Jaundice pathophysiology: Difference between revisions

Jump to navigation Jump to search
No edit summary
Line 6: Line 6:
[[Bilirubin]] is the [[catabolic]] product of the [[heme]] which is the main component of the [[red blood cells]]. Bilirubin is formed in [[Liver|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 [[Bile|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 of the newborn|hemolytic disease]], [[ABO incompatibility (patient information)|ABO incompatibility disease]], and hemolytic disease due to [[Glucose-6-phosphate dehydrogenase deficiency|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|Crigler-Najjar syndrome type I and II]], [[Lucey-Driscoll syndrome]], [[Dubin-Johnson syndrome]], and [[Rotor syndrome]].  
[[Bilirubin]] is the [[catabolic]] product of the [[heme]] which is the main component of the [[red blood cells]]. Bilirubin is formed in [[Liver|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 [[Bile|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 of the newborn|hemolytic disease]], [[ABO incompatibility (patient information)|ABO incompatibility disease]], and hemolytic disease due to [[Glucose-6-phosphate dehydrogenase deficiency|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|Crigler-Najjar syndrome type I and II]], [[Lucey-Driscoll syndrome]], [[Dubin-Johnson syndrome]], and [[Rotor syndrome]].  
==Pathophysiology==
==Pathophysiology==
===Bilirubin formation and metabolism===
 
*[[Bilirubin]] is the final [[catabolic]] product of the [[heme]]. The heme is a component of various body substances and [[enzymes]] but it is mainly incorporated in the [[hemoglobin]] which is the main component of the [[red blood cells]].<ref name="pmid58240772">{{cite journal| author=Berk PD, Howe RB, Bloomer JR, Berlin NI| title=Studies of bilirubin kinetics in normal adults. | journal=J Clin Invest | year= 1969 | volume= 48 | issue= 11 | pages= 2176-90 | pmid=5824077 | doi=10.1172/JCI106184 | pmc=297471 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5824077  }}</ref><ref name="pmid154220032">{{cite journal| author=LONDON IM, WEST R, SHEMIN D, RITTENBERG D| title=On the origin of bile pigment in normal man. | journal=J Biol Chem | year= 1950 | volume= 184 | issue= 1 | pages= 351-8 | pmid=15422003 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15422003  }}</ref>
=== For more information about viral hepatitis pathophysiology [[Viral hepatitis|click here]] ===
*[[Bilirubin]] is formed mainly in [[Liver|the liver]] and [[spleen]] through two steps which include the following:<ref name="pmid37005512">{{cite journal| author=Knobloch E, Hodr R, Herzmann J, Houdková V| title=Kinetics of the formation of biliverdin during the photochemical oxidation of bilirubin monitored by column liquid chromatography. | journal=J Chromatogr | year= 1986 | volume= 375 | issue= 2 | pages= 245-53 | pmid=3700551 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3700551  }}</ref><ref name="pmid50388682">{{cite journal| author=Bissell DM, Hammaker L, Schmid R| title=Liver sinusoidal cells. Identification of a subpopulation for erythrocyte catabolism. | journal=J Cell Biol | year= 1972 | volume= 54 | issue= 1 | pages= 107-19 | pmid=5038868 | doi= | pmc=2108858 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5038868  }}</ref>
 
**[[Heme oxygenase|Heme oxygenase enzyme]] dysregulates the [[porphyrin]] ring of the [[heme]] and breaks it down. 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
=== For more information about cirrhosis pathophysiology [[Cirrhosis pathophysiology|click here]] ===
 
