When to investigate mildly elevated bilirubin in adults?

From the Guidelines

A workup for mildly elevated bilirubin in adults should be initiated when total bilirubin exceeds 1.5-2.0 mg/dL, especially if persistent over multiple measurements or accompanied by symptoms. Initial evaluation should include a comprehensive history focusing on alcohol use, medications, family history of liver or blood disorders, and a complete physical examination looking for signs of liver disease. Laboratory testing should include liver function tests (ALT, AST, alkaline phosphatase, GGT), complete blood count, direct and indirect bilirubin fractions, and hepatitis serologies 1. If indirect (unconjugated) bilirubin predominates, consider Gilbert's syndrome, hemolysis, or ineffective erythropoiesis. For predominantly direct (conjugated) hyperbilirubinemia, focus on hepatobiliary causes. Additional testing may include abdominal ultrasound to evaluate the liver and biliary tract, particularly if direct bilirubin or other liver enzymes are elevated. Specialized testing such as hemolysis workup or genetic testing for conditions like Gilbert's syndrome may be warranted based on initial findings. The workup is important because even mild elevations can indicate underlying conditions ranging from benign disorders like Gilbert's syndrome (affecting 5-10% of the population) to more serious conditions like early liver disease, hemolytic anemia, or biliary obstruction that require specific management.

Key Considerations

• The most recent and highest quality study, published in 2019 in the Journal of the American College of Radiology 1, provides guidance on the evaluation of jaundice, which is relevant to the investigation of mildly elevated bilirubin.
• The study emphasizes the importance of differentiating between unconjugated and conjugated hyperbilirubinemia, as this distinction can help guide further evaluation and management.
• The American College of Gastroenterology recommends additional laboratory testing, including liver function tests and hepatitis serologies, for patients with conjugated hyperbilirubinemia 1.
• Abdominal ultrasound is a useful initial imaging test for evaluating the liver and biliary tract, particularly if direct bilirubin or other liver enzymes are elevated 1.
• Specialized testing, such as hemolysis workup or genetic testing, may be warranted based on initial findings, and referral to a hepatology clinic may be necessary for further evaluation and management 1.

Laboratory Testing

• Liver function tests (ALT, AST, alkaline phosphatase, GGT)
• Complete blood count
• Direct and indirect bilirubin fractions
• Hepatitis serologies
• Additional testing as indicated by initial findings, such as hemolysis workup or genetic testing for conditions like Gilbert's syndrome.

Imaging Studies

• Abdominal ultrasound to evaluate the liver and biliary tract
• Additional imaging studies, such as CT or MRI, may be warranted based on initial findings and clinical suspicion.

From the Research

Evaluation of Mildly Elevated Bilirubin in Adults

• Mildly elevated bilirubin levels can be an indicator of underlying disease, and evaluation should start with a careful history and physical examination, followed by laboratory tests and imaging assessments 2, 3, 4.
• The initial laboratory evaluation should include fractionated bilirubin, complete blood count, liver function tests, and coagulation studies to determine the cause of hyperbilirubinemia 2, 4.
• Imaging studies such as ultrasonography or computed tomography can help differentiate between extrahepatic obstructive and intrahepatic parenchymal disorders 2, 4.

Causes of Hyperbilirubinemia

• Unconjugated hyperbilirubinemia can occur due to increased bilirubin production or impaired bilirubin conjugation, such as in hemolytic disorders or Gilbert syndrome 2.
• Conjugated hyperbilirubinemia can occur due to hepatocellular damage or cholestatic disorders, such as viral hepatitis or biliary obstruction 2, 3.
• Certain medications, such as ceftriaxone, can also cause hyperbilirubinemia, particularly in patients with underlying liver disease or sickle cell disease 5.

Association with Atherosclerotic Diseases

• Mildly elevated bilirubin levels have been associated with protection against oxidative stress-mediated diseases, including atherosclerotic conditions 6.
• Studies have shown that subjects with mild elevation of serum unconjugated bilirubin have a lower prevalence of coronary heart disease and peripheral vascular disease 6.