Hereditary hyperbilirubinemias
The hereditary hyperbilirubinemias are inherited disorders of bilirubin handling that split into a benign, common unconjugated group (Gilbert syndrome, Crigler-Najjar types I and II) from defective UGT1A1 conjugation and a benign conjugated group (Dubin-Johnson and Rotor syndromes) from defective canalicular excretion. Diagnosis rests on the fractionated bilirubin pattern with otherwise normal liver chemistries, and management ranges from reassurance alone in Gilbert, Dubin-Johnson, and Rotor to phototherapy and liver transplant in Crigler-Najjar type I and phenobarbital in type II.
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What this article covers
- Overview
Definition: the hereditary hyperbilirubinemias are inherited bilirubin metabolism disorders producing chronic or intermittent jaundice with an otherwise normal liver, split by which bilirubin fraction is elevated.
- Epidemiology
Gilbert syndrome is common, affecting roughly 5-10% of the population, the most frequent hereditary hyperbilirubinemia, more often recognized in males and often first noted in a pubescent or young adult during a stressful illness.
- Risk factors
Family history and consanguinity: Crigler-Najjar, Dubin-Johnson, and Rotor are autosomal recessive, and Gilbert syndrome behaves as a common promoter polymorphism with variable penetrance, so an affected sibling or parent raises suspicion.
- Pathophysiology
Normal handling: senescent red cells break down to unconjugated bilirubin, which travels albumin-bound to the liver, is taken up by hepatocytes, conjugated by UGT1A1 to the water-soluble conjugated…
- Clinical features
Intermittent scleral icterus in Gilbert syndrome: jaundice appearing during a stressful trigger (infection, fasting, dehydration, exercise, surgery) that resolves once the trigger passes, without other symptoms.
- Differential diagnosis
Hemolysis (hereditary spherocytosis, sickle cell disease, autoimmune hemolytic anemia): unconjugated hyperbilirubinemia with low haptoglobin, elevated LDH and reticulocytes, and conjunctival pallor…
- Diagnosis
Establish the diagnosis with the fractionated bilirubin pattern in the correct clinical context: direct versus indirect fractionation of an isolated hyperbilirubinemia, with normal aminotransferases…
- Management
First, confirm which condition is present, because that determines everything downstream: Gilbert, Dubin-Johnson, and Rotor need reassurance only; Crigler-Najjar type II needs pharmacologic therapy…
- Complications
Kernicterus in Crigler-Najjar type I: the dominant, life-threatening complication, from unconjugated bilirubin deposition in the basal ganglia and brainstem, causing lethargy, tone abnormalities…
- Prognosis
Gilbert, Dubin-Johnson, and Rotor syndromes carry a normal life expectancy with no progression to fibrosis, cirrhosis, or liver failure.
- Prevention
No screening for Gilbert, Dubin-Johnson, or Rotor syndromes because all three are benign; testing follows incidental discovery of isolated hyperbilirubinemia, not routine population screening.
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