The number of patients with alcoholic liver disease

Transcription

1 December 2000 EDITORIALS 1787 Pentoxifylline and Alcoholic Hepatitis See article on page The number of patients with alcoholic liver disease (ALD) in the United States is unknown and probably underestimated because of underreporting but likely exceeds 2 million persons. 1 ALD remains a major cause of liver-related morbidity and mortality (and cause for liver transplantation) in the United States. 2 Indeed, patients with cirrhosis and superimposed alcoholic hepatitis have more than a 60% mortality over a 4-year period, with most of the deaths occurring within the first year. 3 Alcoholic hepatitis is an acute form of alcoholic liver injury. The clinical hallmarks of alcoholic hepatitis are jaundice and neutrophilic inflammation, manifested as elevated white blood cell count, fever, and tender hepatomegaly. Many patients have ascites and, when tested using sensitive instruments, hepatic encephalopathy. Aspartate aminotransferase level is moderately elevated (2 5 times the upper limit of normal [ULN]); alanine aminotransferase is normal or mildly elevated ( 2 times ULN). The characteristic liver pathologic features of alcoholic hepatitis are neutrophilic infiltration of the hepatic parenchyma and fibrosis, both interstitial and perivenular. Hepatocytes are often abnormal, displaying hydropic changes, macrovesicular fat, Mallory bodies, and megamitochondria. Alcoholic hepatitis frequently coexists with alcoholic cirrhosis. In the United States, 20% 40% of patients with alcoholic hepatitis are infected with hepatitis C virus. The severity of alcoholic hepatitis may be measured using Maddrey s discriminate function (DF, defined as 4.6 [prothrombin time above control in seconds] bilirubin in mg/dl). 4 Approximately 30% 40% of patients with a DF 32 die within 6 months, a 6-month mortality rate higher than breast, colon, prostatic, or lung cancer. Patients who survive the initial episode of alcoholic hepatitis have a chance of long-term survival if they can maintain abstinence. Alcoholic hepatitis can resolve, leaving minimal chronic liver damage. Abstinent patients with advanced cirrhosis are potential candidates for liver transplantation. Glucocorticoids have been the most intensively studied treatment for alcoholic hepatitis. Twelve randomized, controlled clinical trials have been published: 5 reported improved survival with glucocorticoids and 7 found no difference in survival. Most meta-analyses conclude that glucocorticoids are beneficial, reducing mortality by approximately 25%. 5 After reviewing the published clinical trials on treatment of alcoholic hepatitis and obtaining input from clinical experts, the major GI societies recommended glucocorticoid treatment in patients with severe alcoholic hepatitis (DF 32). 5 The recommended regimen is prednisolone, 40 mg/day for 28 days, followed by a taper. Approximately 7 patients with alcoholic hepatitis need to be treated with glucocorticoids to prevent one death. However, many physicians are reluctant to use this regimen because of the potential risk of steroid side effects in this patient population. The Food and Drug Administration (FDA) has not approved glucocorticoids, or any other medicine, for treatment of alcoholic hepatitis. The mechanisms involved in the development and progression of ALD are not well defined, and this lack of understanding has been a major impediment to the development of preventive or therapeutic modalities. Nutritional abnormalities, oxidative stress, free radical generation, lipid peroxidation, dysregulated cytokine metabolism, acetaldehyde adduct formation, and impaired immunologic response are some of the multiple putative etiologic factors in the development of alcohol-related liver injury. Many investigators have focused on cytokines such as tumor necrosis factor (TNF) in alcoholic hepatitis because TNF can induce many of the metabolic abnormalities observed in this disease (anorexia, neutrophilia, fever, or muscle wasting) and can cause liver injury. 6,7 Dysregulated TNF metabolism in alcoholic hepatitis was first described over a decade ago with the observation that cultured peripheral blood monocytes (surrogate marker for Kupffer cells) from patients with alcoholic hepatitis spontaneously produced TNF and produced significantly more TNF in response to an endotoxin, lipopolysaccharide (LPS), stimulus. 7 Several groups subsequently reported elevation of admission serum TNF concentration in alcoholic hepatitis, and TNF values correlated with disease severity and mortality A

