Muhammad Y. Sheikh

Rifaximin Treatment in Hepatic Encephalopathy

BACKGROUND Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

Hepatitis C virus infection: Molecular pathways to metabolic syndrome

Chronic infection with hepatitis C virus (HCV) can induce insulin resistance (IR) in a genotype‐dependent fashion, thus contributing to steatosis, progression of fibrosis and resistance to interferon therapy. The molecular mechanisms in genotype 1 patients that lead to metabolic syndrome are still ambiguous. Based on our current understanding, HCV proteins associate with mitochondria and endoplasmic reticulum and promote oxidative stress. The latter mediates signals involving the p38 mitogen‐activated protein kinase and activates nuclear factor kappa B. This transcription factor plays a key role in the expression of cytokines, tumor necrosis factor alpha (TNF‐α), interleukin 6, interleukin 8, tumor growth factor beta, and Fas ligand. TNF‐α inhibits the function of insulin receptor substrates and decreases the expression of the glucose transporter and lipoprotein lipase in peripheral tissues, which is responsible for the promotion of insulin resistance. Furthermore, reduced adiponectin levels, loss of adiponectin receptors, and decreased anti‐inflammatory peroxisome proliferator‐activated receptor alpha in the liver of HCV patients may contribute to reduced fatty acid oxidation, inflammation, and eventually lipotoxicity. This chain of events may be initiated by HCV‐associated IR and provides a direction for future research in the areas of therapeutic intervention. (HEPATOLOGY 2008.)

Peginterferon Alfa-2a and Ribavirin in Latino and Non-Latino Whites with Hepatitis C

BACKGROUND Race has been shown to be a factor in the response to therapy for hepatitis C virus (HCV) infection, and limited data suggest that ethnic group may be as well; however, Latinos and other ethnic subpopulations have been underrepresented in clinical trials. We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously. METHODS In a multicenter, open-label, nonrandomized, prospective study, 269 Latino and 300 non-Latino whites with HCV infection received peginterferon alfa-2a, at a dose of 180 microg per week, and ribavirin, at a dose of 1000 or 1200 mg per day, for 48 weeks, and were followed through 72 weeks. The primary end point was a sustained virologic response. We enrolled Latinos whose parents and grandparents spoke Spanish as their primary language; nonwhite Latinos were excluded. RESULTS Baseline characteristics were similar in the Latino and non-Latino groups, although higher proportions of Latino patients were 40 years of age or younger, had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of more than 27 or more than 30, and had cirrhosis. The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001). The absence of HCV RNA in serum was more frequent in non-Latino whites at week 4 (P=0.045) and throughout the treatment period (P<0.001 for all other comparisons). Latino or non-Latino background was an independent predictor of the rate of sustained virologic response in an analysis adjusted for baseline differences in BMI, cirrhosis, and other characteristics. Adherence to treatment did not differ significantly between the two groups. The numbers of patients with adverse events and dose modifications were similar in the two groups, but fewer Latino patients discontinued therapy because of adverse events. CONCLUSIONS Treatment with peginterferon alfa-2a and ribavirin for 48 weeks resulted in rates of sustained virologic response among patients infected with HCV genotype 1 that were lower among Latino whites than among non-Latino whites. Strategies to improve the sustained virologic response in Latinos are needed. (ClinicalTrials.gov number, NCT00107653.)

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of GS-9450 in Subjects With Nonalcoholic Steatohepatitis

In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS‐9450 has a potential for altering the course of the liver disease. In this phase 2, double‐blind study, 124 subjects with biopsy‐proven NASH were randomized to once‐daily placebo or 1, 5, 10, or 40 mg GS‐9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase‐3–cleaved cytokeratin (CK)‐18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40‐mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40‐mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK‐18 fragment levels had decreased to 393 (723) U/L in the GS‐9450 10‐mg group and 125 (212) U/L in the 40‐mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment‐emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS‐9450 treatment groups versus 35% in the placebo group. Conclusion: GS‐9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK‐18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH. (Hepatology 2012)

Rifaximin Is Safe and Well Tolerated for Long-term Maintenance of Remission From Overt Hepatic Encephalopathy

