Chapter 42. Alcoholic Liver Disease

• In the United States, excessive alcohol use is defined as ingestion of >14 drinks/week in women and >21 drinks/week in men (1 drink = 12 oz beer, 1.0 oz malt liquor, 5 oz wine, or 1.5 oz 80 proof "hard liquor").
• Factors accelerating liver injury in alcoholic liver disease (ALD) include female gender, Latino and African-American ethnicity, chronic hepatitis C infection, acetaminophen overdose, and hereditary hemochromatosis.
• 75% of Asians have decreased ability to metabolize ethanol, resulting in acetaldehyde accumulation and subsequent flushing.
• Diagnosis of excessive alcohol use is suggested by increased serum ALT and AST levels, AST:ALT ratio of 2–3:1, and MCV >100.
• Accurate history of substance intake and CAGE or Alcohol Use Disorders Identification Test (AUDIT) questionnaires aid in the diagnosis of alcohol abuse.
• Liver biopsy and liver imaging cannot distinguish ALD from nonalcoholic steatohepatitis (NASH).
• Although 90–100% of heavy drinkers will develop hepatic steatosis, only 10–35% will develop alcoholic hepatitis, and 5–15% will develop cirrhosis.

Alcohol use in human history has played an important role in social interactions, politics, religion, medicine, and nutrition. The first use of alcohol dates back to the late stone-age Neolithic period (circa 10,000 BC) with the archeological discovery of beer jugs. Egyptian pictographs suggest wine consumption as early as 4000 BC. The use of wine and beer for medical purposes began circa 2000 BC. Sentiment toward moderation in drinking was documented in a Chinese imperial edict in the 12th century BC. The association of alcohol with liver disease appeared to have been noticed by the ancient Egyptians, who linked the use of beer with ascites, and the ancient Greeks, who described the association with jaundice and gastrointestinal bleeding.

Incidence and Societal Costs

Alcohol-related health problems contribute to significant health care costs worldwide. In 2003, the prevalence of alcohol-related disorders was 1.7% worldwide, and alcohol was the third leading cause of death in the United States. Data from the NIH-sponsored NESARC study suggest that 4.65% and 3.81% of American adults meet the criteria for alcohol abuse and alcohol dependence, respectively. Studies have shown that per capita alcohol consumption in both men and women is associated with mortality from liver cirrhosis.

Not all those who consume alcohol will develop Alcoholic Liver Disease (ALD) and liver cirrhosis. Among heavy drinkers, 90–100% will develop hepatic steatosis in 10 years, but only 10–35% will develop steatohepatitis and 5–15% will develop cirrhosis in the same period (Figure 42–1).

Definition

Epidemiologic research involving alcohol use is not without limitations. The definition of one alcohol drink varies globally and individually. In the United States, the definition used by the Centers for Disease Control and Prevention is about 0.5 oz, or 13.7 g of pure alcohol. This is equivalent to 12 oz of beer, 8 oz of malt liquor, 5 oz of wine, or 1.5 oz of 80-proof "hard liquor." In the United Kingdom and Japan, one drink equals 8 g and 19.75 g, respectively.

Cofactors that Potentiate the Development of Alcoholic Liver Disease

The amount of alcohol consumption required for progression to liver cirrhosis reported by Lelback and colleagues in 1975 was 80 g of ethanol daily (equivalent to 1 L of wine, a half pint of hard liquor, or 8 beers) consumed for 10–20 years. However, as noted, not all who ingest significant amounts of alcohol will develop cirrhosis. Several cofactors are known to accelerate progression of liver disease, and the risk for ALD increases with ingestion of more than 35 drinks per week. A "safe" amount is believed to be 21 drinks per week for men and 14 drinks per week for women, in the absence of the cofactors listed below.

