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Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis.

ABSTRACT: Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver-damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC.

SUBMITTER: Kamath BM

PROVIDER: S-EPMC7496162 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis.

Kamath Binita M BM Stein Philip P Houwen Roderick H J RHJ Verkade Henkjan J HJ

Liver international : official journal of the International Association for the Study of the Liver 20200622 8

Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion ...[more]

PMID: 32492754

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Project description:BackgroundProgressive familial intrahepatic cholestasis is a rare, heterogeneous group of liver disorders of autosomal recessive inheritance, characterised by an early onset of cholestasis with pruritus and malabsorption, which rapidly progresses, eventually culminating in liver failure. For children and their parents, PFIC is an extremely distressing disease. Significant pruritus can lead to severe cutaneous mutilation and may affect many activities of daily living through loss of sleep, irritability, poor attention, and impaired school performance.MethodsDatabases including MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.ResultsThree systematic reviews and twenty-two studies were eligible for inclusion for the epidemiology of PFIC including a total of 2603 patients. Study periods ranged from 3 to 33 years. Local population prevalence of PFIC was reported in three studies, ranging from 9.0 to 12.0% of children admitted with cholestasis, acute liver failure, or splenomegaly. The most detailed data come from the NAPPED study where native liver survival of >15 years is predicted in PFIC2 patients with a serum bile acid concentration below 102 µmol/L following bile diversion surgery. Burden of disease was mainly reported through health-related quality of life (HRQL), rates of surgery and survival. Rates of biliary diversion and liver transplant varied widely depending on study period, sample size and PFIC type, with many patients have multiple surgeries and progressing to liver transplant. This renders data unsuitable for comparison.ConclusionUsing robust and transparent methods, this systematic review summarises our current knowledge of PFIC. The epidemiological overview is highly mixed and dependent on presentation and PFIC subtype. Only two studies reported HRQL and mortality results were variable across different subtypes. Lack of data and extensive heterogeneity severely limit understanding across this disease area, particularly variation around and within subtypes.

Dataset Information

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis.

Publications

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis.

Similar Datasets

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