Gary A. Abrams

A Randomized, Double-Blinded, Placebo-Controlled Multicenter Trial of Etanercept in the Treatment of Alcoholic Hepatitis

BACKGROUND & AIMS Alcoholic hepatitis is a cause of major morbidity and mortality that lacks effective therapies. Both experimental and clinical evidence indicate that the multifunctional cytokine tumor necrosis factor-alpha (TNF-alpha) contributes to pathogenesis and clinical sequelae of alcoholic hepatitis. A pilot study demonstrated that the TNF-alpha-neutralizing molecule etanercept could be an effective treatment for patients with alcoholic hepatitis. METHODS Forty-eight patients with moderate to severe alcoholic hepatitis (Model for End-Stage Liver Disease score > or = 15) were enrolled and randomized to groups that were given up to 6 subcutaneous injections of either etanercept or placebo for 3 weeks. Primary study end points included mortality at 1- and 6-month time points. RESULTS There were no significant baseline differences between the placebo and etanercept groups in demographics or disease severity parameters including age, gender, and Model for End-Stage Liver Disease score. The 1-month mortality rates of patients receiving placebo and etanercept were similar on an intention-to-treat basis (22.7% vs 36.4%, respectively; OR, 1.8; 95% CI, 0.5-6.5). The 6-month mortality rate was significantly higher in the etanercept group compared with the placebo group (57.7% vs 22.7%, respectively; OR, 4.6; 95% CI, 1.3-16.4; P = .017). Rates of infectious serious adverse events were significantly higher in the etanercept group compared with the placebo group (34.6% vs 9.1%, respectively, P = .04). CONCLUSIONS In patients with moderate to severe alcoholic hepatitis, etanercept was associated with a significantly higher mortality rate after 6 months, indicating that etanercept is not effective for the treatment of patients with alcoholic hepatitis.

Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: A new approach

BACKGROUND & AIMS We have reported that contrast echocardiography is a sensitive screening test for the hepatopulmonary syndrome (HPS). However, contrast echocardiography lacks specificity because many cirrhotic patients have positive study results with normal arterial blood gases and therefore do not fulfill criteria for HPS. The aim of this study was to assess the role of macroaggregated albumin lung perfusion scans (MAA scans) in the diagnosis of HPS. METHODS MAA scans were performed in 25 patients with HPS, 25 cirrhotic patients without HPS, and 15 hypoxemic subjects with intrinsic lung disease alone. An MAA shunt fraction was calculated from brain and lung counts. RESULTS MAA scan results were positive in 21 of 25 patients with HPS and negative in all controls. All 21 patients with positive MAA scans had PO2 values of <60 mm Hg. There was a strong inverse correlation between the degree of the MAA shunt fraction and arterial hypoxemia (r = -0.726). CONCLUSIONS A positive MAA scan result in cirrhosis is specific for the presence of moderate to severe HPS. We speculate that MAA scans may be particularly useful in evaluating the contribution of HPS to the hypoxemia in cirrhotic patients with intrinsic lung disease.

High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo.

NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is an important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role in NAFLD initiation and progression to the more serious condition of NASH (non-alcoholic steatohepatitis). Herein we hypothesize that mitochondrial defects induced by exposure to a HFD (high fat diet) contribute to a hypoxic state in liver and this is associated with increased protein modification by RNS (reactive nitrogen species). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories (1 cal≈4.184 J) from fat respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, NO (nitric oxide)-dependent control of respiration, and 3-NT (3-nitrotyrosine), a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triacylglycerols, increased CYP2E1 (cytochrome P450 2E1) and iNOS (inducible nitric oxide synthase) protein, and significantly enhanced hypoxia in the pericentral region of the liver. Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls. In addition, accumulation of 3-NT paralleled the hypoxia gradient in vivo and 3-NT levels were increased in mitochondrial proteins. Liver mitochondria from mice fed the HFD for 16 weeks exhibited depressed state 3 respiration, uncoupled respiration, cytochrome c oxidase activity, and mitochondrial membrane potential. These findings indicate that chronic exposure to a HFD negatively affects the bioenergetics of liver mitochondria and this probably contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins.

Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women

The upper limit of normal for ALT activity has been recommended to be lowered to ≤30 U/L in men and ≤19 U/L in women. These changes have been suggested to be diagnostically useful in subjects with nonalcoholic fatty liver disease (NAFLD). Our aim was to investigate the prevalence and spectrum of NAFLD with regard to the new ALT guidelines in 233 women with class II/III obesity. We compared our prior reference range for ALT (ULN ≤ 30 U/L in women) with the new standard. Our study demonstrates that only 86 patients (36.9%) would be classified as having normal ALT levels compared with 169 patients (72.5%) by the new and old standards, respectively. In patients with normal ALT activity (new vs. old standard), the prevalence of fatty liver (FL: 39.5% vs 40.2%), portal fibrosis, and steatosis (IPF: 37.2% vs. 33.7%) and nonalcoholic steatohepatitis (NASH: 23.3% vs. 26%) were similar. In comparison, newly defined patients with elevated ALT levels (>19 U/L) demonstrated an increased prevalence of FL (36%) and IPF (11.6%) but a 23.8% decrease in the prevalence of NASH as compared with the old standard. The sensitivity and specificity for NASH were 42% and 80% (ALT > 30 U/L) compared with 74% and 42% (ALT > 19 U/L). In conclusion, a significant increase in the prevalence of FL and IPF is detected in subjects with elevated ALT levels with the application of the new standard. However, the diagnostic utility for ALT to identify NASH or IPF remains poor, and significant healthcare expenditures may be incurred if this standard is adopted. (HEPATOLOGY 2005.)

Portal fibrosis and hepatic steatosis in morbidly obese subjects: A spectrum of nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can lead to hepatic fibrosis and cirrhosis. Portal fibrosis in the absence of NASH, called isolated portal fibrosis (IPF), has received less attention and has not been classified as a spectrum of NAFLD. The aims of this study were to determine the prevalence of IPF in subjects undergoing gastric bypass surgery, to identify biochemical variables associated with IPF, and to assess the metabolic syndrome as defined by the AdultTreatment Panel III criteria. We analyzed liver biopsies from 195 morbidly obese subjects after excluding all other causes of liver disease. The prevalence of fatty liver (FL) only, IPF, and NASH was 30.3%, 33.3%, and 36.4%, respectively. Several biochemical parameters significantly trended across the 3 groups, with IPF falling between FL and NASH. Hyperglycemia was the only metabolic parameter associated with NASH (OR, 5.4; 95% CI, 2.4‐12; P < .0001) and IPF (OR, 2.8; 95% CI, 1.2‐6.5; P = .01). Subjects with diabetes had the greatest risk for NASH (OR, 8; 95% CI, 3.3‐19.7; P < .0001) and IPF (OR, 4.3; 95% CI, 1.6‐11.6; P = .003). The metabolic syndrome was identified in 78.5% of subjects, and a significant trend for the number of metabolic criteria was observed across the spectrum of FL, IPF, and NASH. In conclusion, a significant subset of morbidly obese individuals has portal fibrosis in the absence of NASH that is associated with glycemic dysregulation. Therefore, IPF should be considered a spectrum of NAFLD that may prelude NASH in morbid obesity. (HEPATOLOGY 2004;40:475–483.)

Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial

BACKGROUND Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING Bristol-Myers Squibb.

Endothelin-1 in the rat bile duct ligation model of hepatopulmonary syndrome: correlation with pulmonary dysfunction

BACKGROUND/AIMS Models of hepatopulmonary syndrome require both hepatic injury and portal hypertension to develop pulmonary microvascular and gas exchange abnormalities. Recently, increased endothelin-1 levels associated with vasodilatation, have been observed in cirrhosis. We investigated endothelin-1 production in common bile duct ligated animals with hepatopulmonary syndrome in comparison to partial portal vein ligated animals that do not develop hepatopulmonary syndrome. METHODS Organ and plasma endothelin-1 were measured in sham, bile duct ligated and portal vein ligated rats, and Northern analysis and immunohistochemistry were performed in liver. Plasma endothelin-1 levels were correlated with pulmonary endothelial nitric oxide synthase levels and alveolar-arterial oxygen gradients. RESULTS Hepatic and plasma endothelin-1 increased only after bile duct ligation, and were accompanied by increased hepatic endothelin-1 mRNA and increased endothelin-1 protein in biliary epithelium. Plasma endothelin-1 levels correlated directly with both pulmonary endothelial nitric oxide synthase levels and alveolar-arterial gradients. CONCLUSIONS Enhanced hepatic production and increased plasma levels of endothelin-1 occur after bile duct ligation, but not after portal vein ligation, and correlate with associated molecular and gas exchange alterations in the lung. Endothelin-1 may contribute to the pathogenesis of hepatopulmonary syndrome.

