Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to have alcohol use disorder in any 12-month period (see Alcohol Use Disorders and Rehabilitation). The male:female ratio is about 2:1. Disorders that occur in alcohol abusers, often in sequence, include
(See also the 2018 American College of Gastroenterology’s practice guidelines for Alcoholic Liver Disease.)
Hepatocellular carcinoma may also develop in patients with cirrhosis, especially if iron accumulation coexists.
The main risk factors for alcoholic liver disease are
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 45 mL of an 80-proof (40% alcohol) beverage is 18 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-ounce (oz) glass of beer contains between about 5 to 20 g of alcohol, and a 5-oz glass of wine contains between about 12 to 18 g, and a 1 1/2-oz shot of hard liquor contains about 14 g.
Risk of liver disease increases markedly for men who drink > 40 g, particularly > 80 g, of alcohol/day (eg, about 2 to 8 cans of beer, 3 to 6 shots of hard liquor, or 3 to 6 glasses of wine) for > 10 years. For cirrhosis to develop, consumption must usually be > 80 g/day for > 10 years. If consumption exceeds 230 g/day for 20 years, 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, more intact alcohol reaches the liver.
Other risk factors include iron accumulation in the liver (not necessarily related to iron intake) and concomitant hepatitis C.
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:
ADH, a cytoplasmic enzyme, oxidizes alcohol into acetaldehyde. Genetic polymorphisms in ADH account for some individual differences in blood alcohol levels after the same alcohol intake but not in susceptibility to alcoholic liver disease.
Acetaldehyde dehydrogenase (ALDH), a mitochondrial enzyme, then oxidizes acetaldehyde into acetate. Chronic alcohol consumption enhances acetate formation. Asians, who have lower levels of ALDH, are more susceptible to toxic acetaldehyde effects (eg, flushing); the effects are similar to those of disulfiram, which inhibits ALDH.
These oxidative reactions generate hydrogen, which converts nicotinamide-adenine dinucleotide (NAD) to its reduced form (NADH), increasing the redox potential (NADH/NAD) in the liver.
The increased redox potential inhibits fatty acid oxidation and gluconeogenesis, promoting fat accumulation in the liver.
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 oxygen species, increasing oxidative stress and formation of oxygen-free radicals.
Fat (triglycerides) accumulates throughout the hepatocytes for the following reasons:
Export of fat from the liver is decreased because hepatic fatty acid oxidation and lipoprotein production decrease.
Input of fat is increased because the decrease in hepatic fat export increases peripheral lipolysis and triglyceride synthesis, resulting in hyperlipidemia.
Hepatic fat accumulation may predispose to subsequent oxidative damage.
Oxidative stress is increased by
Liver hypermetabolism, caused by alcohol consumption
Free radical–induced lipid peroxidative damage
Reduction in protective antioxidants (eg, glutathione, vitamins A and E), caused by alcohol-related undernutrition
Binding of alcohol oxidation products, such as acetaldehyde, to liver cell proteins, forming neoantigens and resulting in inflammation
Accumulation of neutrophils and other white blood cells (WBCs), which are attracted by lipid peroxidative damage and neoantigens
Inflammatory cytokines secreted by WBCs
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.
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.
Hepatic steatosis, alcoholic hepatitis, and cirrhosis are often considered separate, progressive manifestations of alcoholic liver disease. However, their features often overlap.
Hepatic steatosis (fatty liver) is the initial and most common consequence of excessive alcohol consumption. Hepatic steatosis 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 hepatic steatosis, 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 Cirrhosis: Pathophysiology).
Symptoms usually become apparent in patients during their 30s or 40s; severe problems appear about a decade later.
Hepatic steatosis 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, portosystemic 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, hepatic steatosis 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 gastrointestinal bleeding, splenomegaly, ascites, and portosystemic 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 contracture of the palmar fascia, vascular spiders, myopathy, 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 encephalopathy and Korsakoff psychosis result mainly from thiamin deficiency. Pancreatitis is common. Hepatitis C occurs in > 25% of alcoholics; this combination markedly worsens the progression of liver disease.
