(See also the American College of Gastroenterology's practice guideline Alcoholic Liver Disease: Proposed Recommendations for the American College of Gastroenterology.)
Alcohol consumption is high in most Western countries. In the US, > 10% of people abuse or are dependent on alcohol. The male:female ratio is about 2:1. Disorders that occur in alcohol abusers, often in sequence, include
Hepatocellular carcinoma may also develop, especially in association with iron accumulation.
The main causative factors in alcoholic liver disease are
Quantity of alcohol:
Among susceptible people, a linear correlation generally exists between the amount and duration of alcohol use and the development of liver disease.
Alcohol content is estimated to be the beverage volume (in mL) multiplied by its percentage of alcohol. For example, the alcohol content of 40 mL of an 80-proof (40% alcohol) beverage is 16 mL by volume. Each mL contains about 0.79 g of alcohol. Although values can vary, the percentage of alcohol averages 2 to 7% for most beers and 10 to 15% for most wines. Thus, a 12-oz glass of beer contains about 3 to 10 g of alcohol, and an 8-oz glass of wine contains about 10 to 15 g.
Risk increases markedly for men who drink > 40 g, particularly > 80 g, of alcohol/day for > 10 yr (eg, 3 to 6 cans of beer, 3 to 6 shots of hard liquor, 4 to 8 glasses of wine). For cirrhosis to develop, consumption must usually be > 80 g/day for > 10 yr. If consumption exceeds 230 g/day for 20 yr, risk of cirrhosis is about 50%. But only some chronic alcohol abusers develop liver disease. Thus, variations in alcohol intake do not fully explain variations in susceptibility, indicating that other factors are involved.
Women are more susceptible to alcoholic liver disease, even after adjustment for body size. Women require only 20 to 40 g of alcohol to be at risk—half of that for men. Risk in women may be increased because they have less alcohol dehydrogenase in their gastric mucosa; thus, first-pass oxidation of alcohol is decreased.
Alcoholic liver disease often runs in families, suggesting genetic factors (eg, deficiency of cytoplasmic enzymes that eliminate alcohol).
Undernutrition, particularly protein-energy undernutrition, increases susceptibility, as does a diet high in unsaturated fat and obesity.
Other risk factors include iron accumulation in the liver (not necessarily related to iron intake) and concomitant hepatitis C.
Alcohol absorption and metabolism:
Alcohol (ethanol) is readily absorbed from the stomach, but most is absorbed from the small intestine. Alcohol cannot be stored. A small amount is degraded in transit through the gastric mucosa, but most is catabolized in the liver, primarily by alcohol dehydrogenase (ADH) but also by cytochrome P-450 2E1 (CYP2E1) and the microsomal enzyme oxidation system (MEOS).
Metabolism via the ADH pathway involves the following:
Chronic alcoholism induces the MEOS (mainly in endoplasmic reticulum), increasing its activity. The main enzyme involved is CYP2E1. When induced, the MEOS pathway can account for 20% of alcohol metabolism. This pathway generates harmful reactive O2 species, increasing oxidative stress and formation of O2-free radicals.
Hepatic fat accumulation:
Fat (triglycerides) accumulates throughout the hepatocytes for the following reasons:
Hepatic fat accumulation may predispose to subsequent oxidative damage.
Endotoxins in the gut:
Alcohol changes gut permeability, increasing absorption of endotoxins released by bacteria in the gut. In response to the endotoxins (which the impaired liver can no longer detoxify), liver macrophages (Kupffer cells) release free radicals, increasing oxidative damage.
Oxidative stress is increased by
Accumulation of hepatic iron, if present, aggravates oxidative damage. Iron can accumulate in alcoholic liver disease through ingestion of iron-containing fortified wines; most often, the iron accumulation is modest. This condition must be differentiated from hereditary hemochromatosis.
