Rotor syndrome

Overview

Rotor syndrome is a rare, benign, hereditary liver disorder characterized by chronic, mild jaundice due to elevated levels of conjugated (direct) and unconjugated (indirect) bilirubin in the blood. It is considered a type of hereditary hyperbilirubinemia and shares some clinical features with Dubin–Johnson syndrome but differs in underlying mechanism and liver histology.

First described in the 1940s by Dr. Arturo Rotor, the syndrome is typically diagnosed in childhood or early adulthood and is not associated with liver damage or other serious complications. Although individuals with Rotor syndrome often exhibit visible jaundice (yellowing of the skin and eyes), they generally have a normal lifespan and good quality of life without the need for extensive medical intervention.

Causes

Rotor syndrome is caused by mutations in two genes that encode liver-specific organic anion transporting polypeptides:

• SLCO1B1 (solute carrier organic anion transporter family member 1B1)

• SLCO1B3 (solute carrier organic anion transporter family member 1B3)

These genes produce proteins responsible for transporting bilirubin and other compounds from the blood into the liver cells. In Rotor syndrome, the absence or dysfunction of these transporters impairs the reuptake of conjugated bilirubin from the blood back into hepatocytes, resulting in its accumulation in the bloodstream.

Genetic Inheritance:

• Rotor syndrome is inherited in an autosomal recessive pattern.

• Both copies of either the SLCO1B1 or SLCO1B3 gene must be mutated for the condition to manifest.

• Parents of affected individuals are typically asymptomatic carriers.

Symptoms

Rotor syndrome is usually asymptomatic except for mild to moderate jaundice. The condition does not lead to liver enlargement, liver dysfunction, or other systemic issues. Symptoms may be intermittent and are often noticed during illness, fasting, or stress.

Common Clinical Features:

• Mild jaundice: Yellowing of the skin and sclera (whites of the eyes)

• Hyperbilirubinemia: Elevated levels of both conjugated and unconjugated bilirubin

• Fatigue: Occasionally reported but not definitively linked to the syndrome

Notable Absences:

• No pruritus (itching)

• No hepatosplenomegaly (enlargement of liver or spleen)

• No liver enzyme abnormalities

Diagnosis

Diagnosis of Rotor syndrome is based on laboratory findings, imaging studies, and exclusion of other causes of jaundice. Genetic testing can provide definitive confirmation.

Laboratory Tests:

• Total bilirubin: Elevated, usually <2–5 mg/dL

• Conjugated (direct) bilirubin: Predominantly increased

• Liver function tests: Normal alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP)

• Urinary coproporphyrin analysis: Increased total coproporphyrin with >65% being coproporphyrin I (a distinguishing feature)

Imaging and Functional Studies:

• Hepatobiliary scintigraphy: Shows delayed hepatic uptake and excretion of radiotracers

• CT or ultrasound: Normal liver structure without signs of disease

Genetic Testing:

• Mutational analysis of SLCO1B1 and SLCO1B3 can confirm the diagnosis

Differential Diagnosis:

• Dubin–Johnson syndrome: Also features conjugated hyperbilirubinemia, but liver is pigmented (black) and coproporphyrin I excretion is lower (~80%)

• Gilbert syndrome: Unconjugated hyperbilirubinemia with no elevation in conjugated bilirubin

• Hemolytic anemia or liver disease: Usually have abnormal liver enzymes or blood smear findings

Treatment

There is no specific treatment for Rotor syndrome, as it is a benign and non-progressive condition. Management focuses on reassurance, patient education, and monitoring if necessary. Most individuals do not require medical therapy.

Management Strategies:

• Reassurance: Educating patients and families that the condition is harmless

• Avoidance of unnecessary treatment: No need for liver-directed medications or interventions

• Monitoring: Periodic checks of bilirubin levels may be performed, especially during illness or pregnancy

Medications to Avoid:

• Drugs that inhibit organic anion transporters may worsen bilirubin levels

• Examples: rifampin, indinavir (consult with a hepatologist before using such medications)

Prognosis

The prognosis for individuals with Rotor syndrome is excellent. It is a lifelong condition, but it does not progress to liver disease, cause organ damage, or shorten life expectancy. Most people live normal lives and remain asymptomatic aside from mild jaundice.

With proper diagnosis, patients can avoid unnecessary investigations or treatments for liver disease. Genetic counseling may be offered to families to explain inheritance and carrier status, particularly in consanguineous populations where autosomal recessive conditions are more prevalent.