Endothelin-1 stimulation of endothelial nitric oxide synthase in the pathogenesis of hepatopulmonary syndrome.

Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas exchange abnormalities that characterize the hepatopulmonary syndrome. This vasodilatation correlates with increased levels of pulmonary microcirculatory endothelial nitric oxide synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Prehepatic portal hypertension induced by portal vein ligation (PVL) does not cause similar changes, suggesting that ET-1 in cirrhosis may modulate pulmonary eNOS and vascular tone. We assessed whether ET-1 altered eNOS expression and nitric oxide production in bovine pulmonary artery endothelial cells (BPAECs) and if a 2-wk low-level intravenous ET-1 infusion in PVL animals modulated pulmonary eNOS levels, microcirculatory tone, and gas exchange. ET-1 caused a 2.5-fold increase in eNOS protein in BPAECs, inhibitable with an endothelin B receptor antagonist, and an increase in eNOS mRNA and nitrite production. ET-1 infusion in PVL animals caused increased pulmonary eNOS levels, intrapulmonary vasodilatation, and gas exchange abnormalities without increasing pulmonary arterial pressure. ET-1 produced during hepatic injury may contribute to the hepatopulmonary syndrome by modulating eNOS and inducing pulmonary microcicrulatory vasodilatation.Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas exchange abnormalities that characterize the hepatopulmonary syndrome. This vasodilatation correlates with increased levels of pulmonary microcirculatory endothelial nitric oxide synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Prehepatic portal hypertension induced by portal vein ligation (PVL) does not cause similar changes, suggesting that ET-1 in cirrhosis may modulate pulmonary eNOS and vascular tone. We assessed whether ET-1 altered eNOS expression and nitric oxide production in bovine pulmonary artery endothelial cells (BPAECs) and if a 2-wk low-level intravenous ET-1 infusion in PVL animals modulated pulmonary eNOS levels, microcirculatory tone, and gas exchange. ET-1 caused a 2.5-fold increase in eNOS protein in BPAECs, inhibitable with an endothelin B receptor antagonist, and an increase in eNOS mRNA and nitrite production. ET-1 infusion in PVL animals caused increased pulmonary eNOS levels, intrapulmonary vasodilatation, and gas exchange abnormalities without increasing pulmonary arterial pressure. ET-1 produced during hepatic injury may contribute to the hepatopulmonary syndrome by modulating eNOS and inducing pulmonary microcicrulatory vasodilatation.

Cost-effectiveness of screening, surveillance, and primary prophylaxis strategies for esophageal varices.

OBJECTIVE:Screening for varices is recommended in patients with cirrhosis to institute primary prophylaxis to prevent variceal bleeding. Our aim was to compare the cost-effectiveness of four strategies, including no screening/no prophylaxis, universal screening and primary prophylaxis with β-blockers, universal screening and primary prophylaxis with variceal ligation, and universal institution of primary prophylaxis with β-blockers without screening.METHODS:We constructed a Markov simulation model in two hypothetical cohorts of 50-yr-old patients with cirrhosis (one compensated and one decompensated), who were followed for 5 yr. Transition probabilities were derived from the medical literature, and costs reflected Medicare reimbursement rates at our institution.RESULTS:In patients with compensated cirrhosis, screening and primary prophylaxis with β-blockers is associated with an incremental cost-effectiveness ratio of

Treatment of hepatopulmonary syndrome with Allium sativum L. (Garlic): A pilot trial

3605 per year of life saved. The results were most sensitive to the prevalence of varices and risk of variceal bleeding. In patients with decompensated liver disease, primary prophylaxis without screening was associated with an incremental cost-effectiveness ratio of