Age

Despite the legal alcohol drinking age of 21 years in the United States, a 2004 study revealed that 50% of high school students drank some amount of alcohol, and 20% of all alcohol consumption is suspected to be in individuals younger than age 21. Early alcohol use is associated with alcoholism later in life. At the opposite end of spectrum, an emergency department screening study revealed that 24.5% of subjects older than 65 years met criteria for alcohol abuse. However, the highest rate of alcohol abuse morbidity occurs among individuals aged 45–64 years, with a prevalence rate of 94.8 per 100,000.

Gender

The overall prevalence of alcohol abuse and related liver disease is higher among men than women. However, women are more prone than men to alcohol-related liver injury and fibrosis progression for the same amount of alcohol consumption. This may be due to different rates of alcohol metabolism, lower body mass index, effects of estrogens, or an increased intestinal permeability to endotoxin.

Ethnicity

Susceptibility to ALD is believed to vary among different ethnic groups. In the United States, alcoholic cirrhosis–related deaths are highest in Hispanic males, followed by black non-Hispanics, white non-Hispanics, and black Hispanics. The prevalence among females is highest in black non-Hispanics, followed by white Hispanics, white non-Hispanics, and black Hispanics. Studies in the United Kingdom suggest that South Asian men are more susceptible to alcohol-related liver injury than European men. It is unclear whether these differences are due to genetic polymorphisms, types of alcohol consumed, or access to health care.

Hepatitis C (HCV) Infection

Between 14% and 36% of individuals with ALD also have chronic hepatitis C. The combination of HCV and ALD accelerates the progression and severity of liver disease, increases the risk for hepatocellular carcinoma, and decreases the likelihood of virologic response to interferon alfa therapy. The acceleration of liver disease has been postulated to be due to an increase in viral replication, a decrease in liver regenerative capability, and an increase in quasispecies complexity. Patients with HCV who consume excessive alcohol succumb at an earlier age. This affects the mortality in women more than men.

Hepatitis B (HBV) Infection

In a large population study performed in Taiwan, the data suggest that chronic HBV infection and alcohol consumption increase the risk for the development of hepatocellular carcinoma.

Hepatocellular Carcinoma

ALD and hepatitis C are the two most common causes of hepatocellular carcinoma. In a Veterans Administration study of patients between 1993 and 1998, the prevalence rate of hepatocellular carcinoma in patients with cirrhosis secondary to alcohol use was 9.1 per 100,000, whereas the rate was 7.0 per 100,000 in patients with HCV. The risk of hepatocellular carcinoma increases after consuming more than 60 g of alcohol per day for more than 10 years. Recent studies have also shown that there has been a dramatic increase in the incidence of hepatocellular carcinoma associated with hepatitis C infection, and the incidence may be comparable to that of ALD. The effect of alcohol and HCV in the development of hepatocellular carcinoma appears to be synergistic.

Medications

Patients with ALD appear to be at an increased risk for liver injury after ingestion of multiple or above recommended therapeutic doses of acetaminophen. This is believed to be due to rapid depletion of glutathione stores and competition with cytochrome P450 (CYP) 2E1. Although other medications may also compete with CYP450, there are limited data on increased hepatotoxicity in the setting of ALD.

Iron Overload

The liver is able to tolerate high levels of intrahepatic iron without progression to fibrosis. However, when a cofactor, such as alcohol, is involved, liver damage is accelerated. Similar synergistic effects are also seen in nonalcoholic fatty liver disease, chronic HCV, and porphyria cutanea tarda. Both iron and alcohol generate reactive oxygen species that promote lipid peroxidation with consequent damage to cellular integrity. Alcohol has also been shown to suppress hepcidin activity in animal models. Excessive alcohol consumption (>60 g/day) in patients with hemochromatosis is associated with accelerated fibrogenesis, increased risk for hepatocellular cancer, and lower long-term survival. Because consumption of more than three drinks daily is associated with increased serum markers (ferritin) of iron overload from ALD, HFE genetic testing can differentiate ALD from hereditary hemochromatosis. Primary iron overload may be distinguished from secondary iron overload when the hepatic iron index is greater than 1.9 micromole per gram dry weight of liver per year of life.