Resultant inflammation, cell death, and fibrosis:
A vicious circle of worsening inflammation occurs: Cell necrosis and apoptosis result in hepatocyte loss, and subsequent attempts at regeneration result in fibrosis. Stellate (Ito) cells, which line blood channels (sinusoids) in the liver, proliferate and transform into myofibroblasts, producing an excess of type I collagen and extracellular matrix. As a result, the sinusoids narrow, limiting blood flow. Fibrosis narrows the terminal hepatic venules, compromising hepatic perfusion and thus contributing to portal hypertension. Extensive fibrosis is associated with an attempt at regeneration, resulting in liver nodules. This process culminates in cirrhosis.
Fatty liver, alcoholic hepatitis, and cirrhosis are often considered separate, progressive manifestations of alcoholic liver disease. However, their features often overlap.
Fatty liver (steatosis) is the initial and most common consequence of excessive alcohol consumption. Fatty liver is potentially reversible. Macrovesicular fat accumulates as large droplets of triglyceride and displaces the hepatocyte nucleus, most markedly in perivenular hepatocytes. The liver enlarges.
Alcoholic hepatitis (steatohepatitis) is a combination of fatty liver, diffuse liver inflammation, and liver necrosis (often focal)—all in various degrees of severity. The damaged hepatocytes are swollen with a granular cytoplasm (balloon degeneration) or contain fibrillar protein in the cytoplasm (Mallory or alcoholic hyaline bodies). Severely damaged hepatocytes become necrotic. Sinusoids and terminal hepatic venules are narrowed. Cirrhosis may also be present.
Alcoholic cirrhosis is advanced liver disease characterized by extensive fibrosis that disrupts the normal liver architecture. The amount of fat present varies. Alcoholic hepatitis may coexist. The feeble compensatory attempt at hepatic regeneration produces relatively small nodules (micronodular cirrhosis). As a result, the liver usually shrinks. In time, even with abstinence, fibrosis forms broad bands, separating liver tissue into large nodules (macronodular cirrhosis—see Fibrosis and Cirrhosis: Pathophysiology).
Symptoms and Signs
Symptoms usually become apparent in patients during their 30s or 40s; severe problems appear about a decade later.
Fatty liver is often asymptomatic. In one third of patients, the liver is enlarged and smooth, but it is not usually tender.
Alcoholic hepatitis ranges from mild and reversible to life threatening. Most patients with moderate disease are undernourished and present with fatigue, fever, jaundice, right upper quadrant pain, tender hepatomegaly, and sometimes a hepatic bruit. About 40% deteriorate soon after hospitalization, with consequences ranging from mild (eg, increasing jaundice) to severe (eg, ascites, portal-systemic encephalopathy, variceal bleeding, liver failure with hypoglycemia, coagulopathy). Other manifestations of cirrhosis may be present.
Cirrhosis, if compensated, may be asymptomatic. The liver is usually small; when the liver is enlarged, fatty liver or hepatoma should be considered. Symptoms range from those of alcoholic hepatitis to the complications of end-stage liver disease, such as portal hypertension (often with esophageal varices and upper GI bleeding, splenomegaly, ascites, and portal-systemic encephalopathy). Portal hypertension may lead to intrapulmonary arteriovenous shunting with hypoxemia (hepatopulmonary syndrome), which may cause cyanosis and nail clubbing. Acute renal failure secondary to progressively decreasing renal blood flow (hepatorenal syndrome) may develop. Hepatocellular carcinoma develops in 10 to 15% of patients with alcoholic cirrhosis.
Chronic alcoholism, rather than liver disease, causes Dupuytren's contracture of the palmar fascia, vascular spiders, and peripheral neuropathy. In men, chronic alcoholism causes signs of hypogonadism and feminization (eg, smooth skin, lack of male-pattern baldness, gynecomastia, testicular atrophy, changes in pubic hair). Undernutrition may lead to multiple vitamin deficiencies (eg, of folate and thiamin), enlarged parotid glands, and white nails. In alcoholics, Wernicke's encephalopathy and Korsakoff's psychosis result mainly from thiamin deficiency. Hepatitis C occurs in > 25% of alcoholics; this combination markedly worsens the progression of liver disease.
