AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. The pathogenesis is not completely understood.

Patients who are severely affected present with subacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (eg, jaundice, coagulopathy), and manifestations of portal hypertension (eg, ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any symptoms.

Upon microscopic examination, the liver exhibits characteristic centrilobular ballooning necrosis of hepatocytes, neutrophilic infiltration, megamitochondria, and Mallory hyaline inclusions. Steatosis (fatty liver) and cirrhosis frequently accompany alcoholic hepatitis.

Disease that is sufficiently severe to cause an acute development of encephalopathy is associated with substantial early mortality, which may be ameliorated by treatment with glucocorticoids.

Alcoholic hepatitis usually persists and progresses to cirrhosis if heavy alcohol use continues. If alcohol use ceases, alcoholic hepatitis resolves slowly over weeks to months, sometimes without permanent sequelae but often with residual cirrhosis.

Pathophysiology

Although the association of alcohol and liver disease has been known since antiquity, the precise mechanism of alcoholic liver disease remains in dispute. Genetic, environmental, nutritional, metabolic, and, more recently, immunologic factors and cytokines have been invoked.

Ethanol metabolism

Most tissues of the body, including the skeletal muscles, contain the necessary enzymes for the oxidative or nonoxidative metabolism of ethanol. However, the major site of ethanol metabolism is the liver. Within the liver, the following 3 enzyme systems can oxidize ethanol:

• Cytosolic alcohol dehydrogenase (ADH) uses nicotinamide adenine dinucleotide (NAD) as an oxidizing agent. ADH exists in numerous isoenzyme forms in the human liver and is encoded by 3 separate genes, designated as ADH1, ADH2, and ADH3. Variations in ADH isoforms may account for significant differences in ethanol elimination rates.
• The microsomal ethanol-oxidizing system (MEOS) uses nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen. The central enzyme of MEOS is cytochrome P-450 2E1 (CYP2E1). This enzyme, in addition to catalyzing ethanol oxidation, is also responsible for the biotransformation of other drugs, such as acetaminophen, haloalkanes, and nitrosamines. Ethanol up-regulates CYP2E1, and the proportion of alcohol metabolized via this pathway increases with the severity and duration of alcohol use.
• Peroxisomal catalase uses hydrogen peroxide as an oxidizing agent.

The product of all 3 reactions is acetaldehyde, which is then further metabolized to acetate by acetaldehyde dehydrogenase (ALDH). Acetaldehyde is a reactive metabolite that can produce injury in a variety of ways.

Mechanisms of liver injury

Genetic factors

Although the evidence to prove a genetic predilection to alcoholism is adequate, the role of genetic factors in determining susceptibility to alcoholic liver injury is much less clear. Most people who are alcoholics do not develop severe or progressive liver injury. Attempts to link persons who are susceptible with specific HLA groups have yielded inconsistent results, as have studies of genetic polymorphisms of collagen, ADH, ALDH, and CYP2E1.

Similar conclusions were reached in a recent meta-analysis of 50 studies pertaining to the association of alcoholic liver disease and genetic polymorphism.⁵⁷ Nonetheless, the fact remains that only a small fraction of even heavy alcoholics develop severe liver disease (ie, cirrhosis). Thus, future case-control studies investigating the genetic basis of alcohol-induced liver disease are urgently needed.

The genetic factor that most clearly affects susceptibility is sex. For a given level of ethanol intake, women are more susceptible than men to developing alcoholic liver disease (see Sex).

Malnutrition

Most patients with alcoholic hepatitis exhibit evidence of protein-energy malnutrition (PEM). In the past, nutritional deficiencies were assumed to play a major role in the development of liver injury. This assumption was supported by several animal models in which susceptibility to alcohol-induced cirrhosis could be produced by diets deficient in choline and methionine. This view changed in the early 1970s after key studies by Lieber and DeCarli performed in baboons demonstrated that alcohol ingestion could lead to steatohepatitis and cirrhosis in the presence of a nutritionally complete diet.²⁵ However, more recent studies suggest that enteral or parenteral nutritional supplementation in patients with alcoholic hepatitis may improve survival.

Toxic effects on cell membranes

Ethanol and its metabolite, acetaldehyde, have been shown to damage liver cell membranes. Ethanol can alter the fluidity of cell membranes, thereby altering the activity of membrane-bound enzymes and transport proteins. Ethanol damage to mitochondrial membranes may be responsible for the giant mitochondria (megamitochondria) observed in patients with alcoholic hepatitis. Acetaldehyde-modified proteins and lipids on the cell surface may behave as neoantigens and trigger immunologic injury.

Hypermetabolic state of the hepatocyte

Hepatic injury in alcoholic hepatitis is most prominent in the perivenular area (zone 3) of the hepatic lobule. This zone is known to be sensitive to hypoxic damage. Ethanol induces a hypermetabolic state in the hepatocytes, partially because ethanol metabolism via the MEOS does not result in energy capture via formation of ATP. Rather, this pathway leads to loss of energy in the form of heat. In some studies, antithyroid drugs, such as propylthiouracil, that reduce the basal metabolic rate of the liver have shown to be beneficial in the treatment of alcoholic hepatitis.

Generation of free radicals and oxidative injury

Free radicals, superoxide and hydroperoxides, are generated as byproducts of ethanol metabolism via the microsomal and peroxisomal pathways. In addition, acetaldehyde reacts with glutathione and depletes this key element of the hepatocytic defense against free radicals. Other antioxidant defenses, including selenium, zinc, and vitamin E, are often reduced in individuals with alcoholism. Peroxidation of membrane lipids accompanies alcoholic liver injury and may be involved in cell death and inflammation.

Steatosis

Oxidation of ethanol requires conversion of NAD to the reduced form NADH. Because NAD is required for the oxidation of fat, its depletion inhibits fatty acid oxidation, thus causing accumulation of fat within the hepatocytes (steatosis). Some of the excess NADH may be reoxidized in the conversion of pyruvate to lactate. Accumulation of fat in hepatocytes may occur within days of alcohol ingestion; with abstinence from alcohol, the normal redox state is restored, the lipid is mobilized, and steatosis resolves. Although steatosis has generally been considered a benign and reversible condition, rupture of lipid-laden hepatocytes may lead to focal inflammation, granuloma formation, and fibrosis, and it may contribute to progressive liver injury. Nonoxidative metabolism of ethanol may lead to the formation of fatty acid ethyl esters, which may also be implicated in the pathogenesis of alcohol-induced liver damage.

Formation of acetaldehyde adducts

Acetaldehyde may be the principal mediator of alcoholic liver injury. The deleterious effects of acetaldehyde include impairment of the mitochondrial beta-oxidation of fatty acids, formation of oxygen-derived free radicals, and depletion of mitochondrial glutathione. In addition, acetaldehyde may bind covalently with several hepatic macromolecules, such as amines and thiols, in cell membranes, enzymes, and microtubules to form acetaldehyde adducts. This binding may trigger an immune response through formation of neoantigens, impair function of intracellular transport through precipitation of intermediate filaments and other cytoskeletal elements, and stimulate hepatic stellate cells to produce collagen.