2 1788 EDITORIALS GASTROENTEROLOGY Vol. 119, No. 6 TNF promoter polymorphism has been linked with susceptibility to alcoholic steatohepatitis, suggesting that a subset of people who drink alcohol may be genetically predisposed to development of alcoholic hepatitis. 11 Elevated serum concentrations of TNFinducible cytokines such as interleukin (IL)-6 and IL-8, as well as adhesion molecules such as ICAM, were reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute-phase response, liver function, and clinical outcome. 6,12 15 Concomitant with these human studies, complementary studies in rats, mice, and tissue culture focused on the role of cytokines (especially TNF) in experimental models of liver disease. TNF has been shown to play a role in most forms of experimental liver disease (reviewed by Hill et al. 16 ). The liver is normally resistant to toxic effects of TNF. However, when excess TNF is produced or there are inadequate defenses against TNF, liver injury can occur. Approximately a decade ago it was shown that rats chronically fed alcohol were more sensitive to hepatotoxic effects of injected LPS. 17 Subsequent studies showed that rats chronically fed alcohol had much higher LPS-stimulated plasma levels of TNF than control rats, and liver injury could be attenuated by giving a prostaglandin analogue that down-regulated TNF production. 18 Work from Nanji s laboratory using the intragastric alcohol feeding model demonstrated that the development of liver injury coincided with an increase in the message level for TNF (TNF mrna) in the liver. 19 Using the same intragastric feeding model, Tsukamoto s laboratory showed that isolated Kupffer cells from rats chronically fed alcohol had increased spontaneous and LPS-stimulated secretion of TNF as well as increased TNF mrna. 20 Rats intragastrically fed ethanol also had high blood endotoxin levels and had induction of cytochrome P450 2E1 that could cause generation of reactive oxygen species. 21 Indeed, markers for oxidative stress and lipid peroxidation were noted in these animals. 22 Several strategies were than devised to decrease oxidative stress, decrease endotoxin levels, or decrease cytokine production/activity in an attempt to block or attenuate liver injury. Animals were fed antibiotics in an attempt to sterilize the intestine, or Lactobacillus to alter gut flora and decrease the source for endotoxin production. 23,24 Gadolinium chloride was administered to rats in an attempt to destroy hepatic Kupffer cells. 25 Nanji s laboratory administered agents to decrease CYP2E1 in an attempt to decrease generation of reactive oxygen species. 21 All of these strategies aimed at inhibiting stimuli or sources for cytokine production were successful in attenuating alcohol-induced liver injury in rats (reviewed by McClain et al. 6 ). Perhaps the most compelling data relating TNF to alcohol-induced liver injury come from Thurman s research group, which showed that TNF receptor-1 knockout mice were resistant to alcohol-induced liver injury. 26 They also successfully used TNF antibody (anti-tnf) to prevent liver injury in alcohol-fed rats. 27 Pentoxifylline (PTX) is a nonselective phosphodiesterase inhibitor. PTX treatment increases intracellular concentrations of adenosine 3,5 -cyclic monophosphate (camp) and guanosine 3,5 -cyclic monophosphate (cgmp), a potential mechanism for inhibiting TNF production. The reported pharmacologic effects of PTX include an increase in red blood cell deformability. PTX, at a dose of 400 mg 3 times daily, is FDA-approved for treatment of claudication. The drug is relatively safe at this dose. Approximately 12 years ago, PTX was noted to decrease TNF gene transcription. 28 During the past decade PTX has been found to affect multiple steps in the cytokine/chemokine inflammatory pathway, either directly or indirectly by inhibition of TNF. Reported effects of PTX include inhibition of cytokine/chemokine synthesis (e.g., monocyte chemoattractant protein-1, IL-8, macrophage inflammatory protein (MIP)- 1a, MIP-1b, IL-6), decreased expression of adhesion molecules on endothelial cells, decreased activation of neutrophils, decreased proliferation of lymphocytes and monocytes, and decreased binding and transmigration of leukocytes PTX also reduced fibroblast proliferation and secretion of collagen and other interstitial matrix proteins. 35,36 In animals, PTX decreased the development of cirrhosis. 37 PTX has been reported to blunt anorexia and muscle wasting in animal models of chronic inflammation; this effect may be relevant to the wasting observed in many patients with alcoholic hepatitis. 38,39 In humans, PTX improved a variety of inflammatory skin disorders and Behçet s syndrome Anticytokine drugs have been shown to have great efficacy in certain chronic inflammatory disease states; anti-tnf is FDA-approved for both Crohn s disease and rheumatoid arthritis. Major trials using anti-tnf have not been performed in alcoholic hepatitis, at least in part because of the potential concern that totally blocking TNF (and TNF-inducible cytokines such as

