Subscription requiredDec 10, Author: Many treatments discussed in this section remain investigational. 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 corticosteroids alcoholic liver disease 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.
BMJ Best Practice
Dec 10, Author: Many treatments discussed in this section remain investigational. 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 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. 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 2 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. 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.
Better-designed controlled clinical trials are probably necessary to resolve the controversy and avoid a possible type I error. 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 2 encouraging pilot studies in a small number of subjects, a large, randomized, double-blinded, placebo-controlled trial in subjects with acute alcoholic hepatitis showed significant improvement in short-term survival. 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 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.
The above landmark study was confirmed in a meta-analysis of 5 randomized control trials that included patients with alcoholic hepatitis who were treated with anabolic-androgenic steroids: Insulin and glucagon are hepatotropic hormones that may play an important role in promoting liver cell regeneration in response to injury. 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.
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 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 can act as free-radical scavengers and promote the formation of reduced glutathione, an important element of hepatic antioxidant defense.
A randomized, double-blinded, placebo-controlled trial in patients with alcoholic hepatitis resulted in improved survival of patients who received SAM compared with controls. 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.
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 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 s 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. 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 subjects. 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.
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 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 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.
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. 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. 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.
Patients suffering from infection before corticosteroid administration had a 2-month survival rate Louvet et al also observed that postadmission infection developed more frequently in patients who were nonresponders to corticosteroid therapy Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing the increased capillary permeability.
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