual, possibly genetic, susceptibility must exist, but as yet {1987} no definite markers of susceptibility have been defined. The metabolic effects of alcohol on the liver cell are complex and, and to some extent, obscure. The liver contains three pathways for alcohol metabolism--the alcohol dehydrogenase pathway (ADH), the microsomal oxidizing system, and a catalase sytstem (*). Of these, the ADH-mediated conversion of ethanol to acetaldehyde seems to be the major pathway (Fig. 17-18). Acetaldehyde induces liver cell damage by covalent binding to proteins as well as by initiating lipid peroxidation of cell membranes. The conversion of alcohol to acetaldehyde and the subsequent oxidation of acetaldehyde require NAD, which in turn is reduced to NADH. These reactions alter the NADH/NAD ratio, leading to an increase in the reducing potential within the cell. This has ripple effects on the metabolism of pyruvates, urates, and fatty acids. In particular, fatty acid oxidation is impaired, contributing to the fatty liver associated with alcohol ingestion. Other factors important in the pathogenesis of alcohol-induced fatty liver include increased flux of free fatty acids into the liver, increased esterification to triglycerides, and reduced secretion of lipoproteins (p. 17). Although acetaldehyde has .... [ Snipped ] [ discussion of immune reactions -- Snipped ] Baboons fed an isocaloric diet containing excess alcohol develop fatty liver and eventually cirrhosis without an intervening stage of alcoholic hepatitis. To explain this sequence it has been postulated that ethanol itself or its metabolites may directly trigger cells with fibrogenic potential. Indeed, lactate and acetaldehyde can stimulate collagen synthesis in vitro (*), but whether similar mechanisms operate in vivo is a matter of conjecture at the present time. [ Snipped ] CLINICAL COURSE. There is a broad range of clinical presentations of alcohol-induced liver disease, some of which are depicted in Figure 17-19. At one end of the spectrum is the patient with the asymptomatic hepatomegaly of the fatty liver. Infrequently, there is accompanying jaundice. At the other end is the wasted, jaundiced, cirrhotic patient with hepatic failure. Usually the first signs of cirrhosis relate to portal hypertension, resulting in the classic picture of a grossly distended abdomen filled with ascitic fluid along with wasted extremities and a pathetically drawn face. In some cases, the first manifestation is jaundice. The hyperbilirubinemia is of both conjugated and unconjugated forms (p. 566). Not infrequently, despite the cirrhotic damage, the patient is asymptomatic untill some stress upsets the balance. A massive hemorrhage from esophageal varices may be followed by hepatic insufficiency or even hepatic failure. Sometimes such bleeding is the first sign of the submerged cirrhosis. Intercurrent infections may also trigger hepatic decompensation. The host of abnormalities described as hepatic failure then becomes manifest. Alcoholic hepatitis may be mild and virtually asymptomatic. More often it presents in the same manner as viral hepatitis, with nausea, vomiting, anorexia, jaundice, and tenderhepatomegaly. AScites, edema, and, in severe cases, hepatic encephalopathy may ensue. Alcoholic hepatitis may be superimposed on cirrhosis. Such acute exacerbations may occur at any stage in the development of cirrhosis and may be recurrent. Therefore, it must not be assumed that hepatic insufficiency or failure implies the advanced fibrotic stage of the disease. Each bout of alcoholic hepatitis carries with it a high mortality rate, ranging from 10 to 20% (*). The long-term outlook for patients with cirrhosis is very unpredictable. Numerous reports indicate that the disease can be arrested if the patient will abstain from alcohol. The five-year survival of abstainers approaches 90% in those without jaundice, ascites, or hematemesis, but drops to 50 to 60% in those who continue to imbibe. The causes of death are predominantly liver failure, intercurrent hemorrhage, and hepatocellular carcinoma, in that order. The source of fatal hemorrhage is usually esophageal varices, but it may be peptic ulceration or esophageal laceration. * END QUOTED TEXT * Whew. So there you have it. Just so no one gets mad at me for copywright violation or such ... Go out and BUY this book. It seems ok. Better yet. BUY me a copy :) (snail mail box available on request) Peter Jordan