From the Guidelines
Elevated bilirubin levels should be followed up with a comprehensive evaluation to determine the underlying cause, starting with calculating the proportion of conjugated bilirubin, which should be less than 20%-30% of the total bilirubin, as recommended by consensus guidelines 1. To evaluate elevated bilirubin, the following steps should be taken:
- Schedule a follow-up appointment within 1-2 weeks for repeat blood tests, including a complete liver panel (ALT, AST, alkaline phosphatase, GGT), complete blood count, and fractionated bilirubin to distinguish between conjugated and unconjugated hyperbilirubinemia.
- Consider genetic testing for DNA mutations of uridine 5'-diphospho-glucuronyl-transferase for definitive confirmation of Gilbert's Syndrome, especially when total bilirubin elevations occur in combination with elevated ALP and aminotransferases 1.
- If the aetiology of prolonged hyperbilirubinaemia is unclear, a breakdown of the direct bilirubin fraction to conjugated and delta bilirubin should be considered, as recommended by consensus guidelines 1.
- Additional testing may include abdominal ultrasound to evaluate the liver, gallbladder, and bile ducts for obstruction or structural abnormalities.
- If the elevation is significant (>3 mg/dL) or accompanied by symptoms like jaundice, abdominal pain, or dark urine, follow-up should occur sooner, within 2-3 days.
- During the waiting period, avoid alcohol consumption and medications that can stress the liver, including acetaminophen, and stay well-hydrated, reporting worsening symptoms immediately 1.
- Bilirubin elevation can result from various conditions including hemolysis (increased red blood cell breakdown), liver dysfunction, or bile duct obstruction, and the pattern of elevation (conjugated vs. unconjugated) and accompanying lab abnormalities will guide diagnosis and treatment, which may range from observation for mild Gilbert's syndrome to more aggressive intervention for hepatitis or biliary obstruction.
From the Research
Follow-up for Elevated Bilirubin
Elevated bilirubin levels can be an indicator of significant underlying disease, and the evaluation of jaundice relies on history, physical examination, and laboratory tests 2. The initial laboratory evaluation should include:
- Fractionated bilirubin
- Complete blood count
- Alanine transaminase
- Aspartate transaminase
- Alkaline phosphatase
- γ-glutamyltransferase
- Prothrombin time and/or international normalized ratio
- Albumin
- Protein
Differentiating Between Unconjugated and Conjugated Hyperbilirubinemia
Unconjugated hyperbilirubinemia occurs with increased bilirubin production caused by red blood cell destruction, such as hemolytic disorders, and disorders of impaired bilirubin conjugation, such as Gilbert syndrome 2. Conjugated hyperbilirubinemia occurs in disorders of hepatocellular damage, such as viral and alcoholic hepatitis, and cholestatic disorders, such as choledocholithiasis and neoplastic obstruction of the biliary tree 2, 3.
Imaging and Further Evaluation
Imaging with ultrasonography or computed tomography can differentiate between extrahepatic obstructive and intrahepatic parenchymal disorders 2. A more extensive evaluation may include additional cancer screening, biliary imaging, autoimmune antibody assays, and liver biopsy 2, 3. The evaluation of albumin and prothrombin levels evaluates the hepatic function per se, allowing to differentiate between acute and chronic diseases 4.
Interpretation of Liver Function Tests
Liver function tests should be interpreted correctly, considering not only the basic panel of liver function tests (bilirubin, ALT, AST, GGT, and ALP) but also other biochemical parameters, especially albumin, INR, and platelet count 5. 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 5.