=== 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]].<ref name="pmid5824077">{{cite journal| author=Berk PD, Howe RB, Bloomer JR, Berlin NI| title=Studies of bilirubin kinetics in normal adults. | journal=J Clin Invest | year= 1969 | volume= 48 | issue= 11 | pages= 2176-90 | pmid=5824077 | doi=10.1172/JCI106184 | pmc=297471 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5824077  }}</ref><ref name="pmid15422003">{{cite journal| author=LONDON IM, WEST R, SHEMIN D, RITTENBERG D| title=On the origin of bile pigment in normal man. | journal=J Biol Chem | year= 1950 | volume= 184 | issue= 1 | pages= 351-8 | pmid=15422003 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15422003  }}</ref>
*[[Bilirubin]] is formed mainly in [[Liver|the liver]] and [[spleen]] through two steps which include:<ref name="pmid3700551">{{cite journal| author=Knobloch E, Hodr R, Herzmann J, Houdková V| title=Kinetics of the formation of biliverdin during the photochemical oxidation of bilirubin monitored by column liquid chromatography. | journal=J Chromatogr | year= 1986 | volume= 375 | issue= 2 | pages= 245-53 | pmid=3700551 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3700551  }}</ref><ref name="pmid5038868">{{cite journal| author=Bissell DM, Hammaker L, Schmid R| title=Liver sinusoidal cells. Identification of a subpopulation for erythrocyte catabolism. | journal=J Cell Biol | year= 1972 | volume= 54 | issue= 1 | pages= 107-19 | pmid=5038868 | doi= | pmc=2108858 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5038868  }}</ref>
**[[Heme oxygenase|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|Biliverdin reductase enzyme]] catalyzes the formation of [[bilirubin]] from [[biliverdin]].
**[[Biliverdin reductase|Biliverdin reductase enzyme]] catalyzes the formation of [[bilirubin]] from [[biliverdin]].
*Bilirubin is a [[toxic]] metabolite so, the body has [[physiologic]] processes in order to eliminate the [[bilirubin]]. Bilirubin elimination includes the following process:<ref name="pmid123598232">{{cite journal| author=Paludetto R, Mansi G, Raimondi F, Romano A, Crivaro V, Bussi M et al.| title=Moderate hyperbilirubinemia induces a transient alteration of neonatal behavior. | journal=Pediatrics | year= 2002 | volume= 110 | issue= 4 | pages= e50 | pmid=12359823 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12359823  }}</ref>
*Bilirubin is a [[toxic]] metabolite so, the body has [[physiologic]] processes to eliminate the [[bilirubin]]. Bilirubin elimination process includes:<ref name="pmid12359823">{{cite journal| author=Paludetto R, Mansi G, Raimondi F, Romano A, Crivaro V, Bussi M et al.| title=Moderate hyperbilirubinemia induces a transient alteration of neonatal behavior. | journal=Pediatrics | year= 2002 | volume= 110 | issue= 4 | pages= e50 | pmid=12359823 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12359823  }}</ref>
**[[Hepatic]] uptake:<ref name="pmid68660152">{{cite journal| author=Weiss JS, Gautam A, Lauff JJ, Sundberg MW, Jatlow P, Boyer JL et al.| title=The clinical importance of a protein-bound fraction of serum bilirubin in patients with hyperbilirubinemia. | journal=N Engl J Med | year= 1983 | volume= 309 | issue= 3 | pages= 147-50 | pmid=6866015 | doi=10.1056/NEJM198307213090305 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6866015  }}</ref>
**'''[[Hepatic]] uptake:'''<ref name="pmid6866015">{{cite journal| author=Weiss JS, Gautam A, Lauff JJ, Sundberg MW, Jatlow P, Boyer JL et al.| title=The clinical importance of a protein-bound fraction of serum bilirubin in patients with hyperbilirubinemia. | journal=N Engl J Med | year= 1983 | volume= 309 | issue= 3 | pages= 147-50 | pmid=6866015 | doi=10.1056/NEJM198307213090305 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6866015  }}</ref>
***After the formation of the bilirubin and its secretion into the [[bloodstream]], bilirubin becomes bound to the [[albumin]] to facilitate its transportation to [[Liver|the liver]].
***After the formation of the bilirubin and its secretion into the [[bloodstream]], bilirubin becomes bound to the [[albumin]] to facilitate its transportation to [[Liver|the liver]].