Levels of acetaldehyde in the liver represent a balance between its rate of formation (determined by the alcohol load and activities of the 3 alcohol-dehydrogenating enzymes) and its rate of degradation by ALDH. ALDH is down-regulated by long-term ethanol abuse, with resultant acetaldehyde accumulation.

Role of the immune system

Active alcoholic hepatitis often persists for months after cessation of drinking. In fact, its severity may worsen during the first few weeks of abstinence. This observation suggests that an immunologic mechanism may be responsible for perpetuation of the injury. Levels of serum immunoglobulins, especially the immunoglobulin A class, are increased in persons with alcoholic hepatitis. Antibodies directed against acetaldehyde-modified cytoskeletal proteins can be demonstrated in some individuals. Autoantibodies, including antinuclear and anti–single-stranded or anti–double-stranded DNA antibodies, have also been detected in some patients with alcoholic liver disease.

B and T lymphocytes are noted in the portal and periportal areas, and natural killer lymphocytes are noted around hyalin-containing hepatocytes. Patients have decreased peripheral lymphocyte counts with an associated increase in the ratio of helper cells to suppressor cells, signifying that lymphocytes are involved in a cell-mediated inflammatory process. Lymphocyte activation upon exposure to liver extracts has been demonstrated in patients with alcoholic hepatitis. Immunosuppressive therapy with glucocorticoids appears to improve survival and accelerate recovery in patients with severe alcoholic hepatitis.

Cytokines

Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death (apoptosis) in liver cells. Several studies have demonstrated extremely high levels of TNF and several TNF-inducible cytokines, such as interleukin (IL)–1, IL-6, and IL-8, in the sera of patients with alcoholic hepatitis. Both inflammatory cytokines (TNF, IL-1, IL-8) and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant role in modulating certain metabolic complications in alcoholic hepatitis, and they are probably instrumental in the liver injury of alcoholic hepatitis and cirrhosis (see Media files 1-2).

Role of concomitant viral disease

Alcohol consumption may exacerbate injury caused by other pathogenic factors, including hepatitis viruses. Extensive epidemiologic studies suggest that the risk of cirrhosis in patients with chronic hepatitis C infection is greatly exacerbated by heavy alcohol ingestion. Possible mechanisms include the impairment of immune-mediated viral killing or enhanced virus gene expression due to the interaction of alcohol and hepatitis C virus.

Acetaminophen-alcohol interactions

Long-term alcohol abuse has been established as potentiating acetaminophen toxicity via induction of CYP2E1 and depletion of glutathione. Alcoholic patients may develop severe, even fatal, toxic liver injury after ingestion of standard therapeutic doses of acetaminophen.

Frequency

United States

Alcohol abuse is the most common cause of serious liver disease in Western societies. In the United States alone, alcoholic liver disease affects more than 2 million people (ie, approximately 1% of the population). The true prevalence of alcoholic hepatitis, especially of its milder forms, is unknown because patients may be asymptomatic and never seek medical attention.

International

The prevalence appears to differ widely among different countries. In the Western hemisphere, when liver biopsies were performed in people who drank moderate-to-heavy amounts of alcohol and were asymptomatic, the prevalence of alcoholic hepatitis was found to be approximately 25-30%.

Mortality/Morbidity

Mild alcoholic hepatitis is a benign disorder with negligible short-term mortality. However, when alcoholic hepatitis is of sufficient severity to cause hepatic encephalopathy, jaundice, or coagulopathy, mortality can be substantial.

• The overall 30-day mortality rate in patients hospitalized with alcoholic hepatitis is approximately 15%; however, in patients with severe liver disease, the rate approaches or exceeds 50%. In those lacking encephalopathy, jaundice, or coagulopathy, the 30-day mortality rate is less than 5%. Overall, the 1-year mortality rate after hospitalization for alcoholic hepatitis is approximately 40%.
• In a recent study, the overall mortality among patients with severe alcoholic hepatitis was 66%. Age, white blood cell count, prothrombin time (PT), and female gender were all independent risk factors for the dismal outcome.¹⁹
• The long-term prognosis depends heavily on whether patients have established cirrhosis and whether they continue to drink. With abstinence, patients with alcoholic hepatitis exhibit progressive improvement in liver function over months to years and histologic features of active alcoholic hepatitis resolve. If alcohol abuse continues, alcoholic hepatitis invariably persists and progresses to cirrhosis over months to years.

Race

Although no genetic predilection is noted for any particular race, alcoholism and alcoholic liver disease are more common in minority groups, particularly among Native Americans. Likewise, since the 1960s, death rates of alcoholic hepatitis and cirrhosis have consistently been far greater for the nonwhite population than the white population. The nonwhite male rate of alcoholic hepatitis is 1.7 times the white male rate, 1.9 times the nonwhite female rate, and almost 4 times the white female rate.

Sex

Women are more susceptible than men to the adverse effects of alcohol. Women develop alcoholic hepatitis after a shorter period and smaller amounts of alcohol abuse than men, and alcoholic hepatitis progresses more rapidly in women than in men.

• The estimated minimum daily ethanol intake required for the development of cirrhosis is 40 g for men and 20 g for women older than 15-20 years. Furthermore, for patients who continue to drink after a diagnosis of alcoholic liver disease, the 5-year survival rate is approximately 30% for women compared with 70% for men.
• To date, no single factor can account for this increased female susceptibility to alcoholic liver damage. Lower gastric mucosal ADH content in women has been suggested to possibly lead to less first-pass clearance of alcohol in the stomach. A higher prevalence of autoantibodies has been found in the sera of alcoholic females compared with alcoholic males, but their clinical significance is questionable. Perhaps hormonal influences on the metabolism of alcohol or the higher prevalence of immunologic abnormalities is responsible for the differences described in the prevalence of alcoholic liver damage between men and women.

Age

Alcoholic hepatitis can develop at any age. However, its prevalence parallels the prevalence of ethanol abuse in the population, with a peak incidence in individuals aged 20-60 years.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
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• Workup
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• Follow-up
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History

Heavy alcohol use is a prerequisite for the development of alcoholic hepatitis. The history is usually apparent; however, in some patients, alcohol use may be covert.

