Background
Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. The pathogenesis is not completely understood.
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, 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.
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.
Pathophysiology
Although the association of alcohol and liver disease has been known since antiquity, the precise mechanism of alcoholic liver disease remains in dispute. Genetic, environmental, nutritional, metabolic, and, more recently, immunologic factors and cytokines 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, the following 3 enzyme systems can oxidize ethanol.
- Cytosolic alcohol dehydrogenase (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 up-regulates 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.
Mechanisms of liver injury
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 HLA groups have yielded inconsistent results, as have studies of genetic polymorphisms of collagen, ADH, ALDH, and CYP2E1.
Similar conclusions were reached in a recent meta-analysis of 50 studies pertaining to the association of alcoholic liver disease and genetic polymorphism. 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.
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.However, more recent studies suggest 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 the MEOS does not result in energy capture via formation of ATP. Rather, this pathway leads to loss of energy in the form of heat. In some studies, antithyroid drugs, such as propylthiouracil, 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, superoxide 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.
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.
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 down-regulated 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 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. Both 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.
Role of concomitant viral disease
Alcohol consumption may exacerbate injury caused by other pathogenic factors, including hepatitis viruses. 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.
Frequency
United States
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 never seek medical attention.
International
The prevalence 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%.
Mortality/Morbidity
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%.
- The long-term prognosis depends heavily on whether patients have established cirrhosis and whether they continue to drink. With abstinence, patients with alcoholic hepatitis 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.
Race
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.
Sex
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 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.
Age
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.
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 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
- 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.
- 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).
- 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.
- 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.
- 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
- 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.
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.
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.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.
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.
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.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,
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.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.
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
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.
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.
Drug Category: 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.
| Drug Name | Methylprednisolone (Solu-Medrol, Adlone, Medrol, Depo-Medrol) |
|---|---|
| Description | 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 Dose | 32 mg/d PO/IV for 30 d; taper and discontinue over 2-4 wk |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; active sepsis; GI bleeding; acute pancreatitis |
| Interactions | 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 |
| 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 |
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