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