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Metabolic (dysfunction)-associated fatty liver disease (MAFLD) affects a third of the population and is a leading cause of liver-related death. Since no effective treatments exist, novel approaches to drug development are required. Unfortunately, outdated terminology and definitions of the disease are hampering efforts to develop new drugs and treatments. An international consensus panel has put forth an influential proposal for the disease to be renamed from nonalcoholic fatty liver disease (NAFLD) to MAFLD, including a proposal for how the disease should be diagnosed. As allies with the many stakeholders in MAFLD care―including patients, patients’ advocates, clinicians, researchers, nurse and allied health groups, regional societies, and others―we are aware of the negative consequences of the NAFLD term and definition. We share the sense of urgency for change and will act in new ways to achieve our goals. Although there is much work to be done to overcome clinical inertia and reverse worrisome recent trends, the MAFLD initiative provides a firm foundation to build on. It provides a roadmap for moving forward toward more efficient care and affordable, sustainable drug and device innovation in MAFLD care. We hope it will bring promising new opportunities for a brighter future for MAFLD care and improve care and outcomes for patients of one of the globe’s largest and costliest public health burdens. From this viewpoint, we have revisited this initiative through the perspectives of drug development and regulatory science.

Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01051-5.

Background & Aims Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH. Methods In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48. Results Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (−14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (−16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation. Conclusions Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH. Lay summary A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease. Clinical trial identifier NCT02787304 .

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events. Electronic supplementary material The online version of this article (10.1007/s40264-020-01014-2) contains supplementary material, which is available to authorized users.

Background The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials. Aims This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH. Methods This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic. Results Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules. Conclusions This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.

We implemented a guideline for appropriate acid suppressant use in hematology-oncology patients. This intervention resulted in a sustained reduction in proton pump inhibitor (PPI) use without an increase in rates of gastrointestinal bleeding. Practice guidelines are effective in reducing PPI use, which is associated with risk of Clostridioides difficile infection.

Volixibat is a potent inhibitor of the apical sodium-dependent bile acid transporter in development for the treatment of nonalcoholic steatohepatitis. This phase 1, open-label study investigated the absorption, distribution, metabolism, and excretion of [14C]-volixibat in heathy men. Eligible men (n = 8) aged 18–50 years (body mass index 18.0–30.0 kg/m2; weight >50 kg) received a single oral dose of [14C]-volixibat 50 mg containing ~5.95 µCi radioactivity. The primary objectives were to assess the pharmacokinetics of [14C]-volixibat and to determine the total radioactivity in whole blood, plasma, urine, and feces at pre-selected time points over 6 days. The secondary objectives were to characterize metabolites and to assess the safety and tolerability. Low concentrations of volixibat (range 0–0.179 ng/mL) were detected in plasma up to 8 h following administration; the pharmacokinetic parameters could not be calculated. No radioactivity was observed in plasma or whole blood. The percentage (mean ± standard deviation) of total radioactivity in urine was 0.01 ± 0.007%. The vast majority (92.3 ± 5.25%) of volixibat was recovered in feces (69.2 ± 33.1% within 24 h). Unchanged volixibat was the only radioactive component detected in feces. Adverse events were mild in severity and mostly gastrointestinal. Changes in laboratory values were not clinically meaningful. Following oral administration, [14C]-volixibat was excreted unchanged from the parent compound almost exclusively via fecal excretion, indicating that the drug is minimally absorbed. Consistent with other studies, adverse events were primarily gastrointestinal in nature. ClinicalTrials.gov identifier NCT02571192.