• Clues to the presence of alcoholism include a history of multiple motor vehicle accidents, convictions for driving while intoxicated, and poor interpersonal relationships. Alcoholism exhibits a genetic predisposition, and a history of alcoholism in a close relative may also indicate that a patient is at risk.
• Patients with clinically symptomatic alcoholic hepatitis typically present with nonspecific symptoms of nausea, malaise, and low-grade fever.
• The clinical presentation may be precipitated by complications of impaired liver function or portal hypertension, such as upper gastrointestinal hemorrhage from esophageal varices, confusion and lethargy from hepatic encephalopathy, or increased abdominal girth from ascites.
• A person who uses alcohol heavily may come to medical attention because of an intercurrent medical illness that produces altered mental status or persistent vomiting, which, in turn, triggers alcohol withdrawal symptoms. In such instances, the clinician must be alert to the presence of a precipitating illness (eg, subdural hematoma, acute pancreatitis, gastrointestinal hemorrhage) and to the likelihood of alcohol withdrawal symptoms (eg, seizures, delirium tremens) in addition to the problems associated with alcoholic hepatitis.

Physical

The diagnosis of alcoholic hepatitis is straightforward and requires no further diagnostic studies in patients presenting with a history of alcohol abuse, typical symptoms and physical findings, evidence of liver functional impairment, and compatible liver enzyme levels. In milder cases of alcoholic hepatitis, a mild elevation of the aspartate aminotransferase (AST) level may be the only diagnostic clue.

• Patients with alcoholic hepatitis are commonly febrile with tachycardia. Mild tachypnea with primary respiratory alkalosis may be observed. The liver is usually enlarged, often with mild hepatic tenderness. Hepatomegaly results from both steatosis and swelling of injured hepatocytes.
• Manifestations of hepatic failure or portal hypertension may include scleral icterus with darkening of the urine, splenomegaly, asterixis (a flapping tremor characteristic of metabolic encephalopathies), peripheral edema, and bulging flanks with shifting abdominal dullness (indicating the presence of ascites).
• Spider angiomata, proximal muscle wasting, altered hair distribution, and gynecomastia may be observed, although these findings most commonly reflect coexistent cirrhosis.

Causes

Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. Heavy alcohol use is a prerequisite for the development of alcoholic hepatitis.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Other common considerations in alcoholic patients with jaundice include chronic pancreatitis with biliary strictures and pancreaticobiliary neoplasms.

A disorder histologically resembling alcoholic hepatitis can occur in patients who do not use alcohol. This syndrome, termed nonalcoholic steatohepatitis (NASH), is being recognized with increasing frequency. It occurs most frequently in the setting of obesity, hyperlipidemia, or type 2 diabetes mellitus. It is also observed in the setting of chronic parenteral hyperalimentation and in individuals who undergo jejunoileal bypass surgery for treatment of obesity. In most cases, NASH is indolent; however, in some individuals, it may progress insidiously to cirrhosis. NASH is currently believed to be responsible for a large fraction of cases of what was previously termed cryptogenic cirrhosis. In most patients with NASH, the ratio of AST to alanine aminotransferase (ALT) is less than 1, unless cirrhosis is present.

WORKUP

Section 5 of 11  

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• Follow-up
• Miscellaneous
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Lab Studies

• CBC count
  
  
  • A CBC count commonly reveals some degree of neutrophilic leukocytosis with bandemia. Usually, this is moderate; however, rarely, it is severe enough to provide a leukemoid picture.
  • Alcohol is a direct marrow suppressant, and moderate anemia may be observed. In addition, alcohol use characteristically produces a moderate increase in mean corpuscular volume.
  • Thrombocytosis may be observed as part of the inflammatory response; conversely, myelosuppression or portal hypertension with splenic sequestration may produce thrombocytopenia.
• Liver enzyme levels
  
  
  • Liver enzyme levels exhibit a characteristic pattern. In most patients, the AST level is moderately elevated, while the ALT level is in the reference range or only mildly elevated. This is the opposite of what is observed in most other liver diseases. An AST/ALT ratio greater than 1 is almost universal in persons with alcoholic hepatitis. Even in severe disease, the elevations of aminotransferase levels are modest, and an AST level greater than 500 U/L should raise suspicion of an alternative diagnosis. An AST/ALT ratio greater than 1 may accompany cirrhosis of any cause and, therefore, is less diagnostically specific in the setting of cirrhosis.
  • Alkaline phosphatase level elevations are typically mild in persons with alcoholic hepatitis. Levels greater than 500 U/L occur in a small percentage of patients, but abnormalities of this magnitude suggest a coexisting infiltrative or biliary obstructive process.
  • The gamma-glutamyl transpeptidase level is elevated markedly by alcohol use. While a normal value helps to exclude alcohol as a cause of liver disease, an elevated level is of no value in distinguishing between simple alcoholism and alcoholic hepatitis.
• Liver function tests
  
  
  • Common liver function tests include albumin level, PT, and bilirubin level.
  • Hypoalbuminemia occurs because of decreased hepatic synthetic function and coexisting PEM.
  • Hyperbilirubinemia is typically a mixture of unconjugated and conjugated bilirubin, with the latter predominating. Bilirubinuria is normally present in patients who are icteric.
  • Coagulopathy predominantly affects the extrinsic pathway of coagulation (measured by PT). It is usually unresponsive to vitamin K.
  • The severity of hyperbilirubinemia and coagulopathy reflects the severity of alcoholic hepatitis and is of prognostic value.
• Serum biomarkers
  
  
  • Ash test: The diagnostic value of serum biomarkers, such as the Ash test (ie, the 6 components of the FibroTest-ActiTest plus AST), was tested and validated in 275 patients with alcoholic hepatitis. Both the sensitivity and the specificity of the Ash test in predicting alcoholic steatohepatitis were impressive (0.80 and 0.84, respectively).⁵¹
  • Carbohydrate-deficient transferrin (CDT): CDT is perhaps the most reliable marker of chronic alcoholism, irrespective of the presence of liver disease.³⁵ Recently, serum CDT has been proposed as a reliable biomarker in the differentiation of NASH from alcoholic hepatitis.⁴²
  • C-reactive protein (CRP): Recent studies have indicated that serum CRP is an accurate marker of alcoholic hepatitis (ie, sensitivity, 41%; specificity, 99%; positive predictive value [PPV], 98%; negative predictive value [NPV], 88%).⁵⁴
    
• Electrolyte panel
  
  
  • Electrolyte disorders may reflect the effects of vomiting, portal hypertension with decreased circulating volume, alcoholic ketoacidosis, or respiratory alkalosis.
  • Hypophosphatemia and hypomagnesemia are common consequences of coexistent malnutrition.
• Screening blood tests to exclude other conditions (appropriate in any patient with alcoholic hepatitis)
  
  
  • Hepatitis B surface antigen detects hepatitis B.
  • Anti–hepatitis C virus by enzyme-linked immunosorbent assay detects hepatitis C.
  • Ferritin and transferrin saturation detect hemochromatosis.
  • Marked elevation of aminotransferase levels should raise concern for viral hepatitis or drug hepatotoxicity. In particular, people who are alcoholics may develop severe liver necrosis from standard therapeutic doses of acetaminophen.
  • Rapid deterioration of liver function should raise the possibility of hepatocellular carcinoma, which can be tested for by determination of alpha-fetoprotein levels.
  • Jaundice with fever can be caused by gallstones producing cholangitis and is suggested by a disproportionate elevation of the alkaline phosphatase level.

