Neonatal 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
Pathophysiology
Bilirubin formation and metabolism
- Bilirubin is the final catabolic product of the heme. The heme is a component of some of the body substances and enzymes but it is mainly incorporated in the hemoglobin which is the main component of the red blood cells.[1][2]
- Bilirubin is formed mainly in the liver and spleen through two steps which include the following:[3][4]
- Heme oxygenase enzyme dysregulates the porphyrin ring of the heme breaking it. A green substance called biliverdin is then formed as a result of the previous reaction. Carbon monoxide is a result of the reaction as well
- Biliverdin reductase enzyme then forms the bilirubin from the biliverdin.
- Bilirubin is a toxic metabolite so, the body has physiologic processes in order to eliminate the bilirubin. Bilirubin elimination includes the following process:[5]
- Hepatic uptake:[6]
- After the formation of the bilirubin and its secretion into the bloodstream.
- The bilirubin becomes bound to the albumin in order to transport it to the liver.
- The hepatocytes then reuptake the bilirubin and prepare it for excretion.
- Conjugation:[7][8]
- To excrete the bilirubin into the bile, it must be water soluble first.
- Conjugation of the bilirubin with the glucuronic acid makes it water-soluble and the final product is bilirubin diglucuronide.
- The conjugation process occurs by the glucuronosyltransferase enzyme in the liver cells.
- Clearance and excretion:[9]
- 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 will end up with a small amount of excreted bile.
- The remaining conjugated bilirubin will be unconjugated by the beta-glucuronidase enzyme in the neonatal intestine.
- The unconjugated bilirubin can be 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.
- Hepatic uptake:[6]
Pathogenesis
- Neonatal jaundice may be a result of physiologic or pathological mechanisms. The different mechanisms of developing jaundice are concluded into either an increase in the bilirubin production, or increase the enterohepatic circulation, or decrease bilirubin elimination.[10]
- Physiological jaundice:[11][12]
- The child has red blood cells twice or more than what the adults have and with shorter life span.
- Increase rate of the red blood cells destruction produce more levels of bilirubin which end up with jaundice.
- The newborn gastrointestinal gut is considered sterile so, a little amount of the unconjugated is converted to conjugated and excreted. Most of the unconjugated is recirculated through the enterohepatic circulation.
- Unconjugated hyperbilirubinemia is the predominent form of physiological jaundice.
- Physiologic jaundice is a benign case and resolves within a 10 to 14 days of life.
- Pathological jaundice: [13]
- The majority of neonatal jaundice are due to pathological conditions. Pathological neonatal jaundice is due to acquired or inhereted conditions.
- The result of an increase in the level of unconjugated bilirubin which is named as "Indirect hyperbilirubinemia".
- 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 pahthological neonatal jaundice develops mainly due to hemolysis of the red blood cells via three main diseases:[14]
- Rhesus (Rh) hemolytic disease
- ABO blood group incompatibility
- Glucose 6 phosphate dehydrogenase enzyme deficiency (G6PD deficiency)
- Inhereted pathological neonatal jaundice occurs due to a defect in the bilirubin metabolism process and it includes the following:[15]
- Defective hepatic uptake and storage of the bilirubin
- Defective bilirubin conjugation to glucuronic acid and it includes the following syndromes:
- 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 ciruclation. This syndrome called Rottor 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 | |
| ABO blood group incompatibility | |
| G6PD deficiency |
References
- ↑ Berk PD, Howe RB, Bloomer JR, Berlin NI (1969). "Studies of bilirubin kinetics in normal adults". J Clin Invest. 48 (11): 2176–90. doi:10.1172/JCI106184. PMC 297471. PMID 5824077.
- ↑ LONDON IM, WEST R, SHEMIN D, RITTENBERG D (1950). "On the origin of bile pigment in normal man". J Biol Chem. 184 (1): 351–8. PMID 15422003.
- ↑ Knobloch E, Hodr R, Herzmann J, Houdková V (1986). "Kinetics of the formation of biliverdin during the photochemical oxidation of bilirubin monitored by column liquid chromatography". J Chromatogr. 375 (2): 245–53. PMID 3700551.
- ↑ Bissell DM, Hammaker L, Schmid R (1972). "Liver sinusoidal cells. Identification of a subpopulation for erythrocyte catabolism". J Cell Biol. 54 (1): 107–19. PMC 2108858. PMID 5038868.
- ↑ Paludetto R, Mansi G, Raimondi F, Romano A, Crivaro V, Bussi M; et al. (2002). "Moderate hyperbilirubinemia induces a transient alteration of neonatal behavior". Pediatrics. 110 (4): e50. PMID 12359823.
- ↑ Weiss JS, Gautam A, Lauff JJ, Sundberg MW, Jatlow P, Boyer JL; et al. (1983). "The clinical importance of a protein-bound fraction of serum bilirubin in patients with hyperbilirubinemia". N Engl J Med. 309 (3): 147–50. doi:10.1056/NEJM198307213090305. PMID 6866015.
- ↑ Chowdhury JR, Chowdhury NR, Wu G, Shouval R, Arias IM (1981). "Bilirubin mono- and diglucuronide formation by human liver in vitro: assay by high-pressure liquid chromatography". Hepatology. 1 (6): 622–7. PMID 6796486.
- ↑ Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR; et al. (1994). "Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man". J Biol Chem. 269 (27): 17960–4. PMID 8027054.
- ↑ Vítek L, Zelenka J, Zadinová M, Malina J (2005). "The impact of intestinal microflora on serum bilirubin levels". J Hepatol. 42 (2): 238–43. doi:10.1016/j.jhep.2004.10.012. PMID 15664250.
- ↑ Ullah S, Rahman K, Hedayati M (2016). "Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article". Iran J Public Health. 45 (5): 558–68. PMC 4935699. PMID 27398328.
- ↑ Dennery PA, Seidman DS, Stevenson DK (2001). "Neonatal hyperbilirubinemia". N Engl J Med. 344 (8): 581–90. doi:10.1056/NEJM200102223440807. PMID 11207355.
- ↑ Brouillard RP (1974). "Measurement of red blood cell life-span". JAMA. 230 (9): 1304–5. PMID 4479604.
- ↑ Ullah S, Rahman K, Hedayati M (2016). "Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article". Iran J Public Health. 45 (5): 558–68. PMC 4935699. PMID 27398328.
- ↑ Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker MW, Spitzer AR; et al. (2009). "Complex multifactorial nature of significant hyperbilirubinemia in neonates". Pediatrics. 124 (5): e868–77. doi:10.1542/peds.2009-0460. PMID 19858149.
- ↑ Memon N, Weinberger BI, Hegyi T, Aleksunes LM (2016). "Inherited disorders of bilirubin clearance". Pediatr Res. 79 (3): 378–86. doi:10.1038/pr.2015.247. PMC 4821713. PMID 26595536.