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Alcohol-Related Liver Disease

(Alcoholic Liver Disease; Alcohol-Associated Liver Disease)

By

Whitney Jackson

, MD, University of Colorado School of Medicine

Reviewed/Revised Jul 2023
View PATIENT EDUCATION
Topic Resources

Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol use disorder Alcohol Use Disorder and Rehabilitation Alcohol use disorder involves a pattern of alcohol use that typically includes craving and manifestations of tolerance and/or withdrawal along with adverse psychosocial consequences. Alcoholism... read more , in 2021, 11.3% of US adults age 18 and older had alcohol use disorder in the past year (see National Institute on Alcohol Abuse and Alcoholism [NIAAA]: Alcohol Use Disorder (AUD) in the United States). The NIAAA reported a 25.5% increase in deaths involving alcohol use, from approximately 79,000 to more than 99,000 per year from 2019 to 2020, up from the 2.2% increase per year over the previous two decades, suggesting an increase due to the COVID-19 pandemic (1 Reference Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Reference ).

Disorders of the liver that occur in people with alcohol use disorder, often in sequence, but sometimes coexisting, include

(See also the 2019 American Association for the Study of Liver Disease’s practice guidelines for Alcohol-Associated Liver Disease.)

Reference

Risk Factors for Alcohol-Related Liver Disease

The main risk factors for alcohol-related liver disease are

  • Quantity and duration of alcohol use

  • Sex

  • Genetic and metabolic traits

  • Obesity

Quantity of alcohol

A standard alcoholic drink contains 14 grams of alcohol, the amount found in a 12-ounce (355-mL) bottle of 5% beer, a 5-ounce (148-mL) glass of wine, or 1.5 ounces (44-mL) of a beverage of 80-proof distilled spirits containing 40% alcohol by volume. (See National Institute on Alcohol Abuse and Alcoholism (NIAAA): Drinking Patterns and Their Definitions).

There appears to be a threshold effect above which the amount and duration of alcohol use increases the risk of the development of liver disease. That threshold is not known and varies by individual risk factors (1 Risk factors references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Risk factors references ).

The NIAAA defines moderate drinking as one standard drink per day for women and two standard drinks per day for men (see also Dietary Guidelines for Americans, 2020-2025). However, the World Health Organization stated that there is no safe level of alcohol consumption that does not affect health (2 Risk factors references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Risk factors references ).

The NIAAA defines "at-risk" (heavy) drinking in males as more than 14 standard drinks per week, or more than 4 drinks per day, and in females as more than 7 standard drinks per week, or more than 3 drinks per day (see NIAAA: Drinking Levels Defined).

Binge drinking may also increase alcohol-related liver disease. The NIAAA defines binge drinking as a pattern of drinking that brings blood alcohol concentration levels to 0.08 g/dL, which typically occurs after 4 drinks for women and 5 drinks for men, in about 2 hours (see NIAAA: Drinking Levels Defined).

The American Association for the Study of Liver Diseases (AASLD) recommends that patients receiving care in primary care and gastroenterology/hepatology outpatient clinics, emergency departments, and in hospitals (as inpatients) be screened routinely for alcohol use with validated questionnaires. Brief intervention, pharmacotherapy, and referral to treatment should be offered to patients engaged in hazardous drinking (ie, heavy or binge drinking) (3 Risk factors references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Risk factors references , 4 Risk factors references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Risk factors references ). The AASLD recommends using the Alcohol Use Disorders Inventory Test (AUDIT) if excessive alcohol use is suspected (3 Risk factors references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Risk factors references ).

Alcohol biomarkers, such as urine or hair ethyl glucuronide, urine ethyl sulfate, and phosphatidylethanol (PEth), can be used to support patient history and aid in recovery.

Sex

Women are more susceptible to alcohol-related liver disease, even after adjustment for body size. Women require only 20 to 40 g of alcohol/day 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.

Genetic factors

Alcohol-related liver disease often runs in families, suggesting genetic factors (eg, deficiency of cytoplasmic enzymes that eliminate alcohol).

Nutritional status

A diet high in unsaturated fat increases susceptibility, as does obesity.