***[[Hepatocytes|The hepatocytes]] then reuptake the [[bilirubin]] and prepare it for excretion.
***[[Hepatocytes|The hepatocytes]] then reuptake the [[bilirubin]] and prepare it for excretion.
**[[Conjugation]]:<ref name="pmid67964862">{{cite journal| author=Chowdhury JR, Chowdhury NR, Wu G, Shouval R, Arias IM| title=Bilirubin mono- and diglucuronide formation by human liver in vitro: assay by high-pressure liquid chromatography. | journal=Hepatology | year= 1981 | volume= 1 | issue= 6 | pages= 622-7 | pmid=6796486 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6796486  }}</ref><ref name="pmid80270542">{{cite journal| author=Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR et al.| title=Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. | journal=J Biol Chem | year= 1994 | volume= 269 | issue= 27 | pages= 17960-4 | pmid=8027054 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8027054  }}</ref>
**'''[[Conjugation]]:'''<ref name="pmid6796486">{{cite journal| author=Chowdhury JR, Chowdhury NR, Wu G, Shouval R, Arias IM| title=Bilirubin mono- and diglucuronide formation by human liver in vitro: assay by high-pressure liquid chromatography. | journal=Hepatology | year= 1981 | volume= 1 | issue= 6 | pages= 622-7 | pmid=6796486 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6796486  }}</ref><ref name="pmid8027054">{{cite journal| author=Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR et al.| title=Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. | journal=J Biol Chem | year= 1994 | volume= 269 | issue= 27 | pages= 17960-4 | pmid=8027054 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8027054  }}</ref>
***Bilirubin is then [[Conjugated bilirubin|conjugated]] with [[glucuronic acid]] producing [[bilirubin diglucuronide]] which is [[water]] soluble.
***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]].
***Being water soluble, hence, the [[conjugated bilirubin]] can be excreted into [[bile]].
***[[Conjugation|The conjugation]] process occurs by the [[Glucuronosyltransferase|glucuronosyltransferase enzyme]] in the [[liver cells]].
***[[Conjugation|The conjugation]] process occurs by the [[Glucuronosyltransferase|glucuronosyltransferase enzyme]] in the [[liver cells]].
**[[Clearance (medicine)|Clearance]] and [[excretion]]:<ref name="pmid156642502">{{cite journal| author=Vítek L, Zelenka J, Zadinová M, Malina J| title=The impact of intestinal microflora on serum bilirubin levels. | journal=J Hepatol | year= 2005 | volume= 42 | issue= 2 | pages= 238-43 | pmid=15664250 | doi=10.1016/j.jhep.2004.10.012 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15664250  }}</ref>
**'''[[Clearance (medicine)|Clearance]] and [[excretion]]:'''<ref name="pmid15664250">{{cite journal| author=Vítek L, Zelenka J, Zadinová M, Malina J| title=The impact of intestinal microflora on serum bilirubin levels. | journal=J Hepatol | year= 2005 | volume= 42 | issue= 2 | pages= 238-43 | pmid=15664250 | doi=10.1016/j.jhep.2004.10.012 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15664250  }}</ref>
***After [[conjugation]] of the [[bilirubin]] in [[Liver|the liver]], it is secreted into the [[bile]] then into the [[gastrointestinal tract]].
***After [[conjugation]] of the [[bilirubin]] in [[Liver|the liver]], it is secreted into the [[bile]] then into the [[gastrointestinal tract]].
***In the GIT, [[Conjugated bilirubin|the conjugated bilirubin]] is metabolized by [[Gut|the gut]] [[enzymes]] into [[urobilinogen]] which is [[oxidized]] into [[urobilin]].
***In the GIT, [[Conjugated bilirubin|the conjugated bilirubin]] is metabolized by [[Gut|the gut]] [[enzymes]] into [[urobilinogen]] which is [[oxidized]] into [[urobilin]].
***[[Metabolism]] of the conjugated bilirubin occurs properly in the adults. However, [[Newborns|the newborns]] have [[Gastrointestinal tract|sterile gastrointestinal canal]] which impedes the catalyzation of the [[conjugated bilirubin]].
