From the Guidelines
The work-up of elevated total bilirubin should begin with a thorough history and physical examination, followed by laboratory testing to determine if the hyperbilirubinemia is predominantly unconjugated (indirect) or conjugated (direct), as recommended by the most recent guidelines 1.
Initial Evaluation
The initial evaluation should include a fractionated bilirubin test to distinguish between unconjugated and conjugated hyperbilirubinemia, along with liver function tests including ALT, AST, alkaline phosphatase, GGT, and albumin.
- For unconjugated hyperbilirubinemia, evaluate for hemolysis with CBC, reticulocyte count, haptoglobin, and peripheral blood smear.
- Consider genetic testing for conditions like Gilbert's syndrome or Crigler-Najjar syndrome, as the diagnosis of Gilbert's Syndrome should be determined by calculating the proportion of conjugated bilirubin which should be less than 20%‐30% of the total bilirubin 1.
Further Testing
For conjugated hyperbilirubinemia, assess for biliary obstruction or hepatocellular damage with ultrasound of the liver and biliary tract.
- Additional imaging may include MRCP, ERCP, or CT scan depending on initial findings.
- If biliary obstruction is identified, intervention may be required via ERCP with stent placement or surgery.
- For hepatocellular causes, further testing may include viral hepatitis serologies, autoimmune markers, iron studies, ceruloplasmin, and alpha-1 antitrypsin levels.
Pattern of Liver Enzyme Elevation
The pattern of liver enzyme elevation can help guide diagnosis - predominantly elevated transaminases suggest hepatocellular injury, while elevated alkaline phosphatase and GGT suggest cholestatic disease, as noted in the guidelines for detection, assessment and management of suspected acute drug-induced liver injury 1.
Medication Review
Medication review is essential as many drugs can cause hyperbilirubinemia through various mechanisms, and persistent isolated elevations of direct bilirubin in patients with cholestatic liver disease should be closely monitored, as this may be a sign of DILI, especially in patients with underlying synthetic function impairment 1.
From the Research
Approach to Evaluating Elevated Total Bilirubin
To work up elevated total bilirubin, the following steps can be taken:
- Start with a careful history and physical examination to identify any underlying disease states 2
- Directed imaging of the biliary tree and liver can help identify any liver lesions or bile duct defects 2, 3
- Measure serum bilirubin levels using various analytical methods, such as diazo transfer reaction, high-performance liquid chromatography (HPLC), or direct spectrophotometry 3
- Assess alterations in bilirubin concentrations in relation to patient anamnesis, the degree of the alteration, and the pattern of concurrent biochemical alterations 3
Common Causes of Hyperbilirubinemia
Some common causes of hyperbilirubinemia include:
- Excess bilirubin production (e.g., pathologic hemolysis) 3
- Impaired liver uptake or conjugation of bilirubin 3
- Bile clearance defects, such as defects in clearance proteins or inability of the bile to reach the small bowel through bile ducts 3
- Hemolytic anemia, which can be diagnosed using serum levels of erythrocyte adenylate kinase or plasma free hemoglobin 4, 5, 6
Diagnostic Evaluation
The diagnostic evaluation of hyperbilirubinemia may involve:
- Laboratory tests, such as serum bilirubin, lactate dehydrogenase (LDH), and reticulocyte count 5, 6
- Imaging studies, such as ultrasound or computed tomography (CT) scans, to evaluate the liver and biliary tree 2
- Measurement of plasma free hemoglobin or erythrocyte adenylate kinase to diagnose hemolytic anemia 5, 6