Other factors

Risk factors references

  • 1. Rehm J, Taylor B, Mohapatra S, et al: Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev 29(4):437-445, 2010. doi:10.1111/j.1465-3362.2009.00153.x

  • 2. Anderson BO, Berdzuli N, Ilbawi A, et al: Health and cancer risks associated with low levels of alcohol consumption. Lancet Public Health 8(1):e6-e7, 2023. doi: 10.1016/S2468-2667(22)00317-6

  • 3. Crabb DW, Im GY, Szabo G, et al: Diagnosis and Treatment of Alcohol-Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases. Hepatology 71(1):306-333, 2020. doi:10.1002/hep.30866

  • 4. Saunders JB, Aasland OG, Babor TF, et al: Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption--II. Addiction 88(6):791-804, 1993. doi:10.1111/j.1360-0443.1993.tb02093.x

Pathophysiology of Alcohol-Related Liver Disease

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).

Overview of Alcohol-Related Liver Disease
VIDEO

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 alcohol-related liver disease.

  • Acetaldehyde dehydrogenase (ALDH), a mitochondrial enzyme, then oxidizes acetaldehyde into acetate. Chronic alcohol consumption enhances acetate formation. People of Asian descent often have lower levels of ALDH and 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 excessive alcohol consumption 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.

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 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 alcohol-related liver disease through ingestion of iron-containing fortified wines; most often, the iron accumulation is modest. This condition can be differentiated from 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 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 Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced and insufficiently degraded. The trigger... read more . 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 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 . Extensive fibrosis is associated with an attempt at regeneration, resulting in liver nodules. This process culminates in 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 .

Pathology of Alcohol-Related Liver Disease

Hepatic steatosis, alcoholic hepatitis, and cirrhosis are often considered separate, progressive manifestations of alcohol-related liver disease. However, their features often overlap.

Alcohol-related 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 and Signs of Alcohol-Related Liver Disease

Symptoms usually become apparent in patients during their 30s or 40s; severe problems appear about a decade later.

Alcohol-related 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 (HCC) 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 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 Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) 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 Dupuytren Contracture 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 Overview of Undernutrition Undernutrition is a form of malnutrition. (Malnutrition also includes overnutrition.) Undernutrition can result from inadequate ingestion of nutrients, malabsorption, impaired metabolism, loss... read more 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).

Diagnosis of Alcohol-Related Liver Disease

  • Confirmed history of alcohol use

  • Alcohol biomarkers

  • Liver tests and complete blood count (CBC)

  • Sometimes liver biopsy

Alcohol is suspected as the cause of liver disease in any patient who chronically consumes excess alcohol, particularly > 80 g per day. Patients can be screened for alcohol use disorder Alcohol Use Disorder and Rehabilitation Alcohol use disorder involves a pattern of alcohol use that typically includes craving and manifestations of tolerance and/or withdrawal along with adverse psychosocial consequences. Alcoholism... read more using the CAGE questionnaire (need to Cut down, Annoyed by criticism, Guilty about drinking, and need for a morning Eye-opener; see Detecting alcoholism. The CAGE questionnaire) or AUDIT (see Alcohol Use Disorders Identification Test). When the patient's alcohol consumption is in doubt, history can be confirmed by family members or alcohol biomarkers. Urine or hair ethyl glucuronide, urine ethyl sulfate, and phosphatidylethanol (PEth) are not affected by liver disease. PeTH is particularly useful because it has a half‐life of approximately 10 to14 days, longer with chronic heavy alcohol consumption. There is no specific test for alcohol-related liver disease, but if the diagnosis is suspected, liver tests (prothrombin time [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 people with alcohol use disorder who are undernourished. Indexes of the severity of liver disease are

  • Serum bilirubin, which represents secretory function

  • Prothrombin time or international normalized ratio, which reflects synthetic ability

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 Imaging Tests of the Liver and Gallbladder 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 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 , 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 and insufficiently degraded. 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:

  • Unclear clinical diagnosis (eg, equivocal clinical and laboratory findings, unexplained persistent elevations of aminotransferase levels)

  • Clinical suspicion of > 1 cause of liver disease (eg, alcohol plus viral hepatitis)

  • 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 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 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 Screening Hepatocellular carcinoma (HCC) 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 their low anticipated survival (1 Diagnosis reference Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Diagnosis reference ).

Diagnosis reference

Treatment of Alcohol-Related Liver Disease

  • Abstinence

  • Supportive care

  • Corticosteroids and enteral nutrition for severe alcoholic hepatitis

  • Sometimes transplantation

Restricting alcohol intake

Abstinence is the mainstay of treatment; it prevents further damage from alcohol-related 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 Maintenance Alcohol use disorder involves a pattern of alcohol use that typically includes craving and manifestations of tolerance and/or withdrawal along with adverse psychosocial consequences. Alcoholism... read more ), brief interventions by primary care clinicians, and therapies that explore and clarify the motivation to abstain (motivational enhancement therapy).