BACKGROUND & AIMS Rifaximin is a gut-selective, oral antimicrobial agent shown to reduce the recurrence of overt hepatic encephalopathy (HE) and HE-related hospitalizations in a 6-month, randomized, controlled trial (RCT). We performed a phase 3, open-label maintenance study to assess the safety and rate of hospitalization with long-term rifaximin use. METHODS We conducted a 24-month, open-label maintenance study of rifaximin (550 mg, twice daily) in patients with HE who participated in the previous RCT of rifaximin or new patients enrolled from March 2007 to December 2010. Safety was assessed (adverse events, clinical laboratory parameters) for the integrated population of all patients, who were given rifaximin 550 mg twice daily (all-rifaximin population, N = 392). Safety and hospitalization data were compared between the group given placebo in the original RCT (n = 159) and those given rifaximin (n = 140). RESULTS In the all-rifaximin population, the median exposure to rifaximin was 427.0 days (range, 2-1427 d), with 510.5 person-years of exposure. The profile and rate of adverse events with long-term rifaximin treatment were similar to those of the original RCT. There was no increase in the rate of infections, including with Clostridium difficile, or development of bacterial antibiotic resistance. Rates of hospitalizations with long-term rifaximin administration remained low: the HE-related hospitalization rate, normalized for exposure (0.21; all-rifaximin population), was similar to that of the rifaximin group in the original RCT (0.30), and lower than that for the placebo group (0.72). CONCLUSIONS Long-term treatment (≥24 mo) with rifaximin (550 mg, twice daily) appears to provide a continued reduction in the rate of HE-related and all-cause hospitalization, without an increased rate of adverse events. ClinicalTrials.gov number: NCT00686920.

Effect of Long-Term Trimethoprim-Sulfamethoxazole Prophylaxis on Ascites Formation, Bacterial Translocation, Spontaneous Bacterial Peritonitis, and Survival in Cirrhotic Rats

Selective intestinal decontamination withnorfloxacin is useful in preventing spontaneousbacterial peritonitis in cirrhotic patients and also incirrhotic rats. The emergence of norfloxacin-resistantinfections in these patients warrants a search foralternative therapies. The aim of this study was toevaluate the effect of long-termtrimethoprimsulfamethoxazole administration on carbontetrachloride (CCl4)-induced cirrhosis inrats with specific attention to intestinal flora,bacterial translocation, spontaneous bacterialperitonitis (SBP), and survival. Male Sprague-Dawleyrats received CCl4 administered weekly bygavage. After eight weeks of CCl4administration rats were randomly allocated into twogroups. Group I received daily overnighttrimethoprim-sulfamethoxazole diluted in phenobarbital water during follow-up and groupII did not. The rats were killed when gravely ill, anda laparotomy was performed to culture samples of cecalstool, mesenteric lymph nodes, and portal and inferior vena caval blood. There was a trendtoward a reduction in the incidence of bacterialtranslocation (8/17 vs 11/14, respectively) and SBP(5/17 vs 7/14, respectively) in treated rats that werekilled just before death compared to untreated rats.A decrease in the incidence of bacterial translocationcaused by gramnegative bacilli was observed in group I(17.6% vs 78.6% , P < 0.01). The development of ascites was delayed in group I (P < 0.05)and survival was prolonged in group I (P < 0.05),despite a higher CCl4 dose in this group (P< 0.05). In conclusion, long-term prophylactic trimethoprim-sulfamethoxazole administration inCCl4-induced cirrhosis in rats delayed thedevelopment of ascites, prolonged survival, and reducedthe incidence of gramnegative bacterial translocation but not of SBP, without increasinggram-positive episodes. These data suggest thattrimethoprim-sulfamethoxazole might be a goodalternative to norfloxacin for preventing gram-negativebacterial translocation.

Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis

BACKGROUND & AIMS: Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. METHODS: We collected data from 3 large U.S. studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. RESULTS: Premenopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory‐Denk bodies than men and also at an increased risk of lobular inflammation and Mallory‐Denk bodies than postmenopausal women (P < .01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory‐Denk bodies in premenopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in postmenopausal women (P < .05). CONCLUSIONS: Being a premenopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress.

Prevalence of cirrhosis in patients with thrombocytopenia who receive bone marrow biopsy.