Diet and Lifestyle

There are limited data on dietary and lifestyle factors that may influence the natural history of ALD. Coffee may be protective in ALD and related cirrhosis. Studies on the effect of tobacco have been conflicting. Some studies have suggested that obesity (basal metabolic index >25 kg/m2) for more than 10 years accelerates progression of ALD. Pork products, on the other hand, have been shown to be associated with alcoholic hepatitis and cirrhosis but not steatosis. Other lifestyle factors that may be associated with ALD progression include single status, urban dwelling, unemployment, lower socioeconomic background, daily alcohol ingestion, and variable alcoholic beverage ingestion.

Alcohol Metabolism

The metabolic breakdown products of alcohol are essential in the progression of ALD. Ethanol is metabolized by alcohol dehydrogenase in the hepatic cytosol to acetaldehyde, which is subsequently metabolized in the mitochondria by acetaldehyde dehydrogenase. There are various acetaldehyde dehydrogenase isoforms. Seventy-five percent of Asians have a deficiency in acetaldehyde dehydrogenase 2, which results in accumulation of acetaldehyde, causing flushing. A similar mechanism is seen with the drug disulfiram (Antabuse), which inhibits acetaldehyde dehydrogenase, causing acetaldehyde accumulation and resultant flushing, tachycardia, nausea, vomiting, hypotension, and headache within 15–30 minutes of alcohol ingestion.

Ethanol may also be metabolized in minor hepatic pathways involving the microsomal enzyme oxidation system, via CYP2E1, and the enzyme catalase. The stomach can metabolize ethanol via gastric alcohol dehydrogenase. Women have less gastric alcohol dehydrogenase than men, offering a possible explanation for the observed increased female susceptibility to the effect of alcohol.

Cellular Mechanisms

Although detailed mechanisms of ethanol-induced liver injury are incompletely understood, recent scientific advances have furthered our understanding of cellular and immunologic mechanisms through the use of in vitro and in vivo models.

Animal models of alcohol ingestion have demonstrated susceptibility of the hepatic pericentral area to hypoxemia due to competitive oxygen consumption by ethanol metabolism. Decreased intestinal permeability during alcohol ingestion results in an increase in serum endotoxin (lipopolysaccharide) levels, leading, in turn, to activation of Kupffer cells, which secrete cytokines such as tumor necrosis factor α (TNFα). It is believed that TNFα can induce cytotoxicity through caspase-dependent and caspase-independent pathways, leading to increased mitochondrial permeability and ultimately cell death. Both ethanol and decreased glutathione levels can sensitize the liver to TNFα-induced cytotoxicity.

Immunologic Mechanisms

In alcoholic hepatitis, elevated interleukin (IL)-18 levels result in neutrophil accumulation in the liver. Subsequently, neutrophil release of reactive oxygen species results in hepatocyte injury. Acute ethanol ingestion may also result in a suppressed T-cell response, decreased monocyte function, and increased levels of IL-1 and IL-6.

Ethanol metabolites, acetaldehyde and hydroxyethyl, may potentially play a major role in alcoholic liver injury. These metabolites bind to proteins to form adducts that result in altered intracellular protein function, and these adducts may also act as a neoantigen that can stimulate immune-mediated injury. Autoantibodies to various structures of the liver, such as liver membrane antigen, liver-specific protein, and CYP450, can be found in patients with ALD.

Symptoms and Signs

In the early stages, patients with ALD exhibits subtle and often no abnormal physical findings. It is usually not until development of advanced liver disease that stigmata of chronic liver disease become apparent. Early ALD is usually discovered during routine health examinations when liver enzyme levels are found to be elevated. These usually reflect alcoholic hepatosteatosis. Microvesicular and macrovesicular steatosis with inflammation are seen in liver biopsy specimens. These histologic features of ALD are indistinguishable from those of nonalcoholic fatty liver disease. The presence of cholestasis would favor the diagnosis of alcoholic hepatitis, as it is not seen in nonalcoholic steatohepatitis. Steatosis usually resolves after discontinuation of alcohol use. Continuation of alcohol use will result in a higher risk of progression of liver disease and cirrhosis.