Introduction: Advanced unresectable gastroesophageal cancers continue to confer a dismal patient prognosis. Limited options remain once the cancer is refractory to cytotoxics/biologics (like irinotecan, taxane, and ramucirumab). Recently, anti-programmed death-1 (anti-PD-1) inhibitors have been used with limited efficacy in select patients with adenocarcinoma. Similarly, irinotecan-based therapy has marginal efficacy. We combined irinotecan plus a fluoropyrimidine with an anti-PD-1 antibody, nivolumab, with hopes of having a higher advantage for patients. Objectives: Primary objective was to assess safety judged by toxicities, dose delays, or dose reductions. Secondary endpoints included the assessment of response, overall survival (OS), and progression-free survival (PFS). Methods: We treated 15 patients with this combination during July 2017 to April 2019. Patients were included if they had follow-up at our institution. Results: Median doses given were nivolumab 240 mg + irinotecan 120 mg/m2 + 5-FU 2,000 mg/m2 over 46–48 h (or capecitabine 1,250 mg/m2/day; 7 days on, 7 days off) given every 2 weeks. Median age of the patients was 55 years, and all patients had an ECOG performance status of 0–1. The patients had a median of 1 prior therapy. Slightly over half of the patients had PD-L1 expression. The median number of cycles was 7. Five patients (33%) had a dose delay or dose adjustment. The most common reason for dose delay or adjustment was grade 2 fatigue. Disease control (response or stability) on first scan was 73.3% (n = 11). Median PFS and OS for the entire group was 7 and 13.3 months, respectively. Conclusion: In this small cohort of patients, we conclude that this combination is quite feasible and resulted in prolonged stability in some patients. Further development of this regimen is warranted.

Background Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat. Methods Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids. Results All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0–4) to 2 (0–8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of − 0.70 mmol/L (range − 2.8 to 0.4) and − 0.6990 mmol/L (− 3.341 to 0.570), respectively. Conclusions This study indicates that maximal inhibition of bile acid reabsorption, as assessed by FBA excretion, occurs at volixibat doses of ≥20 mg/day in obese and overweight adults, without appreciable change in gastrointestinal tolerability. These findings guided dose selection for an ongoing phase 2 study in patients with non-alcoholic steatohepatitis. Trial registration ClinicalTrials.gov identifier: NCT02287779 (registration first received 6 November 2014). Electronic supplementary material The online version of this article (10.1186/s40360-018-0200-y) contains supplementary material, which is available to authorized users.

Background Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). Methods Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). Results Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6–3.2 times higher in HVs (643.73–1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3–5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. Conclusions Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013). Electronic supplementary material The online version of this article (10.1186/s12876-017-0736-0) contains supplementary material, which is available to authorized users.

The objective of this study was to investigate the effects of insulin and insulin-like growth factor I on transepithelial Na(+) transport across porcine glandular endometrial epithelial cells grown in primary culture. Insulin and insulin-like growth factor I acutely stimulated Na(+) transport two- to threefold by increasing Na(+)-K(+) ATPase transport activity and basolateral membrane K(+) conductance without increasing the apical membrane amiloride-sensitive Na(+) conductance. Long-term exposure to insulin for 4 d resulted in enhanced Na(+) absorption with a further increase in Na(+)-K(+) ATPase transport activity and an increase in apical membrane amiloride-sensitive Na(+) conductance. The effect of insulin on the Na(+)-K(+) ATPase was the result of an increase in V(max) for extracellular K(+) and intracellular Na(+), and an increase in affinity of the pump for Na(+). Immunohistochemical localization along with Western blot analysis of cultured porcine endometrial epithelial cells revealed the presence of alpha-1 and alpha-2 isoforms, but not the alpha-3 isoform of Na(+)-K(+) ATPase, which did not change in the presence of insulin. Insulin-stimulated Na(+) transport was inhibited by hydroxy-2-naphthalenylmethylphosphonic acid tris-acetoxymethyl ester [HNMPA-(AM)(3)], a specific inhibitor of insulin receptor tyrosine kinase activity, suggesting that the regulation of Na(+) transport by insulin involves receptor autophosphorylation. Pretreatment with wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase as well as okadaic acid and calyculin A, inhibitors of protein phosphatase activity, also blocked the insulin-stimulated increase in short circuit and pump currents, suggesting that activation of phosphatidylinositol 3-kinase and subsequent stimulation of a protein phosphatase mediates the action of insulin on Na(+)-K(+) ATPase activation.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. With the current obesity epidemic, its prevalence is increasing among both adults and children at an alarming rate. NAFLD occurs in individuals who do not drink excessive alcohol, yet have hepatic histology that mimics alcoholic liver disease. NAFLD is often associated with type 2 diabetes mellitus, central obesity, dyslipemia, and/or hypertension—conditions which comprise the metabolic syndrome. The spectrum of NAFLD ranges from simple steatosis, which is typically nonprogressive, to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and its complications. Patients are usually asymptomatic, and histologic evaluation via liver biopsy is the gold standard for both diagnosing NAFLD and differentiating between simple steatosis and NASH. Patients with simple steatosis typically have a benign, nonprogressive disease course, while people with NASH have a progressive disease course, with an estimated 20 % advancing to cirrhosis. While clinical trials of numerous medications have been performed, there are currently no pharmacological agents approved for treatment. Management includes lifestyle modification comprising weight reduction, nutritional alterations, and exercise, in addition to aggressive treatment of other components of the metabolic syndrome.

