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(See also the American College of Gastroenterology's practice guideline Alcoholic Liver
Disease: Proposed Recommendations for the American College of Gastroenterology.)
Alcohol causes a spectrum of liver injury that can progress from fatty liver to alcoholic hepatitis (often considered an intermediate stage) to cirrhosis.
Alcohol consumption is high in most Western countries. In the US, annual ingestion is estimated at 10 L of pure ethanol equivalent per person; 15 million people abuse or are dependent on alcohol. The male:female ratio is 11:4.
Risk Factors
The major causative factors in alcoholic liver disease are quantity of alcohol consumed, duration of alcohol abuse (usually > 8 yr), nutritional status, and genetic and metabolic traits. Among susceptible people, a linear correlation generally exists between the amount and duration of alcohol use and the development of liver disease. As little as 20 g of alcohol in women or 60 g in men can cause serious liver damage when consumed daily for several years. Consuming more than 60 g/day for 2 to 4 wk produces fatty liver even in otherwise healthy men; 80 g/day may lead to alcoholic hepatitis; and 160 g/day over a decade can lead to cirrhosis. Alcohol content is estimated to be the beverage volume (in mL) multiplied by its percentage of alcohol. For example, 16 mL of alcohol is contained in roughly 40 mL of an 80‑proof (40% alcohol) beverage. Each mL of alcohol contains about 0.79 g. Although values can vary, the percentage of alcohol is about 2 to 7% for most beers and 10 to 15% for most wines.
Only 10 to 20% of alcoholics develop cirrhosis. Women are more susceptible than men (even when adjusting for smaller body size), probably because women have less alcohol dehydrogenase in their gastric mucosa, which lessens the first-pass oxidation of alcohol. Alcoholic liver disease often runs in families, suggesting genetic factors (eg, deficiency of cytoplasmic enzymes that eliminate alcohol). Malnutrition, particularly protein-energy malnutrition, increases susceptibility. Other risk factors include a diet high in unsaturated fat, iron deposition in the liver, and concomitant hepatitis C virus infection.
Pathophysiology
Alcohol is readily absorbed from the stomach and small intestine. It cannot be stored; > 90% is metabolized through oxidation. The first breakdown product is acetaldehyde, which is produced by three enzymatic pathways: alcohol dehydrogenase (responsible for about 80% of metabolism), cytochrome P‑450 2E1 (CYP2E1), and catalase.
Acetaldehyde is converted to acetate by mitochondrial aldehyde dehydrogenase. Chronic alcohol consumption enhances acetate formation. The processes generate hydrogen, which converts nicotinamide-adenine dinucleotide (NAD) to its reduced form (NADH), increasing the redox potential in the liver. This replaces fatty acids as a fuel, lowers fatty acid oxidation, and allows triglycerides to accumulate, causing fatty liver and hyperlipidemia. The excess hydrogen also converts pyruvate to lactate, which decreases glucose production (hypoglycemia can result), causing renal acidosis, reduced urate excretion, hyperuricemia, and thus gout.
Alcohol metabolism may also make the liver hypermetabolic, causing hypoxia and free radical–induced lipid peroxidative damage. Alcohol and undernutrition deplete antioxidants, such as glutathione and vitamins A and E, which predispose to such damage.
Acetaldehyde initiates much of the inflammation and fibrosis of alcoholic hepatitis. It transforms the stellate (Ito) cells lining liver blood channels (sinusoids) into fibroblasts that develop myocontractile elements and actively produce collagen. The sinusoids narrow and fill, limiting transport and blood flow. Gut endotoxins, which the impaired liver can no longer detoxify, lead to production of inflammatory cytokines. Acetaldehyde and lipid peroxidation products recruit leukocytes, resulting in production of more inflammatory cytokines. This elicits a vicious circle of inflammation that culminates in fibrosis and loss of hepatocytes.
Fat is deposited throughout the hepatocytes, a result of increased input from peripheral adipose tissue, elevated triglyceride synthesis, decreased lipid oxidation, and reduced lipoprotein production that impairs fat export from the liver.
