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

• Bilirubin is the final catabolic product of the heme. The heme is a component of various biological molecules and enzymes but, it is mainly incorporated in the hemoglobin which is the primary component of the red blood cells.
• Bilirubin is formed mainly in the liver and spleen through two steps which include:
  • Heme oxygenase enzyme degrades the porphyrin ring of the heme and breaks it down. A green compound called biliverdin is then formed as a result of the previous reaction. Carbon monoxide is released as a result of the reaction.
  • Biliverdin reductase enzyme catalyzes the formation of bilirubin from biliverdin.
• Bilirubin is a toxic metabolite so, the body has physiologic processes to eliminate the bilirubin. Bilirubin elimination process includes:
  • Hepatic uptake:
    • After the formation of the bilirubin and its secretion into the bloodstream, bilirubin becomes bound to the albumin to facilitate its transportation to the liver.
    • The hepatocytes then reuptake the bilirubin and prepare it for excretion.
  • Conjugation:
    • Bilirubin is then conjugated with glucuronic acid producing bilirubin diglucuronide which is water soluble.
    • Being water soluble, hence, the conjugated bilirubin can be excreted into bile.
    • The conjugation process occurs by the glucuronosyltransferase enzyme in the liver cells.
  • Clearance and excretion:
    • After conjugation of the bilirubin in the liver, it is secreted into the bile then into the gastrointestinal tract.
    • In the GIT, the conjugated bilirubin is metabolized by the gut enzymes into urobilinogen which is oxidized into urobilin.
    • Metabolism of the conjugated bilirubin occurs properly in the adults. However, the newborns have sterile gastrointestinal canal which impedes the catalyzation of the conjugated bilirubin.
    • The sterile tract ends up with a small amount of excreted bile.
    • The remaining conjugated bilirubin is unconjugated by the beta-glucuronidase enzyme in the neonatal intestine.
    • The unconjugated bilirubin is reabsorbed back into the blood and to the liver through the enterohepatic circulation of bilirubin.
    • A small amount of bilirubin is cleared into the urine as urobilinogen.

Pathogenesis

• Neonatal jaundice may be a result of physiological or pathological mechanisms. The different mechanisms for development of jaundice may be concluded into either an increase in the bilirubin production, increase the enterohepatic circulation, or decrease bilirubin elimination.
• Physiological jaundice:
  • The children have red blood cells twice or more than twice the number compared with the adults have and with shorter lifespan.
  • Increased rate of the red blood cells destruction produces elevated levels of bilirubin which ends up in jaundice.
  • The newborn gastrointestinal gut is considered sterile so, a small amount of the unconjugated bilirubin is converted to conjugated and excreted. Most of the unconjugated bilirubin is recirculated through the enterohepatic circulation.
  • Unconjugated hyperbilirubinemia is the predominant form of physiological jaundice.
  • Physiological jaundice is benign and resolves within 10 to 14 days of life.
• Pathological jaundice:
  • The majority of neonatal jaundice is due to pathological conditions. Pathological neonatal jaundice is due to acquired or inherited conditions.
  • Pathological jaundice is the result of an increase in the level of unconjugated bilirubin which is named as "Indirect hyperbilirubinemia".
  • It includes some features like the appearance of jaundice within the first day of life, persistent jaundice manifestations more than two weeks, and dark urine.
  • Acquired pathological neonatal jaundice develops mainly due to hemolysis of the red blood cells via three main diseases:
    • Rhesus (Rh) hemolytic disease
    • ABO blood group incompatibility
    • Glucose-6-phosphate dehydrogenase enzyme deficiency (G6PD deficiency)
  • Inherited pathological neonatal jaundice occurs due to a defect in the bilirubin metabolism and it include:
    • Defective hepatic uptake and storage of the bilirubin
    • Defective bilirubin conjugation to glucuronic acid and it include:
      • Gilbert syndrome
      • Crigler-Najjar syndrome
      • Lucey-Driscoll syndrome
      • Breast milk jaundice
    • Defective excretion of bilirubin into the bile and this syndrome called Dubin-Johnson syndrome
    • Defective reuptake of the conjugated bilirubin through the enterohepatic circulation. This syndrome called Rotor syndrome.