Among many factors, elevated lipids and lipid peroxide levels in blood are major risk factors in the development of cardiovascular disease in diabetic patients. This study has examined whether oral supplementation of vitamin E, an antioxidant, has any effect on blood lipid peroxidation products (LP) and lipid profile of diabetic patients. Thirty-five diabetics(D) were supplemented with DL-alpha-tocopherol (E) capsule (orally, 100 IU/d) or placebo (P) for three months in double-blind clinical trials. Plasma E was analyzed by HPLC and LP by the thiobarbituric acid-reactivity; serum lipids by auto-analyzer. Data were analyzed using paired t-test and Wilcoxon Signed Rank Test. Vitamin E supplementation significantly lowered LP and lipid levels in diabetic patients; there were no differences in these parameters after P supplementation. There were no differences in the duration of diabetes and ages of D between P- and E- supplemented groups. This study suggests that vitamin E supplementation significantly lowers blood LP and lipid levels in diabetic patients.

When I began my career as a hepatologist in 1988 there were no treatments for viral hepatitis. In fact, hepatitis C (HCV), then known as non-A, non-B (NANB) hepatitis, was not discovered until the following year. Almost a decade passed before treatment for HCV became available that resulted in acceptable Sustained Virologic Response (SVR) rates (now known to be consistent with virologic cure) - a combination of Interferon alpha (IFN) plus Ribavirin (RBV). Prior to this pairing, less than 10% of HCV patients achieved a SVR when treated with IFN alone. With combination therapy, SVR rates rose to approximately 40-50%.

Major Components of the Gastrointestinal System and Their Role in Digestion Monica Van Dongen and Gerard E. Mullin Malabsorption Babatunde Adeyefa and Carla W. Brady The Role of the Gut Microbiota and Probiotics in Gastrointestinal Disease Prevention and Management Gerard E. Mullin Short Bowel Syndrome Laura E. Matarese Celiac Disease S. Devi Rampertab Food Allergy and Food Intolerance John Leung and Sheila E. Crowe Anatomy and Physiology of the Liver Melissa Palmer Nutrition and Alcoholic Liver Disease Melissa Palmer Nutrition and Nonalcoholic and Viral Liver Diseases Melissa Palmer General Nutritional Guidelines for Liver Disease, Cirrhosis, and Its Complications Melissa Palmer Nutrition and Liver Transplantation Melissa Palmer Nutritional Considerations in Acute and Chronic Pancreatitis Deepa Gosine, Mohammed Kaleel, and Vikesh K. Singh Nutrition in Irritable Bowel Syndrome Gerard E. Mullin and Ashley Koff Inflammatory Bowel Disease S. Devi Rampertab, Amy Brown, and Gerard E. Mullin Nutrition and Colorectal Disease Myles R. Joyce and Victor W. Fazio Nutrition and Colorectal Cancer Mitra Rangarajan and Gerard E. Mullin The Influence of Bitter, Aromatic, and Pungent Medicinal Plants on Gut Function James Snow and Kevin Spelman Obesity and Nutrition Katrina B. Seidman and Lawrence J. Cheskin Micronutrients Omar S. Khokhar and Timothy O. Lipman The Role of Fiber, Prebiotics, and Probiotics in Gastrointestinal Health and Disease Martin H. Floch and Violeta B. Popov An Overview of Genomics and Gastrointestinal Health and Disease Ruth DeBusk Enteral Access and Enteral Nutrition Amy Berry and Mark H. DeLegge Parenteral Nutrition Mandy Corrigan, Bijo K. John, and Ezra Steiger Pediatric Enteral and Parenteral Nutrition Jenifer Hampsey and Tiffani Hays Drug-Drug and Drug-Nutrient Interactions in Gastrointestinal Disease Mark G. Klang Nutrition Assessment Tina Colaizzo-Anas Critical Care Nutrition Tara Nealon and Jonathan Waitman Perioperative Nutrition Support Jill Schuman and Kishore R. Iyer Bariatric Surgery Scott A. Shikora, Kerri Anne Hawkins, and Meghan Ariagno Home Parenteral Nutrition (HPN) Alice Illian, Kevn McNamara, and Carol Ireton-Jones An Integrative Nutrition Approach to Eating Disorders Carolyn Coker Ross and Gerard E. Mullin Ethical and Medical-Legal Considerations Julie O'Sullivan Maillet

