https://pubmed.ncbi.nlm.nih.gov/34016879/ Cholestasis

J Pediatr Gastroenterol Nutr. 2021 May 13.
doi: 10.1097/MPG.0000000000003153.Online ahead of print.

Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children with Monogenic Cholestasis

Heather van Doren 1, Paula M Hertel, Laura N Bull, Richard J Thompson, Nathan P Goodrich, Wen Ye, John C Magee, Robert H Squires, Lee M Bass, James E Heubi, Grace E Kim, Sarangarajan Ranganathan, Kathleen B Schwarz, Molly A Bozic, Simon P Horslen, Matthew S Clifton, Yumirle P Turmelle, Frederick J Suchy, Riccardo A Superina, Kasper S Wang, Kathleen M Loomes, Binita M Kamath, Ronald J Sokol, Benjamin L Shneider, Childhood Liver Disease Research Network (ChiLDReN)

Abstract
Objectives: To advance our understanding of monogenic forms of intrahepatic cholestasis.

Methods: Analyses included participants with pathogenic biallelic mutations in ABCB11 (bile salt export pump; BSEP) or ATP8B1 (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in ABCB4 (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between 11/2007-12/2013. 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 4 monoallelic) deficiency were analyzed. Thirty-five had 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 study of larger cohorts.