Imaging Studies

• Imaging studies are rarely required for the diagnosis of alcoholic hepatitis, but they can be useful in excluding other causes of liver disease.
• Ultrasonography
• • In general, real-time ultrasonography is the preferred study because it is inexpensive, noninvasive, and widely available. It provides a good evaluation of the liver and other viscera, and it permits guided liver biopsy.
  • On ultrasonograms, the liver in patients with alcoholic hepatitis appears enlarged and diffusely hyperechoic.
  • Features suggestive of coexistent portal hypertension and/or cirrhosis include the presence of varices, splenomegaly, and ascites.
  • Ultrasonography is also helpful in excluding gallstones, bile duct obstruction, and hepatic or biliary neoplasms. Jaundice with fever can be caused by gallstones producing cholangitis; ultrasonographic examination of the abdomen is usually sufficient to exclude this possibility. However, if stones are found or fever persists, cholangiography may be necessary.
  • Rapid deterioration of liver function should raise the possibility of hepatocellular carcinoma, which can be tested for by performing imaging studies (eg, ultrasonography, CT scanning, MRI) of the liver.
• Other imaging tests
• • Similar and complementary information can be obtained by CT scanning or MRI of the abdomen.
  • These imaging studies are more expensive and are usually required only in atypical cases. They are more sensitive and accurate if cancer is suspected.

Procedures

• Liver biopsy: This is not always required in the evaluation of alcoholic hepatitis, but it may be useful in establishing the diagnosis, in determining the presence or absence of cirrhosis, and in excluding other causes of liver disease.
• Percutaneous liver biopsy
• • Percutaneous biopsy can be performed at the bedside by an experienced practitioner, usually a gastroenterologist or a hepatologist.
  • Real-time ultrasonographic guidance may be desirable to optimize biopsy site selection and to reduce the risk of complications.
  • Usually, a biopsy should be avoided in the presence of severe thrombocytopenia or coagulopathy because of the risk of serious (possibly fatal) hemorrhage.
• Transjugular liver biopsy
• • If biopsy information is considered essential and the risk of percutaneous biopsy appears excessive, an alternative approach is to perform a biopsy angiographically via a catheter passed into the hepatic vein under fluoroscopic guidance. In principle, the risk of hemorrhage should be reduced because the puncture site is contained within the venous system.
  • At the time of transjugular liver biopsy, the angiographer can determine the transhepatic venous pressure gradient.
  • In alcoholic hepatitis and cirrhosis, the pressure measurement obtained with a catheter wedged retrograde in a branch of the hepatic vein accurately reflects the portal venous pressure.

Histologic Findings

In alcoholic hepatitis, injury is characteristically most prominent in centrilobular (perivenular) areas (zone 3 of Rappaport). Hepatocytes exhibit ballooning with necrosis. Focal accumulation of polymorphonuclear leukocytes is noted in areas of injury (see Media file 3).  Lymphocytes may also be present, especially in portal tracts.

Ropy eosinophilic hyaline inclusions termed Mallory bodies may be observed in the perinuclear cytoplasm. With electron microscopy, Mallory bodies may be observed to be composed of fibril clumps that histochemically are identifiable as intermediate filaments. Mallory bodies are characteristic of alcoholic hepatitis, but they are not always present in this disease, and, occasionally, they can be observed in a variety of other disorders.

Macrovesicular steatosis, perivenular fibrosis, and frank cirrhosis commonly coexist with alcoholic hepatitis.

TREATMENT

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Medical Care

In most patients with alcoholic hepatitis, the illness is mild. Their short-term prognosis is good, and no specific treatment is required. Hospitalization is not always necessary. Alcohol use must be stopped. Care should be taken to ensure good nutrition. Providing supplemental vitamins and minerals, including folate and thiamine, is reasonable. Patients who are coagulopathic should receive vitamin K parenterally. Anticipate symptoms of alcohol withdrawal, and manage them appropriately.

In contrast, patients with severe acute alcoholic hepatitis are at high risk of early death, at a rate of 50% or greater within 30 days. In multiple studies, the strongest factor predictive of short-term mortality was hepatic encephalopathy. In some studies, a combination of hyperbilirubinemia and coagulopathy has also been found to independently predict a high short-term mortality rate. Individuals with these findings or with other complications, such as azotemia or gastrointestinal bleeding, should be hospitalized. Usually, observing the patient in an intensive care unit until liver function is stable and the patient is clinically improving is prudent.

Patients with severe alcoholic hepatitis may benefit over the short term from specific therapies directed toward reducing liver injury, enhancing hepatic regeneration, and suppressing inflammation. Glucocorticosteroids are widely used for this purpose, although their benefits have not been proven unequivocally. Various other treatments remain experimental. For the long term, goals include improvement of liver function, prevention of progression to cirrhosis, and reduction of mortality. Only prolonged alcohol abstinence is of demonstrated benefit in all these areas.

• Cessation of alcohol use is the mainstay of treatment of alcoholic hepatitis.
• • In general, alcoholic hepatitis resolves or improves greatly following 6-12 months of alcohol abstinence, and continued improvement may be observed for several years. Mild alcoholic hepatitis often resolves completely, but, following severe alcoholic hepatitis, residual cirrhosis can usually be demonstrated. If alcohol abuse persists, alcoholic hepatitis invariably persists and progresses to cirrhosis, and the prognosis is dramatically worse.
  • Some experts have questioned whether complete abstinence is necessary or whether reduced amounts of alcohol would be sufficient for recovery in most patients. Given the addictive nature of alcohol in most patients who use it heavily, counseling complete abstinence is prudent. Patients should be referred to a program of rehabilitation and support, and they should be strongly encouraged to attend. Also, patients should be fully informed regarding the serious potential health consequences of continued ethanol use.
• Additional treatment includes nutritional support.
  
