Alcoholic Liver Disease Harrison
Alcoholic Liver Disease Harrison
Alcoholic Liver Disease Harrison
Chronic infection with hepatitis C (HCV) (Chap. 300) is an important comorbidity in the progression of alcoholic liver disease to
cirrhosis in chronic and excessive drinkers. Even moderate alcohol intake of 2050 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 >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pathogenic mechanism has been replaced by the understanding that the hepatic metabolism of alcohol initiates a pathogenic process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.
Figure 301-1
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 (Chap.
303), 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 >400 IU, and the AST/ALT ratio >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.
Prognosis
Critically ill patients with alcoholic hepatitis have short-term (30 day) mortality rates >50%. Severe alcoholic hepatitis is heralded by
coagulopathy (prothrombin time > 5 s), anemia, serum albumin concentrations <25 g/L (2.5 mg/dL), serum bilirubin levels > 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 > 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.
Figure 301-3