Rotor syndrome (also known as Rotor type hyperbilirubinemia)
is a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia, relatively
benign,
autosomal recessive bilirubin
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
disorder characterized by non-hemolytic jaundice due to the chronic elevation of predominantly conjugated bilirubin.
Rotor type hyperbilirubinemia is a distinct yet similar disorder to
Dubin–Johnson syndrome[ – both diseases cause an increase in conjugated bilirubin. Whereas rotor syndrome differs in that it is a result of impaired hepatocellular storage of conjugated bilirubin that leaks into plasma causing hyperbilirubinemia.]
Signs and symptoms
Rotor syndrome has many features in common with Dubin–Johnson syndrome, an exception being that the liver cells are not pigmented. The main symptom is a non-itching jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
. There is a rise in bilirubin
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
in the patient's serum
Serum may refer to:
*Serum (blood), plasma from which the clotting proteins have been removed
**Antiserum, blood serum with specific antibodies for passive immunity
* Serous fluid, any clear bodily fluid
* Truth serum, a drug that is likely to mak ...
, mainly of the conjugated type.
It can be differentiated from Dubin–Johnson syndrome in the following ways:
Rotor syndrome may exacerbate toxic side effects of the medication irinotecan.
Pathophysiology
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
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical ...
, 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
Cholescintigraphy or hepatobiliary scintigraphy is scintigraphy of the hepatobiliary tract, including the gallbladder and bile ducts. The image produced by this type of medical imaging, called a cholescintigram, is also known by other names depen ...
using sulfobromophthalein
Bromsulfthalein (also known as bromsulphthalein, bromosulfophthalein, and BSP) is a phthalein dye
Phthalein dyes are a class of dyes mainly used as pH indicators, due to their ability to change colors depending on pH. They are formed by the reac ...
(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.
Genetics
Rotor syndrome is inherited in an autosomal recessive manner.[ The '' SLCO1B1'' and '' SLCO1B3'' genes are involved in Rotor syndrome.] Mutations in both genes are required for the condition to occur. The ''SLCO1B1'' and ''SLCO1B3'' genes provide instructions for making similar proteins, called organic anion transporting polypeptide
Members of the Organo Anion Transporter (OAT) Family (organic-anion-transporting polypeptides, OATP) are membrane transport proteins or 'transporters' that mediate the transport of mainly organic anions across the cell membrane. Therefore, OATPs a ...
1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), respectively. Both proteins are found in liver cells; they transport bilirubin and other compounds from the blood into the liver so that they can be cleared from the body. In the liver, bilirubin is dissolved in a digestive fluid called bile and then excreted from the body. The ''SLCO1B1'' and ''SLCO1B3'' gene mutations that cause Rotor syndrome lead to abnormally short, nonfunctional OATP1B1 and OATP1B3 proteins or an absence of these proteins. Without the function of either transport protein, bilirubin is less efficiently taken up by the liver and removed from the body. The buildup of this substance leads to jaundice in people with Rotor syndrome.
Diagnosis
Increased conjugated hyperbilirubinemia is the hallmark for diagnosing Rotor syndrome. There is no distinct black pigmentation of the liver as seen in a similar, Dubin-Johnson Syndrome. Genes, ''SLCO1B1'' and ''SLCO1B3'' that result in complete functional deficiencies of both protein products (OATP1B1 and OATP1B3, respectively), are also present.
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
The enzyme alkaline phosphatase (EC 3.1.3.1, alkaline phosphomonoesterase; phosphomonoesterase; glycerophosphatase; alkaline phosphohydrolase; alkaline phenyl phosphatase; orthophosphoric-monoester phosphohydrolase (alkaline optimum), systematic ...
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 the 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 Dubin Johnson syndrome. 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
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.
History
Rotor syndrome is named after the Filipino internist Arturo Belleza Rotor
Arturo Belleza Rotor (June 7, 1907 – April 9, 1988) was a Filipino medical doctor, civil servant, musician, and writer.
Medical and government career
Rotor was born in the Philippines and attended the University of the Philippines. He ...
(1907–1988).
See also
* Jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
* Bilirubin metabolism
* Gilbert's syndrome
* Crigler–Najjar syndrome
References
External links
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* Mentioned in
{{DEFAULTSORT:Rotor Syndrome
Syndromes
Heme metabolism disorders
Rare diseases
Autosomal recessive disorders
Hepatology