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
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Fatty liver (in > 90%)
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Alcoholic hepatitis (in 10 to 35%)
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Cirrhosis (in 10 to 20%)
Hepatocellular carcinoma may also develop, especially in association with iron accumulation.
Risk Factors
The main causative factors in alcoholic liver disease are
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Quantity and duration of alcohol use (usually > 8 yr)
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Sex
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Genetic and metabolic traits
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Nutritional status
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.
Sex: 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—½ 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.
Genetic factors: Alcoholic liver disease often runs in families, suggesting genetic factors (eg, deficiency of cytoplasmic enzymes that eliminate alcohol).
Nutritional status: Undernutrition, particularly protein-energy undernutrition, increases susceptibility, as does a diet high in unsaturated fat and obesity.
Other factors: Other risk factors include iron accumulation in the liver (not necessarily related to iron intake) and concomitant hepatitis C.
Pathophysiology
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:
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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.
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Acetaldehyde dehydrogenase (ALDH), a mitochondrial enzyme, then oxidizes acetaldehyde to 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.
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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.
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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 O2species, increasing oxidative stress and formation of O2-free radicals.
Hepatic fat accumulation: Fat (triglycerides) accumulates throughout the hepatocytes for the following reasons:
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Export of fat from the liver is decreased because hepatic fatty acid oxidation and lipoprotein production decrease.
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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.
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 damage: Oxidative stress is increased by
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Liver hypermetabolism, caused by alcohol consumption
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Free radical–induced lipid peroxidative damage
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Reduction in protective antioxidants (eg, glutathione, vitamins A and E), caused by alcohol-related undernutrition
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Binding of alcohol oxidation products, such as acetaldehyde, to liver cell proteins, forming neoantigens and resulting in inflammation
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Accumulation of neutrophils and other WBCs, which are attracted by lipid peroxidative damage and neoantigens
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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.
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.
Pathology
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 1/3 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).
Diagnosis
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Confirmed history of alcohol use
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Liver function tests and CBC
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Sometimes liver biopsy
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 and 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
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Serum bilirubin, which represents secretory function
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PT or INR, which reflects synthetic ability
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:
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Unclear clinical diagnosis (eg, equivocal clinical and laboratory findings, unexplained persistent elevations of aminotransferase levels)
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Clinical suspicion of > 1 cause of liver disease (eg, alcohol plus viral hepatitis)
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Desire for a precise prediction of prognosis
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: Primary 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
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.