Rowen K. Zetterman, MD, MACP, MACG

Disclosures

January 04, 2010

A 42-year-old man presents with low-grade fever, anorexia, dark urine, light-colored stools, and right upper quadrant aching discomfort of 2 weeks' duration. He indicates that he has consumed a pint of whiskey daily for the past 10 years and denies use of illicit drugs or exposure to hepatitis. His physical examination reveals sclera icterus, cutaneous jaundice, proximal muscle wasting, asterixis, a palpable liver and spleen, and peripheral edema. Laboratory studies include an aspartate aminotransferase (AST) of 102 IU, a normal alanine aminotransferase (ALT), an elevated alkaline phosphatase, bilirubin of 6.5 mg/dL, and prothrombin time of 19 seconds (control of 12 seconds). On the basis of his history of chronic alcohol consumption, fever, hepatosplenomegaly, cholestasis and an AST/ALT ratio of greater than 2 to 1, you make a presumptive diagnosis of acute alcoholic hepatitis. His Maddrey discriminant function score is 39. What is the best approach to his treatment?

Alcoholic Liver Disease

Chronic alcoholism is a frequent cause of liver disease and a common cause of cirrhosis in Western countries. The risk of developing cirrhosis is increased by coexisting hepatitis C virus (HCV) infection. No specific amount of ethanol consumption is associated with liver injury, although it typically follows high daily intake of 10 to 20 years' duration or longer[1] because patients with sustained blood alcohol levels are most likely to develop liver disease. When alcoholic cirrhosis develops, continued ethanol consumption worsens the prognosis. Chronic alcohol consumption not only causes liver disease (fatty liver, alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma), it also increases the risk for tumors such as squamous cell carcinomas eg, pharyngeal, esophageal).[2] Although alcoholic liver disease is associated with excessive ethanol intake, it is not simply a consequence of ethanol per se[1] because end-stage liver disease develops in only 10% of alcoholics.[3] Acetaldehyde, the proximate metabolite of ethanol, may be the metabolite responsible for the development of alcoholic liver disease.[4]

Ethanol Metabolism

Ethanol is principally metabolized by hepatocyte alcohol dehydrogenase (ADH) to acetaldehyde, which is further metabolized by aldehyde dehydrogenase (ALDH) to acetate. The microsomal cytochrome P450 system (CYP2E1) plays a greater role in the metabolism of ethanol when there is excessive alcohol consumption. Catalase has a minor role in ethanol metabolism. Variants of both ADH and AlDH could be related to the development of liver disease.[5] More rapid formation of acetaldehyde by ADH enzyme variants or a reduction in clearance of acetaldehyde by variants of ALDH (eg, ALDH2*2) could increase the exposure of hepatocytes to highly reactive acetaldehyde.[6]

Epidemiology

Approximately 6%-7% of Americans are alcoholics (11% of men and 6% of women)[7] and alcoholic hepatitis and cirrhosis will develop in approximately 10% of chronic alcoholics. What separates those who develop advanced liver disease from those who do not is unclear. Suggested factors include gender, ethnicity, presence of obesity or hepatic iron overload, and the daily quantity of ethanol consumed. Genetic predisposition may play a role in alcohol dependence.[8] Women are at greater risk than men for development of cirrhosis.[9] The risk for cirrhosis in women develops at 7-13 drinks per week and for men, at 14-27 drinks per week.[1] Blacks and Hispanics may be at higher risk for cirrhosis mortality.[10] Other factors that may be important in the development of alcoholic hepatitis and cirrhosis include hepatocyte damage related to:

  • Immune cytokines released in response to ethanol metabolites, or acetaldehyde-protein adducts;

  • An altered redox state or hypermetabolic state related to ethanol metabolism;

  • Formation of free radicals during ethanol metabolism, producing oxidative stress or lipid peroxidation;

  • Increased endotoxin levels as a consequence of enhanced small intestinal permeability, concurrent nutritional deficiency or coexisting hepatitis C[11,12]; and

  • Concurrent nutritional deficiency or coexisting hepatitis C.