Increasing use of liver transplantation and new treatment regimens necessitate an accurate estimate of prognosis in primary biliary cirrhosis. To test the usefulness of the Mayo model for this purpose, the R value of the model was calculated for a group of 28 patients after each patient encounter and plotted against time. The data were best described by two linear regressions. For the period 10-2 years before death, the average increase in R value was 0.23 annually [R = 7.1-0.23 x time (in years)]. In the last 2 years of life, the average increase in R value was 1.4. This period could be fit by the expression R = 8.2-1.4 x time (in years). The increase in R value represents the natural progression of primary biliary cirrhosis and can be used for evaluating treatment of patients.

A prospective randomized trial was undertaken to test the efficacy of low and standard doses of pegylated interferon alpha-2b in combination with ribavirin for the initial treatment of chronic hepatitis C. By nature of its design the study also provided data on response to therapy over a spectrum of doses of both pegylated interferon alpha-2b and ribavirin calculated on a body weight basis.Fifty micrograms of pegylated interferon alpha-2b or 100 microg for patients weighing75 kg or 150 microg for patientsor=75 kg were administered weekly with 1000 mg ribavirin daily for 48 wk if serum hepatitis C virus (HCV) RNA was undetectable after the first 24 wk of therapy.Overall sustained viral response (SVR) was 45% for standard dose and 33% for low dose, p=0.02. For genotypes 2 and 3 SVR was 65% for standard dose, and 56% for low dose, p=0.51. For genotype 1 SVR was 38% for standard dose, and 24% for low dose, p=0.03. For genotype 1 patients whose doses exceeded the 1-2-5 threshold, that isor=1.25 microg/kg body weight pegylated interferon alpha-2b weekly andor=12.5 mg/kg body weight ribavirin daily, SVR was 51%.The results of this study underscore the importance of adequate dosing of ribavirin as well as pegylated interferons in achieving an SVR when treating genotype 1 chronic hepatitis C patients with combination therapy.

The objective of this study was to investigate the mechanism of uridine 5'-triphosphate (UTP)-dependent inhibition of Na(+) absorption in porcine endometrial epithelial cells. Acute stimulation with UTP (5 microM) produced inhibition of sodium absorption and stimulation of chloride secretion. Experiments using basolateral membrane-permeabilized cell monolayers demonstrated a reduction in benzamil-sensitive Na(+) conductance in the apical membrane after UTP stimulation. The UTP-dependent inhibition of sodium transport could be mimicked by PMA (1 microM). Several PKC inhibitors, including GF109203X and Gö6983 (both nonselective PKC inhibitors) and rottlerin (a PKCdelta selective inhibitor), were shown to prevent the UTP-dependent decrease in benzamil-sensitive current. The PKCalpha-selective inhibitors, Gö6976 and PKC inhibitor 20-28, produced a partial inhibition of the UTP effect on benzamil-sensitive Isc. Inhibition of the benzamil-sensitive Isc by UTP was observed in the presence of BAPTA-AM (50 microM), confirming that activation of PKCs, and not increases in [Ca(2+)](i), were directly responsible for the inhibition of apical Na(+) channels and transepithelial Na(+) absorption.

Publisher Summary This chapter discusses the calcium-dependent anion secretion in endometrial epithelial cells. The endometrial epithelium is similar to secretory epithelia in the lung and gastrointestinal tractm, where signaling molecules that increase intracellular cAMP or calcium will elicit anion secretion. Little is known about calcium-activated chloride channels in endometrial epithelial cells. However, the emerging data from the mouse and porcine endometrium demonstrates the existence and physiological role of calcium-activated chloride channels in calcium-dependent anion secretion. In porcine endometrial cells, attempts at a molecular characterization of the channel indicate that it is distinct from previously characterized (CLCA) channels and may represent either a new member of the existing CLCA family or perhaps a new family of Ca 2+ -activated chloride channels. In any case, the importance of its role in anion secretion in the endometrium is evident. Data from porcine endometrial epithelial cells suggest that mobilization of intracellular calcium is responsible for activating an apical Ca 2+ -activated chloride channel and basolateral K + channels, which are essential for anion secretion. Anion secretion, along with the coupled paracellular movement of Na + ions, sets up an osmotic driving force for the movement of fluid into the glandular lumen.

