Table.

Test Characteristics

Bilirubin is the normal by-product of the breakdown of hemoglobin. Bilirubin circulates in the blood bound to albumin and is taken up by hepatocytes in the liver. Within hepatocytes, bilirubin is conjugated with glucuronic acid, a process catalysed by uridine diphosphoglucuronate-glucuronyltransferase (UDP-GT). Conjugated (direct) bilirubin is secreted into bile. This process is normally highly efficient so plasma unconjugated (indirect) bilirubin concentrations remain low. Hyperbilirubinemia can be caused by conditions leading to predominantly unconjugated hyperbilirubinemia and those characterized by predominantly conjugated hyperbilirubinemia (Figure). Diseases that increase the rate of bilirubin formation (eg, hemolysis, dyserythropoiesis), reduce hepatic uptake of bilirubin (eg, medications [gemfibrozil, irinotecan and the protease inhibitors, atazanavir, and indinavir]; portosystemic shunts), or reduce the rate of bilirubin conjugation (eg, Gilbert syndrome) result in increased levels of indirect bilirubin (Figure).

Gilbert syndrome, also known as Gilbert-Meulengracht syndrome, is a hereditary condition with incomplete penetrance, characterized by intermittent unconjugated hyperbilirubinemia in the absence of hepatocellular disease or hemolysis.¹ Gilbert syndrome is present in 5% to 10% of Western European populations and patients are frequently unaware of their diagnosis.^2,3 A genetic variant in the promoter region of theUGT1A1 gene, which encodes for UDP-GT, is associated with Gilbert syndrome and there is an additional thymine-adenine (TA) base pair in the TATA box instead of the normal 6 pairs.² In Gilbert syndrome, there is a 70% reduction in the liver’s ability to conjugate bilirubin that can lead to intermittent episodes of nonpruritic jaundice, which are precipitated by fasting, infection, and overexertion.³ Several therapeutic drugs including gemfibrozil, irinotecan, atazanavir, and indinavir inhibit UDP-GT activity and can trigger jaundice episodes in Gilbert syndrome.⁴

The diagnosis of Gilbert syndrome as the cause of hyperbilirubinemia should only be made after excluding other liver and hematologic disorders. Patients with Gilbert syndrome are asymptomatic and typically have otherwise normal liver serum chemistries. If the unconjugated bilirubin fraction predominates, hemolytic disorders and rare familial hyperbilirubinemias must be considered. In Gilbert syndrome, the degree of hyperbilirubinemia is typically less than 5 mg/dL and the conjugated bilirubin is typically less than 20% of the total bilirubin fraction.³ The Medicare midpoint reimbursement for a total and direct serum bilirubin is $9.25 for each.⁵ The cost ofUGT1A1 gene analysis ranges from $75 to $103, although it is rarely used for diagnosis.⁶

Application of Test Results to This Patient

Gilbert syndrome is the most likely cause of the unconjugated hyperbilirubinemia in the setting of normal liver enzymes and in the absence of medications that reduce hepatic uptake of bilirubin or symptoms suggesting hepatobiliary disease or hemolysis. Dubin-Johnson syndrome is another benign hereditary condition characterized by a predominantly conjugated hyperbilirubinemia but would not explain the unconjugated hyperbilirubinemia.

Gilbert syndrome is typically diagnosed in the first 3 decades of life and no specific management is required for most patients. The Gilbert syndrome genotype is associated with an increased risk of gallstones^1,7 and adverse reactions to multiple drugs, including chemotherapy.^1,4,6,7 It is possible but unclear if elevated serum bilirubin levels protect against cardiovascular or other diseases.^8,9 A recent study reported an association of Gilbert syndrome with a 50% reduction in mortality compared with the general population (24 vs 50 deaths per 10 000 person-years).¹⁰ Another study suggested that Gilbert syndrome may be associated with an increased risk for breast cancer.^1,4

What Are Alternative Diagnostic Testing Approaches?

Hemolysis and drug-induced hyperbilirubinemia should be excluded. Presence of hemolysis can be evaluated with a peripheral blood smear and levels of lactate dehydrogenase and haptoglobin. Provocation tests, including observing an increase in unconjugated bilirubin after a 48-hour fast, are not recommended.³ The diagnosis of Gilbert syndrome can be made in patients who continue to have normal laboratory results (other than the elevation in serum bilirubin) during the next 12 months. For cases in which diagnostic uncertainty remains, such as total bilirubin of greater than 5 mg/dL, genetic testing for aUGT1A1 mutation can be performed athough this is rarely necessary. Liver or biliary imaging and referral to a specialist are typically not needed. Overtesting may be deleterious to otherwise healthy patients with this benign condition.

Patient Outcome

In this patient, a peripheral blood smear, lactate dehydrogenase, and haptoglobin levels confirmed the absence of hemolysis. Repeat bilirubin measured 6 and 12 months later was elevated and a diagnosis of Gilbert syndrome was made. The patient remains well and follows up with his primary care physician for routine medical care.

Acknowledgments

Funding/Support: Dr VanWagner reports receipt of support from the National Institutes of Health (1 F32 HL116151-01), the American Liver Foundation Postdoctoral Research Fellowship Award and the American Association for the Study of Liver Diseases Foundation.

Role of the Sponsors: The sponsors had no role in the preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Footnotes

REFERENCES