The precise mechanism(s) causing advanced alcoholic liver disease remain unknown.

Fatty Metamorphosis of the Liver

Fatty liver is the most common hepatic manifestation of chronic alcoholism. Fatty change of hepatocytes can develop within 2 days of ethanol excess[13] and resolve within 2 weeks of discontinuation of ethanol.[14]Patients with alcoholic fatty livers are typically asymptomatic although they may have mild right upper quadrant pain and hepatomegaly. Aminotransferases can be elevated and gamma-glutamyl transpeptidase (GGT) levels are often increased as a result of ethanol-induced microsomal enzyme activity. Alcoholic fatty liver can be difficult to differentiate from non-alcoholic fatty liver disease. A careful history for alcohol consumption, lack of findings of metabolic syndrome, an AST/ALT ratio > 2, and a markedly elevated GGT suggest alcoholic fatty liver. Hepatic ultrasound can identify changes consistent with fatty liver and a liver biopsy specimen, if obtained, demonstrates macrovesicular fat of perivenular (centrizonal) hepatocytes. In an occasional alcoholic patient, severe microvesicular fatty change of hepatocytes (alcoholic foamy degeneration) may develop as a consequence of mitochondrial dysfunction associated with severe hepatic encephalopathy and hyperbilirubinemia, and this patient has an increased risk for death. The treatment of patients with alcoholic fatty liver is cessation of ethanol consumption and provision of nutritional support for patients with coexisting nutritional deficiencies.

Alcoholic Hepatitis

Alcoholic hepatitis develops in approximately 10% of those with long-term daily ethanol consumption. Patients present with symptoms of fatigue, anorexia, fever, jaundice, weight loss, right upper quadrant pain, and an enlarged liver. Signs of hepatic decompensation including ascites and encephalopathy may be present. Occasionally an arterial bruit will be heard over the liver in the patient with alcoholic hepatitis. Hepatic bruits are also occasionally heard in patients with hepatocellular carcinoma.

Laboratory studies in alcoholic hepatitis

  • Modest leukocytosis (12-14,000/mm3) but may occasionally present as a leukemoid reaction;

  • AST/ALT > 2:1;

  • Elevated alkaline phosphatase and GGT;

  • Hypothrombinemia;

  • Hyperbilirubinemia;

  • Cholestasis; and

  • Hypoalbuminemia.

Histology of alcoholic hepatitis. Liver histology is characterized by perivenular hepatocellular necrosis and ballooning degeneration, macro- and microvesicular steatosis, and polymorphonuclear leukocyte inflammation with or without fibrosis or Mallory's hyaline.

  • Hepatocellular necrosis;

  • Ballooning degeneration of hepatocytes;

  • Macro- and microvesicular steatosis/fatty metamorphosis of hepatocytes;

  • Polymorphonuclear leukocyte inflammation;

  • Cholestasis;

  • Mallory's hyaline; and

  • Pericellular fibrosis.

Fatty change of liver cells may or may not be present. Fibrosis is initially pericellular and progresses to bridging fibrosis. Alcoholic hepatitis is a clinically severe hepatic disorder with a 35%-45% mortality[15,16] that correlates with the severity of associated malnutrition.[17]

Alcoholic Cirrhosis

Patients with alcoholic cirrhosis may be asymptomatic or present with symptoms and signs of end-stage liver disease and portal hypertension including ascites, encephalopathy, or variceal hemorrhage. Laboratory findings include an elevated prothrombin time, abnormal liver tests and hypoalbuminemia. Hepatic ultrasound may identify a nodular, dense liver with evidence of portal hypertension including splenomegaly, portal vein enlargement, altered portal vein flows, and ascites. All patients with suspected alcoholic cirrhosis should undergo upper endoscopy to screen for esophageal varices.

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