***[[Metabolism]] of the conjugated bilirubin occurs properly in the adults. However, [[Newborns|the newborns]] have [[Gastrointestinal tract|sterile gastrointestinal canal]] which impedes the catalyzation of the conjugated bilirubin.
***The sterile tract will end up with a small amount of [[Bile|excreted bile]].
***The sterile tract ends up with a small amount of [[Bile|excreted bile]].
***The remaining conjugated bilirubin will be unconjugated by the [[Beta-glucuronidase|beta-glucuronidase enzyme]] in the [[neonatal]] [[intestine]].
***The remaining conjugated bilirubin is unconjugated by the [[Beta-glucuronidase|beta-glucuronidase enzyme]] in the [[neonatal]] [[intestine]].
***The [[unconjugated bilirubin]] can be reabsorbed back into [[Blood|the blood]] and to the liver through the [[enterohepatic circulation]] of [[bilirubin]].
***The [[unconjugated bilirubin]] is reabsorbed back into [[Blood|the blood]] and to the liver through the [[enterohepatic circulation]] of [[bilirubin]].
***A small amount of bilirubin is cleared into the urine as [[urobilinogen]].
***A small amount of [[bilirubin]] is cleared into the [[urine]] as [[urobilinogen]].
===Pathogenesis===
===Pathogenesis===
*Jaundice may be a result of [[physiological]] or [[pathological]] mechanisms. The different mechanisms of developing jaundice are concluded into either an increase in the [[bilirubin]] production, increase the [[enterohepatic circulation]], or decrease bilirubin [[Elimination reaction|elimination]].<ref name="pmid273983283">{{cite journal| author=Ullah S, Rahman K, Hedayati M| title=Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article. | journal=Iran J Public Health | year= 2016 | volume= 45 | issue= 5 | pages= 558-68 | pmid=27398328 | doi= | pmc=4935699 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27398328  }}</ref>
*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 reaction|elimination]].<ref name="pmid27398328">{{cite journal| author=Ullah S, Rahman K, Hedayati M| title=Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article. | journal=Iran J Public Health | year= 2016 | volume= 45 | issue= 5 | pages= 558-68 | pmid=27398328 | doi= | pmc=4935699 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27398328  }}</ref>
*'''Physiological jaundice:'''<ref name="pmid112073552">{{cite journal| author=Dennery PA, Seidman DS, Stevenson DK| title=Neonatal hyperbilirubinemia. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 8 | pages= 581-90 | pmid=11207355 | doi=10.1056/NEJM200102223440807 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11207355  }}</ref><ref name="pmid44796042">{{cite journal| author=Brouillard RP| title=Measurement of red blood cell life-span. | journal=JAMA | year= 1974 | volume= 230 | issue= 9 | pages= 1304-5 | pmid=4479604 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4479604  }}</ref>
*'''Physiological jaundice:'''<ref name="pmid11207355">{{cite journal| author=Dennery PA, Seidman DS, Stevenson DK| title=Neonatal hyperbilirubinemia. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 8 | pages= 581-90 | pmid=11207355 | doi=10.1056/NEJM200102223440807 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11207355  }}</ref><ref name="pmid4479604">{{cite journal| author=Brouillard RP| title=Measurement of red blood cell life-span. | journal=JAMA | year= 1974 | volume= 230 | issue= 9 | pages= 1304-5 | pmid=4479604 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4479604  }}</ref>
**The child has [[red blood cells]] twice or more than what the adults have and with shorter [[lifespan]].
**The children have [[red blood cells]] twice or more than twice the number compared with the adults have and with shorter [[lifespan]].
**Increase rate of the red blood cells destruction produces more levels of [[bilirubin]] which end up with [[jaundice]].
**Increased rate of the red blood cells destruction produces elevated levels of [[bilirubin]] which ends up in [[jaundice]].
**The newborn [[Gastrointestinal tract|gastrointestinal gut]] is considered [[sterile]] so, a little amount of the unconjugated bilirubin is converted to conjugated and excreted. Most of the [[unconjugated bilirubin]] is recirculated through the [[enterohepatic circulation]].
