What is the treatment for an adult with hyperbilirubinemia?

Treatment of Hyperbilirubinemia in Adults

The treatment of hyperbilirubinemia in adults must be directed at the underlying cause, with initial diagnostic workup including fractionated bilirubin, complete blood count, liver function tests, and appropriate imaging to distinguish between hepatocellular and cholestatic disorders. 1

Diagnostic Approach

Initial Laboratory Evaluation

• Fractionated bilirubin (conjugated vs. unconjugated) is essential to determine the type of hyperbilirubinemia and guide further investigation 1
• Complete blood count to assess for hemolysis 1
• Liver function tests including ALT, AST, alkaline phosphatase, γ-glutamyltransferase 1
• Prothrombin time/INR, albumin, and protein to assess liver synthetic function 1
• When hyperbilirubinemia is due to drug-induced liver injury (DILI), the fraction of direct bilirubin should be measured and is usually greater than 35% 2

Imaging

• Ultrasonography is the initial imaging method of choice - least invasive and least expensive method to differentiate between extrahepatic obstructive and intrahepatic parenchymal disorders 1
• CT or MRI may be necessary for further evaluation if ultrasonography is inconclusive 2

Treatment Based on Type of Hyperbilirubinemia

Unconjugated (Indirect) Hyperbilirubinemia

Gilbert's Syndrome

• No specific treatment required as this is a benign condition 2
• Diagnosis is confirmed by calculating the amount of conjugated bilirubin, which should be less than 20%-30% of the total bilirubin, in the absence of hemolysis 2
• Genetic testing for DNA mutations of uridine 5'-diphospho-glucuronyl-transferase should be considered when diagnosis is unclear 2

Hemolytic Disorders

• Treatment directed at the underlying hemolytic process 1
• Monitor for development of gallstones which can occur with chronic hemolysis 3

Conjugated (Direct) Hyperbilirubinemia

Drug-Induced Liver Injury (DILI)

• Discontinuation of the offending medication is the primary treatment 4
• Close monitoring of persistent isolated elevations in direct bilirubin, especially in patients with underlying liver disease 2
• In cases of antiviral therapy-induced hyperbilirubinemia, modification in drug choice or dose may be required in cases of liver injury or significant hemolysis 4

Cholestatic Disorders

• For choledocholithiasis: endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction 1
• For malignant biliary obstruction: stent placement or surgical intervention depending on the location and nature of the obstruction 2
• For cholestatic liver diseases (e.g., PBC, PSC): ursodeoxycholic acid is commonly used 2
• Monitor for fat-soluble vitamin deficiencies in patients with chronic cholestasis 2
• Parenteral vitamin K supplementation should be attempted to correct prolonged INR in cholestatic patients before assigning causality to liver failure 2

Hepatocellular Disorders

• Viral hepatitis: antiviral therapy as appropriate for the specific virus 1
• Alcoholic hepatitis: alcohol cessation, nutritional support, and consideration of corticosteroids in severe cases 1
• Autoimmune hepatitis: immunosuppressive therapy 1

Inherited Disorders of Conjugated Hyperbilirubinemia

• Dubin-Johnson and Rotor syndromes typically require no specific treatment as they are benign conditions 5
• However, patients with these conditions may have increased susceptibility to drug toxicity and should be monitored accordingly 5

Special Considerations

Patients with Pre-existing Liver Disease

• More vigilant monitoring is required as these patients may not manifest the same degree of ALT elevation expected with DILI 2
• Patients with advanced cirrhosis typically have an altered AST to ALT ratio >1.0, instead of the normal ratio of 0.8 2
• Non-adherence to ursodeoxycholic acid in patients with cholestatic liver diseases can lead to abrupt elevations of liver tests that can mimic DILI 2

Monitoring and Follow-up

• Repeat liver function tests to monitor response to treatment 2
• For prolonged INR, repeat testing within 2-5 days to confirm the value and determine trajectory 2
• If the etiology of prolonged hyperbilirubinemia is uncertain, a breakdown of the direct bilirubin fraction to conjugated and delta bilirubin should be considered 2

Pitfalls and Caveats

• Do not confuse "direct" and "conjugated" hyperbilirubinemia, which are often incorrectly used interchangeably. Direct bilirubin includes both the conjugated fraction and delta bilirubin (bound to albumin) 2
• Isolated elevation of total bilirubin without aminotransferase elevation, even when it is predominantly direct hyperbilirubinemia, should not be considered DILI according to some guidelines, but this may not apply to patients with underlying cholestatic liver disease 2
• In patients with Gilbert's Syndrome (5-10% of the population), misdiagnosis may result in unnecessary diagnostic testing 2