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Updated: Dec 14 2021

Hereditary Hyperbilirubinemia

  • Snapshot
    • A 28-year-old man comes to the clinic with complaints of “yellow eyes.” The patient reports noticing that the whites of his eyes were yellow since 2 days ago. He denies any other symptoms including right upper quadrant pain, fever, or malaise. He does not drink alcohol but reports that he has been under immense stress as he is preparing for a presentation at work. Laboratory tests are largely normal except for a high level of indirect bilirubin. (Gilbert syndrome)
  • Introduction
    • Refers to conditions where levels of bilirubin are elevated secondary to inherited deficiencies in the conjugation and/or clearance of bilirubin
      • all are inherited in an autosomal recessive manner
    • Pathogenesis
      • defect in UDP-glucuronosyltransferase (UGT)
        • Crigler-Najjar syndrome
        • Gilbert syndrome
      • impaired hepatic excretion/storage
        • Dubin-Johnson syndrome
        • Rotor syndrome
  • Crigler-Najjar Syndrome
    • Mutation in gene coding for UGT, which normally catalyzes the conjugation of bilirubin and glucuronic acid within hepatocytes
    • Presentation
      • type I
        • absent UGT activity
        • intense jaundice within the first days of life with high risk for kernicterus
        • life-threatening, especially without swift treatment
      • type II
        • markedly reduced level of UGT activity
        • lower serum bilirubin levels, kernicterus is rare
        • good prognosis
    • Studies
      • normal liver histology and liver function tests in both types
      • due to the lack of/decrease UGT activity, patients will have elevated unconjugated (indirect) bilirubin
      • type I has high serum bilirubin concentration (20-50 mg/dL)
      • type II has lower serum bilirubin concentration (< 20 mg/dL)
    • Treatment
      • type I
        • phototherapy
        • plasmapheresis rapidly removes albumin, which is tightly bound to bilirubin
        • liver transplantation is the only definitive treatment
      • type II
        • responsive to phenobarbital, which induces residual UGT activity
          • its usage can differentiate between type I and II
          • reduction of serum bilirubin is expected within 2-3 weeks
        • no other treatments are usually indicated
    • Complications
      • kernicterus is more common in type I
  • Gilbert Syndrome
    • Autosomal recessive disease caused by defect in the promotor of the gene that encodes UGT
      • leads to decreased UGT activity leading to impaired bilirubin conjugation
    • Presentation
      • recurrent episodes of jaundice that may be triggered by dehydration, fasting, disease, menstruation, or overexertion
      • otherwise asymptomatic besides jaundice
    • Studies
      • normal laboratory tests including hepatic function
      • isolated unconjugated (indirect) hyperbilirubinemia
      • serum bilirubin concentration is usually < 3 mg/dL
    • Treatment
      • benign condition
      • no treatment required
    • Complications
      • associated with increased risk of cholelithiasis
      • increased severity and duration of neonatal jaundice
      • drug-interaction and increased susceptibility to toxic effects with irinotecan
  • Dubin-Johnson Syndrome
    • Mutation of the canalicular multiple drug-resistance protein (MRP2) gene leads to impaired biliary excretion of bilirubin glucuronides
    • Presentation
      • patients are generally asymptomatic with mild, non-pruritic jaundice
      • mild constitutional symptoms including abdominal pain or weakness
    • Imaging
      • gallbladder and biliary system cannot be visualized via oral cholecystography
    • Studies
      • normal laboratory studies including hepatic function, alkaline phosphatase, and albumin
      • elevated conjugated (direct; at least 50%)) and unconjugated (indirect) hyperbilirubinemia
      • serum bilirubin concentrations usually between 2-5 mg/dL
      • normal total urinary coproporphyrin level but will have elevated coproporphyrin I level compared to normal individuals
      • histologically normal except for the presence of dense pigment ("black liver")
    • Treatment
      • benign condition
      • no treatment required
  • Rotor Syndrome
    • Associated with mutations of the SLCO1B1 and SLCO1B3 genes leading to defect in the hepatic storage of conjugated bilirubin
      • leads to subsequent leakage of conjugated bilirubin into the plasma
    • Presentation
      • similar presentation to that of Dubin-Johnson syndrome
      • patient are asymptomatic with non-pruritic jaundice
    • Imaging
      • gallbladder can be visualized via oral cholecystogram
    • Studies
      • normal laboratory studies including hepatic function, alkaline phosphatase, and albumin
      • elevated conjugated (the majority) and unconjugated hyperbilirubinemia
      • increased total urinary coproporphyrin excretion
      • normal liver histology with no pigmentation
    • Treatment
      • benign condition
      • no treatment required
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