eMedicine Specialties > Gastroenterology > Liver

Alcoholic Hepatitis: Treatment & Medication

Author: 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
Coauthor(s): Patrick D Hung, MD, Senior Fellow, Department of Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine; Douglas M Heuman, MD, FACP, Director of Hepatology, McGuire Veterans Affairs Medical Center, Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Contributor Information and Disclosures

Updated: Jun 30, 2008

Treatment

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

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

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.


Methylprednisolone (Solu-Medrol, Adlone, Medrol, Depo-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. May be preferable to other glucocorticoids (eg, prednisone) because hepatic metabolism is not required.

Adult

32 mg/d PO/IV for 30 d; taper and discontinue over 2-4 wk

Pediatric

Not established

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor for hypokalemia when taking concurrently with diuretics

Documented hypersensitivity; active sepsis; GI bleeding; acute pancreatitis

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Only sodium succinate salt should be administered IV; commonly leads to impaired glucose tolerance and increases insulin requirements in diabetes; femoral osteonecrosis; increased susceptibility to fungal and other infections; impaired wound healing; increased risk of peptic ulcer hemorrhage or perforation; altered mental status with depression or psychosis

More on Alcoholic Hepatitis

Overview: Alcoholic Hepatitis
Differential Diagnoses & Workup: Alcoholic Hepatitis
Treatment & Medication: Alcoholic Hepatitis
Follow-up: Alcoholic Hepatitis
Multimedia: Alcoholic Hepatitis
References
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References

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Further Reading

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Keywords

alcoholic steatohepatitis, alcoholic steatonecrosis, sclerosing hyaline necrosis, subacute alcoholic cirrhosis, florid alcoholic cirrhosis, fatty liver with hepatic failure, acute hepatic insufficiency of patients with chronic alcoholism, steatosis, cirrhosis, alcoholism, alcoholic cirrhosis, alcoholic liver disease, chronic alcoholism, alcohol-induced cirrhosis, alcohol-induced hepatitis, hepatomegaly, portal hypertension, ascites, variceal hemorrhage, hepatic encephalopathy, Mallory hyaline inclusions, protein-energy malnutrition, PEM, giant mitochondria, megamitochondria, hepatitis C infection, acetaminophen-alcohol interactions, jaundice, coagulopathy, delirium tremens, respiratory alkalosis, scleral icterus, splenomegaly, flapping tremor, spider angiomata, gynecomastia, heavy intake of ethanol

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Contributor Information and Disclosures

Author

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 Federation for Clinical Research, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, Gastroenterology Research Group, Sigma Xi, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Coauthor(s)

Patrick D Hung, MD, Senior Fellow, Department of Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Disclosure: Nothing to disclose.

Douglas M Heuman, MD, FACP, Director of Hepatology, McGuire Veterans Affairs Medical Center, Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Douglas M Heuman, MD, FACP is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association
Disclosure: Nothing to disclose.

Medical Editor

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: Humana Press Consulting fee Consulting; Novartis Consulting fee Review panel membership

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

James L Achord, MD, Professor Emeritus, Department of Medicine, Division of Digestive Diseases, University of Mississippi School of Medicine
James L Achord, MD 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 Medical Association, American Society for Gastrointestinal Endoscopy, Mississippi State Medical Association, New York Academy of Sciences, Sigma Xi, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
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