From the Guidelines
The workup for indirect (unconjugated) bilirubin elevation should begin with a thorough history and physical examination, followed by targeted laboratory testing, as recommended by the most recent guidelines 1. The initial step in evaluating indirect bilirubin elevation is to distinguish between increased bilirubin production and decreased hepatic clearance.
- Increased bilirubin production is typically due to hemolysis, which can be suspected based on laboratory tests such as complete blood count with peripheral smear, reticulocyte count, lactate dehydrogenase (LDH), and haptoglobin 1.
- Decreased hepatic clearance, on the other hand, can be due to conditions such as Gilbert syndrome, which is an inherited disorder of metabolism leading to impaired conjugation of bilirubin 1. Initial labs should include:
- Complete blood count with peripheral smear
- Reticulocyte count
- Liver function tests (AST, ALT, alkaline phosphatase, GGT)
- Direct and indirect bilirubin levels
- Lactate dehydrogenase (LDH)
- Haptoglobin If hemolysis is suspected, additional tests like Coombs test, G6PD level, and hemoglobin electrophoresis should be ordered 1. For suspected Gilbert syndrome, genetic testing for UGT1A1 mutations may be considered, though this is often a diagnosis of exclusion 1. Imaging studies are generally not necessary for isolated indirect hyperbilirubinemia unless liver disease is suspected, in which case an abdominal ultrasound would be appropriate 1. Management depends on the underlying cause - hemolytic conditions may require treatment of the underlying disorder, while Gilbert syndrome typically needs no specific treatment 1. Patients with significant hemolysis may need supportive care including hydration and, in severe cases, blood transfusions 1. The workup focuses on distinguishing between increased bilirubin production (typically from hemolysis) and decreased hepatic clearance (as in Gilbert syndrome), as unconjugated bilirubin elevations result from either excessive red blood cell breakdown or impaired uptake and conjugation of bilirubin by the liver 1.
From the Research
Initial Evaluation
- A comprehensive medical history, review of systems, and physical examination are essential for differentiating potential causes of indirect bilirubin elevation, such as hemolysis or hepatitis 2.
- Initial laboratory evaluation should include assays for bilirubin (total and fractionated), a complete blood cell count, aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, alkaline phosphatase, albumin, prothrombin time, and international normalized ratio 2.
Diagnostic Approach
- Measuring fractionated bilirubin allows for determination of whether the hyperbilirubinemia is conjugated or unconjugated, which can help guide further evaluation 2.
- Ultrasonography of the abdomen, computed tomography with intravenous contrast media, and magnetic resonance cholangiopancreatography are first-line options for patients presenting with jaundice, depending on the suspected underlying etiology 2.
- Evaluation of patients with jaundice starts with a careful history and physical examination, followed by directed imaging of the biliary tree and liver 3.
Further Testing
- If the etiology of jaundice is unclear despite laboratory testing and imaging, liver biopsy may be required to establish the diagnosis, prognosis, and management of the disease 2.
- Algorithm models that incorporate bilirubin levels in their predictor models for outcomes in patients with chronic liver disease, such as the model for end-stage liver disease, can be useful in evaluating patients with jaundice 3.