  
  • PEM is almost universal in patients hospitalized for alcoholic hepatitis. In a large Veterans Administration Cooperative Study of Alcoholic Hepatitis, the severity of PEM correlated with the severity of alcoholic hepatitis and the predicted mortality rate. In patients with alcoholic hepatitis and severe PEM, the mortality rate was 50%, compared with a mortality rate of less than 10% in patients with mild PEM.
  • Some studies have suggested that improved energy and protein intake may improve the survival rate in patients with severe alcoholic hepatitis. However, complications associated with parenteral hyperalimentation (eg, sepsis, hemothorax) or enteral hyperalimentation (eg, aspiration pneumonia) may outweigh the benefits of these approaches. Thus, if patients are able to take food orally, this is the route of choice, and formal nutritional support can be reserved for those instances in which patients are unable to ingest enough by mouth to meet their needs. Energy (caloric) intake should be carefully measured to ensure adequate consumption. Use of nutritional supplements and appetite stimulants may be appropriate.
  • Except in patients with severe encephalopathy, protein restriction is unnecessary and should be avoided because a protein-deficient diet impairs liver regeneration and worsens liver function. Even in the presence of hepatic encephalopathy, patients are usually able to ingest a minimum of 60-100 g/d of dietary protein if other measures to control encephalopathy have been aggressively pursued. In rare instances, restricting dietary proteins may be necessary. In these cases, alternatives include provision of high-quality protein via the parenteral route or provision of oral amino acid supplements that are selectively enriched with branched-chain amino acids.
• Use of medications in alcoholic hepatitis remains controversial.
• • Despite decades of research and multiple clinical trials, a consensus has not been reached regarding effective therapy for alcoholic hepatitis. At present, only glucocorticosteroid treatment can be considered of probable established benefit, and even this well-studied therapy continues to be a source of controversy.
  • Treatments discussed in Medication have met with limited success in small clinical trials but have not been evaluated thoroughly and should be considered investigational.

Surgical Care

Patients with acute alcoholic hepatitis are at high risk of developing hepatic failure following general anesthesia and major surgery. Because postoperative mortality rates are high, surgery should be avoided in the setting of acute alcoholic hepatitis unless it is absolutely necessary. If patients remain abstinent, alcoholic hepatitis usually resolves over time, permitting surgery to be undertaken with a substantially reduced risk.

• Orthotopic liver transplantation is widely used in patients with end-stage liver disease. Most patients with active alcoholic hepatitis are excluded from transplantation because of ongoing alcohol abuse. In most US programs, patients must abstain from alcohol for at least 6 months before they can be considered for transplantation, and a thorough psychosocial evaluation must demonstrate that patients have a low likelihood of reverting to alcohol abuse.
  
• Current policies pertaining to liver transplantation in patients with end-stage alcoholic liver disease (ie, cirrhosis), especially those with severe alcoholic hepatitis, have been recently challenged.⁴³
  
  • First, the societal aspects of the issue (ie, the public perception and reservation regarding the use of donated livers for self-inflicted disease) should not be any different than those of IV drug addicts with the hepatitis C virus or even the fast-food generation of obese persons with NASH.
    
  • Second, the current fixed interval of ethanol abstinence, often at the behest of third-party payers, as a prerequisite for transplantation remains controversial as a predictor of future alcoholic relapse (ie, recidivism).^{55, 27}
    
  • Finally, other investigators have proposed the conduct of pilot studies, on only a small cohort of patients, to determine whether liver transplantation improves the survival of patients with severe alcoholic hepatitis.³¹ 
    
    
• Patients with alcoholic hepatitis may be informed that their liver injury can be expected to subside and liver function will improve following at least 6 months of abstinence. If they still develop cirrhosis and its complications, they can be considered for transplantation if they remain committed to sustained abstinence. 
  
  
• The prospect of liver transplantation can be a powerful motivational tool for encouraging abstinence.

Consultations

Largely, mild and moderate alcoholic hepatitis can be managed on a hospital medical floor, requiring only a brief hospital stay. In fact, patients with the mildest forms of the disease may never seek medical attention, or they can be treated safely in outpatient settings. By contrast, severe acute alcoholic hepatitis requires intensive medical care and often a multidisciplinary approach.

• Adequate nutritional support is of paramount importance for the survival and recovery of patients with alcoholic hepatitis. The complexity of the disease and the wide variation in nutritional regimens and modalities mandate consultation with a nutritionist. Customarily, the gastroenterology service of the hospital should be able to handle this issue and should be instrumental in treatment.
• The onset of acute renal failure may indicate the development of hepatorenal syndrome or, alternatively, an episode of acute tubular necrosis resulting either from the use of nephrotoxic drugs or from acute intravascular volume changes. In these instances, obtaining consultation with a nephrologist is advisable.
• If a patient with alcoholic hepatitis exhibits mental status changes, focal neurologic findings, or seizures, consider consultation with a neurologist.
• The fever and leukocytosis that accompany alcoholic hepatitis often raise concerns regarding possible sepsis or other infectious processes. Routine evaluation with urinalysis, chest radiography, and cultures of blood and urine is appropriate, and findings from these tests are usually negative. If concerns persist, consultation with an infectious disease specialist is appropriate.
• In patients with alcoholic hepatitis who have developed cirrhosis, especially those with coexistent chronic viral hepatitis B or C, consider periodic surveillance for hepatocellular carcinoma. A common algorithm includes determination of serum alpha-fetoprotein levels at 6-month intervals along with annual diagnostic ultrasonography. The finding of a liver nodule or an elevated alpha-fetoprotein level should lead to referral to a liver specialist and additional diagnostic studies.
• In general, for patients with severe alcoholic hepatitis or cirrhosis, observation by a gastroenterologist or a hepatologist is desirable, particularly if the illness is of sufficient severity or complexity to require intensive care.

Diet

• See Medical Care.
• For patients with milder alcoholic hepatitis, a general diet containing 100 g/d of protein is appropriate.
• Provide supplemental multivitamins and minerals, including folate and thiamine.
• Salt restriction may be required in patients with ascites.

MEDICATION

Section 7 of 11  

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Infliximab (Remicade) is a monoclonal antibody against TNF-alpha that has been used successfully in immunologically mediated inflammatory diseases, such as Crohn disease and rheumatoid arthritis. In 2 small pilot studies of subjects with alcoholic hepatitis, infliximab improved the Maddrey scores, serum bilirubin and C-reactive protein levels, and, more importantly, patient survival.^{49, 53}

In contrast, a subsequent randomized, double-blinded, controlled trial of 36 subjects with severe alcoholic hepatitis failed to confirm the findings of the pilot studies.⁴⁰ In fact, the trial was discontinued because of the high rate of infections and because of mortality in the infliximab group. This study was criticized for the concomitant use of corticosteroids, the high dose of infliximab (10 mg/kg vs 5 mg/kg), and the selection of infliximab instead of an anti-TNF agent with a limited duration and action (ie, etanercept). Better-designed controlled clinical trials are probably necessary to resolve the controversy and avoid a possible type I error. Currently, corticosteroids are the only recommended pharmaceutical therapy for severe alcoholic hepatitis (ie, Maddrey discriminant factor >32).