Pathology
Fatty liver, alcoholic hepatitis, and cirrhosis often are considered separate, progressive manifestations of alcoholic liver disease. Their features, however, often overlap.
Fatty
liver (steatosis) is the initial and most common consequence of excessive alcohol ingestion. It is potentially reversible. Fatty liver is the accumulation of macrovesicular fat as large droplets of triglyceride that displaces the hepatocyte nucleus. Less often, fat appears in a microvesicular form as small droplets that do not displace the nucleus. Microvesicular fat represents mitochondrial damage. The liver enlarges, and the cut surface is yellow.
Alcoholic
hepatitis (steatohepatitis) is a combination of fatty liver, diffuse liver inflammation, and liver necrosis (often focal), all in various degrees of severity. Cirrhosis may be present as well. The damaged hepatocytes either 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. Collagen accumulation and fibrosis of the terminal hepatic venules compromise hepatic perfusion and contribute to portal hypertension. Histologic features that predict progression to cirrhosis include perivenular fibrosis, microvesicular fat, and giant mitochondria.
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), shrinking the liver. In time, particularly with abstinence, this can progress to macronodular cirrhosis (see Fibrosis and Cirrhosis: Pathophysiology).
Iron
accumulation in the liver occurs in up to 10% of alcoholics with normal, fatty, or cirrhotic livers. Accumulation is not predicted by iron intake or body iron stores.
Symptoms and Signs
Symptoms match the stage and severity of disease. Symptoms generally become apparent in patients during their 30s; severe problems appear about a decade later.
Fatty liver usually causes no symptoms. In 1⁄3 of patients, the liver is enlarged, smooth, and occasionally tender.
Alcoholic hepatitis ranges from a mild, reversible illness to a life-threatening disease. In moderate cases, patients usually are malnourished and present with fatigue, fever, jaundice, right upper quadrant pain, tender hepatomegaly, and, sometimes, a hepatic bruit. Their condition often deteriorates in the first few weeks of hospitalization. Severe cases may involve jaundice, ascites, hypoglycemia, electrolyte abnormalities, hepatic insufficiency with coagulopathy or portal-systemic encephalopathy, or other manifestations of cirrhosis. If severe hyperbilirubinemia > 20 mg/dL (> 360 μmol/L), prolonged PT or INR (unresponsive to vitamin K sc), and encephalopathy are present, the risk of death is 20 to 50%, and the risk of cirrhosis is 50%.
Cirrhosis may cause symptoms ranging from minimal to those of alcoholic hepatitis or the complications of end-stage liver disease. Commonly, portal hypertension (often with esophageal varices and upper GI bleeding, ascites, portal-systemic encephalopathy), hepatorenal syndrome, or even hepatocellular carcinoma is present.
In any chronic alcoholic liver disease, Dupuytren's contracture of the palmar fascia, vascular spiders, peripheral neuropathy, Wernicke's encephalopathy, Korsakoff's psychosis, and, in men, signs of hypogonadism and feminization (eg, smooth skin, lack of male-pattern baldness, gynecomastia, testicular atrophy) may be present. These manifestations more likely reflect the effect of alcoholism than of liver disease. Malnutrition may lead to enlarged parotid glands. Hepatitis C virus infection occurs in about 25% of alcoholics, a combination that markedly worsens the progression of liver disease.
Diagnosis
Alcohol is suspected as the cause of liver disease in any patient whose consumption exceeds 80 g/day. If the diagnosis is suspected, liver function tests, CBC, and hepatitis serology are performed. No specific test exists for alcoholic liver disease.