Acquired pathological neonatal jaundice

• The following table contains the different hemolytic mechanisms which lead to neonatal jaundice:

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 forms antibodies (IgG) against the fetal Rh antigen but the first born is not affected. In the second birth, if the fetus is a Rh-positive, the pre-formed maternal anti-Rh antibodies will cause hemolysis to the fetal blood. This condition may lead to either mild or severe hemolytic anemia and may occasionally end up with hydrops fetalis.
ABO blood group incompatibility	ABO blood group incompatibility is another form of the alloimmunization of the maternal blood cells against the fetal erythrocytes. ABO incompatibility occurs when the mother has O group of the blood and pregnant with a fetus with A or B blood group. The maternal blood cells will form anti-A antibodies or anti-B antibodies (IgM) which can cross the placenta and causes hemolysis of the fetal erythrocytes causing increased unconjugated bilirubin and jaundice. This condition, unlike RHDN, develops in the first newborn.
G6PD deficiency	Glucose-6-phosphate dehydrogenase (G6PD) is an important enzyme found in the red blood cells and incorporated in the hexose monophosphate pathway. G6PD collaborates in the production of NADPH and reduction of glutathione thus, helping in decrease the oxidative stress around the RBCs. A deficiency in the G6PD occurs due to a genetic defect which leads to increased oxidative stress in the RBCs and the hemolysis of the fetal blood cells.

Inherited pathological neonatal jaundice

• The following table includes the different causes of inherited neonatal jaundice:

Defective mechanism		Pathogenesis
Defective bilirubin hepatic reuptake and storage		Defective hepatic uptake and storage of bilirubin are 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 to cause the dysfunction of the GSTM1 enzyme and defective hepatic uptake of bilirubin
Disorder of bilirubin conjugation	Gilbert syndrome:	Gilbert syndrome, the most common inherited neonatal jaundice syndrome, is an autosomal recessive disease which is one of the causes of neonatal jaundice due to a defect (not total absence) in the Uridine diphosphate Glucuronsyl Transferase (UGT) enzyme. It is accompanied by several gene mutations (about 100 different mutations). The most common gene mutation occurs in the TA sequence of the TATAA box of the promoter region of UGT1A1 gene.
	Crigler-Najjar syndrome type I:	Crigler-Najjar syndrome type I is characterized by a total absence of the UGT1A1 enzyme, unlike Gilbert syndrome. Gene mutation of the UGT1A1 enzyme occurs due to deletion of the amino acid sequences of the exons of the UGT1A1 enzyme. Genetic mutations in the introns may also lead to frameshift of the amino acid sequences or create prematu1e stop codons which result in cessation of the enzyme formation.
	Crigler-Najjar syndrome type II (Arias syndrome):	Crigler-Najjar syndrome type II has a reduced activity of the UGT1A1 enzyme (not completely inactive). The gene mutation in the UGT1A1 gene is point mutation which results in amino acid substitution not stop codon. Hereby, reduction in the UGT enzyme activity occurs.
	Lucey-Driscoll syndrome:	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:	Breast milk jaundice is one of the benign causes of neonatal jaundice with no specific pathogenesis. It is considered as the continuation of physiologic jaundice beyond one week. It is believed that a combination of genetic mutation and environmental (breast milk components) factors lead to the development of jaundice. 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:	Dubin-Johnson syndrome is a result of a genetic mutation in the ABCC2/MRP2 transporter resulting 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):	Rotor syndrome is an autosomal recessive disease which results in a defect of the hepatic reuptake of the bilirubin. Genetic mutation of SLCO1B1/OATP1B1 and SLCO1B3/OATP1B3 leads to absence of the OATP1B1 and OATP1B3 transporters of bilirubin.

References

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