Pentoxifylline (Trental) is a hemorheologic agent that lowers blood viscosity and has been shown to decrease portal hypertension in experimental animals with cirrhosis. Recently, pentoxifylline was found to have inhibitory effects on TNF. Following 2 encouraging pilot studies in a small number of subjects, a large, randomized, double-blinded, placebo-controlled trial in 101 subjects with acute alcoholic hepatitis was conducted and showed significant improvement in short-term survival.¹ The benefit of pentoxifylline appears to be related to a significant decrease in the risk of developing hepatorenal syndrome.

Anabolic steroids (eg, oxandrolone) have been used to treat alcoholic hepatitis because of their ability to stimulate protein synthesis and cell repair. They may also enhance nutrition through increased appetite. In a large study of 273 subjects with severe alcoholic hepatitis, treatment with both oxandrolone and nutritional supplementation showed no benefit on survival when the results of all subjects were analyzed. However, when subjects were stratified according to their nutritional status upon admission to the hospital, a significant improvement in short- and long-term survival was noted in those with moderate malnutrition. The survival rate in subjects who were severely malnourished did not improve.³⁴

This landmark study was recently confirmed in a meta-analysis of 5 randomized control trials that included 499 patients with alcoholic hepatitis who were treated with anabolic-androgenic steroids. According to the study results, anabolic steroids had no significant effect on mortality, liver-related mortality, liver complications, or liver histology.⁴⁵

To date, propylthiouracil has been used in several clinical trials in patients with alcoholic hepatitis. The combined results of 6 randomized clinical trials, which included 710 patients, were recently reported in a meta-analytical study.⁴⁶ According to the authors' assessment, propylthiouracil had no beneficial effect on all-cause mortality, liver-related mortality, liver complications, or liver histology.

Insulin and glucagon are hepatotropic hormones that may play an important role in promoting liver cell regeneration in response to injury. In 2 clinical trials, administration of insulin and glucagon along with glucose (to prevent hypoglycemia) led to a modest improvement of liver function in patients with alcoholic hepatitis; however, severe insulin-induced hypoglycemia resulted in several deaths. Other promoters of hepatic regeneration include prostaglandins and malotilate, which appeared to improve survival in a multicenter European trial. Peptide growth factors, such as hepatocyte growth factor, are candidates for future study.

Colchicine interferes with transcellular movement and transport of collagen from the cytoplasm to the extracellular space, thus inhibiting fibrogenesis. In the 2 randomized double-blinded trials in the literature, colchicine was ineffective in treating patients with severe alcoholic hepatitis. By contrast, of 7 studies on the use of colchicine in patients with cirrhosis (mostly alcoholic), 4 studies demonstrated improvement and 3 studies demonstrated a tendency toward improvement.

Penicillamine inhibits collagen synthesis in vitro by decreasing cross-linking. Penicillamine has been used successfully for other liver diseases (eg, Wilson disease) for its copper-chelating properties. No controlled trial with this agent has been performed in alcoholic hepatitis.

Sulfhydryl agents can act as free radical scavengers and promote formation of reduced glutathione, an important element of hepatic antioxidant defense. S-adenosyl-l-methionine (SAM) protects against alcoholic liver injury in animal models. A recent, randomized, double-blinded, placebo-controlled trial in patients with alcoholic hepatitis resulted in improved survival of patients administered SAM compared with controls.

N-acetyl-L-cysteine (NAC) is widely used as an antidote to acetaminophen hepatotoxicity. Data from limited case-controlled studies suggest a beneficial effect of NAC in alcoholic liver disease. The beneficial effect is particularly apparent in patients who are alcoholics and also consume therapeutic doses of acetaminophen; however, preliminary evidence from prospective randomized trials did not show benefit. Vitamin E, a potent antioxidant substance, has been found to be hepatoprotective in both experimental animals and humans. However, a double-blinded trial among patients with alcoholic liver disease failed to improve liver chemistry, the hospitalization rate, and the cumulative mortality rate when the patients were administered 500 mg of vitamin E daily compared with the placebo-treated control group.

Polyunsaturated lecithin (PPC, phosphatidyl choline) has been studied because of the empiric observation that choline deficiency in rats (which impairs endogenous lecithin synthesis) increases sensitivity to alcoholic liver injury. The precise mechanism is unknown. Beneficial effects have also been demonstrated in preventing alcoholic liver injury in baboons. PPC failed to demonstrate any hepatoprotective effects in alcohol-induced liver injury in a recent multicenter Veterans Affairs cooperative study among 789 subjects.²⁶ In fact, approximately 20% of these subjects showed progressive liver fibrosis with continued moderated amounts of alcohol ingestion. Thus, PPC does not appear to have a viable role in acute alcoholic hepatitis.

Several preliminary reports on alcoholic hepatitis have indicated a beneficial effect from calcium channel blockers (eg, diltiazem, verapamil); however, the only randomized double-blinded trial of amlodipine failed to demonstrate any improvement in patients with alcoholic hepatitis.

Hepatoprotective bile acids include ursodeoxycholic acid (Ursodiol), a tertiary bile acid that has been used extensively either as monotherapy or as an adjuvant therapy in various cholestatic liver diseases, such as primary biliary cirrhosis and primary sclerosing cholangitis. Preliminary data from a small clinical trial in patients with alcoholic hepatitis showed a significant improvement in liver chemistry test results.

Herbal agents have been tried. Silymarin is the active ingredient in milk thistle, is a member of the flavonoids, and has shown remarkable hepatoprotective effects in experimental toxic liver injury. The precise mechanism of its hepatoprotective mediation is not known, but it is probably related to its antioxidant properties. In humans with mild alcoholic hepatitis, silymarin improves liver chemistry test results. In a single controlled trial among 170 subjects with alcoholic liver disease, silymarin reduced the liver-related deaths. However, in a recent meta-analysis of 13 clinical trials (about half of them double-blind), it was concluded that milk thistle did not significantly influence the clinical course of patients with alcoholic hepatitis.⁴⁷

Cyanidanol-3 (catechin) is a naturally occurring flavonoid with antioxidant properties. As a hepatoprotective agent, it has been studied extensively in experimental toxic liver injury. Cyanidanol gained popularity in Europe in the mid 1980s and was used for a wide variety of liver diseases. Unfortunately, prospective randomized trials in subjects with alcoholic hepatitis failed to show any benefit. Moreover, the administration of cyanidanol is associated with adverse effects, such as allergic hyperthermia and autoimmune hemolytic anemia.