Rarely, patients with hepatic steatosis or cirrhosis present with Zieve 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. When the patient's alcohol consumption is in doubt, 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 aspartate aminotransferase (AST) to alanine aminotransferase (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 gamma-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 mean corpuscular volume > 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 of the liver are not routinely needed for diagnosis. If done for other reasons, abdominal ultrasonography or CT may suggest hepatic steatosis or show splenomegaly, evidence of 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 hepatic steatosis, 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 as the cause.
For stable patients with cirrhosis, the American Association for the Study of Liver Diseases (AASLD) recommends that liver ultrasonography, with or without alpha-fetoprotein (AFP) measurement, should be done every 6 months to screen for hepatocellular carcinoma. They also suggest that surveillance not be done for patients with Child’s class C cirrhosis unless they are on the transplant waiting list because of the low anticipated survival for these patients (1).
Prognosis is determined by the degree of hepatic fibrosis and inflammation. Hepatic steatosis and alcoholic hepatitis without fibrosis are reversible if alcohol is avoided. With abstinence, hepatic steatosis may completely resolve within 6 weeks. Fibrosis and cirrhosis are usually 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 may be used; it is calculated from the following formula:
For this formula, bilirubin level is measured in mg/dL (converted from bilirubin in micromol/L by dividing by 17). A value of > 32 is associated with a high short-term mortality rate (eg, after 1 month, 35% without encephalopathy and 45% with encephalopathy). Other indexes include the Model for End-Stage Liver Disease (MELD) score, Glasgow alcoholic hepatitis score, and Lille model. For patients ≥ 12 years of age, the MELD score is calculated using the following formula:
Once cirrhosis and its complications (eg, ascites, bleeding) develop, the 5-year 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.
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 Alcohol Use Disorders and Rehabilitation: Maintenance), 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 gamma-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 hours 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 portosystemic 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 encephalopathy, Korsakoff psychosis, electrolyte abnormalities, portal hypertension, ascites, portosystemic encephalopathy—see elsewhere in THE MANUAL ).
Corticosteroids (eg, prednisolone 40 mg/day orally for 4 weeks, followed by tapered doses) improve outcome in patients who have severe acute alcoholic hepatitis (Maddrey discriminant function ≥ 32) and who do not have infection, gastrointestinal bleeding, renal failure, or pancreatitis (1).
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 (TNF)-alpha, and aiming to reduce inflammation have had mixed results in small trials. Pentoxifylline, a phosphodiesterase inhibitor that inhibits TNF-alpha synthesis, had mixed results in clinical trials in patients with severe alcoholic hepatitis. When biologic agents that inhibit TNF-alpha (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-year 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 months of abstinence before transplantation is done; recent data suggest that earlier transplantation may offer a survival advantage, but currently, this approach is not standard of care.
Rambaldi A, Saconato HH, Christensen E, et al: Systematic review: Glucocorticosteroids for alcoholic hepatitis—A Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther 27(12):1167-1178, 2008. doi: 10.1111/j.1365-2036.2008.03685.x.
Risk of alcoholic liver disease increases markedly in men if they ingest > 40 g, particularly > 80 g, of alcohol/day (eg, about 2 to 8 cans of beer, about 3 to 6 glasses of wine, or 3 to 6 shots of hard liquor) for > 10 years; risk increases markedly in women if they ingest about half that amount.
Screen patients using the CAGE questionnaire, and when in doubt about the patient's alcohol consumption, consider asking family members.
To estimate prognosis, consider unfavorable histologic findings (eg, neutrophils, perivenular fibrosis) and use of a formula (eg, Maddrey discriminant function, Model for End-Stage Liver Disease [MELD] score).
Emphasize abstinence, provide supportive care, and hospitalize and give corticosteroids to patients with severe acute alcoholic hepatitis.
Consider transplantation for abstinent patients.
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