In patients with acute alcoholic hepatitis, clinical manifestations include fever, jaundice, hepatomegaly, and possible hepatic decompensation with hepatic encephalopathy, variceal bleeding, and ascites accumulation. Tender hepatomegaly may be present, but abdominal pain is unusual. Occasionally, the patient may be asymptomatic. Table 42–1 summarizes diagnostic features of ALD.

Laboratory Findings

In patients with alcoholic hepatitis, the serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is greater than 2:1. AST and ALT levels are almost always less than 500. The elevated AST to ALT ratio is due to deficiency of pyridoxal-6-phosphate, which is required in the ALT enzyme synthetic pathway. Furthermore, alcohol metabolite–induced injury of hepatic mitochondria results in AST isoenzyme release. Other laboratory findings include red blood cell macrocytosis (mean corpuscular volume >100) and elevations of serum γ-glutamyl transferase, alkaline phosphatase, and bilirubin levels. Folate level is reduced in alcoholic patients due to decreased intestinal absorption, increased bone marrow requirement for folate in the presence of alcohol, and increased urinary loss. The magnitude of leukocytosis reflects severity of liver injury.

Histologic features include Mallory bodies, giant mitochondria, hepatocyte necrosis, and neutrophil infiltration at the perivenular area. Mallory bodies, which are also present in other liver diseases, are condensations of cytokeratin components in the hepatocyte cytoplasm and do not contribute to liver injury. Up to 70% of patients with moderate to severe alcoholic hepatitis already have cirrhosis identifiable on biopsy examination at the time of diagnosis.

Imaging Studies

Radiographic imaging may show features suggestive of cirrhosis, such as a nodular liver surface, reversal of portal vein flow, splenomegaly, and gallbladder wall edema. Other findings such as enlarged caudate lobe and right posterior hepatic notch are suggestive of liver disease. Characteristic findings on ultrasound, computed tomography, and magnetic resonance imaging are summarized in Table 42–1.

Liver Biopsy

Liver biopsy is not mandatory for the diagnosis of ALD or acute alcoholic hepatitis, but it may be helpful when the diagnosis is uncertain. The histology may help determine prognosis and perhaps encourage alcohol cessation. In the setting of severe thrombocytopenia or a hypercoagulation state, transjugular liver biopsy is the procedure of choice. The need for liver biopsy in this situation should be decided on an individual basis, considering the risk of the procedure and potential adverse effects of corticosteroid therapy.

Screening for Alcohol Abuse

Screening for alcohol abuse is an important part of a routine history and physical examination. Several standard screening questionnaires have been developed. The most commonly used is the CAGE questionnaire. Nearly all alcoholic patients will have two positive responses, and 50% will have positive responses to all four questions listed below.

1. Have you felt the need to cut down drinking?

2. Have you ever felt annoyed by criticism of drinking?

3. Have you had guilty feelings about drinking?

4. Do you ever take a morning eye opener?

The World Health Organization has developed the Alcohol Use Disorders Identification Test (AUDIT) which consists of 10 questions aimed to identify heavy drinkers and those with alcohol dependency. This questionnaire has a higher sensitivity and specificity than the shorter instruments and provides more detailed information about risk.

It must be emphasized that accurate assessment of alcohol use still requires obtaining a careful history from the patient or family members. New laboratory tests have been developed to screen for recent or chronic alcohol use, but these are seldom used due to lack of commercial availability. The carbohydrate-deficient transferrin (CDT) test is based on a decreased carbohydrate moiety to transferrin caused by chronic alcohol use. However, CDT levels may be affected by serum transferrin concentrations, hypertension, primary biliary cirrhosis, liver malignancy, chronic viral hepatitis, decompensated liver disease, female sex, and age. The new turbidimetric CDT assay appears to have fewer limitations. Other experimental serologic tests for recent alcohol use include 5-hydroxytryptophol, ethyl glucuronide, phosphatidyl ethanol, sialic acid level, β-hexosaminidase, mitochondrial AST levels, and alcohol metabolites such as erythrocyte acetaldehyde and acetaldehyde adducts.

