Etiology
The exact etiology is unknown but seems to be related to a deficiency in the intracellular storage capacity of the liver for organic anions including bilirubin diglucuronide.[8][9]
An analysis of 8 Rotor syndrome (RS) families found that the syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. The study suggested the potential for a risk of life-threatening toxicities with certain drugs in RS.[10]
Four inherited defects of bilirubin metabolism are recognized: Gilbert syndrome and Crigler-Najjar syndrome (type I and II) are associated with unconjugated hyperbilirubinemia, and Dubin-Johnson syndrome (DJS) and RS are associated with conjugated hyperbilirubinemia. Bilirubin is the by-product of the catabolism of heme. [Figure caption and citation for the preceding image starts]: Schematic representation of bilirubin (B) metabolism within the hepatocyteFrom the collection of Dr Coelho [Citation ends].
Normal disposition of bilirubin (B) involves its transport to the liver via an albumin carrier (alb-B). In the hepatocyte, it is conjugated with the sugar molecule, glucuronic acid (G) to bilirubin glucuronate (BG), a water-soluble compound that can easily be excreted in the feces. The donor is uridine diphosphate glucuronic acid (UDPGA) and the reaction is catalyzed by the enzyme, UDP-glucuronyltransferase (UGT1A1-specific isoform). A decrease in the activity of this enzyme is associated with Gilbert syndrome and Crigler-Najjar syndrome (type I and II). Glutathione-S-transferase (GST) acts as an intracellular carrier protein for certain organic molecules.[11] It has been suggested that patients with RS may have a deficiency in hepatic GST.[12] A deficiency would result in impaired uptake of bilirubin within the cytosol. In addition, bilirubin conjugates are bound to GST while awaiting excretion from the hepatocytes into the canalicular lumen, so deficiencies in intracellular storage will lead to leakage of bilirubin conjugates back into the circulation.[13] The canalicular multidrug resistance protein 2 (MRP2) seems to be important for canalicular secretion of bilirubin. A defect in MRP2 results in DJS.
RS is inherited as an autosomal-recessive trait. In one study, RS was coexistent with other inherited disorders (glucose-6-phosphate dehydrogenase [G6PD] deficiency and heterozygous beta-thalassemia), suggesting a possible interaction between coinherited genes.[7]
Pathophysiology
Dye clearance studies using sulfobromophthalein (BSP) have shown that, in RS, the transport capacity of the dye into bile is reduced by <50%. In addition, the storage capacity in the hepatocytes is decreased more than 5-fold compared with normal values.[14]
The impairment in storage and excretion of bilirubin and other organic anions leads to defective secretion of conjugated bilirubin into the bile, which results in its reabsorption into the blood and excretion in the urine. The excess circulation and accumulation of bilirubin (hyperbilirubinemia) results in jaundice. Unlike Dubin-Johnson syndrome, there is no hepatic pigmentation.
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