Rotors syndrome (also known as Rotor type hyperbilirubinemia) is an autosomal recessive disease and a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia. The disease is characterized by non-hemolytic jaundice due to chronic elevation of predominantly conjugated bilirubin. This phenomenon is a result of impaired hepatocellular storage of conjugated bilirubin that leaks into plasma causing hyperbilirubinemia. Its presenting symptom is jaundice, but Rotor Syndrome is a benign, self-limiting disorder that does not require treatment.
Rotor syndrome is an autosomal recessive disorder caused by homozygous mutations in both the SLCO1B1 and SLCO1B3 genes on chromosome 12. These genes provide instructions for making organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3, respectively). These proteins are found in liver cells and mediate sodium-independent cellular uptake of compounds including bilirubin glucuronide, bile acids, and steroid and thyroid hormones as well as numerous drugs, toxins, and their conjugates. In a normal liver, a majority of bilirubin is conjugated by hepatocytes and secreted back into the blood. It is then reabsorbed in downstream hepatocytes by the OATP1B1 and OATP1B3 proteins. In Rotor syndrome, the OATP1B1 and OATP1B3 proteins are abnormally short; therefore, the bilirubin is less efficiently taken up by the liver and removed from the body, causing a buildup of bilirubin in the blood and urine which results in jaundice and dark urine.
Rotor Syndrome was first described in 1948. Since then, cases have been reported worldwide. It is the second most rare hereditary cause of hyperbilirubinemia, the first being Crigler-Najjar type I. Furthermore, there is no gender predisposition seen with Rotor syndrome. The disease tends to present shortly after birth or during childhood.
As mentioned, Rotor syndrome is caused by mutations in two proteins responsible for transporting bilirubin and other compounds from the blood to the liver to be metabolized and cleared from the body. Coproporphyrin I, a major coproporphyrin isomer in bile, is transported from the hepatocyte back into the circulation and is excreted in the urine. Thus, urine coproporphyrin is elevated in Rotor syndrome. Cholescintigraphy using sulfobromophthalein (BSP) have shown that the transport capacity of dye into bile is reduced by less than 50%, and the storage capacity in the hepatocytes is decreased more than 5-fold compared with normal values in this disease.
Liver biopsy is not required to make the diagnosis of Rotor syndrome, but if done, liver biopsy in patients with the disease reveals normal histology. Liver biopsy may be helpful in distinguishing Rotor syndrome for other, more serious liver diseases. Since Rotor syndrome is clinically similar to Dubin-Johnson syndrome (DJS), it is imperative to distinguish between these two conditions; the absence of dark melanin-like pigments on liver biopsy distinguishes Rotor Syndrome from DJS.
History and Physical
Patients with Rotor syndrome are typically asymptomatic; however, generalized non-pruritic jaundice can present at birth or early childhood. These symptoms may come and go. Some patients only have scleral icterus. Patients will also complain about passing dark-colored urine. Additionally, around 5% to 30% of patients may also experience abdominal pain, gastric mucosal abnormalities, and fever.
Rotor syndrome is largely a diagnosis of exclusion. Serological abnormalities in Rotor syndrome only include elevated total serum bilirubin (typically elevated between 2 to 5 mg/dL but may be as high as 20 mg/dL). Most of the time, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase levels are normal, but mild elevations can be seen. If any of these lab values are markedly elevated, investigation for other, more serious conditions is warranted. Imaging studies cannot diagnose Rotor syndrome but can help rule out other diseases that cause hyperbilirubinemia. For example, ultrasound of the liver and biliary tree can help investigate the causes of extra-hepatic biliary obstruction. The gallbladder is visualized on oral cholecystography in Rotor syndrome while it is not visualized in DJS. Ultimately, the best method of diagnosing the disease is the analysis of urine coproporphyrin excretion. The total urine coproporphyrin excretion in Rotor syndrome has a 2- to 5-fold elevation, with 65% constituting coproporphyrin I.
Treatment / Management
Rotor syndrome is a benign disease requiring no treatment. Jaundice is a lifelong finding, but the disease is not associated with morbidity or mortality, and life expectancy is not affected. Most individuals with Rotor syndrome are born to consanguineous couples, and its diagnosis may coincidently identify consanguinity. Distinguishing Rotor syndrome from other more serious disorders is important to avoid unnecessary workup and interventions. It is also critical to reassure and calm patients or family members of patients with Rotors syndrome that the condition is benign.
The many causes of hyperbilirubinemia can be divided into causes of unconjugated versus conjugated hyperbilirubinemia and then further classified. Some conditions that can cause hyperbilirubinemia include:
- Dubin-Johnson syndrome
- Gilbert syndrome
- Crigler-Najjar syndrome (type I and type II)
- Extra-hepatic biliary obstruction
- Familial intra-hepatic cholestasis
- Benign recurrent intrahepatic cholestasis (BRIC)
- Drug-induced hepatotoxicity
- Cholestasis of pregnancy
- Viral hepatitis
- Autoimmune hepatitis
- Wilson disease
- Alpha-1-antitrypsin deficiency
It is important to differentiate Rotor syndrome from other diseases causing hyperbilirubinemia. Normal levels of alkaline phosphatase and gamma-glutamyltranspeptidase help distinguish Rotor syndrome from disorders associated with biliary obstruction. Abnormal urinary coproporphyrin excretion and normal liver histology help distinguish this entity from DJS.
Rotor syndrome is a benign disease with no effect on life expectancy. No adverse drug effects have been documented in people with Rotor syndrome, but the absence of the hepatic proteins OATP1B1 and OATP1B3 may lead to serious issues with liver uptake. OATP1B1 plays a role in drug detoxification, and with a reduced activity of this protein, certain drugs such as anticancer agents, methotrexate, and statins can accumulate and result in drug toxicity. Caution should be taken before administering these drugs.
Pearls and Other Issues
Making a correct and early diagnosis of Rotor syndrome is crucial, as misdiagnoses of this disease often lead to a more costly, lengthy, and invasive workup that can place a patient at risk of avoidable complications and financial burden.
As this disease is generally diagnosed in the pediatric population, it is important to reassure concerned family members that Rotor syndrome is benign with no effect on life expectancy and the occasional appearance of jaundice.
Enhancing Healthcare Team Outcomes
Rotor syndrome is a benign disorder with no morbidity and is best managed by an interprofessional team that includes pharmacists and nurses. Liver biopsy is not required to make the diagnosis of Rotor syndrome, but if done, liver biopsy in patients with the disease reveals normal histology. A liver biopsy may be helpful in distinguishing Rotor syndrome for other, more serious liver diseases. Since Rotor syndrome is clinically similar to Dubin-Johnson syndrome (DJS), it is imperative to distinguish between these two conditions; the absence of dark melanin-like pigments on liver biopsy distinguishes Rotor Syndrome from DJS.
The outcomes for patients with Rotor syndrome are excellent.