Hyperbilirubinemia

Bilirubin Physiology

  • Bilirubin: tetrapyrrole formed by the breakdown of hemoglobin and other hemoproteins
    • Bilirubin is highly insoluble in water
  • Bilirubin Metabolism: due to water insolubility of bilirubin, it needs to be converted into a soluble conjugate before it can be excreted
    • Hepatic uridine disphosphate (UDP)-gluconyl transferase (UGT) converts bilirubin (via an esterification reaction) to conjugated bilirubin (a mixture of bilirubin monoglucuronide and bilirubin diglucuronide)
    • Conjugated bilirubin is excreted into the bile by an ATP-dependent transporter
    • Bilirubin diglucuronide accounts for 80% of the pigment in normal human bile (this percentage decreases in patients with decreased UGT activity)
    • As the conjugation and excretion process is normally very efficient, plasma concentrations of unconjugated bilirubin are normally low
  • Renal Filtration of Bilirubin: the kidneys do not filter unconjugated bilirubin (as it is avidly bound to albumin)
    • Therefore, the presence of bilirubinuria indicates the presence of conjugated bilirubinemia

Laboratory Assay of Bilirubin

  • Assay: assay of bilirubin involves its cleavage in the presence of diazotized sulfanilic acid to generate a colored azodipyrrole, which is assayed spectrophtometrically
    • Due to limited water solubility, unconjugated bilirubin reacts slowly in absence of an accelerator (such as ethanol), while conjugated bilirubin reacts rapidly
    • Total Bilirubin: measured in presence of accelerator
    • Direct Bilirubin: measured in absence of accelerator
      • Approximates the conjugated bilirubin concentration in most cases, but is not necessarily the same thing
    • Indirect Bilirubin: calculated by subtracting total-direct bilirubin
      • Approximates the unconjugated bilirubin concentration in most cases, but is not necessarily the same thing
  • Clinical Patterns
    • Predominantly unconjugated bilirubinemia -> indicates the presence of a disease with either increased bilirubin production, impaired bilirubin conjugation, or impaired hepatic bilirubin uptake
    • Predominantly conjugated bilirubinemia -> indicates presence of hepatobiliary diesase
    • Mixed unconjugated and conjugated bilirubinemia -> indicates presence of disease which impairs the secretion of conjugated bilirubin into bile or disease which impairs the flow of bile into intestine

Etiology of Hyperbilirubinemia (see also Elevated Liver Function Tests, [[Elevated Liver Function Tests]])

Unconjugated (Indirect) Hyperbilirubinemia

Increased Bilirubin Production

  • Dyserthropoiesis
    • Primary Shunt Hyperbilirubinemia (Idiopathic Dyserythropoietic Jaundice)
  • Hematoma
  • Hemolytic Anemia (Extravascular/Intravascular) (see Hemolytic Anemia, [[Hemolytic Anemia]])

Impaired Hepatic Bilirubin Uptake

  • Congestive Hepatopathy (Passive Hepatic Congestion) (see Congestive Hepatopathy, [[Congestive Hepatopathy]]): due to congestive heart failure (CHF)
  • Drugs
    • Bunamiodyl Cholecystographic Contrast Agent
    • Flavaspidic Acid
    • Probenecid (see Probenecid, [[Probenecid]])
    • Rifamycins (see Rifamycins, [[Rifamycins]])
      • Rifabutin (see Rifabutin, [[Rifabutin]])
      • Rifampin (Rifampicin, Rifadin) (see Rifampin, [[Rifampin]])
      • Rifapentine (Priftin) (see Rifapentine, [[Rifapentine]])
  • Gilbert Syndrome (see Gilbert Syndrome, [[Gilbert Syndrome]])
    • Physiology: impaired hepatic bilirubin uptake occurs in some cases
  • Portosystemic Shunt
  • Wilson Disease (see Wilson Disease, [[Wilson Disease]])
    • Physiology
      • Coombs-Negative Hemolytic Anemia (see Hemolytic Anemia, [[Hemolytic Anemia]]): may occur in some cases
      • Decreased Hepatic Bilirubin Uptake and Conjugation

Impaired Bilirubin Conjugation

  • Breast Milk Jaundice
  • Crigler-Najjar Syndrome (see Crigler-Najjar Syndrome, [[Crigler-Najjar Syndrome]])
  • Ethinyl Estradiol (see Estrogen, [[Estrogen]]): found in almost all oral contraceptives (see Oral Contraceptives, [[Oral Contraceptives]])
  • Gilbert Syndrome (see Gilbert Syndrome, [[Gilbert Syndrome]]): decreased hepatic bilirubin uptake and/or decreased conjugation
  • Hyperthyroidism (see Hyperthyroidism, [[Hyperthyroidism]])
  • Hypothyroidism (see Hypothyroidism, [[Hypothyroidism]])
  • Liver Disease
    • Chronic Hepatitis
    • Cirrhosis (see Cirrhosis, [[Cirrhosis]])
    • Wilson Disease (see Wilson Disease, [[Wilson Disease]])
      • Physiology
        • Coombs-Negative Hemolytic Anemia (see Hemolytic Anemia, [[Hemolytic Anemia]]): may occur in some cases
        • Decreased Hepatic Bilirubin Uptake and Conjugation
  • Maternal Serum Jaundice
  • Neonatal Physiologic Jaundice

Conjugated (Direct) Hyperbilirubinemia

Inherited Disorders

  • Rotor Syndrome (see Rotor Syndrome, [[Rotor Syndrome]])
    • Physiology: defective sinusoidal reuptake of conjugated bilirubin
  • Dubin-Johnson Syndrome (see Dubin-Johnson Syndrome, [[Dubin-Johnson Syndrome]])
    • Physiology: defective canalicular organic anion transport

Intrahepatic Cholestasis

Extrahepatic Cholestasis (Biliary Obstruction)


References

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