Approach

Typically, patients are asymptomatic, and the jaundice and conjugated hyperbilirubinemia are often discovered incidentally. Rotor syndrome is mainly a diagnosis of exclusion.

History

The condition is largely benign. Some patients may describe mild symptoms, such as fatigue and vague abdominal pain. They may report long-term jaundice and passing dark-colored urine.

Physical exam

The patient will have chronic jaundice. Excess circulation and accumulation of bilirubin results in yellow-orange discoloration of the tissues that is most easily visible as icteric (yellowish) discoloration in the sclera of the eyes. Unlike other cholestatic disorders, pruritus is not seen.

Laboratory tests

  • Serum bilirubin will be elevated and mostly in the conjugated form.[16]​ Typically, it is elevated to between 2 and 5 mg/dL, but may be as high as 20 mg/dL.

  • Typically, liver function tests (serum aminotransferases, alkaline phosphatase, and gamma-GT) are normal, although occasional mild elevations may be seen.

  • Serum bile acids are normal in contrast to some cholestatic disorders, which also present with a conjugated hyperbilirubinemia and jaundice (e.g., benign recurrent intrahepatic cholestasis).

  • To differentiate from hemolytic anemia, there will be no evidence of hemolysis. Hemoglobin, reticulocyte count, blood smear, and haptoglobin concentration will be normal.

  • Total urinary coproporphyrin excretion is increased 2.5- to 5-fold in RS patients compared with healthy controls. While coproporphyrin excretion is elevated in both RS and Dubin-Johnson syndrome (DJS), the proportion of coproporphyrin I to coproporphyrin III differs between the two conditions. In RS, approximately 65% of the total coproporphyrin is excreted as coproporphyrin I and in DJS >80% is excreted as coproporphyrin I.[4]

  • The sulfobromophthalein (BSP) plasma retention test will be prolonged because the transport capacity of the dye into bile is reduced by <50%.[8][17]

  • Targeted sequencing of the SLCO1B1 and SLCO1B3 genes. Bi-allelic pathogenic variants in SLCO1B1 and SLCO1B3 confirm the diagnosis.[10][18][19]​ If there are existing genetic test results, do not perform repeat testing unless there is uncertainty about the existing result, e.g., the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[20]

Imaging

Ultrasound of liver and biliary tree

  • May be helpful in investigating other causes of extra-hepatic biliary obstruction that also give rise to conjugated hyperbilirubinemia. In RS, ultrasound scan of the liver and biliary tree will be normal.

Cholecystography

  • Used to differentiate from Dubin-Johnson syndrome. In RS, the gall bladder is usually visualized on an oral cholecystogram.[4]

Cholescintigraphy with 99mTc-HIDA

  • Used when the diagnosis is equivocal. Shows an absent or very faint uptake and prolonged visualization of the cardiac pool.[21] The pattern is not different from that seen in patients with hepatocellular disease and markedly elevated bilirubin levels. However, combined with clinical information and laboratory findings it may be helpful in diagnosing RS.[22]

Liver biopsy

As RS is mainly a diagnosis of exclusion, it is important to demonstrate a normal liver histology, thereby excluding other more serious liver conditions. In RS, the liver biopsy is typically normal with no hepatocellular pigment.[4]

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