Introduction
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.1
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, shown below, 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.
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.
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 immunologic factors, as well as 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.
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 meta-analysis of 50 studies pertaining to the association of alcoholic liver disease and genetic polymorphism.2 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.3 However, subsequent studies have suggested 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.4
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, as shown below.
Ethanol (ETOH) and cytokine production.
Mechanisms of cytokine injury.
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 one 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.5
- 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
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.
More on Alcoholic Hepatitis |
 Overview: Alcoholic Hepatitis |
| Differential Diagnoses & Workup: Alcoholic Hepatitis |
| Treatment & Medication: Alcoholic Hepatitis |
| Follow-up: Alcoholic Hepatitis |
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Further Reading
Clinical guidelines
AASLD practice guidelines: evaluation of the patient for liver transplantation.
American Association for the Study of Liver Diseases - Private Nonprofit Research Organization. 2000 Jan (revised 2005 Jun). 26 pages. NGC:004333
American Gastroenterological Association medical position statement on the management of hepatitis C.
American Gastroenterological Association Institute - Medical Specialty Society. 2006 Jan. 6 pages. NGC:004765
Clinical trials
Randomized, Controlled Trial of S-adenosylmethionine in Alcoholic Liver Disease (RCT SAMe)
Related eMedicine topics
Alcoholic Fatty Liver
Cirrhosis
Alcoholism
Alcohol and Substance Abuse Evaluation
Hepatitis C
Keywords
alcoholic hepatitis, hepatitis, cirrhosis, alcoholic liver disease, fatty liver, steatosis, alcoholic liver, liver hepatitis, alcohol hepatitis, alcoholic steatohepatitis, alcoholic cirrhosis, alcoholic liver disease, alcohol-induced cirrhosis, alcohol-induced hepatitis, respiratory alkalosis, scleral icterus
