Liver Disease, Alcohol-Associated

Essentials of Diagnosis

• Chronic alcohol intake usually exceeds 80 g/day in men and 30–40 g/day in women with alcohol-associated hepatitis or cirrhosis

• Fatty liver is often asymptomatic

• In alcohol-associated hepatitis, fever, right upper quadrant pain, tender hepatomegaly, and jaundice; or asymptomatic

• Aspartate aminotransferase (AST) is often elevated but infrequently above 300 units/L (6 mckat/L)

• AST is greater than alanine aminotransferase (ALT), usually by a factor of 2 or more

• Often reversible, but it is the most common precursor of cirrhosis in the United States

General Considerations

• Excessive alcohol intake can lead to fatty liver, alcohol-associated hepatitis, and cirrhosis

• Many of the adverse effects of alcohol are probably mediated by tumor necrosis factor and by the oxidative metabolite acetaldehyde, which contributes to lipid peroxidation and induction of an immune response

• Alcohol-associated hepatitis is characterized by acute or chronic inflammation and parenchymal necrosis

• Deficiencies of vitamins and calories probably contribute to development of alcohol-associated hepatitis and its progression to cirrhosis

Demographics

• Over 80% of patients have been drinking 5 years or more before developing any liver symptoms

• The longer the duration of drinking (10–15 or more years) and the larger the alcoholic consumption, the greater the probability of developing alcohol-associated hepatitis and cirrhosis

Symptoms and Signs

• Can vary from an asymptomatic hepatomegaly to a rapidly fatal acute illness (acute-on-chronic liver failure) or to an end-stage cirrhosis

• Recent period of heavy drinking

• Anorexia and nausea

• Hepatomegaly and jaundice in hepatitis

• Abdominal pain and tenderness, splenomegaly, ascites, fever, and/or encephalopathy in cirrhosis

• Infection, including invasive aspergillosis, is common in patients with severe alcohol-associated hepatitis

Differential Diagnosis

• Nonalcoholic fatty liver disease

• Viral hepatitis

• Drug-induced hepatitis

• Cirrhosis

• Biliary tract disease

• Pneumonia

• Cholecystitis

• Cholelithiasis

Laboratory Tests

LIVER PANEL

• AST is usually elevated up to 300 units/L, but not higher

• AST is > ALT, usually by a factor of 2 or more

• Serum alkaline phosphatase is generally elevated, but seldom more than three times the normal value

• Serum bilirubin is increased in 60–90% of patients with alcohol-associated hepatitis

COMPLETE BLOOD COUNT

• Anemia (usually macrocytic) may be present

• Leukocytosis with shift to the left is common with severe alcohol-associated hepatitis

• Leukopenia is occasionally seen and resolves after cessation of drinking

• About 10% of patients have thrombocytopenia related to a direct toxic effect of alcohol on megakaryocyte production or to hypersplenism

OTHER LABORATORY TESTS

• Serum bilirubin levels > 10 mg/dL and marked prolongation of the prothrombin time (≥ 6 seconds above control) indicate severe alcohol-associated hepatitis

• The serum albumin is depressed, and the gamma-globulin level (especially IgA) is elevated in 50–75% of persons with alcohol-associated hepatitis, even in the absence of cirrhosis

• Increased transferrin saturation, hepatic iron stores, and sideroblastic anemia are found in many alcoholic patients

• Folic acid deficiency may coexist

Imaging Studies

• May show hepatic steatosis but not inflammation or fibrosis

• Ultrasonography helps exclude biliary obstruction and identifies subclinical ascites

• CT with intravenous contrast or MRI may be indicated in selected cases to evaluate patients for collateral vessels, space-occupying lesions of the liver, or concomitant disease of the pancreas

Diagnostic Procedures

• Liver biopsy

  • If done, demonstrates various combinations of macrovesicular fat, polymorphonuclear infiltration with hepatic necrosis, Mallory bodies (alcoholic hyaline), and perivenular and perisinusoidal fibrosis

  • Micronodular cirrhosis may be present as well

  • The findings are identical to those of nonalcoholic steatohepatitis

Medications

• Give micronutrients, particularly folic acid, thiamine, and zinc

• Naltrexone, acamprosate, or baclofen may be considered in combination with counseling to reduce the likelihood of recidivism

• Baclofen appears to be safe in persons with end-stage alcohol-associated liver disease but can worsen hepatic encephalopathy

• Glucose administration increases the thiamine requirement and can precipitate Wernicke encephalopathy-Korsakoff syndrome if thiamine is not coadministered

• Corticosteroids

  • Methylprednisolone, 32 mg/day orally for 1 month or the equivalent, may reduce short-term mortality and either encephalopathy or a discriminant function (defined by patient's prothrombin time minus the control prothrombin time multiplied by 4.6 plus the total bilirubin in mg/dL) ≥ 32 or a MELD score ≥ 20

