From the Guidelines
The workup of unconjugated hyperbilirubinemia should begin with a thorough history and physical examination, followed by targeted laboratory testing to determine the underlying cause, as recommended by the most recent guidelines 1. The initial step in evaluating unconjugated hyperbilirubinemia is to obtain a complete blood count, reticulocyte count, peripheral blood smear, liver function tests, and direct and indirect bilirubin levels.
- For hemolytic causes, consider hemoglobin electrophoresis, haptoglobin levels, and Coombs test.
- If Gilbert syndrome is suspected (mild elevation of unconjugated bilirubin without other abnormalities), a 24-48 hour fast may exacerbate the hyperbilirubinemia, supporting this diagnosis.
- For neonates, assess for risk factors of kernicterus and consider phototherapy if bilirubin levels exceed age-specific thresholds, as outlined in the 2024 guidelines for phototherapy in newborns 2. In cases of severe hemolysis, additional testing for specific hemolytic anemias may be necessary. Unconjugated hyperbilirubinemia occurs when there is excessive bilirubin production (typically from hemolysis), impaired bilirubin uptake by hepatocytes, or defective bilirubin conjugation in the liver. The pattern of laboratory abnormalities helps distinguish between these mechanisms - elevated reticulocytes and decreased haptoglobin suggest hemolysis, while normal values with isolated unconjugated hyperbilirubinemia point toward Gilbert syndrome or other conjugation defects, as noted in the 2018 guidelines on the management of abnormal liver blood tests 3. It is essential to evaluate the underlying cause or causes of hyperbilirubinemia in infants who require phototherapy, including measuring glucose-6-phosphate dehydrogenase enzyme activity in any infant with jaundice of unknown cause whose total serum bilirubin (TSB) rises despite intensive phototherapy 2.
From the Research
Workup of Unconjugated Hyperbilirubinemia
To work up unconjugated hyperbilirubinemia, the following steps can be taken:
- Initial laboratory evaluation should include fractionated bilirubin, a complete blood count, alanine transaminase, aspartate transaminase, alkaline phosphatase, ?-glutamyltransferase, prothrombin time and/or international normalized ratio, albumin, and protein 4, 5
- Measuring fractionated bilirubin allows for determination of whether the hyperbilirubinemia is conjugated or unconjugated 5
- Imaging with ultrasonography or computed tomography can differentiate between extrahepatic obstructive and intrahepatic parenchymal disorders 4
- A more extensive evaluation may include additional cancer screening, biliary imaging, autoimmune antibody assays, and liver biopsy 4
Causes of Unconjugated Hyperbilirubinemia
Unconjugated hyperbilirubinemia can occur due to:
- Increased bilirubin production caused by red blood cell destruction, such as hemolytic disorders 4
- Disorders of impaired bilirubin conjugation, such as Gilbert syndrome 4, 6
- Other causes such as hypothyroidism 7
Diagnostic Evaluation
The diagnostic evaluation of jaundice, which is an indication of hyperbilirubinemia, should start with a careful history and physical examination, followed by directed imaging of the biliary tree and liver 8
- Algorithm models that incorporate bilirubin levels can be used to predict outcomes in patients with chronic liver disease 8
Laboratory Tests
Laboratory tests that can be used to evaluate unconjugated hyperbilirubinemia include:
- Complete blood count 4, 5
- Liver function tests, such as alanine transaminase, aspartate transaminase, alkaline phosphatase, and ?-glutamyltransferase 4, 5
- Bilirubin levels, including fractionated bilirubin 4, 5
- Other tests, such as prothrombin time and/or international normalized ratio, albumin, and protein 4