Ann Med Surg (Lond). 2024 Dec 19;87(2)

DOI: doi: 10.1097/MS9.0000000000002813

PMID: 40110281

Israa Sharabati, Ruaa Mustafa Qafesha, Mohamed M.M. Mustafa, Mahmoud Diaa Hindawi, Heba Rasras, Sami Bannoura, Mohammed Abdulrazzak, Ibrahim Shamasneh

Highlights:

This case report describes a novel homozygous ABCB4 variant (c.2870G>T, p.Arg957Leu) in a 16-year-old female with progressive familial intrahepatic cholestasis type 3 (PFIC-3), who achieved complete biochemical remission on ursodeoxycholic acid (UDCA) without requiring liver transplantation. Accompanied by a review of 108 previously published PFIC-3 cases, the study highlights how genotype (particularly missense vs. truncating mutations) correlates with disease severity, UDCA responsiveness, and transplant risk, reinforcing the value of early genetic testing in atypical presentations of cholestasis.

Background:

Progressive familial intrahepatic cholestasis (PFIC) is a rare group of autosomal recessive liver disorders. PFIC-3, caused by mutations in the ABCB4 gene (encoding MDR3, a canalicular phospholipid transporter), typically presents later than PFIC-1/2, sometimes in adolescence or adulthood, and can be misdiagnosed as contraceptive-induced cholestasis or intrahepatic cholestasis of pregnancy in females.

Objective and methods:

The authors report a case of PFIC-3 in a 16-year-old female with recurrent abdominal pain, jaundice, and progressive liver dysfunction, and conducted a literature review of previously published PFIC-3/ABCB4 cases via PubMed to contextualise genotype-phenotype patterns.

Material and Methods:

Following comprehensive workup (biochemistry, imaging, ERCP, liver biopsy, and exclusion of viral, autoimmune, and metabolic liver diseases), whole blood was sequenced using Illumina NovaSeq 6000 (150×150 bp paired-end reads). Variant pathogenicity was assessed using PolyPhen-2, SIFT, and FATHMM. A structured PubMed search (ABCB4/MDR3 AND PFIC3, case reports/series) retrieved comparator cases, tabulated by mutation type, zygosity, UDCA response, transplant need, and mortality.

Results:

Sequencing revealed a novel homozygous c.2870G>T (p.Arg957Leu) ABCB4 variant, absent from ClinVar and gnomAD, predicted damaging/pathogenic by all three in silico tools. The patient was started on UDCA and vitamins, with full normalisation of liver enzymes and bilirubin and sustained remission at follow-up. The literature review identified 108 cases from 36 studies: missense mutations were most common (n=118) and generally associated with milder, later-onset disease and better UDCA response, while truncating/null mutations more often required liver transplantation (46/108 cases) or were associated with mortality (7 cases).

Conclusion:

Identification of ABCB4 mutations can meaningfully guide PFIC-3 management, as illustrated by this patient's UDCA responsiveness and avoidance of transplantation. The marked variability in presentation and outcomes across the reviewed cohort supports a genotype-informed, personalised approach to diagnosis and treatment, with gene therapy noted as an emerging future option.

Keywords: ATP binding cassette subfamily B member 4 (ABCB4) gene, case report, multidrug-resistant protein 3 (MDR3), progressive familial intrahepatic cholestasis type 3