Results 196 responses were analyzed (9 GI, 27 FIM, 90 PMS, and 70 CMS). Analysis identified differences in knowledge of HCV curability (p

This study examines the effect of high glucose levels on the markers of oxidative stress, phosphatidylserine (PS) externalization, and induction of coagulation by high-glucose-treated red blood cells (RBCs). Washed normal RBCs were suspended to 15% hematocrit in phosphate-buffered saline and incubated with different concentrations of glucose for 24 hours in a shaking water bath at 37 degrees C. This treatment caused depletion of vitamin E and accumulation of vitamin E-quinone and malondialdehyde ([MDA] an end product of lipid peroxidation), externalization of PS in the membrane bilayer, and induction of coagulation by RBCs. Pretreatment of RBCs with N-acetylcysteine (NAC) and vitamin E reduced membrane lipid peroxidation, PS externalization, and the tendency of high-glucose-treated RBCs to clot plasma. This study provides further evidence for the increased oxidative stress in RBCs exposed to high glucose levels. In addition, it suggests a role for membrane lipid peroxidation in the PS externalization in the membrane bilayer and in the induction of clotting by RBCs exposed to hyperglycemia. It also suggests that certain antioxidants can decrease cellular damage and restore certain cellular functions in diabetes.

OBJECTIVE To study the effect of vitamin E supplementation on platelet hyperaggregability in type 1 diabetic patients. RESEARCH DESIGN AND METHODS Written informed consent according to the Institutional Review Board on Human Experimentation guidelines was obtained from diabetic patients (n = 29) and their age-matched normal siblings (n = 21) to participate in this study. Diabetic patients were supplemented with DL-α-tocopherol (vitamin E) capsule (orally, 100 IU/day) or placebo for 3 months in a double-blind clinical trial. Alternate diabetic patients were assigned to vitamin E or placebo during regular visits to the clinic. Fasting blood was collected from each diabetic patient before the start and after the vitamin E or placebo supplementation. Platelet aggregability was assessed by competitive enzyme-linked immunosorbent assay of the blood TxB2 (a stable thromboxane metabolite). Plasma vitamin E and MDA (malondialdehyde, a product of lipid peroxidation) was assessed by high-performance liquid chromatography. Data were analyzed statistically on 12 diabetic patients on vitamin E and 12 on placebo supplementation. RESULTS Diabetic patients (n = 29) had 62% higher (P < 0.05) levels of TxB2 and 15% higher levels (P < 0.05) of MDA in comparison to normal subjects (n = 21). Plasma TxB2 levels had a significant correlation with MDA levels (r = 0.45, P < 0.02) but not with the HbA1 (r = −0.08), glucose (r = −0.13), duration of diabetes (r = −0.04), or age (r = 0.12) of diabetic patients. Vitamin E supplementation lowered MDA levels by 30% (P < 0.04), TxB2 levels by 51% (P < 0.03), and triglyceride levels by 22% (P < 0.04) in diabetic patients. There were no differences in these parameters before versus after placebo supplementation. CONCLUSIONS The elevated blood level of TxB2 (hyperaggregability of platelets) is significantly related to the level of lipid peroxidation products (oxidative stress) in type 1 diabetic patients. Supplementation of modest doses of vitamin E (100 IU/day) significantly lowers blood TxB2 and lipid peroxidation products levels in type 1 diabetic patients.

To The Editor: I read with interest the practice guidelines on nonalcoholic fatty liver disease (NAFLD),1 in which the authors fail to reference the association between high fructose corn syrup (HFCS) and NAFLD. The intake of HFCS, a combination of glucose and fructose, has increased over time and parallels both the obesity and NAFLD epidemics.2 Numerous studies demonstrate that the mechanism by which HFCS causes NAFLD is due to fructose. In animal models, fructose causes steatosis and fibrosis3,4 by either increasing hepatic lipogenesis, causing activation of pyruvate dehydrogenase,5 activating inflammatory pathways,6 or up-regulating the expression of sterol regulatory element-binding protein (SREBP).7 In humans, excessive fructose intake can lead to increased hepatic lipid deposition, greater insulin resistance, and hypertriglyceridemia.8 NAFLD patients have been found to drink more HFCS soft drinks compared with healthy controls.9 A retrospective analysis of 341 NAFLD adults found that those consuming high fructose diets had more fibrosis than those consuming low fructose diets.10 A prospective controlled trial with histologic endpoints is needed to define the amount of HFCS safe for NAFLD patients and to determine the extent to which fructose contributes to the pathogenesis and progression of NAFLD. However, there are currently sufficient data to recommend that NAFLD patients refrain from excessive consumption of HFCS.

