Alcoholic Liver Disease
Introduction
Chronic and excessive alcohol
ingestion is one of the major causes of liver disease. The pathology of
alcoholic liver disease comprises three major lesions, with the injury rarely
existing in a pure form: (1) fatty liver, (2) alcoholic hepatitis, and (3)
cirrhosis. Fatty liver is present in more than 90% of binge and chronic
drinkers. A much smaller percentage of heavy drinkers will progress to
alcoholic hepatitis, thought to be a precursor to cirrhosis. The prognosis of
severe alcoholic liver disease is dismal; the mortality of patients with
alcoholic hepatitis concurrent with cirrhosis is nearly 60% at 4 years.
Although alcohol is considered a direct hepatotoxin, only between 10 and 20% of
alcoholics will develop alcoholic hepatitis. The explanation for this apparent
paradox is unclear but involves the complex interaction of facilitating and
comorbid factors such as gender, heredity, and immunity.
Etiology and Pathogenesis
Quantity and duration of alcohol
intake are the most important risk factors involved in the development of
alcoholic liver disease (Table 301-1). The roles of beverage type(s), i.e.
wine, beer, or spirits, and pattern of drinking are less clear. Progress of the
hepatic injury beyond the fatty liver stage seems to require additional risk
factors that remain incompletely defined. Women are more susceptible to
alcoholic liver injury when compared to men. They develop advanced liver
disease with substantially less alcohol intake. Hispanic men have a much higher
age-adjusted death rate in the United States from alcoholic cirrhosis than do
non-Hispanic whites and blacks. In general, the time it takes to develop liver
disease is directly related to the amount of alcohol consumed. It is useful in
estimating alcohol consumption to understand that one beer, four ounces of
wine, or one ounce of 80% spirits all contain ~12 g of alcohol. The threshold
for developing alcoholic liver disease in men is an intake of more than 60–80
g/d of alcohol for 10 years, while women are at increased risk for developing
similar degrees of liver injury by consuming 20–40 g/d. Ingestion of 160 g/d is
associated with 25–fold increased risk of developing alcoholic cirrhosis.
Gender-dependent differences result from poorly understood effects of estrogen
and the metabolism of alcohol. Social, immunologic, and heritable factors have
all been postulated to play a part in the development of the pathogenic process.
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Chronic infection with hepatitis
C (HCV) is an important comorbidity in
the progression of alcoholic liver disease to cirrhosis in chronic and
excessive drinkers. Even moderate alcohol intake of 20–50 g/d increases the
risk of cirrhosis and hepatocellular cancer in HCV-infected individuals.
Patients with both alcoholic liver injury and HCV infection develop
decompensated liver disease at a younger age and have poorer overall survival.
Increased liver iron stores and, rarely, porphyria cutanea tarda can occur as a
consequence of the overlapping injurious processes secondary to alcohol abuse
and HCV infection. In addition, alcohol intake of more than 50 g/d by
HCV-infected patients decreases the efficacy of interferon-based antiviral
therapy.
Our understanding of the
pathogenesis of alcoholic liver injury is incomplete. Alcohol is a direct
hepatotoxin, but ingestion of alcohol initiates a variety of metabolic
responses that influence the final hepatotoxic response. The initial concept of
malnutrition as the major pathogenic mechanism has been replaced by the
understanding that the hepatic metabolism of alcohol initiates a pathogenic
process involving production of toxic protein-aldehyde adducts, endotoxins,
oxidative stress, immunologic activity, and pro-inflammatory cytokine release
(Fig. 301-1). The complex interaction of intestinal and hepatic cells is
crucial to alcohol-mediated liver injury. Tumor necrosis factor (TNF-) and intestine-derived endotoxemia facilitate
hepatocyte apoptosis and necrosis. Stellate cell activation and collagen
production are key events in hepatic fibrogenesis. The resulting fibrosis
determines the architectural derangement of the liver following chronic alcohol
ingestion.
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Pathology
The liver has a limited
repertoire in response to injury. Fatty liver is the initial and most common
histologic response to hepatotoxic stimuli, including excessive alcohol
ingestion. The accumulation of fat within the perivenular hepatocytes coincides
with the location of alcohol dehydrogenase, the major enzyme responsible for
alcohol metabolism. Continuing alcohol ingestion results in fat accumulation
throughout the entire hepatic lobule. Despite extensive fatty change and
distortion of the hepatocytes with macrovesicular fat, the cessation of
drinking results in normalization of hepatic architecture and fat content
within the liver. Alcoholic fatty liver has traditionally been regarded as
entirely benign, but similar to the spectrum of nonalcoholic fatty liver disease,
the appearance of steatohepatitis and certain pathologic features such as giant
mitochondria, perivenular fibrosis, and macrovesicular fat may be associated
with progressive liver injury.
The transition between fatty
liver and the development of alcoholic hepatitis is blurred. The hallmark of
alcoholic hepatitis is hepatocyte injury characterized by ballooning
degeneration, spotty necrosis, polymorphonuclear infiltrate, and fibrosis in the
perivenular and perisinusoidal space of Disse. Mallory bodies are often present
in florid cases but are neither specific nor necessary to establishing the
diagnosis. Alcoholic hepatitis is thought to be a precursor to the development
of cirrhosis. However, like fatty liver, it is potentially reversible with
cessation of drinking. Cirrhosis is present in up to 50% of patients with
biopsy-proven alcoholic hepatitis and its regression is uncertain, even with
abstention.
