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Alcoholic Hepatitis

  • Author: Douglas M Heuman, MD, FACP, FACG, AGAF; Chief Editor: BS Anand, MD  more...
 
Updated: Dec 27, 2015
 

Practice Essentials

Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol.

Essential update: 

Signs and symptoms

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

See Clinical Presentation for more detail.

Diagnosis

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.

See Workup for more detail.

Management

In most patients with alcoholic hepatitis, the illness is mild. The short-term prognosis is good, and no specific treatment is required. Hospitalization is not always necessary. Alcohol use must be stopped, and care should be taken to ensure good nutrition; providing supplemental vitamins and minerals, including folate and thiamine, is reasonable.

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. 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. For the long term, the goals include improvement in liver function, prevention of progression to cirrhosis, and reduction of mortality. Only prolonged alcohol abstinence is of demonstrated benefit in all these areas.

See Treatment and Medication for more detail.

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Background

Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol.[1] The pathogenesis is not completely understood.[2]

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 peri Liver biopsy sample shows typical findings of perivenular polymorphonuclear infiltrate and ballooning degeneration of hepatocytes (hematoxylin and eosin [H&E] 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.

The American Association for the Study of Liver Diseases (AASLD) and the American College of Gastroenterology issued guidelines in 2010 for the diagnosis, therapy, and preventive care of alcoholic liver disease (ALD).[3]

See also Alcoholic Fatty Liver, Alcohol and Substance Abuse Evaluation,Alcohol Toxicity, Delirium Tremens,Autoimmune Hepatitis, Hepatitis B, Hepatitis C, and Hepatitis in Pregnancy.

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Etiology and Pathophysiology

Although the association of alcohol and liver disease has been known since antiquity, the precise mechanism of alcoholic liver disease remains in dispute.[1] Genetic, environmental, nutritional, metabolic, and immunologic factors, as well as cytokines and viral disease 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, 3 enzyme systems—the cytosolic alcohol dehydrogenase (ADH) system, microsomal ethanol-oxidizing system (MEOS), and peroxisomal catalase system—can oxidize ethanol.

Cytosolic 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 upregulates 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 human leukocyte antigen (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.[4] 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 Epidemiology).

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.[5] 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 MEOS does not result in energy capture via formation of ATP. Rather, this pathway leads to the loss of energy in the form of heat. In some studies, antithyroid drugs, such as propylthiouracil (PTU), 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, superoxides 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.[6]

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.

The 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 downregulated 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 (IgA) 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. 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 in the images below.

Ethanol (ETOH) and cytokine production. CYP = cyto Ethanol (ETOH) and cytokine production. CYP = cytochrome P; IL = interleukin; NF-κB = nuclear factor-kappa B; ROS = reactive oxygen species; TNF = tumor necrosis factor.
Mechanisms of cytokine injury. IL = interleukin ; Mechanisms of cytokine injury. IL = interleukin ; NO = nitric oxide; O2- = superoxide anion; OH- = hydroxyl radical; PMN = polymorphonuclear lymphocyte; TNF = tumor necrosis factor.

Role of concomitant viral disease

Alcohol consumption may exacerbate injury caused by other pathogenic factors, including hepatitis viruses. Approximately 20% of patients presenting with alcoholic hepatitis have concomitant hepatitis C virus infection.[7] 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.[8]

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Epidemiology

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 may never seek medical attention.

Globally, the prevalence of alcoholic hepatitis 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%.

Racial and age differences in incidence

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.

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.

Sexual differences in incidence

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 alcohol dehydrogenase (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.