Medications, if used, should supplement other interventions. Opioid antagonists (naltrexone or nalmefene) and medications 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.

Supportive care

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 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 Varices , specific nutritional deficiencies, 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 , 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 , electrolyte abnormalities, 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 , 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 ).

Specific treatment

Corticosteroids (eg, prednisolone 40 mg/day orally for 4 weeks, followed by tapered doses) may improve outcomes 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 Treatment references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Treatment references ). In a large prospective randomized controlled trial, prednisolone trended toward a decrease in 28-day mortality but did not achieve statistical significance (2 Treatment references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Treatment references ). As a result, corticosteroids may be stopped prior to completing a 4-week course if there is no response to corticosteroids as determined by the day 7 Lille score (3 Treatment references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Treatment references ).

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 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 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. Medications given to decrease fibrosis (eg, colchicine, penicillamine) and medications 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 Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more for alcohol-associated cirrhosis should be considered for all patients with decompensated liver disease (ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy) despite abstinence. With transplantation, 5-year survival rates are comparable to those whose liver disease is not related to alcohol. The American Association for the Study of Liver Diseases (AASLD) recognizes the limitations of a "6 month rule" of abstinence, instead encouraging candidate evaluation to focus on predicting likelihood of abstinence before and after transplant independent of the length of time of sobriety (see Evaluation for liver transplantation in adults: 2013 practice guideline). During the COVID-19 pandemic, transplant waitlist registrants increased more than 50% from pre-COVID predictions, possibly due to the increase in alcohol use disorder as well as changes in transplant center risk stratification (4 Treatment references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Treatment references , 5 Treatment references Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more Treatment references ).

Treatment references

  • 1. 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

  • 2. Thursz MR, Richardson P, Allison M, et al: Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 372:1619-1628, 2015. doi: 10.1056/NEJMoa1412278

  • 3. Forrest EH, Atkinson SR, Richardson P, et al: Application of prognostic scores in the STOPAH trial: Discriminant function is no longer the optimal scoring system in alcoholic hepatitis. J Hepatol 68(3):511-518, 2018. doi: 10.1016/j.jhep.2017.11.017

  • 4. Anderson MS, Valbuena VSM, Brown CS, et al: Association of COVID-19 With New Waiting List Registrations and Liver Transplantation for Alcoholic Hepatitis in the United States. JAMA Netw Open 4(10):e2131132, 2021. doi:10.1001/jamanetworkopen.2021.31132

  • 5. Bittermann T, Mahmud N, Abt P: Trends in Liver Transplantation for Acute Alcohol-Associated Hepatitis During the COVID-19 Pandemic in the US. JAMA Netw Open 4(7):e2118713, 2021. doi:10.1001/jamanetworkopen.2021.18713

Prognosis for Alcohol-Related Liver Disease

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:

equation

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:

equation

Coexisting iron accumulation or chronic hepatitis C increases risk of hepatocellular carcinoma.

Key Points

  • Risk of alcohol-related liver disease increases markedly in men if they ingest > 40 g, particularly > 80 g, of alcohol per 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 AUDIT or CAGE questionnaire, and when in doubt about the patient's alcohol consumption, consider use of alcohol biomarkers.

  • 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 liver transplantation for patients with decompensated liver disease (ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy) despite abstinence.

Drugs Mentioned In This Article

Drug Name Select Trade
Ablysinol, Nozin
Antabuse
Depade, ReVia, Vivitrol
OPVEE, Revex
ED Baclofen, FLEQSUVY, Gablofen, Lioresal, Lioresal Intrathecal, LYVISPAH, OZOBAX, OZOBAX DS
Campral
Diastat, Dizac, Valium, VALTOCO
AK-Pred, AsmalPred, Econopred, Econopred Plus, Flo-Pred, Hydeltrasol, Inflamase Forte, Inflamase Mild, Millipred , Millipred DP, Millipred DP 12-Day, Millipred DP 6 Day, Ocu-Pred , Ocu-Pred A, Ocu-Pred Forte, Omnipred, Orapred, Orapred ODT, Pediapred, Pred Mild, Predalone, Pred-Forte, Prednoral, Pred-Phosphate , Prelone, Veripred-20
Pentopak, Pentoxil , Trental
AVSOLA, INFLECTRA, Remicade, RENFLEXIS, Zymfentra
Enbrel
ColciGel, Colcrys , GLOPERBA, LODOCO, MITIGARE
Cuprimine, Depen, D-PENAMINE
No brand name available
Milk Thistle XTRA
View PATIENT EDUCATION
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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