From the Guidelines
Elevated bilirubin with otherwise normal bloodwork is most commonly due to Gilbert's syndrome, a benign genetic condition affecting 3-7% of the population, and requires only reassurance as it causes no harm and has no impact on lifespan or quality of life. The condition results from a mutation in the UGT1A1 gene, which reduces the liver's ability to conjugate bilirubin by about 30% 1. Typically, total bilirubin levels range from 1-3 mg/dL, predominantly unconjugated (indirect) bilirubin, and may increase during fasting, stress, illness, or exercise. Other potential causes of isolated hyperbilirubinemia include:
- Hemolysis
- Medication effects
- Rare conditions like Crigler-Najjar syndrome If Gilbert's syndrome is suspected but uncertain, confirming the diagnosis may involve:
- Checking unconjugated vs. conjugated bilirubin levels
- Genetic testing for the UGT1A1 mutation
- A provocative fasting test 1. According to the guidelines on the management of abnormal liver blood tests, most laboratories will routinely report total bilirubin, which comprises unconjugated and conjugated fractions, and elevations of either fraction will lead to a rise in the measured bilirubin concentration 1. The American Gastroenterological Association medical position statement also suggests that elective radiologic and serologic evaluations should be dependent on the clinical scenario specific to an individual patient 1. However, in the context of elevated bilirubin with otherwise normal bloodwork, the most recent and highest quality study suggests that Gilbert's syndrome is the most likely cause, and no further evaluation is necessary unless there are other symptoms or laboratory abnormalities 1.
From the Research
Interpretation of Elevated Bilirubin
Elevated bilirubin levels can indicate various conditions, including liver disease, hemolysis, or biliary tract disorders 2, 3. The interpretation of elevated bilirubin with otherwise unremarkable bloodwork requires a comprehensive medical history, review of systems, and physical examination to differentiate potential causes.
Potential Causes of Elevated Bilirubin
Some potential causes of elevated bilirubin include:
- Alcoholic liver disease
- Biliary strictures
- Choledocholithiasis
- Drug-induced liver injury
- Hemolysis
- Hepatitis
Laboratory Evaluation
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. Measuring fractionated bilirubin allows for determination of whether the hyperbilirubinemia is conjugated or unconjugated.
Imaging Studies
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. 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.
Limitations of Bilirubin as a Marker of Liver Function
Although bilirubin is a well-established marker of liver function, it does not always identify a lesion in this organ 3. Therefore, for accurate diagnosis, alterations in bilirubin concentrations should be assessed in relation to patient anamnesis, the degree of the alteration, and the pattern of concurrent biochemical alterations. Normal values in the baseline liver test panel do not yet rule out advanced chronic liver disease, and high levels of liver function tests do not automatically indicate liver failure 4.