1. The effects of racemic (rac) ibuprofen and its S(+)- and R(-)-enantiomers on functions of human polymorphonuclear cells (PMN) and platelets were studied in vitro. 2. Rac-ibuprofen inhibited PMN functions (O2- generation, beta-glucuronidase release, LTB4 formation). Similar IC50 values (40-100 microM) were obtained for the S(+)- and R(-)-enantiomers. 3. All forms of ibuprofen inhibited cyclooxygenase-related platelet functions (aggregation, thromboxane formation). The S(+)-enantiomer was about twice as active as the racemate while the R(-)-enantiomer was at least 10-fold less active. This demonstrates that the S(+) is the only cyclooxygenase inhibitory component of the racemate. 4. The concentrations of rac-ibuprofen in PMN and platelets were similar to those in the incubation medium and represented equal concentrations of the enantiomers. This indicates that neither interconversion nor tissue accumulation of the compounds occurred. 5. These data indicate that antineutrophil effects of ibuprofen on human PMN are independent of cyclooxygenase inhibition. Therefore, R(-)-ibuprofen may be superior to the S(+)-isomer for the treatment of PMN-dependent inflammatory diseases. However, effective free drug concentrations may not be obtained in vivo.

Twenty-eight patients (19 females, 9 males) were evaluated pre- and posttransplant to determine the frequency and find predictors of excessive weight gain after orthotopic liver transplant. Posttransplant, 21 patients gained and 7 patients lost weight as compared with their pretransplant dry weight. The majority of weight gain occurred between 2 and 16 months; 64.3% of patients (18/28 pts.) became overweight. All patients overweight prior to transplant (11 pts.) were more overweight posttransplant (P less than 0.005). Overweight and nonoverweight patients were similar in age, female predominance, etiology of liver disease, hypercholesterolemia, and hypertriglyceridemia pretransplant, as well as diabetes mellitus and medications including prednisone posttransplant. Overweight patients more commonly had a family history of diabetes mellitus, arteriosclerotic heart disease, and hypertension. They also had more hypertension, hypercholesterolemia, hypertriglyceridemia, abnormal physical findings related to the liver, and abnormal results of hepatic tests posttransplant. Mean rate of weight gain for overweight patients compared with nonoverweight ones during the first 16 months after transplant was 1.5 kg/month +/- 0.9 vs 0.4 kg/month +/- 0.4 for those not overweight. After 16 months mean rate of increase was slower for overweight patients (0.3 kg/month +/- 0.3), whereas weight appeared to stabilize in the nonoverweight ones. We conclude that excessive weight gain after liver transplant is common and occurs early. Since obesity may contribute to, as well as be a separate cause, of hepatic abnormalities, confusion may result when interpreting abnormal results of hepatic tests. Obesity prior to transplant predicts excessive weight gain posttransplant, although all patients may be at risk.

The effects of weight reduction on hepatic test results and physical findings related to the liver were retrospectively evaluated in 39 overweight patients screened to exclude other factors affecting the liver. An additional 11 overweight patients with primary liver disease were retrospectively evaluated to compare the effect of weight reduction in patients with liver disease with its effect in those without primary liver disease. This study showed that in overweight adults without primary liver disease, a weight reduction of greater than or equal to 10% corrected abnormal hepatic test results, decreased hepatosplenomegaly, and resolved some stigmata of liver disease. In similarly studied overweight patients with primary liver disease, some findings improved, but the changes did not correlate with a greater than or equal to 10% weight loss. Increased alanine aminotransferase activity was the most frequent hepatic enzyme abnormality in this population. For every 1% reduction in body weight, alanine aminotransferase activity improved by 8.1%. After other causes of liver disease are eliminated by clinical and biochemical parameters, weight reduction should be tried for overweight patients with abnormal hepatic test results in the absence of obvious primary liver disease as judged by clinical and biochemical parameters before extensive and expensive studies are undertaken.