Several other antioxidant agents have been used in the treatment of alcoholic hepatitis, albeit with little success. In a recent randomized clinical trial, corticosteroids were far superior to a "cocktail" of antioxidants in improving the usually measured clinical parameters and liver histology.⁴⁴

Among future therapeutic directions, gene therapy is perhaps the most appealing modality. Various genes involved in hepatic fibrogenesis, inflammatory response, and oxidative stress are overexpressed in alcoholic hepatitis. Moreover, some candidate genes correlate well with histologic findings and disease severity, thus suggesting that they may be potential targets for such therapy.⁸

Drug Category: Corticosteroids

Strong evidence of immunologic and inflammatory liver injury in alcoholic hepatitis provides the rationale for use of glucocorticosteroids. Over the past 30 years, more than 50 clinical trials have been published evaluating the use of glucocorticosteroids in treating alcoholic hepatitis. In most studies, treatment consists of the equivalent of 30-40 mg/d of prednisolone for 30 days, followed by a rapid taper and withdrawal over the subsequent 2-4 weeks. Study results have not been uniform. Larger studies demonstrate a significant benefit in severe alcoholic hepatitis, including reduction in mortality. Two meta-analyses of 12 randomized, prospective, placebo-controlled trials support the conclusion that glucocorticosteroid treatment reduces early mortality in patients with severe acute alcoholic hepatitis.

All studies conclude that in mild alcoholic hepatitis, no benefit can be demonstrated with glucocorticosteroid treatment; therefore, it is only appropriate in individuals with severe alcoholic hepatitis characterized by encephalopathy, hyperbilirubinemia, and/or coagulopathy.

Glucocorticosteroids may suppress inflammatory and immune-mediated hepatic destruction, but their marked antianabolic effect suppresses regeneration and may slow healing. They may increase complications and mortality associated with gastrointestinal bleeding, pancreatitis, or sepsis, and they should be withheld or used judiciously if any of these are present.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• In the absence of complications, patients generally can be discharged from acute medical inpatient care facilities once alcohol withdrawal symptoms have cleared; liver function has begun to improve; and complications of liver failure, such as encephalopathy, have resolved with appropriate treatment.
• In patients who have a potential for rehabilitation, transferring them to an inpatient substance abuse treatment program rather than discharging them from the hospital may be appropriate.

Further Outpatient Care

• Patients recently discharged from the hospital following an acute bout of alcoholic hepatitis should generally be observed within 2 weeks of their discharge. Subsequent periodic follow-up visits, at intervals ranging from weeks to several months, are appropriate to monitor patients' responses to treatment, including obtaining electrolyte levels and liver test results, and to encourage sobriety.
• In patients with alcoholic hepatitis who have developed cirrhosis, especially those with coexistent chronic viral hepatitis B or C, consider periodic surveillance for hepatocellular carcinoma. A common algorithm includes determination of the serum alpha-fetoprotein level at 6-month intervals along with annual diagnostic ultrasonography. The finding of a liver nodule or an elevated alpha-fetoprotein level should lead to referral to a liver specialist and additional diagnostic studies.
• Immunizing patients with alcoholic liver disease against common infectious pathogens, including hepatitis A virus, hepatitis B virus, pneumococci, and influenza A virus, is prudent.

Transfer

• Patients with alcoholic hepatitis of mild-to-moderate severity can be treated in a primary care setting. In general, for patients with severe alcoholic hepatitis or cirrhosis, observation by a gastroenterologist or a hepatologist is desirable, particularly if the illness is of sufficient severity or complexity to require intensive care.
• If patients become comatose or have complications that may require surgical intervention, the treating physician should consider emergent transfer to a tertiary care center with experience in the treatment of liver failure. In selected cases, the use of novel liver-assist devices (artificial livers) may provide transient improvement in the manifestations of liver failure.

Complications

• Most complications of alcoholic hepatitis are identical to those of cirrhosis.
  
  
  • Variceal hemorrhage: Acute variceal bleeding constitutes one of the most devastating emergencies, not only in gastroenterology but also in medicine at large. Resuscitation of the patient and protection of the airway are the 2 most important steps in the treatment of acute variceal bleeding. Cessation of the acute bleeding is usually achieved in more than 90% of patients with the combination of interventional endoscopy (sclerotherapy or banding ligation) and the intravenous infusion of pharmaceutical agents that lower the pressure within the portal system (somatostatin or one of its long-acting analogues, eg, octreotide). Alternatively and for patients who continue to bleed in spite of interventional endoscopy and drug therapy, more invasive options, such as balloon tamponade, a transjugular intrahepatic portosystemic shunt, and an emergency portal-caval shunt, may be used.
  • Hepatic encephalopathy: The development of encephalopathy in patients with alcoholic hepatitis is invariably associated with a grave prognosis. Treatment consists of close monitoring of the patient and the administration of lactulose or nonabsorbable antibiotics. Low energy or protein intake is not indicated, except transiently in severe cases. The use of benzodiazepine receptor antagonists (ie, flumazenil [Romazicon]) is still experimental. Rarely, rapidly progressive worsening of encephalopathy leading to deep coma may be associated with cerebral edema, as observed in fulminant hepatic failure. In selected instances, aggressive treatment with intracranial pressure monitoring and liver-assist devices may be considered.
  • Coagulopathy and thrombocytopenia: Profound hypoprothrombinemia may ensue in the course of severe alcoholic hepatitis, especially in patients with variceal bleeding. Administer fresh-frozen plasma to temporarily restore the depleted hepatic prothrombin stores. The value of parenteral administration of vitamin K is dubious because the hepatocytes are incapable of synthesizing new prothrombin. Platelet transfusions are not usually necessary to correct thrombocytopenia unless the patient is actively bleeding or undergoes an invasive procedure.
  • Ascites: Acute onset of ascites may develop in patients with alcoholic hepatitis, even in the absence of overtly decompensated liver disease and portal hypertension. The ascites is typically transudative, with a very low albumin concentration (<1 g/dL). In patients who are hemodynamically stable with normal renal function, bed rest and salt restriction may be sufficient to mobilize fluid. The addition of diuretics (typically spironolactone and furosemide) permits clearing of fluid in most patients. In some individuals who do not respond to these measures, periodic large-volume paracentesis with intravenous albumin supplementation may be required. With continued abstinence, the salt-retaining tendency may improve; in many instances, the diuretics can be withdrawn safely after a period of months without any reaccumulation of ascites.
  • Spontaneous bacterial peritonitis: This condition may develop in patients with alcoholic hepatitis and ascites, especially in those with concomitant gastrointestinal bleeding. Following a confirmatory diagnostic paracentesis, broad-spectrum antibiotic therapy with a second- or third-generation cephalosporin is the treatment of choice.
  • Iron overload: Several histopathologic studies have shown that as many as 50% of patients with alcoholic liver disease have increased hepatic iron content compared with healthy controls. This excess deposition of iron may play a significant role in the progression of the alcoholic liver damage. Portosystemic shunts, especially the side-to-side variety, enormously increase the deposition of iron to the liver. Occasionally, this excessive iron deposition leads to a clinical and pathologic entity that is analogous to primary hemochromatosis. Attempts to treat alcoholic liver disease with phlebotomy to reduce iron overload have been hampered by the development of anemia, and no clear benefit has been observed.