Nonalcoholic Steatohepatitis

Alcoholic hepatitis is usually indistinguishable by liver histology from nonalcoholic steatohepatitis (NASH). However, the ALT is usually twice that of AST in NASH, and the AST is rarely greater than 500 in alcoholic hepatitis. Careful review of the patient's history may reveal risk factors suggestive of either disease.

Hemochromatosis

Patients with ALD may have elevated transferrin saturation and ferritin levels similar to those seen in hemochromatosis. In murine models, alcohol causes down-regulation of hepcidin expression in the liver and a subsequent increase in the iron transporters ferroportin and DMT-1 in the duodenum. Genetic testing may reveal the HFE gene, but this does not rule out concurrent alcohol-related liver disease. When genetic testing is equivocal, a hepatic iron concentration (HIC) greater than 71 mcg of iron per gram of dry liver weight and a hepatic iron index greater than 1.9 (HIC divided by patient's age) may help determine the amount of total body iron overload and establish the diagnosis of hereditary hemochromatosis.

Acetaminophen Toxicity

Concurrent intake of alcohol can lower the toxicity threshold of acetaminophen, resulting in AST levels significantly greater than 500 IU/L. A careful history of the amount of alcohol and acetaminophen ingestion, as well as measurements of the serum acetaminophen level, can help determine therapeutic options, including need for liver transplantation referral.

Complications of ALD are similar to those for non–alcohol-related chronic liver disease. During severe acute alcoholic hepatitis, the major causes of death are liver failure, gastrointestinal bleeding, hepatorenal syndrome, and sepsis. Until the introduction of the Maddrey discriminant function (MDF), there was no method for predicting the severity of alcoholic hepatitis. The MDF, which is calculated as 4.6 × [patient's prothrombin time – control prothrombin time] + total bilirubin (mg/dL), identifies patients with a high risk for early mortality. An MDF of 32 or higher is associated with spontaneous survival of 50–65%, whereas MDF below 32 is associated with survival of approximately 90%.

Table 42–2 summarizes the efficacy of various medical therapies that have been used in the treatment of ALD.

Abstinence

Reversal of liver disease and improvement in survival occur with abstinence. With cessation of alcohol use, less than 20% of patients will demonstrate progression of liver disease. Five-year survival improves from 34% to 60% for those with decompensated liver disease. Six months of sobriety, along with treatment programs and support networks, is a good predictor of long-term success. Patients with chronic HCV infection should abstain from any alcohol intake, due to the risk for rapid acceleration of liver disease.

Patients with alcoholic liver disease may or may not admit to alcohol dependency. Psycho-social counseling and support groups (eg, Alcoholics Anonymous) may help maintain abstinence. The use of medications to avoid recidivism should be monitored with collaboration a psychiatrist or addiction specialist. Acamprosate, which modulates the NMDA receptor, appears to help alcohol-dependent patients to avoid relapse according to the recent Cochrane analysis. Opioid antagonist, such as disulfiram, has not been shown to enhance abstinence, and Naltrexone may be hepatotoxic.

Nutrition

Standard fluid, mineral, and vitamin replacement and withdrawal precautions are mandatory for patients hospitalized with decompensated liver cirrhosis. Oral as well as tube feeding has been found to be associated with decreased mortality. Continued enteral nutrition support after hospitalization also improves long-term morbidity. Dietary protein should not be restricted in alcoholic hepatitis for fear of hepatic encephalopathy. In the setting of hepatic encephalopathy, branched-chain amino acids (BCAAs) may be considered.

