• Clinical science

Inherited hyperbilirubinemia


Hyperbilirubinemia describes serum bilirubin levels ≥ 1.1 mg/dL. In contrast to acute or chronic cholestatic liver disorders, which may also lead to increased serum bilirubin levels, syndromes associated with hyperbilirubinemia lead to isolated hyperbilirubinemia and hence do not affect liver enzymes. These syndromes cause a rise in either unconjugated or conjugated bilirubin. The clinical manifestation of hyperbilirubinemia is relatively mild, with the main symptom being transient jaundice. Aside from Crigler-Najjar syndrome type I, there is no need for management of inherited hyperbilirubinemia syndromes. Therefore, patients with hyperbilirubinemia generally have a good prognosis.


Isolated hyperbilirubinemia
↑ Unconjugated (indirect) bilirubin Excess release Hemolytic anemia
Defective conjugation Gilbert syndrome
Crigler‑Najjar syndrome
↑ Conjugated (direct) bilirubin Defective excretion

Dubin‑Johnson syndrome

Rotor syndrome


Gilbert syndrome (Gilbert-Meulengracht syndrome; Meulengracht disease)

  • Epidemiology
    • Most common inherited hyperbilirubinemia: The prevalence is 3–7% in the US.
    • >
    • Age of onset: adolescence
  • Etiology
    • Mutation in the promoter region of UGT1A1 gene ↓ activity of UDP-glucuronosyltransferasedecreased conjugation of bilirubinindirect bilirubin
  • Clinical features
  • Trigger factors of transient jaundice
    • Physical stress (trauma, disease, exhaustion)
    • Fasting periods
    • Alcohol consumption
  • Diagnosis
    • ↑ Indirect bilirubin but < 3 mg/dL (higher levels are possible during episodes of increased bilirubin breakdown)
    • Normal liver function
    • No evidence of hemolysis
    • Detection of mutation using PCR
  • Treatment: no management required


Crigler-Najjar syndrome

Crigler-Najjar syndrome type I

Crigler-Najjar syndrome type II (Arias syndrome)

  • Etiology: activity of UDP-glucuronosyltransferase markedly reduced
  • Inheritance: autosomal recessive
  • Clinical features
    • Often asymptomatic
    • No neonatal jaundice, although jaundice may occur during the patient's first year of life
    • No neurological symptoms
  • Diagnosis
  • Treatment: Patients are less likely to develop kernicterus. Specific treatment may therefore not be required. The following treatment options are, however, available if patients become icteric.
  • Prognosis: usually favorable; management of jaundice allows for normal quality of life


Dubin-Johnson syndrome

  • Etiology: defective MRP2 transporter → impaired movement of conjugated (direct) bilirubin from the hepatocyte to the bile canaliculi
  • Inheritance: autosomal recessive
  • Clinical features
    • Mild to moderate jaundice
      • Onset often occurs during adolescence
      • May worsen because of medication (particularly contraceptives) or pregnancy
    • Splenomegaly may occur in rare cases.
  • Diagnosis
    • Direct hyperbilirubinemia (direct bilirubin/total bilirubin up to 50%)
    • Normal urinary coproporphyrins excretion, but altered distribution of isomers I and III (Dubin‑Johnson: ≥ 80% coproporphyrins of isomer I; normally ∼ 75% are isomer III)
    • Liver biopsy: darker granular pigmentation
  • Treatment: not required
  • Special considerations
    • Be careful when administering medication that is toxic to the liver → may worsen jaundice!
    • Contraindication for oral contraception


Rotor syndrome

  • Etiology: Defective organic anion transport proteins (OATP) 1B1 and 1B3 in hepatocytes impaired transport and reduced storage capacity of conjugated (direct) bilirubin
  • Inheritance: autosomal recessive
  • Clinical features: usually asymptomatic
  • Diagnosis
    • Moderate, direct hyperbilirubinemia and mild, indirect hyperbilirubinemia
    • Normal liver function test
    • ↑ Urinary coproporphyrins I and III (fraction of isomer I < 70% of total)
    • Liver biopsy: normal, no pigmentation
  • Treatment: not required
  • Special considerations
    • Be careful when administering medication that is toxic to the liver → may worsen jaundice!
    • Contraindication for oral contraception