UTILIZATION, PROTEIN GLYCOSYLATION AND VISCOSITY OF HIGH GLUCOSE-TREATED RED BLOOD CELLS Sushi1 K. Jain, Melissa Palmer, Yanyun Chen Department of Pediatrics, Louisiana State University Medical Center, Shreveport, LA 71130 USA Glycosylation of proteins can cause inactivation of enzymes and alterations in the structure and function of collagen and membranes. which may play a role in the long-term complications of diabetes and aging. Lipoic acid has been shown beneficial in reducing diabetic complications. such as. neuropathy. The present study was undertaken to test the hypothesis that lipoic acid increases glucose utilization and thereby reduces protein glycosylation and viscosity of red blood cells (RBC). RBC (15% hematocrit in PBS) were treated with high glucose levels (6-45 mM) with and without lipoic acid (5-200 LM) for 24 hrs in a shakine water bath at 3?‘C. Glucose was ‘determined using gl&ose oxidasel Glycosylated hemoglobin (HbAI) was determined using affinity chromatography to assess protein glycosylation. an: viscositv of washed RBC at tixed hematocrit was determined using computerized Brookfield viscometer. Lipoic acid treatment increased glucose utilization in high glucose (45 mM) exposed RBC by 75-120%. Over untreated fresh RBC, the increase in HbA, level in high glucose treated RBC was reduced by 22-40% in the presence of lipoic acid compared with high glucose alone. Treatment of RBC with high glucose increased viscosity of RBC. However. presence of lipoic acid in the medium significantly blocked increase in viscosity of high glucose-treated RBC. The level of glycated hemoglobin in blood has been considered to reflect the degree of glycation of other proteins that are freely exposed to circulating glucose. Using REX as a model. this study demonstrates that lipoic acid can reduce glycosylation of proteins and viscosity of cells exposed to high glucose. LIPID PEROXIDATION AND ANTIOXIDANT ENZYMES IN IMMUNE COMPLEX DISEASE G. Wbjcicka, A. Marciniak, D. G6my, R. CzabakGarbacz’, A. Korolczuk’, J. Beltowski Dept of Pathophysiologv, ‘Dept of Physiology, 2Dept of Pathomorphology, University of Medicine, Lublin, Poland The purpose of this study was to investigate lipid peroxidation and antioxidant mechanisms during early stage of immunisation and developed type III hypersensitivity. The male New Zeland rabbits (2.5 3 kg) were immunised by i.v. BSA. Four days after BSA administration malonyldialdehyde (MDA) level increased in plasma, renal cortex and renal medulla by 63%, 246% and 140% respectively, conjugated diens (CDs) increased in plasma, renal cortex and renal medulla by 76%, 122% and 63% respectively, lipid hydroperoxides (HPE) increased in plasma by 14%, in renal cortex by 11% and in renal medulla by 85%. Superoxide dismutase (SOD) activity in erythrocytes increased by 17%, blood glutathione peroxidase (Gpx) increased by 63% and total antioxidant status (TAS) decreased by 19%. Proteinuria was maximal 8 days after BSA administration. This day we observed 110% increase in MDA level in renal cortex and 271% increase in renal medulla. CDs increased by 60% in plasma, by 23% in renal cortex and by 40% in renal medulla. HPE in plasma was increased by 20% and in renal cortex by 100%. SOD and Gpx increased by 61% and 57% respectively whereas TAS decreased by 45%.

• The natural history and prognostic factors of primary sclerosing cholangitis (PSC) are poorly defined. We reviewed our experience with PSC to determine its natural history and whether any factors on presentation or during follow-up were indicative of a favorable or unfavorable prognosis. Thirty-eight patients were followed up for 75.1 ± 58.7 months; 17 (45%) had a poor outcome, defined as the occurrence of death (11 patients [29%]), variceal hemorrhage, hepatic encephalopathy, or hepatic transplantation. We found the following: (1) the rate of progression of PSC is highly variable; (2) an asymptomatic presentation may not indicate a more favorable outcome or prolonged survival; (3) a serum bilirubin value of four times or more the upper limit of normal, particularly if sustained so as to exclude a reversible cause, is indicative of late-stage disease with a likelihood of subsequent poor outcome and death; and (4) variceal hemorrhage may occur before the terminal stage of the disease. (Arch Intern Med1987;147:729-731)