To support clinicians in making informed decisions regarding the diagnosis and management of inherited hyperbilirubinemia, including Gilbert syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, and Rotor syndrome, the Inherited and Metabolic Liver Disease Collaboration Group of the Hepatology Branch of the Chinese Medical Association convened a panel of Chinese experts in this field. This multidisciplinary consortium developed the present expert consensus by integrating the latest advances in both clinical practice and basic research.

Bilirubin is a breakdown product of erythrocytes and plays a crucial role in elimination of heme-containing proteins. After its synthesis in the reticuloendothelial system, unconjugated bilirubin is released into plasma and taken up into the liver. In hepatocytes, bilirubin is conjugated and excreted into the gastrointestinal tract via bile, where it is further converted to urobilinoids. There are various genetic factors causing abnormal bilirubin levels in plasma, such as Gilbert syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, and Rotor syndrome. To better understand bilirubin metabolism and its disorders, this study develops a physiologically based computational model incorporating published literature as well as real-world clinical data from the Explorys database. The model simulates bilirubin levels in both healthy individuals and patients with disorders of bilirubin metabolism. Population simulations show that Gilbert syndrome requires a substantial reduction in UDP-glucuronosyltransferase 1A1 activity, while Crigler-Najjar syndrome requires near-complete loss of its function. In contrast, Dubin-Johnson syndrome is characterized by a significant impairment of multidrug resistance-associated protein 2 activity. To also illustrate model behavior under targeted perturbations, we simulated administration of atazanavir in healthy individuals and patients with Gilbert syndrome to investigate its effect on bilirubin levels. Relative to baseline, unconjugated bilirubin maximum concentration (Cmax) increased by 34% in healthy individuals but by 67% in Gilbert syndrome. Overall, this study provides a conceptual and mechanistically informed framework for studying bilirubin homeostasis and the functional consequences of drug administration in health and disease.

Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) is an influx transporter expressed in the basolateral membrane of hepatocytes, playing a key role in the hepatic uptake and clearance of various drugs and endogenous compounds from the plasma. Single nucleotide variants in the SLCO1B1 gene have been shown to alter plasma drug concentration by affecting transporter activity. Furthermore, several variants leading to premature termination of translation have been observed, together with loss-of-function SLCO1B3 variants, in patients with Rotor syndrome. In this study, we investigated whether selected nonsense variations (c.757C>T, c.1738C>T, c.1877T>A, c.1905-1909del, c.1925-1929del, c.1929-1932del, c.1928T>G, c.1968dup, c.1976C>G) affect the transport activity and membrane expression of OATP1B1. HEK293 cells were transduced with baculovirus constructs carrying either a variant or reference SLCO1B1 sequence and the uptake of 2',7'-dichlorofluorescein or rosuvastatin was measured. Protein abundance was measured using a quantitative targeted absolute proteomics approach. Compared to reference OATP1B1, the c.1968dup and c.1976C>G variants, located near the C-terminus, retained 30-40 % of transport activity. In contrast, the remaining variants, located before or in the last transmembrane helix, resulted in complete loss of OATP1B1 function. Furthermore, all variants reduced OATP1B1 expression in the cell membranes. These results suggest that most nonsense variants result in a loss of OATP1B1 activity, but those located in the C-terminal loop may retain some activity. Moreover, carriers of the studied variants may exhibit increased plasma concentrations of OATP1B1 substrates.