Inherited hyperbilirubinemia

Hyperbilirubinemia is characterized by serum bilirubin levels of ≥ 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; transient jaundice is the primary symptom. With the exception of Crigler-Najjar syndrome type I, inherited hyperbilirubinemia syndromes do not require medical management. Patients with hyperbilirubinemia generally have a good prognosis.

Individuals with Crigler-Najjar or Gilbert syndrome cannot ConjuGate bilirubin.

Individuals with Rotor syndrome or Dubin-Johnson syndrome cannot get RiD of DiRect bilirubin.

• Epidemiology
  • Most common inherited hyperbilirubinemia: The prevalence is 3–7% in the US. ^[1]
  • ♂ > ♀
  • Age of onset: adolescence ^[2]
• Etiology ^[3][4]
  • Mutation in the promoter region of UGT1A1 gene → mild reduction of UDP-glucuronosyltransferase activity → ↓ conjugation of bilirubin → ↑ indirect bilirubin
  • Alternative: missense mutation in UGT1A1 gene
  • Impaired hepatic bilirubin uptake
• Inheritance: autosomal recessive or autosomal dominant
• Clinical features
  • Asymptomatic or unspecific symptoms such as fatigue and loss of appetite
  • Transient, usually mild jaundice (varying from mild scleral jaundice to general jaundice) ^[5]
• Triggering factors of transient jaundice
  • Stress (e.g., trauma, illness, exhaustion)
  • Fasting periods
  • Alcohol consumption
• Diagnosis
  • Slightly ↑ 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: not required (benign condition)

Crigler-Najjar syndrome type I

• Etiology: UDP-glucuronosyltransferase is (almost completely) absent.
• Inheritance: autosomal recessive
• Clinical features
  • Excessive, persistent neonatal jaundice
  • Kernicterus: neurological symptoms (onset during infancy or later in childhood)
• Diagnosis
  • ↑ Indirect bilirubin (20–50 mg/dL)
  • Normal liver function tests
  • No evidence of hemolysis
• Treatment
  • Phototherapy: conversion of unconjugated bilirubin (hydrophobic bilirubin) to more polar, water-soluble form → ↑ excretion via urine and/or bile
  • Plasmapheresis during acute rises in serum bilirubin levels
  • Tin protoporphyrin
  • Calcium carbonate
  • Liver transplantation is the only curative treatment.
• Prognosis
  • Without treatment, Crigler-Najjar syndrome type I is incompatible with life because it causes kernicterus.
  • If treated, patients may survive past puberty, but most will eventually develop kernicterus.

Crigler-Najjar syndrome type II (Arias syndrome)

• Etiology: reduced levels of UDP-glucuronosyltransferase
• Inheritance: autosomal recessive or autosomal dominant
• Clinical features
  • Often asymptomatic
  • No neonatal jaundice, although jaundice may occur during the patient's first year of life
  • No neurological symptoms
• Diagnosis
  • ↑ Indirect bilirubin (< 20 mg/dL)
  • Normal liver function tests
  • No evidence of hemolysis
  • Responds to phenobarbital → ↓ serum bilirubin levels
• 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.
  • Phenobarbital: leads to induction of UDP-glucuronosyltransferase
  • Phototherapy (as in type I)
  • Avoid hormonal contraception and hepatic enzyme inhibitors
• Prognosis
  • Usually favorable
  • Management of jaundice allows for normal quality of life.

• Etiology: defective multidrug resistance-associated protein 2 (MRP2); → impaired excretion of conjugated bilirubin from the hepatocytes into 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%)
  • Liver biopsy: dark, granular pigmentation (due to accumulation of epinephrine metabolites)
• Treatment: not required (benign condition)
• Special considerations
  • Be careful when administering a drug that is toxic to the liver, as it may worsen jaundice.
  • Contraindication for oral contraception

In Dubin-Johnson syndrome, the liver appears Dark.

• Etiology: defective organic anion transport proteins (OATP) 1B1 and 1B3 in hepatocytes → impaired transport and reduced storage capacity of conjugated bilirubin (direct bilirubin) ^[6][7]
• Inheritance: autosomal recessive
• Clinical features: usually asymptomatic but mild jaundice may occur (milder presentation compared to Dubin-Johnson syndrome)
• 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 a drug that is toxic to the liver, as it may worsen jaundice.
  • Contraindication for oral contraception

In Rotor syndrome, the liver appears Regular (no dark pigmentation).