What is the appropriate workup for a healthy 28-year-old male with chronically elevated total bilirubin (hyperbilirubinemia)?

From the Guidelines

For a chronically elevated total bilirubin in a healthy 28-year-old male, the initial workup should focus on distinguishing between Gilbert syndrome and other more serious liver conditions, starting with a comprehensive liver panel including direct and indirect bilirubin fractions, as recommended by the most recent guidelines 1. The comprehensive liver panel should include ALT, AST, alkaline phosphatase, GGT, albumin, and total protein to assess liver function and identify any potential liver damage. If the elevation is predominantly indirect (unconjugated) bilirubin with normal liver enzymes, Gilbert syndrome is likely, as it is a common cause of isolated elevated bilirubin concentration, especially in young adults 1. A complete blood count should be ordered to rule out hemolysis as a cause of elevated bilirubin, as hemolysis can also lead to increased levels of indirect bilirubin. Additional testing may include abdominal ultrasound to evaluate liver and biliary anatomy, hepatitis serologies (A, B, and C), iron studies to rule out hemochromatosis, and ceruloplasmin levels to exclude Wilson's disease, as recommended by the American College of Radiology 1. If Gilbert syndrome is suspected, a provocative fasting test may be performed where bilirubin levels are measured after 24 hours of reduced caloric intake (approximately 400 calories per day); a significant increase in unconjugated bilirubin supports this diagnosis, as fasting can exacerbate the condition 1. Gilbert syndrome is a benign condition caused by reduced activity of the enzyme UDP-glucuronosyltransferase, which conjugates bilirubin for excretion, and typically requires no treatment, though patients should be reassured about its benign nature and advised that fasting, stress, or illness may temporarily worsen the hyperbilirubinemia. The latest guidelines from the American College of Radiology recommend using imaging studies such as ultrasound or MRI to evaluate the liver and biliary anatomy in patients with abnormal liver function tests, including those with hyperbilirubinemia 1. In this case, the patient's symptoms and laboratory results should guide the choice of imaging study, with the goal of distinguishing between Gilbert syndrome and other more serious liver conditions. By following this approach, clinicians can provide an accurate diagnosis and appropriate management for patients with chronically elevated total bilirubin, prioritizing their morbidity, mortality, and quality of life. Key points to consider in the workup include:

• Comprehensive liver panel to assess liver function and identify potential liver damage
• Complete blood count to rule out hemolysis
• Abdominal ultrasound to evaluate liver and biliary anatomy
• Hepatitis serologies and iron studies to rule out other liver conditions
• Provocative fasting test to support the diagnosis of Gilbert syndrome
• Imaging studies such as ultrasound or MRI to evaluate the liver and biliary anatomy, as recommended by the latest guidelines 1.

From the Research

Evaluation of Chronically Elevated Total Bilirubin

• The evaluation of a patient with chronically elevated total bilirubin should start with a careful history and physical examination, followed by directed imaging of the biliary tree and liver 2.
• Total bilirubin elevation can occur in either cholestatic or hepatocellular diseases, and elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions 3.
• An elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings 3.

Diagnostic Approach

• The diagnostic approach should include testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency 3.
• A history of prescribed and over-the-counter medicines should be sought, as some medications can cause liver injury 3.
• For the evaluation of an alkaline phosphatase elevation determined to be of hepatic origin, testing for primary biliary cholangitis and primary sclerosing cholangitis should be undertaken 3.

Further Evaluation

• A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible 3.
• Algorithm models that incorporate bilirubin levels in their predictor models for outcomes in patients with chronic liver disease may be useful in evaluating patients with jaundice 2.