Open AccessMutation Analysis and Disease Features at Presentation in a Multi‐Center Cohort of Children With Monogenic Cholestasis
Author(s) -
Hertel Paula M.,
Bull Laura N.,
Thompson Richard J.,
Goodrich Nathan P.,
Ye Wen,
Magee John C.,
Squires Robert H.,
Bass Lee M.,
Heubi James E.,
Kim Grace E.,
Ranganathan Sarangarajan,
Schwarz Kathleen B.,
Bozic Molly A.,
Horslen Simon P.,
Clifton Matthew S.,
Turmelle Yumirle P.,
Suchy Frederick J.,
Superina Riccardo A.,
Wang Kasper S.,
Loomes Kathleen M.,
Kamath Binita M.,
Sokol Ronald J.,
Shneider Benjamin L.
Publication year - 2021
Publication title -
journal of pediatric gastroenterology and nutrition
Language(s) - English
Resource type - Journals
eISSN - 1536-4801
pISSN - 0277-2116
DOI - 10.1097/mpg.0000000000003153
Subject(s) - progressive familial intrahepatic cholestasis , cholestasis , medicine , enterohepatic circulation , gastroenterology , bile salt export pump , liver disease , cohort , endocrinology , bile acid , genetics , biology , liver transplantation , gene , transplantation , transporter
ABSTRACT Objectives: To advance our understanding of monogenic forms of intrahepatic cholestasis. Methods: Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)‐binding cassette subfamily B member 11 ( ABCB11 ) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 ( ATP8B1 ) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)‐binding cassette subfamily B member 4 ( ABCB4 ) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. Results: Ninety‐eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty‐five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. Conclusions: In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype–phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.