Rotor Syndrome: Glucuronidated Bile Acidemia From Defective Reuptake by Hepatocytes

Abstract

Organic anion transporting polypeptide (OATP) 1B1 (gene, solute carrier organic anion transporter family member 1B1 [SLCO1B1]) and OATP1B3 (SLCO1B3) serve as transporters for hepatic uptake of important endogenous substances and several commonly prescribed drugs. Inactivation of both proteins together causes Rotor syndrome. How this OATP1B1/1B3 defect disturbs bile acid (BA) metabolism is largely unknown. In this study, we performed detailed BA analysis in 3 patients with genetically diagnosed Rotor syndrome. We found that BAs glucuronidated at the C‐3 position (BA‐3G) accounted for 50% or more of total BAs in these patients. In contrast but similarly to healthy controls, only trace amounts of BA‐3G were detected in patients with constitutional indocyanine green excretory defect (OATP1B3 deficiency) or sodium‐taurocholate cotransporting polypeptide (NTCP; gene, solute carrier family 10 member 1 [SLC10A1]) deficiency. Therefore, substantial amounts of BA‐3G are synthesized in hepatocytes. The cycling pathway of BA‐3G, consisting of excretion from upstream hepatocytes and uptake by downstream hepatocytes by OATP1B1/1B3 may exist to reduce the burden on upstream hepatocytes. Conclusion: Detailed BA analysis revealed glucuronidated bile acidemia in patients with Rotor syndrome. Further exploration of the physiologic role of glucuronidated BAs is necessary.

Profiling of Urinary Glucuronidated Bile Acids across Age Groups

“…For instance, Rotor syndrome, which is characterized by deficiency of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, can be diagnosed by examining the ratio of the bile acid 3-glucuronides. In these patients, the 3-glucuronides are unable to enter hepatocytes through OATP1B1/B3 and subsequently accumulate in the circulating blood and are preferentially excreted through the urine, accounting for 20-30% of total BA in the urine and 50-70% in the serum [11].…”

Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia–A narrative review

“…Other liver tests are normal and there is no evidence of hemolysis 11 . Bile acids are normal in the majority of DJS patients and increased in RS patients 13 …”

Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis

“…Rotor Syndrome is an autosomal recessive genetic disease characterized by a deficiency in liver uptake and storage of bilirubin ( Kimura et al, 2021 ).…”

“…Patients with Rotor Syndrome often present with a range of symptoms, including jaundice, hepatomegaly, and elevated levels of bilirubin and bile acids ( Kimura et al, 2021 ).…”

“…Diagnosis of Rotor Syndrome typically involves laboratory tests such as bilirubin and bile acid measurements and imaging studies like MRI or CT scan ( Kimura et al, 2021 ). Management of Rotor Syndrome may include supportive measures such as fluid replacement and nutritional support, as well as medications to reduce bilirubin and bile acid levels.…”