Prognosis

• During the past several decades, various formulas and algorithms have been proposed for predicting the outcome of severe alcoholic hepatitis. The single most reliable indicator of severity is the presence of hepatic encephalopathy.
• The discriminant function (DF) of Maddrey and coworkers is based on PT and bilirubin, and it is calculated as follows:
  

  DF = (4.6 X PT prolongation) + total serum bilirubin in mg/dL
  

  • Values greater than 32 indicate severe disease and predict a 30-day mortality rate of approximately 50%, assuming only supportive treatment is given.
  • Subsequent studies have found the DF to be an inexact predictor of mortality in patients with alcoholic hepatitis, especially in those who receive glucocorticoids.
• Other formulas have been proposed for the assessment of prognosis of alcoholic hepatitis, but none has become popular among clinicians. The Combined Clinical and Laboratory Index of the University of Toronto permits a linear estimate of acute mortality in persons with alcoholic hepatitis. Its major disadvantages are the large number (14) of variables that must be scored and the complexity of the calculation itself.
• In contrast to the Combined Clinical and Laboratory Index, a much simpler formula for assessing mortality was proposed in a large series of 142 patients with histologically proven alcoholic hepatitis based on PT, serum bilirubin level, and serum albumin level.³⁶
  
  
  • According to this study, the mortality rate in patients with a serum bilirubin level greater than 2 mg/dL, a serum albumin level less than 2.5 g/dL, and a PT greater than 5 seconds was 75%.
  • Conversely, patients who did not meet all 3 criteria had a much lower mortality rate (approximately 25%).
• Model for end-stage liver disease (MELD) score: In recent years, several retrospective studies have shown that the MELD score is useful in predicting 30- and 90-day mortality in patients with alcoholic hepatitis. Moreover, the MELD score seems to contain some practical and statistical advantages over Maddrey's DF in predicting mortality among these patients. In a cohort of 73 patients with alcoholic hepatitis at the Mayo Clinic, the MELD score was the only independent predictor of mortality.¹⁰ Likewise, in another much larger retrospective study of 202 patients with alcoholic hepatitis, the MELD score was found superior to not only Maddrey's DF but also the classical Child-Turcotte-Pugh (CTP) score.⁵⁰
• Glasgow alcoholic hepatitis score (GAHS): GAHS is one of the most recently described predictors of outcome in patients with alcoholic hepatitis. GAHS uses 5 different variables, including age, bilirubin, BUN, PT, and white blood cell count. The overall accuracy of GAHS, which was validated in 195 patients with alcoholic hepatitis, was 81%, when predicting 28-day outcome. In contrast, the modified DF had an overall accuracy of only 50%.¹²
• Asymmetric dimethylarginine (ADMA) score: The ADMA score is the most recently proposed predictor of adverse clinical outcome in patients with severe alcoholic hepatitis. In a small prospective study of 27 patients with alcoholic hepatitis, the ADMA score was a better predictor of outcome than the CTP score, the DF, or the MELD score.³⁸ 
• Other factors that correlate with poor prognosis include older age, impaired renal function, encephalopathy, and a rise in the white blood cell count in the first 2 weeks of hospitalization.

Patient Education

• Given the addictive nature of alcohol in most patients who use it heavily, counseling complete abstinence is prudent. Refer patients to a program of rehabilitation and support, and strongly encourage them to attend. Also, fully inform patients regarding the serious potential health consequences of continued ethanol use.
• For excellent patient education resources, visit eMedicine's Hepatitis Center; Liver, Gallbladder, and Pancreas Center; and Mental Health and Behavior Center. Also, see eMedicine's patient education articles Alcoholism, Hepatitis B, Hepatitis C, and Cirrhosis.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Tort claims regarding steroid-induced aseptic necrosis of the hip are very common. Physicians treating patients with alcoholic hepatitis for longer than the recommended period should discuss the issue with the patient and the patient's family and obtain consent. Patients with mild forms of alcoholic hepatitis should not be treated with steroids.
• Changes in the mental status of patients with alcoholic hepatitis do not always imply the presence of hepatic encephalopathy. Entities (eg, subdural hematomas) should be excluded by obtaining a CT scan of the brain.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Ethanol (ETOH) and cytokine production.
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Media file 2:  Mechanisms of cytokine injury.
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Media file 3:  Liver biopsy sample shows typical findings of perivenular polymorphonuclear infiltrate and ballooning degeneration of hepatocytes (hematoxylin and eosin stain). Courtesy of H. Robert Lippman, MD.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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2. Aleynik S, Lieber CS. Role of S-adenosylmethionine in hyperhomocysteinemia and in the treatment of alcoholic liver disease. Nutrition. Nov-Dec 2000;16(11-12):1104-8. [Medline].
3. Aleynik SI, Leo MA, Aleynik MK, Lieber CS. Polyenylphosphatidylcholine protects against alcohol but not iron-induced oxidative stress in the liver. Alcohol Clin Exp Res. Feb 2000;24(2):196-206. [Medline].
4. Bird GL, Prach AT, McMahon AD, Forrest JA, Mills PR, Danesh BJ. Randomised controlled double-blind trial of the calcium channel antagonist amlodipine in the treatment of acute alcoholic hepatitis. J Hepatol. Feb 1998;28(2):194-8. [Medline].
5. Bonet H, Manez R, Kramer D, Wright HI, Gavaler JS, Baddour N, et al. Liver transplantation for alcoholic liver disease: survival of patients transplanted with alcoholic hepatitis plus cirrhosis as compared with those with cirrhosis alone. Alcohol Clin Exp Res. Oct 1993;17(5):1102-6. [Medline].
6. Carithers RL Jr, Herlong HF, Diehl AM, Shaw EW, Combes B, Fallon HJ, et al. Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med. May 1 1989;110(9):685-90. [Medline].
7. Christensen E, Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables. Gut. Jul 1995;37(1):113-8. [Medline].
8. Colmenero J, Bataller R, Sancho-Bru P, Bellot P, Miquel R, Moreno M, et al. Hepatic expression of candidate genes in patients with alcoholic hepatitis: correlation with disease severity. Gastroenterology. Feb 2007;132:687-697. [Medline].
9. Daures JP, Peray P, Bories P, Blanc P, Yousfi A, Michel H, et al. [Corticoid therapy in the treatment of acute alcoholic hepatitis. Results of a meta-analysis]. Gastroenterol Clin Biol. 1991;15(3):223-8. [Medline].
10. Dunn W, Jamil LH, Brown LS, Wiesner RH, Kim WR, Menon KV, et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology. Feb 2005;41(2):353-8. [Medline].
11. el-Newihi HM, Mihas AA. Alcoholic hepatitis. Recent advances in pathogenesis and therapy. Postgrad Med. Dec 1994;96(8):61-4, 68-70. [Medline]<