  • Corticosteroids plus N-acetylcysteine

    • Has been reported to improve 1-month but not 6-month survival

    • Reduces risk of hepatorenal syndrome and infections

    • May be superior to corticosteroids alone, but more data are needed

  • Concomitant gastrointestinal bleeding or infection may not preclude treatment with corticosteroids if otherwise indicated

• Pentoxifylline

  • A tumor necrosis factor inhibitor

  • Administer 400 mg three times daily orally for 4 weeks

  • Decreases the risk of hepatorenal syndrome

  • Does not appear to reduce short-term mortality

  • May be used when corticosteroids are contraindicated

• Other experimental therapies

  • Anikinra

  • Zinc

  • Pentoxifylline

  • Propylthiouracil

  • Oxandrolone

  • S-adenosyl-l-methionine

  • Infliximab

  • Antioxidants

  • Granulocyte colony-stimulating factor

  • Modulation of intestinal flora

  • Extracorporeal liver support

• Nephrotoxic drugs should be avoided in patients with severe alcohol-associated hepatitis

Therapeutic Procedures

• Abstinence from alcohol is essential; fatty liver is quickly reversible

• Provide sufficient carbohydrates and calories in anorectic patients to reduce endogenous protein catabolism, promote gluconeogenesis, and prevent hypoglycemia

• Nutritional support (30–40 [and no < 21.5] kcal/kg with 1.0–1.5 g/kg as protein) improves liver disease, but not necessarily survival, in patients with malnutrition

• Intensive enteral nutrition is difficult to implement, however

• Use of liquid formulas rich in branched-chain amino acids does not improve survival beyond that achieved with less expensive caloric supplementation

Complications

ALCOHOLIC CIRRHOSIS

• Occurs in about 10–15% of persons who consume over 50 g of alcohol (4 oz of 100-proof whiskey, 15 oz of wine, or four 12-oz cans of beer) daily for over 10 years (the risk may be lower for wine than for comparable intake of beer or spirits)

• The risk of cirrhosis is lower (5%) in the absence of other cofactors such as chronic viral hepatitis and obesity

• There are associations with polymorphisms of the genes encoding patatin-like phospholipase domain-containing protein 3 (PNPLA3), tumor necrosis factor-α, cytochrome P450 2E1, and glutathione S-transferase

• Women appear to be more susceptible than men, in part because of lower gastric mucosal alcohol dehydrogenase levels

Prognosis

Short term

• Overall mortality rate for alcohol-associated hepatitis is 34% (20% within 1 month) without corticosteroid therapy

• If the prothrombin time prohibits liver biopsy, there is a 42% 1-year mortality rate

• Other unfavorable prognostic factors

  • Older age

  • Serum bilirubin levels > 10 mg/dL (171 mcmol/L)

  • Hepatic encephalopathy

  • Coagulopathy

  • Azotemia

  • Leukocytosis

  • Sepsis and other infections

  • Systemic inflammatory response syndrome

  • Lack of response to corticosteroids

  • Paucity of steatosis on a liver biopsy specimen

  • Reversal of portal blood flow on Doppler ultrasonography

• The Model for End-Stage Liver disease (MELD) score (used to prioritize patients with cirrhosis for liver transplantation, see Cirrhosis) and the Glasgow alcohol-associated hepatitis score also correlate with mortality from alcohol-associated hepatitis

• Histologic features associated with 90-day mortality include

  • Degree of fibrosis and neutrophil infiltration

  • Presence of metamitochondria

  • Bilirubinostasis

Long term

• Overall mortality from alcohol-associated liver disease has declined slightly in the United States since 1980

• Nevertheless, the 3-year mortality rate of persons who recover from acute alcohol-associated hepatitis is ten times greater than that of control individuals of comparable age

• The 5-year mortality rate is as high as 85%

• Histologically severe disease is associated with continued excessive mortality rates after 3 years, whereas the death rate is not increased after the same period in those whose liver biopsies show only mild alcohol-associated hepatitis

• Poor prognosis suggested by

  • Complications of portal hypertension (ascites, variceal bleeding, hepatorenal syndrome)

  • Coagulopathy

  • Severe jaundice following recovery from acute alcohol-associated hepatitis

• Continued excessive drinking (the most important prognostic indicator); a 6-month period of abstinence is generally required before liver transplantation can be considered

• Patients with alcohol-associated liver disease are at higher risk for posttransplant malignancy than those with other types of liver disease because of alcohol and tobacco use

Prevention

• Abstinence from alcohol

When to Refer

• Refer patients who require liver biopsy for diagnosis

When to Admit

• Hepatic encephalopathy

• INR > 1.6

• Total bilirubin ≥ 10 mg/dL

• Inability to maintain hydration