Elevations of aminotransferases are moderate (< 300 IU/L) and do not reflect the extent of the liver damage. Further, AST exceeds ALT by a ratio of > 2. The basis for the low ALT is a dietary deficiency of pyridoxal phosphate (vitamin B6), which is needed for the enzyme to function. Its effect on AST is less pronounced. Serum γ‑glutamyl transpeptidase (GGT) increases as a result of ethanol-induced enzyme induction as well as from use of other drugs, cholestasis, and liver injury. Macrocytosis with an MCV > 100 fL reflects the direct effect of alcohol on the bone marrow as well as the macrocytic anemia resulting from folate deficiency, which is common among malnourished alcoholics. Indices of the severity of liver disease are serum bilirubin, which represents secretory function, and PT or INR, which reflects synthetic ability. Thrombocytopenia can result from the direct toxic effects of alcohol on the bone marrow or from hypersplenism that occurs in portal hypertension.
Imaging tests are not routinely needed for diagnosis. If performed for other reasons, abdominal ultrasound or CT may suggest fatty liver or show evidence of splenomegaly, portal hypertension, or ascites.
Patients with abnormalities suggesting alcoholic liver disease should undergo screening tests for other treatable forms of liver disease, especially viral hepatitis. Because features of fatty liver, alcoholic hepatitis, and cirrhosis overlap, describing the precise findings is more useful than assigning the patient to a specific category, which can only be determined by liver biopsy. Liver biopsy is performed to stage the severity of liver disease (see Testing for Hepatic and Biliary Disorders: Liver Biopsy). In addition to confirming liver disease, biopsy also helps identify excessive alcohol use as the likely cause and establishes the stage of liver injury. If iron accumulation is observed, quantitation of the iron content and genetic testing can eliminate hereditary hemochromatosis as the cause.
Prognosis
and Treatment
The prognosis for alcoholic liver disease 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, complete resolution of fatty liver occurs within 6 wk. Fibrosis and cirrhosis are irreversible. Once cirrhosis and its complications (ascites, bleeding) develop, the 5‑yr survival rate is about 50%: the rate is higher with abstinence and lower if drinking continues. Alcoholic liver disease, particularly with coexisting chronic hepatitis C infection, predisposes to hepatocellular carcinoma.
Abstinence is the mainstay of treatment; it can prevent further damage from alcoholic liver disease and thus prolong life. Because compliance is problematic, a compassionate team approach is essential. Excellent results can come from support groups such as Alcoholics Anonymous as long as the patient is motivated (see Drug Use and Dependence: Maintenance).
General management emphasizes supportive care. A nutritious diet and vitamin supplements (especially B vitamins) are provided, especially during the first few days of abstinence. However, supplements have not proved to affect outcomes, even in hospitalized patients with alcoholic hepatitis. Alcohol withdrawal requires benzodiazepines (eg, diazepam ). Excessive sedation in patients with marked alcoholic liver disease can precipitate hepatic encephalopathy.
Management of 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) are discussed elsewhere in The Manual.
Few specific treatments exist for alcoholic liver disease. The value of corticosteroids in alcoholic hepatitis is controversial, but these drugs may help patients with the most severe disease. Drugs used to decrease fibrosis (eg, colchicine , penicillamine ) or inflammation (eg, pentoxifylline ) have not proved effective. Propylthiouracil may provide some benefit in treating the putative hypermetabolic state of the alcoholic liver but has never gained acceptance. (See also the Cochrane review abstract on use
of propylthiouracil for alcoholic liver disease.) Antioxidants (eg, S-adenosyl-l-methionine, polyunsaturated phosphatidylcholine) show promise in ameliorating liver injury but require further study. (See also the Cochrane review abstract on use of
s-adenosyl-L-methionine for alcoholic liver disease.) Antioxidant remedies, such as silymarin (milk thistle) and vitamins A and E, are unproven. (See also the Agency for Healthcare Research and Quality's Evidence Report Milk
Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse
Effects.)
Liver transplantation can produce 5‑yr survival rates comparable to those for nonalcoholic liver disease—as high as 80% in the absence of active liver disease and 50% with acute alcoholic hepatitis. Because up to 50% of patients resume drinking after transplantation, most programs require 6 mo of abstinence before transplantation is performed.
Last full review/revision November 2005
Content last modified November 2005
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