Clinical Phenotypic Characterization of NTCP Deficiency in Humans: A Case-Control Study Based on SLC10A1 Genotyping Analysis

Background: Sodium taurocholate cotransporting polypeptide (NTCP) is a transporter protein encoded by the gene SLC10A1 and exclusively expressed in the basolateral membrane of the hepatocyte to uptake bile salts. Although mice-based findings have substantially advanced the understanding of the pathophysiology of NTCP deficiency (NTCPD), this disease in humans was reported mainly as sporadic case or case series so far, and due to lacking compelling evidences of case-control study, its genotypic and phenotypic characteristics remains far from being well understood. Methods: The SLC10A1 genotypes of all NTCPD patients were confirmed by screening for the prevalent variant c.800C>T and Sanger sequencing when necessary. The clinical presentations and laboratory changes were collected, reviewed and analyzed, and then compared with the relevant controls qualitatively and quantitatively. Results: A total of 163 NTCPD patients including 113 pediatric and 50 adult cases were diagnosed and 5 SLC10A1 variants detected with c.374dupG and c.682_683delCT as 2 novel pathogenic mutations. Hypercholanemia was observed in 99.38% of the NTCPD patients. Indirect hyperbilirubinemia in affected neonates and intrahepatic cholestasis of pregnancy (ICP) with increased risk of cesarean section and preterm birth in affected female adults both exhibited higher positive rates in comparison to controls. Moreover, during early infancy by 6 months of age, transient cholestatic jaundice, elevated liver enzymes and 25-hydroxyvitamin D (Vit D) deficiency were more commonly observed in patients than in controls. Conclusions: With hypercholanemia as a common clinical feature, NTCPD exhibited other age-dependent phenotypic presentations in humans, including ICP in female adults, transient cholestatic hepatitis in early infancy and indirect hyperbilirubinemia in neonates. The findings enriched the SLC10A1 mutation spectrum and provided comprehensive insights into the phenotypic characteristics of NTCPD. Funding Statement: Our research was supported financially by National Natural Science Foundation of China (NSFC, Nos. 81570793, 81741080 and 81974057). Declaration of Interests: We declare no conflicts of interests. Ethics Approval Statement: This study adheres to the World Medical Association Declaration of Helsinki (WMADH2008), which was adopted by the 59th WMA General Assembly, Seoul, in October 2008, and has been approved by the Medical Ethical Committee, the First Affiliated Hospital, Jinan University (No.KY-2019-052). Written informed consents had also been obtained prior to the study from the research subjects or their guardians.