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Prognosis

The long-term prognosis of individuals with alcoholic hepatitis depends heavily on whether patients have established cirrhosis and whether they continue to drink. With abstinence, patients with this disease 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. In one study, the estimated 5-year survival after hospitalization for severe alcoholic hepatitis was 31.8%. Abstinence was the only independent predictor of long-term survival.[9]

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 (WBC) count, prothrombin time (PT), and female sex were all independent risk factors for the dismal outcome.[10]

Prognostic scoring systems

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 American Association for the Study of Liver Diseases (AASLD) guideline recommends using prognostic scoring systems such as the Maddrey discriminant function (MDF) to stratify illness severity and the risk of poor outcome, both initially and over the course of the illness.[3]

The discriminant function (DF) of Maddrey and coworkers is based on PT and bilirubin levels, and it is calculated as follows: DF = (4.6 × 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. However, 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.[11] 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

Several retrospective studies have shown that the MELD score is useful in predicting 30- and 90-day mortality in patients with alcoholic hepatitis (see the MELD Score calculator). 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.[12] 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 to the classical Child-Turcotte-Pugh (CTP) score.[13]

Glasgow alcoholic hepatitis score (GAHS)

The GAHS is one of the most recently described predictors of outcome in patients with alcoholic hepatitis. This scoring system uses 5 different variables, including age, bilirubin level, blood urea nitrogen (BUN) level, PT, and WBC count. The overall accuracy of GAHS, which was validated in 195 patients with alcoholic hepatitis, was 81%, when predicting 28-day outcome.[14] In contrast, the modified DF had an overall accuracy of only 50%.[14]

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.[15]

Other factors that correlate with poor prognosis include older age, impaired renal function, encephalopathy, and a rise in the WBC count in the first 2 weeks of hospitalization.

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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 patient education see Infections Center, Digestive Disorders Center, Mental Health Center, as well as Alcoholism, Hepatitis B, Hepatitis C, and Cirrhosis.

In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a 1-time blood test for hepatitis C virus (HCV) infection in baby boomers—the generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United States—without prior ascertainment of HCV risk (see Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965).[16] One-time HCV testing in this population could identify nearly 808,600 additional people with chronic infection. All individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventative and/or treatment services, as appropriate.

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Contributor Information and Disclosures
Author

Douglas M Heuman, MD, FACP, FACG, AGAF Chief of Hepatology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center; Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine

Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, American Gastroenterological Association

Disclosure: Received grant/research funds from Novartis for other; Received grant/research funds from Bayer for other; Received grant/research funds from Otsuka for none; Received grant/research funds from Bristol Myers Squibb for other; Received none from Scynexis for none; Received grant/research funds from Salix for other; Received grant/research funds from MannKind for other.

Coauthor(s)

Patrick D Hung, MD Senior Fellow, Department of Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine

Disclosure: Nothing to disclose.

Anastasios A Mihas, MD, DMSc, FACP, FACG Professor, Department of Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine; Consulting Staff, Virginia Commonwealth University Hospitals and Clinics; Chief of GI Clinical Research, Director of GI Outpatient Service, Associate Director of Hepatology, Hunter Holmes McGuire Veterans Affairs Medical Center

Anastasios A Mihas, MD, DMSc, FACP, FACG is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, Sigma Xi, Southern Society for Clinical Investigation, American Federation for Clinical Research, Gastroenterology Research Group

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

George Y Wu, MD, PhD Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine

George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, and Association of American Physicians

Disclosure: Springer Consulting fee Consulting; Gilead Consulting fee Review panel membership; Gilead Honoraria Speaking and teaching; Bristol-Myers Squibb Honoraria Speaking and teaching; Springer Royalty Review panel membership

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Liver biopsy sample shows typical findings of perivenular polymorphonuclear infiltrate and ballooning degeneration of hepatocytes (hematoxylin and eosin [H&E] stain). Courtesy of H. Robert Lippman, MD.
Ethanol (ETOH) and cytokine production. CYP = cytochrome P; IL = interleukin; NF-κB = nuclear factor-kappa B; ROS = reactive oxygen species; TNF = tumor necrosis factor.
Mechanisms of cytokine injury. IL = interleukin ; NO = nitric oxide; O2- = superoxide anion; OH- = hydroxyl radical; PMN = polymorphonuclear lymphocyte; TNF = tumor necrosis factor.
 
 
 
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