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      Placebo‐Controlled Randomized Trial of an Intestinal Bile Salt Transport Inhibitor for Pruritus in Alagille Syndrome

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          Abstract

          Medically refractory, severe, cholestasis‐induced pruritus in Alagille syndrome may be improved by surgical interruption of the enterohepatic circulation. This multicenter trial (NCT02057692) tested the hypothesis that the intestinal bile acid transport inhibitor maralixibat would similarly reduce pruritus in Alagille syndrome. Thirty‐seven children with Alagille syndrome were randomly assigned to double‐blinded administration of placebo, 70, 140, or 280 µg/kg/day of maralixibat for 13 weeks. Pruritus was assessed by caregiver (itch‐reported outcome instrument [ItchRO]) and clinician report (range, 0‐4 [severe]). Liver chemistries and serum bile acids were measured. The primary outcome was the change from baseline to week 13 in ItchRO relative to placebo. In the a priori first analysis of the primary efficacy endpoint, the mean adjusted difference between participants receiving 140 or 280 µg/kg/day and placebo was –0.47 (95% confidence interval [CI], –1.14, 0.20; P = 0.16). Statistically significant decreases were observed with doses of 70 and 140 µg/kg/day (mean adjusted difference, –0.89; 95% CI, –1.70, –0.08; P = 0.032; and mean adjusted difference, –0.91; 95% CI, –1.62, –0.19; P = 0.014) but not 280 µg/kg/day (mean adjusted difference, –0.04; 95% CI, –0.94, 0.86; P = 0.44) or all doses combined (mean adjusted difference, –0.61; 95% CI, –1.24, 0.20; P = 0.055). A 1‐point reduction in pruritus was more common in maralixibat‐treated versus placebo‐treated participants (caregiver ItchRO, 65% versus 25%; P = 0.06; clinician score, 76% versus 25%; P = 0.01). There were no significant changes in liver chemistries or bile acids relative to placebo. Adverse and serious adverse events were similar between maralixibat and placebo. Conclusion: Although the prespecified primary analyses of ItchRO were not all statistically significant, the data suggest that maralixibat is safe and may reduce pruritus in Alagille syndrome.

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          Most cited references 17

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          Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH)

          The Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized clinical trial, was designed to test whether cholesterol lowering induced by the partial ileal bypass operation would favorably affect overall mortality or mortality due to coronary heart disease. The study population consisted of 838 patients (417 in the control group and 421 in the surgery group), both men (90.7 percent) and women, with an average age of 51 years, who had survived a first myocardial infarction. The mean follow-up period was 9.7 years. When compared with the control group at five years, the surgery group had a total plasma cholesterol level 23.3 percent lower (4.71 +/- 0.91 vs. 6.14 +/- 0.89 mmol per liter [mean +/- SD]; P less than 0.0001), a low-density lipoprotein cholesterol level 37.7 percent lower (2.68 +/- 0.78 vs. 4.30 +/- 0.89 mmol per liter; P less than 0.0001), and a high-density lipoprotein cholesterol level 4.3 percent higher (1.08 +/- 0.26 vs. 1.04 +/- 0.25 mmol per liter; P = 0.02). Overall mortality and mortality due to coronary heart disease were reduced, but not significantly so (deaths overall [control vs. surgery], 62 vs. 49, P = 0.164; deaths due to coronary disease, 44 vs. 32, P = 0.113). The overall mortality in the surgery subgroup with an ejection fraction greater than or equal to 50 percent was 36 percent lower (control vs. surgery, 39 vs. 24; P = 0.021). The value for two end points combined--death due to coronary heart disease and confirmed nonfatal myocardial infarction--was 35 percent lower in the surgery group (125 vs. 82 events; P less than 0.001). During follow-up, 137 control-group and 52 surgery-group patients underwent coronary-artery bypass grafting (P less than 0.0001). A comparison of base-line coronary arteriograms with those obtained at 3, 5, 7, and 10 years consistently showed less disease progression in the surgery group (P less than 0.001). The most common side effect of partial ileal bypass was diarrhea; others included occasional kidney stones, gallstones, and intestinal obstruction. Partial ileal bypass produces sustained improvement in the blood lipid patterns of patients who have had a myocardial infarction and reduces their subsequent morbidity due to coronary heart disease. The role of this procedure in the management of hypercholesterolemia remains to be determined. These results provide strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression.
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            Features of Alagille syndrome in 92 patients: frequency and relation to prognosis.

            We have studied 92 patients with Alagille syndrome (AGS) to determine the frequency of clinical manifestations and to correlate the clinical findings with outcome. Liver biopsy specimens showed paucity of the interlobular ducts in 85% of patients. Cholestasis was seen in 96%, cardiac murmur in 97%, butterfly vertebrae in 51%, posterior embryotoxon in 78%, and characteristic facies in 96% of patients. Renal disease was present in 40% and intracranial bleeding or stroke occurred in 14% of patients. The presence of intracardiac congenital heart disease was the only clinical feature statistically associated with increased mortality (P <.001). Initial measures of hepatic function in infancy including absence of scintiscan excretion were not predictive of risk for transplantation or increased mortality. The hepatic histology of these AGS patients showed a significant increase in the prevalence of bile duct paucity (P =.002) and fibrosis (P <.001) with increasing age. Liver transplantation for hepatic decompensation was necessary in 21% (19 of 92) of patients with 79% survival 1-year posttransplantation. Current mortality is 17% (16 of 92). The factors that contributed significantly to mortality were complex congenital heart disease (15%), intracranial bleeding (25%), and hepatic disease or hepatic transplantation (25%). The 20-year predicted life expectancy is 75% for all patients, 80% for those not requiring liver transplantation, and 60% for those who required liver transplantation.
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              Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.