Background/Aim: Thrombocytopenia is a common finding in patients with cirrhosis and may lead to unnecessary referral for bone marrow (BM) biopsy. To date, the prevalence of cirrhosis in patients with thrombocytopenia who receive BM biopsy is largely unknown. Materials and Methods: Between fiscal years 2006-2010, 744 patients (≥18 years) who underwent BM biopsies for thrombocytopenia at our hospital were identified retrospectively. 541 patients were excluded who had hematologic malignancies and received chemotherapy. Remaining 203 patients with predominant isolated thrombocytopenia were included in the study. Results: Of 203 patients, 136 (67%) had a normal and 67 (33%) had an abnormal BM examination. Prevalence of cirrhosis in the study population was 35% (95% CI: 28.4-41.9). 51% patients with normal BM were found to have cirrhosis compared to 3% of patients with abnormal BM exam (P < 0.0001). Common causes of cirrhosis were nonalcoholic steatohepatitis (NASH) (47%), followed by alcohol and Hepatitis C virus infection. Idiopathic thrombocytopenia and myelodysplastic syndrome were most frequent causes of thrombocytopenia in patients without cirrhosis. Patients with NASH had higher body mass index (BMI) (33.4 vs. 25.8, P < 0.001) and lower MELD scores (11.1 vs. 16, P = 0.028) when compared to non-NASH patients with cirrhosis. Conclusion: Approximately, one third (35%) of patients with cirrhosis induced thrombocytopenia may undergo unwarranted BM biopsies. Clinical diagnosis of cirrhosis is still a challenge for many physicians, particularly with underlying NASH. We propose cirrhosis to be the prime cause of isolated thrombocytopenia.

Factors affecting the quantitative liver-spleen scan in normal individuals.

The quantitative liver–spleen scan (QLSS) can estimate the functional hepatic mass and the organ volumes by precise measurement of sulfur colloid (SC) distribution. The normal range determined in prior studies was estimated from patients with absence of chronic liver disease in which intense fasting appeared to produce slightly abnormal values. This study was to determine the effect of fasting or fed status and colloid particle size on quantitative measurements from the QLSS in a small cohort of normal individuals. Twelve persons without any medical problems had QLSS taken twice, 2 weeks apart, one fasting and one postprandial. Patients were scanned after injection of 5–6 mCi of SC; six patients were given solution A (5- to 12-μm particle size) and six patients solution B (2- to 12-μm particle size). SPECT and planar analysis were performed. SC distribution of total counts between the liver and the spleen {[L/(L + S)]t ratio}, liver–spleen index (LSI), and liver–bone marrow index (LBI) were calculated. The perfused hepatic mass (PHM) is the average of the LSI and LBI. Spleen and liver volumes are expressed as milliliters per pound ideal body weight (IBW). Results showed that the liver and spleen volumes (solution B postprandial, 9.27 ± 2.48 and 1.47 ± 0.57 ml/lb IBW, respectively) and LBI were not affected by the type of SC solution or by ingestion status. L/(L + S) total and pixel count ratios were significantly higher for solution B and postprandial studies. [L/(L + S)]t, LSI, and PHM increased significantly (P < 0.05) from fasting to postprandial for solution A (0.71 ± 0.13 vs 0.79 ± 0.08, 80 ± 14 vs 91 ± 8, and 102 ± 10 vs 106 ± 8, respectively) and for solution B (0.81 ± 0.05 vs 0.90 ± 0.02, 86 ± 4 vs 95 ± 3, and 101 ± 5 vs 110 ± 3). Neither fasting nor postprandial LSI and PHM were significantly different between solution A and solution B. We conclude the following. (1) The QLSS functional indices in “true” normal patients fall within the previously reported normal range. (2) Calculated liver and spleen volumes are not altered by fasting or sulfur colloid particle size. (3) Fasting significantly decreased the [L/(L + S)]t, LSI, and PHM. (4) A postprandial scan may be preferable since the normal values for [L/(L + S)]t, LSI, and PHM are greater, with a narrower range, than fasting values.

Seroprevalence of hepatitis b and c infections among healthy volunteer blood donors in the central california valley

Background/Aims The Central California Valley has a diverse population with significant proportions of Hispanics and Asians. This cross-sectional study was conducted to evaluate the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) in healthy blood donors in the Valley. Methods A total of 217,738 voluntary blood donors were identified between 2006 and 2010 (36,795 first-time donors; 180,943 repeat donors). Results Among the first-time donors, the HBV and HCV prevalence was 0.28% and 0.52%, respectively. Higher HBV prevalence seen in Asians (3%) followed by Caucasians (0.05%), African Americans (0.15%), and Hispanics (0.05%). Hmong had a HBV prevalence of 7.63% with a peak prevalence of 8.76% among the 16- to 35-year-old age group. Highest HCV prevalence in Native Americans (2.8) followed by Caucasians (0.59%), Hispanics (0.45%), African Americans (0.38%), and Asians (0.2%). Conclusions Ethnic disparities persist with regard to the prevalence of HBV and HCV in the Central California Valley. The reported prevalence may be an underestimate because our study enrolled healthy volunteer blood donors only. The development of aggressive public health measures to evaluate the true prevalence of HBV and HCV and to identify those in need of HBV and HCV prevention measures and therapy is critically important.