Clinical Features
The clinical manifestations of
alcoholic fatty liver are subtle and characteristically detected as a
consequence of the patient's visit for a seemingly unrelated matter. Previously
unsuspected hepatomegaly is often the only clinical finding. Occasionally,
patients with fatty liver will present with right upper quadrant discomfort,
tender hepatomegaly, nausea, and jaundice. Differentiation of alcoholic fatty
liver from nonalcoholic fatty liver is difficult unless an accurate drinking
history is ascertained. In every instance where liver disease is present, a
thoughtful and sensitive drinking history should be obtained. Standard,
validated questions accurately detect alcohol-related problems. Alcoholic
hepatitis is associated with a wide gamut of clinical features. Cytokine production
is thought to be responsible for the systemic manifestations of alcoholic
hepatitis. Fever, spider nevi, jaundice, and abdominal pain simulating an acute
abdomen represent the extreme end of the spectrum, while many patients will be
entirely asymptomatic. Portal hypertension, ascites, or variceal bleeding can
occur in the absence of cirrhosis. Recognition of the clinical features of
alcoholic hepatitis is central to the initiation of an effective and
appropriate diagnostic and therapeutic strategy. It is important to recognize
that patients with alcoholic cirrhosis often exhibit clinical features
identical to other causes of cirrhosis.
Laboratory Features
Patients with alcoholic liver
disease are often identified through routine screening tests. The typical
laboratory abnormalities seen in fatty liver are nonspecific and include modest
elevations of the aspartate aminotransferase (AST), alanine aminotransferase
(ALT), and -glutamyl transpeptidase (GGTP), accompanied by
hypertriglyceridemia, hypercholesterolemia, and occasionally
hyperbilirubinemia. In alcoholic hepatitis and in contrast to other causes of
fatty liver, the AST and ALT are usually elevated two- to sevenfold. They are
rarely more than 400 IU, and the AST/ALT ratio more than 1 (Table 301-2).
Hyperbilirubinemia is common and is accompanied by modest increases in the
alkaline phosphatase level. Derangement in hepatocyte synthetic function
indicates more serious disease. Hypoalbuminemia and coagulopathy are common in
advanced liver injury. Ultrasonography is useful in detecting fatty
infiltration of the liver and determining liver size. The demonstration by
ultrasound of portal vein flow reversal, ascites, and intraabdominal
collaterals indicates serious liver injury with less potential for complete
reversal of liver disease.
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Note: AST, aspartate aminotransferase;
ALT, alanine aminotransferase; GGTP, gamma-glutamyl transpeptidase; PMN,
polymorphonuclear cells.
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Prognosis
Critically
ill patients with alcoholic hepatitis have short-term (30 day) mortality rates
more than 50%. Severe alcoholic hepatitis is heralded by coagulopathy
(prothrombin time more than 5 s), anemia, serum albumin concentrations less
than25 g/L (2.5 mg/dL), serum bilirubin levels more than 137 mol/L (8 mg/dL),
renal failure, and ascites. A discriminant function calculated as 4.6 x
[prothrombin time control (seconds)] + serum bilirubin (mg/dL) can identify
patients with a poor prognosis (discriminant function more than 32). The
presence of ascites, variceal hemorrhage, deep encephalopathy, or hepatorenal
syndrome predicts a dismal prognosis. The pathologic stage of the injury can be
helpful in predicting prognosis. Liver biopsy should be performed whenever
possible to confirm the diagnosis, to establish potential reversibility of the
liver disease, and to guide the therapeutic decisions.
Alcoholic Liver Disease: Treatment
Complete
abstinence from alcohol is the cornerstone in the treatment of alcoholic liver
disease. Improved survival and the potential for reversal of histologic injury
regardless of the initial clinical presentation are associated with total
avoidance of alcohol ingestion. Referral of patients to experienced alcohol
counselors and/or alcohol treatment programs should be routine in the
management of patients with alcoholic liver disease. Attention should be
directed to the nutritional and psychosocial states during the evaluation and
treatment periods. Because of data suggesting that the pathogenic mechanisms in
alcoholic hepatitis involve cytokine release and the perpetuation of injury by
immunologic processes, glucocorticoids have been extensively evaluated in the
treatment of alcoholic hepatitis. Patients with severe alcoholic hepatitis,
defined as a discriminant function more than 32, were given prednisone, 40 mg/d, or
prednisolone, 32 mg/d, for 4 weeks followed by a steroid taper (Fig. 301-2).
Exclusion criteria included active gastrointestinal bleeding, sepsis, renal
failure, or pancreatitis. Women with encephalopathy from severe alcoholic
hepatitis may be particularly good candidates for glucocorticoids
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Newer
understanding of the role of TNF- expression and receptor activity in alcoholic
liver injury has led to an examination of TNF inhibition as an alternative to
glucocorticoids for severe alcoholic hepatitis. The nonspecific TNF inhibitor,
pentoxifylline, recently demonstrated improved survival in the therapy of
severe alcoholic hepatitis (Fig. 301-3). Preliminary trials of neutralizing
monoclonal antibody specific for TNF have been disappointing because of
increased deaths secondary to infection. Because of inordinate surgical
mortality and the high rates of recidivism following transplantation, patients
with alcoholic hepatitis are not candidates for immediate liver
transplantation. The transplant candidacy of these patients should be
reevaluated after a defined period of sobriety.
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