Alcohol-Related Liver Disease

The main risk factors for alcohol-related liver disease are

Hepatic steatosis, alcoholic hepatitis, and cirrhosis are often considered separate, progressive manifestations of alcohol-related 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 Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more may also be present.

Alcohol-related 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 Pathophysiology Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more ).

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 Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more , portosystemic encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more , variceal bleeding, liver failure with hypoglycemia, coagulopathy). Other manifestations of cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more may be present.

Cirrhosis, if compensated, may be asymptomatic. The liver is usually small; when the liver is enlarged, hepatic steatosis or hepatoma Hepatocellular Carcinoma Hepatocellular carcinoma usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more should be considered. Symptoms range from those of alcoholic hepatitis to the complications of end-stage liver disease, such as portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more (often with esophageal varices Varices Varices are dilated veins in the distal esophagus or proximal stomach caused by elevated pressure in the portal venous system, typically from cirrhosis. They may bleed massively but cause no... read more 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 Hepatocellular Carcinoma Hepatocellular carcinoma usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more develops in 10 to 15% of patients with alcohol-related cirrhosis.

Chronic excessive alcohol consumption, rather than liver disease, causes Dupuytren contracture Dupuytren Contracture Dupuytren contracture is progressive contracture of the palmar fascial bands, causing flexion deformities of the fingers. Treatment is with corticosteroid injection, surgery, or injections of... read more of the palmar fascia, vascular spiders, myopathy, and peripheral neuropathy. In men, chronic excessive alcohol consumption causes signs of hypogonadism Male Hypogonadism Hypogonadism is defined as testosterone deficiency with associated symptoms or signs, deficiency of spermatozoa production, or both. It may result from a disorder of the testes (primary hypogonadism)... read more and feminization (eg, smooth skin, lack of male-pattern baldness, gynecomastia, testicular atrophy, decreased body hair). Undernutrition may lead to multiple vitamin deficiencies (eg, of folate and thiamin), enlarged parotid glands, and white nails. In those with chronic excessive alcohol consumption, Wernicke encephalopathy Wernicke Encephalopathy Wernicke encephalopathy is characterized by acute onset of confusion, nystagmus, partial ophthalmoplegia, and ataxia due to thiamin deficiency. Diagnosis is primarily clinical. The disorder... read more and Korsakoff psychosis Korsakoff Psychosis Korsakoff psychosis is a late complication of persistent Wernicke encephalopathy and results in memory deficits, confusion, and behavioral changes. Korsakoff psychosis occurs in 80% of untreated... read more result mainly from thiamin deficiency Thiamin Deficiency Thiamin deficiency (causing beriberi) is most common among people subsisting on white rice or highly refined carbohydrates in countries with high rates of food insecurity and among people with... read more . Pancreatitis Overview of Pancreatitis Pancreatitis is classified as either acute or chronic. Acute pancreatitis is inflammation that resolves both clinically and histologically. Chronic pancreatitis is characterized by histologic... read more is common. Hepatitis C Hepatitis C, Acute Hepatitis C is caused by an RNA virus that is often parenterally transmitted. It sometimes causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice but may be asymptomatic... read more occurs in > 25% of those with alcohol use disorder; 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 alcohol use disorder 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 alcohol-related liver disease, but if the diagnosis is suspected, liver 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 a mean corpuscular volume > 100 fL reflects the direct effect of alcohol on bone marrow as well as macrocytic anemia resulting from folate deficiency Folate Deficiency Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin... read more , 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 Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more . 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 Imaging Tests of the Liver and Gallbladder Imaging is essential for accurately diagnosing biliary tract disorders and is important for detecting focal liver lesions (eg, abscess, tumor). It is limited in detecting and diagnosing diffuse... read more 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 Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more . Ultrasound elastrography measures liver stiffness and thus detects advanced fibrosis Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced, degraded deficiently, or both. The trigger... read more . This valuable adjunct can obviate the need for liver biopsy to check for cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more and help assess prognosis. Its exact role is under study.

If abnormalities suggest alcohol-related 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 Liver Biopsy Liver biopsy provides histologic information about liver structure and evidence of liver injury (type and degree, any fibrosis); this information can be essential not only to diagnosis but also... read more .

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 Hereditary Hemochromatosis Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders... read more 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 Screening Hepatocellular carcinoma usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more . 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 Diagnosis reference 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... read more ).

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 score. For patients ≥ 12 years of age, the MELD score is calculated using the following formula:

Once cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more and its complications (eg, ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more , 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.