Jaundice pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Overview

Bilirubin is the catabolic product of the heme which is the main component of the red blood cells. Bilirubin is formed in the liver and spleen then it passes through several process in order to be metabolized. Metabolism processes include hepatic uptake, conjugation, clearance and excretion of the bilirubin in the bile. Jaundice develops due to increase the level of bilirubin and deposition under the skin and cause the yellow discoloration of the skin. Pathogenesis of neonatal jaundice includes physiologic process of bilirubin accumulation or pathological mechanism. The pathological jaundice may be acquired or inherited. Acquired neonatal jaundice include Rh hemolytic disease, ABO incompatibility disease, and hemolytic disease due to G6PD enzyme deficiency. Inherited neonatal jaundice is due to defect of one of the processes of bilirubin metabolism and it concludes some inherited syndromes. Inherited neonatal jaundice include Gilbert's syndrome, Crigler-Najjar syndrome type I and II, Lucey-Driscoll syndrome, Dubin-Johnson syndrome, and Rotor syndrome.

Pathophysiology

Bilirubin formation and metabolism

Pathogenesis

Acquired pathological neonatal jaundice

  • The following table contains the different hemolytic mechanisms which lead to neonatal jaundice:[16][17]
Hemolytic disease Pathogenesis
Rhesus factor (Rh) hemolytic disease
  • It is known as the Rh hemolytic disease of the newborns (RHDN).
  • RHDN is the result of alloimmunization of the maternal red blood cells when the mother is pregnant with a Rh-positive fetus.
  • In the first pregnancy, if the fetus is a Rh-positive, some of the fetal blood is mixed with the maternal blood during birth. The maternal body will form antibodies (IgG) against the fetal Rh antigen and the first birth is not affected.
  • In the second birth, if the fetus is a Rh-positive, the formed maternal anti-Rh antibodies will cause hemolysis to the fetal blood. This condition may be mild or severe hemolytic anemia and may end up with hydrops fetalis.
ABO blood group incompatibility
G6PD deficiency

Inherited pathological neonatal jaundice

  • The following table includes the different causes of inherited neonatal jaundice:
Defective mechanism Pathogenesis
Defective bilirubin hepatic reuptake and storage[18]
  • Defective of bilirubin hepatic uptake and storage is not well understood. There are recent studies that revealed the correlation between mutations in the GST gene and neonatal jaundice.
  • The gene deletion in GST-M gene class is believed that it leads to dysfunction of the GSTM1 enzyme and defective hepatic uptake of bilirubin
Disorder of bilirubin conjugation Gilbert syndrome:[19]
Crigler-Najjar syndrome type I:[20][21]
Crigler-Najjar syndrome type II (Arias syndrome):[22]
Lucey-Driscoll syndrome:[23]
  • Also known as the transient familial neonatal hyperbilirubinemia as it is a rare familial disease which results in severe hyperbilirubinemia in the first 24 hours of life.
  • It is believed that Lucey-Driscoll syndrome is associated with an inhibitor of the UGT1A1 enzyme and this inhibitor is unidentified until the moment.
Breast milk jaundice:[24]
  • Breast milk jaundice is one of the benign causes of neonatal jaundice with no specific pathogenesis process. It is considered as the continuation of physiologic jaundice beyond one week. l
  • It is believed that a combination of genetic mutation and environmental (breast milk components) factors lead to the jaundice development.
  • The beta-glucuronidase enzyme, one of the milk substances, may be one of the causes that increase the bilirubin and develop jaundice.
  • In a Japanese study, a correlation between a genetic mutation in UGT1A1 gene and breast milk jaundice has been considered.
Disorders of excretion into Bile Dubin-Johnson syndrome:[25]
  •  Dubin-Johnson syndrome is a result of a genetic mutation in the ABCC2/MRP2 transporter result in absence of the transporter expression.
  • Other mutations which may lead to Dubin-Johnson syndrome include base deletion, nonsense mutation, or exon skipping.
Disorders of reuptake Rotor syndrome (RS):[26]
  • Rotor syndrome is an autosomal recessive disease which results in a defect of the hepatic reuptake of the bilirubin.
  • Genetic mutation of SLCO1B1/OATP1B1 andSLCO1B3/OATP1B3 lead to absence of the OATP1B1 and OATP1B3 transporters of bilirubin.

References

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