Rarely, patients with fatty liver or cirrhosis present with Zieve's syndrome (hyperlipidemia, hemolytic anemia, and jaundice).
Alcohol is suspected as the cause of liver disease in any patient who chronically consumes excess alcohol, particularly > 80 g/day. History should be confirmed by family members. Patients can be screened for alcoholism using the CAGE questionnaire (need to Cut down, Annoyed by criticism, Guilty about drinking, and need for a morning Eye-opener). There is no specific test for alcoholic liver disease, but if the diagnosis is suspected, liver function tests (PT; serum bilirubin, aminotransferase, and albumin levels) and CBC are done to detect signs of liver injury and anemia.
Elevations of aminotransferases are moderate (< 300 IU/L) and do not reflect the extent of liver damage. The ratio of AST to ALT is ≥ 2. The basis for low ALT is a dietary deficiency of pyridoxal phosphate (vitamin B6), which is needed for ALT to function. Its effect on AST is less pronounced. Serum γ-glutamyl transpeptidase (GGT) increases, more because ethanol induces this enzyme than because patients have cholestasis or liver injury or use other drugs. Serum albumin may be low, usually reflecting undernutrition but occasionally reflecting otherwise obvious liver failure with deficient synthesis. Macrocytosis with an MCV > 100 fL reflects the direct effect of alcohol on bone marrow as well as macrocytic anemia resulting from folate deficiency, which is common among undernourished alcoholics. Indexes of the severity of liver disease are
Thrombocytopenia can result from the direct toxic effects of alcohol on bone marrow or from splenomegaly, which accompanies portal hypertension. Neutrophilic leukocytosis may result from alcoholic hepatitis, although coexisting infection (particularly pneumonia and spontaneous bacterial peritonitis) should also be suspected.
Imaging tests are not routinely needed for diagnosis. If done for other reasons, abdominal ultrasonography or CT may suggest fatty liver or show evidence of splenomegaly, portal hypertension, or ascites. Ultrasound elastrography measures liver stiffness and thus detects advanced fibrosis. This valuable adjunct can obviate the need for liver biopsy to check for cirrhosis and help assess prognosis. Its exact role is under study.
If abnormalities suggest alcoholic liver disease, screening tests for other treatable forms of liver disease, especially viral hepatitis, should be done. Because features of fatty liver, alcoholic hepatitis, and cirrhosis overlap, describing the precise findings is more useful than assigning patients to a specific category, which can only be determined by liver biopsy.
Not all experts agree on the indications for liver biopsy. Proposed indications include the following:
Liver biopsy confirms liver disease, helps identify excessive alcohol use as the likely cause, and establishes the stage of liver injury. If iron accumulation is observed, measurement of the iron content and genetic testing can eliminate hereditary hemochromatosis (see Iron Overload: Hereditary Hemochromatosis) as the cause.
For stable patients with cirrhosis, α-fetoprotein measurement and liver ultrasonography should be done to screen for hepatocellular carcinoma (see Liver Masses and Granulomas: Hepatocellular Carcinoma).
Prognosis is determined by the degree of hepatic fibrosis and inflammation. Fatty liver and alcoholic hepatitis without fibrosis are reversible if alcohol is avoided. With abstinence, fatty liver completely resolves within 6 wk. Fibrosis and cirrhosis are irreversible.
Certain biopsy findings (eg, neutrophils, perivenular fibrosis) indicate a worse prognosis. Proposed quantitative indexes to predict severity and mortality use primarily laboratory features of liver failure such as prothrombin time, creatinine (for hepatorenal syndrome) and bilirubin levels. The Maddrey discriminant function is calculated from the formula:
For this formula, bilirubin level is measured in mg/dL (converted from bilirubin in μmol/L by dividing by 17). A value of > 32 is associated with a high short-term mortality rate (eg, after 1 mo, 35% without encephalopathy and 45% with encephalopathy). Other indexes include the Model for End-Stage Liver Disease (MELD), Glasgow alcoholic hepatitis score, and Lille model.
