Medication Summary
Use of medications in alcoholic hepatitis has been considered controversial. Many treatments discussed in this section remain investigational. [26]
The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline does indicate that the following drugs may be considered [4] :
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Naltrexone or acamprosate may be used, in addition to counseling, to assist patients who have achieved abstinence to avoid relapsing.
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Prednisolone should be considered, unless steroids are contraindicated, in patients with severe disease (Maddrey discriminant function [MDF] score ≥ 32); pentoxifylline may also be considered, especially if prednisolone cannot be used. In a clinical trial, the use of prednisolone and pentoxifylline in combination did not result in improved 6-month survival over use of prednisolone alone in patients with severe alcoholic hepatitis. [36]
Note that tort claims regarding steroid-induced aseptic necrosis of the hip are very common. When patients with alcoholic hepatitis are treated with these agents for longer than the recommended period, physicians 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.
The conclusion of the 2010 AASLD ALD guideline report was that the use of complementary and alternative medications for alcoholic hepatitis has not demonstrated convincing benefits, and should be considered investigational only. [4]
Monoclonal antibodies
Infliximab (Remicade) is a monoclonal antibody against tumor necrosis factor–alpha (TNF-alpha) that has been used successfully in immunologically mediated inflammatory diseases, such as Crohn disease and rheumatoid arthritis. In two small pilot studies on subjects with alcoholic hepatitis, infliximab improved the MDF scores, serum bilirubin and C-reactive protein (CRP) levels, and, more importantly, patient survival. [37, 38]
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. [39] 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, MDF score >32).
Hemorheologic agents
Pentoxifylline (Trental) is a hemorheologic agent that lowers blood viscosity and has been shown to decrease portal hypertension in experimental animals with cirrhosis as well as has been found to have inhibitory effects on TNF. Following two encouraging pilot studies in a small number of subjects, a large, randomized, double-blinded, placebo-controlled trial in 101 subjects with acute alcoholic hepatitis showed significant improvement in short-term survival. [40] The benefit of pentoxifylline appears to be related to a significant decrease in the risk of developing hepatorenal syndrome.
Anabolic steroids
Anabolic steroids (eg, oxandrolone) have been used to treat alcoholic hepatitis because of their ability to stimulate protein synthesis and cell repair. These agents may also enhance nutrition through increased appetite.
In a large study of 273 subjects with severe alcoholic hepatitis, although treatment with both oxandrolone and nutritional supplementation showed no benefit on survival when the results of all subjects were analyzed, when subjects were stratified according to their nutritional status upon admission to the hospital, a significant improvement in short-term and long-term survival was noted in those with moderate malnutrition. [41] The survival rate in subjects who were severely malnourished did not improve. [41]
The above landmark study was confirmed in a meta-analysis of 5 randomized control trials that included 499 patients with alcoholic hepatitis who were treated with anabolic-androgenic steroids: anabolic steroids had no significant effect on mortality, liver-related mortality, liver complications, or liver histology. [42]
Thiocarbamide compounds
The 2010 AASLD ALD guideline states that propylthiouracil (PTU) should not be used. [4] Investigators reported the combined results of 6 randomized clinical trials, which included 710 patients, in a meta-analytical study in which PTU had no beneficial effect on all-cause mortality, liver-related mortality, liver complications, or liver histology. [43]
Hepatotropic hormones
Insulin and glucagon are hepatotropic hormones that may play an important role in promoting liver cell regeneration in response to injury. In two clinical trials, the 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, insulin-induced severe 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.
Alkaloid agents
The 2010 AASLD ALD guideline states that colchicine should not be used. [4] This agent interferes with the 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.
Chelating agents
Penicillamine inhibits collagen synthesis in vitro by decreasing cross-linking and has been used successfully for other liver diseases (eg, Wilson disease) for its copper-chelating properties. However, no controlled trial with this agent has been performed in alcoholic hepatitis.