Patients with liver cirrhosis usually have protein malnutrition with decreased BCAAs (leucine, isoleucine, and valine). A decrease in BCAA has been associated with serum hypoalbuminemia and elevated arterial ammonia levels. Recent formulations have resolved the poor taste by incorporation of BCAA into granules. Despite some small clinical studies suggesting benefit in improving metabolite profile and hepatic encephalopathy, there is still a lack of convincing evidence to justify the use of this expensive supplement to significantly improve morbidity and mortality. In patients with alcoholic hepatitis or fulminant hepatic failure, BCAA has not been found to influence short-term or long-term survival.

Corticosteroids

Thirteen randomized controlled trials have examined corticosteroid therapy in severe acute alcoholic hepatitis. Although five studies have shown benefit in survival, mostly in rural populations and/or in patients with concomitant hepatic encephalopathy, the remaining studies have been equivocal. Significant improvement in liver function is evident at 7 days after initiation of therapy. Overall, corticosteroid therapy is beneficial in improving 30- and 60-day mortality only in patients with severe acute alcoholic hepatitis and an MDF greater than 32, in the absence of acute gastrointestinal bleeding, renal failure, acute infection, or pancreatitis. Two-month survival with corticosteroid therapy is about 80%, but up to 40% of patients still die in 6 months. The benefit of corticosteroid therapy may be present up to 1 year. However, the benefit of corticosteroids may not extend to all those with MDF >32. In a VA cooperative study, mortality at 6 months was higher in the group with MDF >54 who received prednisolone than placebo. A recently published algorithm to determine corticosteroid use is recapitulated in Figure 42–2.

A recent study demonstrated the use of the Lille model (formula available online at http://www.lillemodel.com) in attempting to identify poor outcome at 6 months of follow-up in patients with MDF of 32 or higher treated with either prednisolone (40 g/day orally) or methylprednisolone (32 mg/day intravenously) for 28 days. Patients with a score greater than 0.45 using the Lille model had a mortality rate of 76% at 6 months. This study suggests that alternative therapies should be considered in patients with scores above 0.45 after 1 week of treatment with steroids. Recently, the Lille model has also been found to predict survival benefit at 28 days after steroid treatment.

Prednisolone may have a theoretical advantage over prednisone, because it does not require hepatic metabolism for the active component. It is given at a dose of 40 mg daily for 4 weeks and can be discontinued or tapered over a 2–4 week period. Although use of corticosteroids in the treatment of ALD was recommended in a 1998 American College of Gastroenterology guideline, clinical use has been infrequent.

Anti–Tumor Necrosis Factor Therapy

TNF has been implicated in the pathogenesis of ALD, and elevated levels are found in patients with alcoholic hepatitis. Anti-TNF treatment prevents liver injury in a murine model of ALD, and this therapy has also been studied in humans.

Pentoxiphylline, an inhibitor of TNF, at 400 mg orally three times per day, was shown to decrease the risk of hepatorenal syndrome in patients whose MDF is greater than 32. The 28-day mortality for the pentoxiphylline group was 24%, compared with 46% for the placebo group. Survival benefit was related to a reduction in mortality associated with the hepatorenal syndrome. The decrease in serum TNFα levels was not statistically significant when compared with placebo. Pentoxiphylline 400 mg oral daily is a reasonable alternative to corticosteroids in those with contraindications to steroid or early renal failure.

Treatment with anti-TNF monoclonal antibody (infliximab, a chimeric mouse and human antibody that neutralizes soluble TNFα) and etanercept (a p75-soluble TNF receptor Fc fusion protein) has yet to reveal survival benefit in clinical trials for ALD, which are often inadequately sized and include some patients suffering fatal complications.

Other Therapies

Based on the involvement of reactive oxygen species in the pathways of ALD, pilot studies using antioxidants have been performed. Vitamin E (1000 IU daily for 3 months) failed to show a benefit despite improvement in serum levels of bilirubin and the prothrombin time.