3 December 2000 EDITORIALS 1789 IL-6) may impair liver regeneration. Thus, using agents that down-regulate cytokine production (e.g., PTX) but do not totally inhibit their activity may be a logical therapeutic strategy in alcoholic hepatitis. In this issue of GASTROENTEROLOGY, Akriviadis et al. 43 from the University of California Liver Unit report results of a prospective, randomized, doubleblind clinical trial of PTX in severe alcoholic hepatitis (DF 32). Forty-nine patients received 400 mg of PTX orally 3 times daily and 52 received placebo (vitamin B 12 ) for 4 weeks. Primary outcome variables were (1) survival of the index illness and (2) development of hepatorenal syndrome (HRS). A pilot study from the same Unit found PTX treatment resulted in less hepatorenal failure and a trend toward improved survival. 44 PTX treatment improved survival. Twelve PTX patients died (24.5%) compared with 24 (46%) placebo patients (P 0.037; relative risk, 0.59). PTX also decreased HRS as a cause of death. Six of 12 (50%) PTX-treated patients died of renal failure compared with 22 of 24 (92%) control patients (P 0.009; relative risk, 0.29). Multivariate analysis revealed age, serum creatinine at randomization, and treatment with PTX as independent factors associated with survival. All patients had elevated plasma TNF at study entry. There were no differences in TNF plasma level between the 2 treatment groups at randomization or during changes treatment compared with baseline. However, TNF levels markedly increased in nonsurvivors compared with survivors over the study period. How do we assess this study its design, results, pathophysiologic implications/questions, and the implications for treatment of alcoholic hepatitis? The investigators are experienced in clinical trials of alcoholic hepatitis (3 studies with glucocorticoids, 1 with propylthiouracil, and 1 with colchicine). Based on their prior experience with glucocorticoids in alcoholic hepatitis, the investigators chose to compare PTX with placebo rather than with prednisolone (the study was completed before the American College of Gastroenterology recommendations for use of glucocorticoids). Whether or not use of glucocorticoids would have changed the outcome of the study is unknown. However, the observed improvement in survival with PTX is larger than would be expected with glucocorticoids. The study was large (101 patients). Randomization did not result in any significant differences between study groups in demographic or biochemical tests. Although more patients with renal insufficiency (Cr 2.4 mg/dl) at study entry were enrolled into the control group (6 patients) than into the PTX group (3 patients), this does not appear to have altered the conclusions of the study. Medicine consumption was adequate. Survival outcome was available in all patients. The results are impressive: a 40% reduction in mortality and a 65% 70% reduction in HRS. Again, the improvement in survival is greater than what is generally acknowledged for glucocorticoids. Furthermore, glucocorticoids have not been reported to reduce HRS. TNF plasma levels did not decrease with PTX treatment. However, serum levels of TNF tend to be somewhat variable, and serum levels of TNF-inducible cytokines such as IL-6 and IL-8 tend to correlate better with the clinical course of alcoholic hepatitis. 6 Monocyte or ex vivo TNF production may also more directly reflect anticytokine effects. 6 PTX treatment resulted in a 65% reduction in newonset of HRS and a 70% reduction in mortality from HRS. The explanation for the reduction in HRS is not established in this study. There are at least 2 potential explanations that are compatible with the data. First, PTX treatment improved liver function, thereby reducing development of HRS. Second, PTX prevented renal failure, allowing the liver sufficient time to improve. The authors report a highly significant correlation between serum creatinine and plasma TNF level (r 0.43, P ). TNF can cause vasoconstriction and could directly contribute to renal insufficiency. 45 In experimental models, TNF has been implicated as a contributor to renal failure from sepsis. 46 Alternatively, TNF may be elevated in HRS because of decreased renal clearance. It is unknown whether PTX might be useful as a treatment for HRS. In summary, the University of California Liver Unit has reported a striking reduction in mortality in patients with severe alcoholic hepatitis (DF 32) who were treated with 400 mg PTX orally 3 times daily for 4 weeks. PTX treatment was associated with a marked decrease in the incidence of HRS. PTX has multiple effects on the cytokine/chemokine pathway that are potentially beneficial. Further studies are needed to establish the primary pathway by which PTX exerts its beneficial effects in alcoholic hepatitis. Although PTX appears to represent a significant step forward in

4 1790 EDITORIALS GASTROENTEROLOGY Vol. 119, No. 6 the treatment of alcoholic hepatitis, confirmatory studies are needed before PTX can be recommended as the standard treatment for alcoholic hepatitis. TIMOTHY R. MORGAN VA Long Beach Healthcare System Long Beach, California, and Department of Medicine University of California Irvine, California CRAIG J. McCLAIN VA Medical Center Louisville, Kentucky, and Department of Medicine University of Louisville Louisville, Kentucky References 1. Dufour MC, Stinson FS, Caces MF. Trends in cirrhosis morbidity and mortality: United States, Semin Liver Dis 1993; 13: McClain CJ, Hill DB, Schmidt J, Diehl AM. Cytokines and alcoholic liver disease. Semin Liver Dis 1993;13: Chedid A, Mendenhall CL, Gartside P, French SW, Chen T, Rabin L. Prognostic factors in alcoholic liver disease. VA Cooperative Study Group. Am J Gastroenterol 1991;86: Maddrey W. Alcoholic hepatitis: clinicopathologic features and therapy. 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