What conditions are associated with a waxing and waning type of jaundice?

Waxing and Waning Type of Jaundice: Causes and Diagnosis

Gilbert syndrome is the most common cause of waxing and waning jaundice, characterized by intermittent episodes of unconjugated hyperbilirubinemia without underlying liver disease or hemolysis. 1

Causes of Waxing and Waning Jaundice

1. Gilbert Syndrome

• Most common cause affecting 3-7% of the US population 2 and up to 5-15% of the Western population 3
• Characterized by:
  • Asymptomatic episodes of mild jaundice
  • Unconjugated (indirect) hyperbilirubinemia
  • Typically triggered by stress, fasting, intercurrent illness, or strenuous exercise 2
  • Bilirubin levels usually <3 mg/dL but can rarely exceed 6 mg/dL 1
  • Caused by reduced activity (approximately 30% of normal) of the enzyme UDP-glucuronosyltransferase (UGT1A1) 3

2. Other Causes of Fluctuating Jaundice

Intrahepatic Causes

• Drug-induced liver injury (DILI)

  • Can cause cholestatic pattern with fluctuating bilirubin levels
  • Common culprits: acetaminophen, penicillin, oral contraceptives, anabolic steroids, chlorpromazine 4
  • Onset typically between 2-12 weeks from drug initiation, but may occur up to one year later 4

• Autoimmune hepatitis

  • Can present with fluctuating liver enzymes and bilirubin levels 5

Posthepatic (Obstructive) Causes

• Intermittent biliary obstruction

  • Choledocholithiasis (gallstones in bile duct) causing partial or intermittent obstruction 4
  • Presents with conjugated (direct) hyperbilirubinemia 6

• Primary sclerosing cholangitis

  • Progressive inflammatory condition with stricturing of bile ducts
  • Can cause fluctuating jaundice due to varying degrees of obstruction 4

Diagnostic Approach

1. Laboratory Testing

• Determine type of hyperbilirubinemia:

  • Unconjugated (indirect) hyperbilirubinemia: Gilbert syndrome, hemolysis
  • Conjugated (direct) hyperbilirubinemia (>35% of total): suggests hepatocellular or obstructive causes 4

• Additional tests:

  • Liver enzymes (ALT, AST, ALP, GGT)
  • Gilbert syndrome: ALP and GGT typically normal
  • Obstructive causes: elevated ALP and GGT 4

2. Imaging

• Ultrasound: first-line imaging for jaundice

  • High sensitivity (65-95%) for liver parenchymal disease
  • Variable sensitivity (32-100%) for biliary obstruction 4

• CT or MRI: second-line when ultrasound is inconclusive

  • Better for detecting focal lesions and staging fibrosis 5

3. Specialized Testing

• For Gilbert syndrome:

  • Genetic testing for UGT1A1 gene mutations when diagnosis is uncertain 1
  • Typically shows a variant TATAA element in the promoter region 3

• For obstructive causes:

  • MRCP (Magnetic Resonance Cholangiopancreatography) or ERCP (Endoscopic Retrograde Cholangiopancreatography) may be needed to visualize biliary tree

Important Clinical Pearls

• Gilbert syndrome is benign and requires no treatment, but it's important to distinguish it from more serious conditions
• When bilirubin levels exceed 6 mg/dL in suspected Gilbert syndrome, hemolytic and other metabolic diseases must be ruled out 1
• In patients with Gilbert syndrome, concurrent conditions like viral hepatitis or medication use may cause disproportionate elevation of bilirubin
• The presence of delta bilirubin (bound to albumin) can cause prolonged direct hyperbilirubinemia with a half-life of approximately 21 days 4
• Always consider medication history in patients with fluctuating jaundice, as drug-induced liver injury can present with a cholestatic pattern 4

Remember that while Gilbert syndrome is the most common cause of waxing and waning jaundice, other more serious conditions should be excluded through appropriate testing before making this diagnosis.