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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 Unfortunately, outdated terminology and definitions of the disease are hampering efforts to develop new drugs and treatments.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.

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 .

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.

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.

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.

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.

Interruption of bile acid recirculation through inhibition of the apical sodium-dependent bile acid transporter (ASBT) is a promising strategy to alleviate hepatic cholesterol accumulation in non-alcoholic steatohepatitis (NASH), and improve the metabolic aspects of the disease. Potential disease-attenuating effects of the ASBT inhibitor volixibat (5, 15, and 30 mg/kg) were investigated in high-fat diet (HFD)-fed Ldlr-/-.Leiden mice over 24 weeks. Plasma and fecal bile acid levels, plasma insulin, lipids, and liver enzymes were monitored. Final analyses included liver histology, intrahepatic lipids, mesenteric white adipose tissue mass, and liver gene profiling. Consistent with its mechanism of action, volixibat significantly increased the total amount of bile acid in feces. At the highest dose, volixibat significantly attenuated the HFD-induced increase in hepatocyte hypertrophy, hepatic triglyceride and cholesteryl ester levels, and mesenteric white adipose tissue deposition. Non-alcoholic fatty liver disease activity score (NAS) was significantly lower in volixibat-treated mice than in the HFD controls. Gene profiling showed that volixibat reversed the inhibitory effect of the HFD on metabolic master regulators, including peroxisome proliferator-activated receptor-γ coactivator-1β, insulin receptor, and sterol regulatory element-binding transcription factor 2. Volixibat may have beneficial effects on physiological and metabolic aspects of NASH pathophysiology.

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.

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

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.

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.

• 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)