What causes hyperbilirubinemia?

Causes of Hyperbilirubinemia

Hyperbilirubinemia is caused by an imbalance between bilirubin production and elimination, with three major categories of causes: prehepatic (excessive bilirubin production), intrahepatic (impaired bilirubin processing), and posthepatic (biliary obstruction). 1

Classification by Bilirubin Type

Unconjugated (Indirect) Hyperbilirubinemia

Prehepatic Causes

• Hemolytic disorders:

  • Hemolytic anemias (sickle cell disease, thalassemia, hereditary spherocytosis)
  • Glucose-6-phosphate dehydrogenase deficiency
  • Absorption of large hematomas
  • Increased red blood cell destruction 1, 2

• Laboratory findings:

  • Elevated reticulocyte count
  • Decreased hemoglobin
  • Abnormal red cell morphology
  • Increased end-tidal carbon monoxide (ETCOc) 3

Intrahepatic Causes

• Enzyme deficiencies:

  • Gilbert syndrome (reduced glucuronosyltransferase activity) - affects 5% of the population 1
  • Crigler-Najjar syndrome

• Drug-induced:

  • Certain antiviral medications can impair bilirubin conjugation 4

Conjugated (Direct) Hyperbilirubinemia

Intrahepatic Causes

• Hepatocellular injury:

  • Viral hepatitis (A, B, C, D, E, Epstein-Barr virus)
  • Alcoholic liver disease
  • Autoimmune hepatitis
  • Drug-induced liver injury (acetaminophen, penicillin, oral contraceptives, anabolic steroids, chlorpromazine) 1
  • Sepsis or low perfusion states 1

• Cholestatic disorders:

  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Medication-induced cholestasis 1

Posthepatic (Obstructive) Causes

• Intrinsic biliary obstruction:

  • Choledocholithiasis (gallstones in bile duct)
  • Cholangitis
  • Cholangiocarcinoma
  • Gallbladder cancer 1

• Extrinsic biliary compression:

  • Pancreatic tumors
  • Pancreatitis causing biliary obstruction
  • Lymphoma
  • Other malignancies compressing bile ducts 1, 5

Epidemiology of Causes

In the United States, the most common causes of jaundice fall into four categories:

1. Hepatitis
2. Alcoholic liver disease
3. Blockage of common bile duct by gallstone or tumor
4. Toxic reaction to drugs or medicinal herbs 1

In severe jaundice cases, European studies have found malignancy to be the most common cause, followed by sepsis/shock (22%), cirrhosis (21%), common bile duct stones (13%), drugs (0.5%), autoimmune hepatitis (0.2%), and viral hepatitis (0.2%) 1.

Special Populations

Neonates

• 60% of term and 80% of preterm infants develop jaundice in the first week of life 6
• Primarily due to immature liver conjugation systems
• Hemolytic disorders are a common cause of extreme neonatal hyperbilirubinemia 2

Post-procedural

• Severe hyperbilirubinemia after transjugular intrahepatic portosystemic shunts (TIPS) creation indicates poor prognosis
• Risk factors include non-alcoholic liver disease and prolonged prothrombin time 7

Diagnostic Approach

1. Fractionation of bilirubin to determine if elevation is predominantly conjugated or unconjugated 3

   • Direct (conjugated) bilirubin >20-30% of total or >1.0 mg/dL when total bilirubin is ≤5 mg/dL indicates conjugated hyperbilirubinemia

2. Liver function tests:

   • ALT, AST, alkaline phosphatase, GGT, albumin, PT/INR 3

3. Hemolysis evaluation:

   • Complete blood count with differential
   • Blood smear for red cell morphology
   • Reticulocyte count 3

4. Imaging:

   • Abdominal ultrasound is first-line for suspected biliary obstruction (sensitivity 32-100%, specificity 71-97%) 1, 3
   • MRI with MRCP for better biliary anatomy evaluation when obstruction is suspected 3

Common Pitfalls to Avoid

• Delayed evaluation of conjugated hyperbilirubinemia, which always represents pathology requiring prompt investigation 3
• Overdiagnosis and unnecessary testing for mild indirect hyperbilirubinemia 3
• Confusing direct bilirubin with conjugated bilirubin in laboratory reports 3
• Attributing mild indirect hyperbilirubinemia to significant liver disease when it may represent a benign variant like Gilbert's syndrome 3
• Failing to consider drug-induced causes, especially in patients on antiviral medications 4

Understanding the pattern of bilirubin elevation (conjugated vs. unconjugated) is the key first step in determining the underlying cause of hyperbilirubinemia and directing appropriate further evaluation.