What are the implications of an isolated elevated bilirubin level of 37 micromoles per liter (µmol/L) with otherwise normal liver enzymes?

From the Guidelines

For an isolated bilirubin elevation of 37 µmol/L with otherwise normal liver enzymes, the most likely diagnosis is Gilbert's syndrome, which requires no specific treatment. This condition is a benign, hereditary disorder affecting 5-10% of the population, causing mild unconjugated hyperbilirubinemia due to reduced activity of the enzyme UDP-glucuronosyltransferase 1. To confirm this diagnosis, it is essential to observe if the bilirubin increases during fasting, stress, or illness, which is characteristic of Gilbert's syndrome.

Key Considerations

• No medications, dietary changes, or lifestyle modifications are necessary for Gilbert's syndrome.
• It is crucial to rule out other causes of isolated hyperbilirubinemia, such as hemolysis, which would require a complete blood count, reticulocyte count, and peripheral blood smear.
• If the patient is experiencing jaundice (yellowing of skin/eyes), they can be reassured this is harmless.
• Patients with Gilbert's syndrome should mention this condition when undergoing medical evaluations to avoid unnecessary testing when mild hyperbilirubinemia is detected.

Diagnostic Approach

• The guidelines on the management of abnormal liver blood tests suggest that an isolated elevated bilirubin concentration is most commonly caused by Gilbert’s syndrome, which leads to impaired conjugation via reduced activity of the enzyme glucuronyltransferase 1.
• In the absence of haemolysis, the cause of an isolated elevated bilirubin concentration is virtually always Gilbert’s syndrome if the majority of the elevated bilirubin comprises the unconjugated fraction.
• The american gastroenterological association medical position statement also supports the evaluation of liver chemistry tests, including the assessment of bilirubin levels, to determine the underlying cause of abnormal liver function 1.

From the Research

Approach to Isolated Bilirubin Elevation

• Isolated bilirubin elevation of 37 µmol/L with otherwise normal liver enzymes requires a systematic approach to determine the underlying cause 2, 3.
• A comprehensive medical history, review of systems, and physical examination are essential to differentiate potential causes such as hemolysis, liver disease, or biliary tract disease 4.
• Initial laboratory evaluation should include assays for bilirubin (total and fractionated), as measuring fractionated bilirubin allows for determination of whether the hyperbilirubinemia is conjugated or unconjugated 4, 5.

Interpretation of Bilirubin Levels

• Elevated plasma bilirubin levels can be secondary to alterations in any stage of its metabolism, including excess bilirubin production, impaired liver uptake, impaired conjugation, or bile clearance defect 5.
• Serum bilirubin is determined by various analytical methods, including diazo transfer reaction, high-performance liquid chromatography (HPLC), and direct spectrophotometry 5.
• Alterations in bilirubin concentrations should be assessed in relation to patient anamnesis, the degree of the alteration, and the pattern of concurrent biochemical alterations 5.

Next Steps

• If the etiology of isolated bilirubin elevation is unclear, further testing such as ultrasonography of the abdomen, computed tomography with intravenous contrast media, or magnetic resonance cholangiopancreatography may be required 4.
• A liver biopsy may be necessary to establish the diagnosis, prognosis, and management of the disease if the etiology remains unclear despite laboratory testing and imaging 4.