              Partial diversion of bile flow to an external stoma was performed in 6 patients with chronic intrahepatic cholestasis with severe pruritus that had been refractory to medical measures. Four patients with progressive intrahepatic cholestasis and 2 with arteriohepatic dysplasia were treated. Follow-up has been 3-8 yr. Patients with progressive intrahepatic cholestasis have been free of itching since surgery. Serum bile salt concentrations fell from 218-275 microM (normal less than 10) before to less than 10 microM after surgery. Biochemical tests of liver function and histology returned to normal or near normal. Patients with arteriohepatic dysplasia had persistent mild pruritus after surgery. Serum bile salt concentrations fell from 153-317 to 25-37 microM. There was little or no improvement in biochemical tests or histology. Bile volume and bile salt diverted were higher in patients with progressive intrahepatic cholestasis (7.3-13.0 ml/kg.day and 83-137 mumol/kg.day, respectively) than those with arteriohepatic dysplasia (3.2-4.5 ml/kg.day and 21-36 mumol/kg.day). The quality of life since surgery has been excellent in patients with progressive intrahepatic cholestasis, but not as optimal in those with arteriohepatic dysplasia. These findings suggest that partial external biliary diversion can provide effective relief from pruritus and perhaps reversal of liver disease in patients with progressive intrahepatic cholestasis. It should be used in patients with arteriohepatic dysplasia only in those with disabling pruritus.
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                Author and article information

                Contributors
                Benjamin.Shneider@bcm.edu
                Journal
                Hepatol Commun
                Hepatol Commun
                10.1002/(ISSN)2471-254X
                HEP4
                Hepatology Communications
                John Wiley and Sons Inc. (Hoboken )
                2471-254X
                24 September 2018
                October 2018
                : 2
                : 10 ( doiID: 10.1002/hep4.v2.10 )
                : 1184-1198
                Affiliations
                [ 1 ] Section of Pediatric Gastroenterology, Hepatology, and Nutrition Baylor College of Medicine Houston TX
                [ 2 ] School of Public Health University of Michigan Ann Arbor MI
                [ 3 ] Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children University of Toronto Toronto Canada
                [ 4 ] University of Michigan Medical School Ann Arbor MI
                [ 5 ] Pediatrics Division of Gastroenterology, Hepatology, and Nutrition Ann and Robert H. Lurie Children’s Hospital of Chicago Chicago IL
                [ 6 ] Department of Pediatrics‐Pathology Cincinnati Children’s Hospital Medical Center Cincinnati OH
                [ 7 ] Division of Pediatric Gastroenterology, Hepatology, and Nutrition Cincinnati Children’s Hospital Medical Center Cincinnati OH
                [ 8 ] Division of Pediatric Gastroenterology, Hepatology, and Nutrition Indiana University School of Medicine/Riley Hospital for Children Indianapolis IN
                [ 9 ] Section of Pediatric Gastroenterology, Hepatology, and Nutrition Children's Hospital Colorado Aurora CO
                [ 10 ] Children’s Hospital of Pittsburgh Pittsburgh PA
                [ 11 ] Division of Gastroenterology and Hepatology University of Washington School of Medicine, Seattle Children’s Hospital Seattle WA
                [ 12 ] Pediatric Gastroenterology, Hepatology, and Nutrition Children’s Hospital of Philadelphia Philadelphia PA
                [ 13 ] Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics University of California San Francisco San Francisco CA
                [ 14 ] Pediatric Gastroenterology, Hepatology, and Nutrition Emory University School of Medicine/Children’s Healthcare of Atlanta Atlanta GA
                [ 15 ] Pediatric Gastroenterology, Hepatology, and Nutrition University of Utah Salt Lake City UT
                [ 16 ] Department of Gastroenterology Children's Hospital Los Angeles Los Angeles CA
                [ 17 ] Liver Diseases Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD
                [ 18 ] Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics University of Colorado School of Medicine Aurora CO
                Author notes
                [* ] Benjamin L. Shneider, M.D., Pediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine, 10th floor, 6701 Fannin Street, 11th Floor, Houston, TX 77030, Tel: +1‐832‐822‐3608

                E‐mail: Benjamin.Shneider@ 123456bcm.edu

                Article
                HEP41244
                10.1002/hep4.1244
                6167076
                © 2018 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

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                Figures: 6, Tables: 2, Pages: 15, Words: 12621
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                Funding
                Funded by: National Institutes of Health
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases
                Award ID: DK 62436
                Award ID: DK 62452
                Award ID: DK 62453
                Award ID: DK 62456
                Award ID: DK 62470
                Award ID: DK 62481
                Award ID: DK 62497
                Award ID: DK 62500
                Award ID: DK 62503
                Award ID: DK 84536
                Award ID: DK 84575
                Award ID: DK103135
                Award ID: DK103140
                Award ID: DK103149
                Funded by: National Center for Advancing Translational Sciences
                Award ID: UL1TR000005
                Award ID: UL1TR0000777
                Award ID: UL1TR000130
                Award ID: UL1TR000423
                Award ID: UL1TR001067
                Award ID: UL1TR001082
                Award ID: UL1TR001108
                Award ID: UL1TR001422
                Award ID: UL1TR001872
                Award ID: UL1TR001878
                Award ID: UL1TR002378
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                hep41244
                October 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.0 mode:remove_FC converted:01.10.2018

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