Once cirrhosis and its complications (eg, ascites, bleeding) develop, the 5-yr survival rate is about 50%; survival is higher in patients who abstain and lower in patients who continue drinking.
Coexisting iron accumulation or chronic hepatitis C increases risk of hepatocellular carcinoma.
Restricting alcohol intake:
Abstinence is the mainstay of treatment; it prevents further damage from alcoholic liver disease and thus prolongs life. Because compliance is problematic, a compassionate team approach is essential. Behavioral and psychosocial interventions can help motivated patients; they include rehabilitation programs and support groups (see Drug Use and Dependence: Treatment), brief interventions by primary care physicians, and therapies that explore and clarify the motivation to abstain (motivational enhancement therapy).
Drugs, if used, should only supplement other interventions. Opioid antagonists (naltrexone or nalmefene) and drugs that modulate γ-aminobutyric acid receptors (baclofen or acamprosate) appear to have a short-term benefit by reducing the craving and withdrawal symptoms. Disulfiram inhibits aldehyde dehydrogenase, allowing acetaldehyde to accumulate; thus, drinking alcohol within 12 h of taking disulfiram causes flushing and has other unpleasant effects. However, disulfiram has not been shown to promote abstinence and consequently is recommended only for certain patients.
General management emphasizes supportive care. A nutritious diet and vitamin supplements (especially B vitamins) are important during the first few days of abstinence. Alcohol withdrawal requires use of benzodiazepines (eg, diazepam). In patients with advanced alcoholic liver disease, excessive sedation can precipitate hepatic encephalopathy and thus must be avoided.
Severe acute alcoholic hepatitis commonly requires hospitalization, often in an intensive care unit, to facilitate enteral feeding (which can help manage nutritional deficiencies) and to manage specific complications (eg, infection, bleeding from esophageal varices, specific nutritional deficiencies, Wernicke's encephalopathy, Korsakoff's psychosis, electrolyte abnormalities, portal hypertension, ascites, portal-systemic encephalopathy—see elsewhere in The Manual).
Corticosteroids (eg, prednisolone 40 mg/day po for 4 wk, followed by tapered doses improve outcome in patients who have severe acute alcoholic hepatitis and who do not have infection, GI bleeding, renal failure, or pancreatitis.
Other than corticosteroids and enteral feeding, few specific treatments are clearly established. Antioxidants (eg, S-adenosyl-l-methionine, phosphatidylcholine, metadoxine) show promise in ameliorating liver injury during early cirrhosis but require further study. Therapies directed at cytokines, particularly tumor necrosis factor-α (TNF-α), and aiming to reduce inflammation have had mixed results in small trials. Pentoxifylline, a phosphodiesterase inhibitor that inhibits TNF-α synthesis, has some benefit. In contrast, when biologic agents that inhibit TNF-α (eg, infliximab, etanercept) are used, risk of infection outweighs benefit. Drugs given to decrease fibrosis (eg, colchicine, penicillamine) and drugs given to normalize the hypermetabolic state of the alcoholic liver (eg, propylthiouracil) have no proven benefit. Antioxidant remedies, such as silymarin (milk thistle) and vitamins A and E, are ineffective.
Liver transplantation can be considered if disease is severe. With transplantation, 5-yr survival rates are comparable to those for nonalcoholic liver disease—as high as 80% in patients without active liver disease and 50% in those with acute alcoholic hepatitis. Because up to 50% of patients resume drinking after transplantation, most programs require 6 mo of abstinence before transplantation is done.
Last full review/revision June 2009 by Eldon A. Shaffer, MD
Content last modified May 2012