In a small study, SAMe, a precursor to glutathione, at 1200 mg orally per day improved survival in patients with alcoholic liver cirrhosis with Childs-Pugh class A or B. However, this benefit was not substantiated in a Cochrane Review. Colchicine was also determined to be ineffective in alcoholic liver cirrhosis.

Polyenylphosphatidylcholine (PPC), given to 789 patients with alcoholic liver fibrosis in a Veterans Administration Cooperative Trial, benefited those who abstained from alcohol use but not those who continued a moderate amount of alcohol consumption.

Because pericentral (zone 3) hepatocytes are relatively oxygen poor and are sensitive to hypoxic injury caused by alcohol and thyroid hormone, suppression of thyroid hormone using propylthiouracil was attempted in a clinical trial. Survival benefit was seen at 2 years when compared with placebo but only in abstinent patients. However, these findings have not been replicated in other trials.

The use of milk thistle seed has been used for 2000 years in Europe for treatment of liver diseases. The active ingredient is believed to be silymarin, which is made of silybin, silidianin, and silicristin. Silybin is believed to be the most active compound. Silymarin is believed to enhance liver regeneration and protect hepatocytes from toxicity, although the mechanism is still unclear. However, clinical trials have yet to demonstrate a clear benefit.

No benefit was seen using anabolic steroids for alcoholic hepatitis or cirrhosis. Treatment with disulfiram, which inhibits acetaldehyde dehydrogenase, is contraindicated in patients with liver disease.

Therapies related to hepatic regeneration (insulin, glucagons, and malotilate) and extracorporeal support (molecular absorbent recirculating system) have been evaluated in clinical trials, but the use of these agents remains experimental. Future therapies may include antifibrotic agents, IL-10, theophylline, and possibly thalidomide.

In summary, only steroids or pentoxifylline are currently recommended for pharmacologic treatment of alcoholic hepatitis. The combination of these two drugs has not been investigated.

Transplantation

Although in rare cases liver cirrhosis is reversible, the disease process remains mostly irreversible. Liver transplantation remains the only definitive therapy. Today, survival after liver transplantation is similar for patients with ALD and non-ALD. The requirements for transplant listing are the same as those for other types of liver disease, except for a 6-month sobriety prerequisite along with psychiatric evaluation and rehabilitation assistance (ie, Alcoholics Anonymous). Specific requirements vary among the transplant centers. Relapse to alcohol use after transplant listing results in delisting. Re-listing is possible in many institutions, but only after 3–6 months of sobriety.

There are limited data on transplant survival in patients transplanted for acute alcoholic hepatitis, but it is believed to be similar to that in nonacute ALD, non-ALD, and alcoholic hepatitis with MDF less than 32.

See Chapter 50 for further discussion of liver transplantation.

The prognosis for patients with ALD depends on the liver histology as well as cofactors, such as concomitant chronic viral hepatitis. Among patients with alcoholic hepatitis, progression to liver cirrhosis occurs at 10–20% per year, and 70% will eventually develop cirrhosis. Despite cessation of alcohol use, only 10% will have normalization of histology and serum liver enzyme levels.

As previously noted, the MDF has been used to predict short-term mortality (ie, MDF ≥32 associated with spontaneous survival of 50–65% without corticosteroid therapy, and MDF <32 associated with spontaneous survival of 90%). The Model for End-Stage Liver Disease (MELD) score has also been found to have similar predictive accuracy in 30-day (MELD >11) and 90-day (MELD >21) mortality. The Glasgow alcoholic hepatitis score has also been found to be helpful in predicting survival.

Liver cirrhosis develops in 6–14% of those who consume more than 60–80 g of alcohol daily for men and more than 20 g daily for women. Even in those who drink more than 120 g daily, only 13.5% will suffer serious alcohol-related liver injury. Nevertheless, alcohol-related mortality was the third leading cause of death in 2003 in the United States. Worldwide mortality is estimated to be 150,000 per year.