Alcoholic Hepatitis Treatment & 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. 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 a 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 (ICU) 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.

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 the histologic findings and disease severity, thus suggesting that they may be potential targets for such therapy. ^[24]

Surgical considerations

Patients with acute alcoholic hepatitis are at a 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.

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.

Cessation of alcohol use is the mainstay of treatment of alcoholic hepatitis. The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline states that complete abstinence should be enjoined on all alcoholic hepatitis patients. ^[4]

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.

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.

Additional treatment includes nutritional support. The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline recommends testing all patients with alcoholic hepatitis for protein-energy malnutrition (PEM) and for vitamin and mineral deficiencies. ^[4]

Protein-energy malnutrition is almost universal in patients hospitalized for alcoholic hepatitis. In a large Veterans Administration Cooperative Study of Alcoholic Hepatitis, the severity of protein-energy malnutrition correlated with the severity of alcoholic hepatitis and the predicted mortality rate. ^[25] In patients with alcoholic hepatitis and severe protein-energy malnutrition, the mortality rate was 50%, compared with a mortality rate of less than 10% in patients with mild protein-energy malnutrition. ^[25]

Oral intake vs parenteral/enteral hyperalimentation

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. The use of nutritional supplements and appetite stimulants may be appropriate.

The 2010 AASLD ALD guideline states that patients with advanced disease should receive aggressive enteral nutritional therapy. ^[4] Patients with mild to moderate alcoholic hepatitis (Maddrey discriminant function [MDF] score < 32, no liver encephalopathy) that improves during the first week of hospitalization (ie, lower serum bilirubin level or decreased MDF) and who are treated with nutritional therapy and abstinence will probably neither need nor benefit from other interventions, but these individuals should be monitored closely. ^[4]

Protein restriction vs normal protein intake

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 has been considered controversial. Many treatments discussed in the Medication section are still investigational. ^[26] However, according to the 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline ^[4] : (1) Naltrexone or acamprosate may be used, in addition to counseling, to assist patients who have achieved abstinence to avoid relapsing; and (2) in patients with severe disease (Maddrey discriminant function [MDF] score ≥32), unless steroids are contraindicated, prednisolone should be considered. Pentoxifylline may be considered, especially if prednisolone cannot be used.

Prednisolone and pentoxifylline are recommended for the treatment of severe alcoholic hepatitis, ^[1] but uncertainty about their benefit persists.

Results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial involving 1,103 subjects showed that treatment with the steroid prednisolone reduced 28-day mortality in patients with severe alcoholic hepatitis, whereas treatment with the oral phosphodiesterase inhibitor pentoxifylline did not. ^{[27, 28]}  However, the benefit of prednisolone did not extend beyond 28 days. There was no difference in the mortality rates between the two treatments at 1 year. Mortality at 28 days was 13.5% with prednisolone and pentoxifylline combined, 14.3% with prednisolone and placebo, 19.4% with pentoxifylline and placebo, and 16.7% with double placebo. For all patients treated with prednisolone, the mortality rate was 13.9%; for those treated only with pentoxifylline or placebo, the rate was 18.0%. Mortality rates were similar in patients who received pentoxifylline treatment (16.4%) and those who did not (15.5%). ^{[27, 28]}

Significant predictors of 28-day mortality included prednisone use, prothrombin time ratio, bilirubin level, age, white blood cell count, urea level, creatinine level, and hepatic encephalopathy. ^{[27, 28]} Neither treatment was significantly associated with a survival benefit beyond 28 days. Infections were significantly more frequent in the prednisolone group than in the no-prednisolone group. Patients who did not reduce or increased their alcohol use had a 3-fold increased risk of death compared with those who abstained. ^{[27, 28]}

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.

Orthotopic liver transplantation is widely used in patients with end-stage liver disease. ^{[1, 29]}  Most patients with active alcoholic hepatitis are excluded from transplantation because of ongoing alcohol abuse. In most liver transplantation programs in the United States, 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.

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.

Challenges to liver transplantation policies

Current policies pertaining to liver transplantation in patients with end-stage alcoholic liver disease (ie, cirrhosis), especially those with severe alcoholic hepatitis, have been challenged. ^{[30, 31]}

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 intravenous (IV) drug addicts with the hepatitis C virus or even the fast-food generation of obese persons with nonalcoholic steatohepatitis (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). ^{[32, 33]}

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. ^[34]

2010 AASLD ALD recommendation

The recommendation of the 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline report is that patients with end-stage alcoholic liver disease be evaluated for liver transplantation in the same way as other possible candidates, after medical and psychosocial factors have been carefully evaluated. ^[4] A formal assessment of the probability of long-term abstinence should be included in the evaluation. ^[4]

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.

Nutrition services and gastroenterology/hepatology

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.

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 the determination of serum alpha-fetoprotein (AFP) levels at 6-month intervals along with annual diagnostic ultrasonography. The finding of a liver nodule or an elevated AFP 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.

Nephrology

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.

Neurology

If a patient with alcoholic hepatitis exhibits mental status changes, focal neurologic findings, or seizures, consider consultation with a neurologist.

Infectious disease

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 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 the 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.

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 (AFP) level at 6-month intervals along with annual diagnostic ultrasonography. The finding of a liver nodule or an elevated AFP 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.