Sulfhydryl agents
Sulfhydryl agents can act as free-radical scavengers and promote the formation of reduced glutathione, an important element of hepatic antioxidant defense. The 2010 AASLD ALD guideline recommends only investigational use of S-adenosyl-l-methionine (SAM). [4] This agent protects against alcoholic liver injury in animal models. A randomized, double-blinded, placebo-controlled trial in patients with alcoholic hepatitis resulted in improved survival of patients who received SAM compared with controls.
Antidotes
N-acetyl-L-cysteine (NAC) is widely used as an antidote for 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 who also consume therapeutic doses of acetaminophen; however, preliminary evidence from prospective randomized trials did not show benefit.
Antioxidants
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.
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 randomized clinical trial, corticosteroids were far superior to a "cocktail" of antioxidants in improving the usually measured clinical parameters and liver histology. [44]
Nutritional supplements
Polyunsaturated lecithin (PPC, phosphatidyl choline) has been studied because of the empiric observation that choline deficiency in rats (which impairs endogenous lecithin synthesis) increases the 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 multicenter Veterans Affairs cooperative study among 789 subjects. [45] In fact, approximately 20% of these subjects showed progressive liver fibrosis with continued moderated amounts of alcohol ingestion. [45] Thus, PPC does not appear to have a viable role in acute alcoholic hepatitis.
Calcium channel blockers
Several preliminary reports on alcoholic hepatitis have indicated a beneficial effect of 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.
Bile acids
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 cholangitis 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
Herbal agents have also been tried in alcoholic hepatitis. Silymarin is the active ingredient in milk thistle; it 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 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. [46]
Corticosteroids
Class Summary
Strong evidence of immunologic and inflammatory liver injury in alcoholic hepatitis provides the rationale for the 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, this treatment 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 anti-anabolic effect suppresses regeneration and may slow healing. They may increase the complications and mortality associated with gastrointestinal bleeding, pancreatitis, or sepsis, and they should be withheld or used judiciously if any of these are present.
When Louvet et al investigated whether the presence of infection in patients with severe alcoholic hepatitis contraindicates corticosteroid treatment, the investigators determined that infection was not independently associated with patient survival and although infection screening is warranted in patients with severe alcoholic hepatitis, it should not contraindicate steroid use. [47] Prednisolone was administered to 246 patients suffering from severe alcoholic hepatitis, including to 63 patients in whom infection—specifically, spontaneous bacterial peritonitis or bacteremia (n=28), pulmonary infection (n=8), urinary tract infection (n=20), or other infection (n=7)—was present at hospital admission.
Patients suffering from infection before corticosteroid administration had a 2-month survival rate (70.9%) that was similar to that of the study's other patients (71.6%). Louvet et al also observed that postadmission infection developed more frequently in patients who were nonresponders to corticosteroid therapy (42.5%) than it did in responders (11.1%). [47] In addition, in a multivariate analysis, only the Lille model yielded an independent prediction of infection upon steroid use. [48, 49]
Methylprednisolone (Solu-Medrol, Medrol, Depo-Medrol)
Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing the increased capillary permeability. This agent may be preferable to other glucocorticoids (eg, prednisone), because hepatic metabolism is not required.
Prednisolone (Orapred ODT, Prelone, Pred Forte, Omnipred)
Prednisolone decreases autoimmune reactions, possibly by suppressing key components of the immune system. This agent does not need to undergo hepatic metabolism.
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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.
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Ethanol (ETOH) and cytokine production. CYP = cytochrome P; IL = interleukin; NF-κB = nuclear factor-kappa B; ROS = reactive oxygen species; TNF = tumor necrosis factor.
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Mechanisms of cytokine injury. IL = interleukin; NO = nitric oxide; O2- = superoxide anion; OH- = hydroxyl radical; PMN = polymorphonuclear lymphocyte; TNF = tumor necrosis factor.