**The newborn [[Gastrointestinal tract|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.
**Unconjugated [[hyperbilirubinemia]] is the predominant form of [[physiological]] jaundice.
**Physiological jaundice is a benign case and resolves within a 10 to 14 days of life.
**Physiological jaundice is benign and resolves within 10 to 14 days of life.
*'''Pathological jaundice:''' <ref name="pmid2739832822">{{cite journal| author=Ullah S, Rahman K, Hedayati M| title=Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article. | journal=Iran J Public Health | year= 2016 | volume= 45 | issue= 5 | pages= 558-68 | pmid=27398328 | doi= | pmc=4935699 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27398328  }}</ref>
*'''Pathological jaundice:''' <ref name="pmid273983282">{{cite journal| author=Ullah S, Rahman K, Hedayati M| title=Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article. | journal=Iran J Public Health | year= 2016 | volume= 45 | issue= 5 | pages= 558-68 | pmid=27398328 | doi= | pmc=4935699 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27398328  }}</ref>
**The majority of jaundice is due to pathological conditions. Pathological jaundice is due to acquired or [[inherited]] conditions.
**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]]".
**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]].
**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:<ref name="pmid198581492">{{cite journal| author=Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker MW, Spitzer AR et al.| title=Complex multifactorial nature of significant hyperbilirubinemia in neonates. | journal=Pediatrics | year= 2009 | volume= 124 | issue= 5 | pages= e868-77 | pmid=19858149 | doi=10.1542/peds.2009-0460 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19858149  }}</ref>
**[[Acquired]] pathological neonatal jaundice develops mainly due to [[hemolysis]] of the [[red blood cells]] via three main diseases:<ref name="pmid19858149">{{cite journal| author=Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker MW, Spitzer AR et al.| title=Complex multifactorial nature of significant hyperbilirubinemia in neonates. | journal=Pediatrics | year= 2009 | volume= 124 | issue= 5 | pages= e868-77 | pmid=19858149 | doi=10.1542/peds.2009-0460 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19858149  }}</ref>
***[[Rhesus|Rhesus (Rh)]] [[hemolytic disease]]
***[[Rhesus|Rhesus (Rh)]] [[hemolytic disease]]
***[[ABO incompatibility (patient information)|ABO blood group incompatibility]]
***[[ABO incompatibility (patient information)|ABO blood group incompatibility]]
***[[Glucose-6-phosphate dehydrogenase deficiency|Glucose-6-phosphate dehydrogenase enzyme deficiency (G6PD deficiency)]]
***[[Glucose-6-phosphate dehydrogenase deficiency|Glucose-6-phosphate dehydrogenase enzyme deficiency (G6PD deficiency)]]
**[[Inherited]] pathological [[neonatal jaundice]] occurs due to a defect in the [[bilirubin metabolism]] process and it includes the following:<ref name="pmid265955362">{{cite journal| author=Memon N, Weinberger BI, Hegyi T, Aleksunes LM| title=Inherited disorders of bilirubin clearance. | journal=Pediatr Res | year= 2016 | volume= 79 | issue= 3 | pages= 378-86 | pmid=26595536 | doi=10.1038/pr.2015.247 | pmc=4821713 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26595536  }}</ref>
**Inherited pathological neonatal jaundice occurs due to a defect in the [[bilirubin metabolism]] and it include:<ref name="pmid26595536">{{cite journal| author=Memon N, Weinberger BI, Hegyi T, Aleksunes LM| title=Inherited disorders of bilirubin clearance. | journal=Pediatr Res | year= 2016 | volume= 79 | issue= 3 | pages= 378-86 | pmid=26595536 | doi=10.1038/pr.2015.247 | pmc=4821713 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26595536  }}</ref>
***Defective [[hepatic]] uptake and storage of the [[bilirubin]]
***Defective [[hepatic]] uptake and storage of the [[bilirubin]]
***Defective [[bilirubin]] [[conjugation]] to [[glucuronic acid]] and it includes the following syndromes:
***Defective [[bilirubin]] [[conjugation]] to [[glucuronic acid]] and it include:
****[[Gilbert syndrome]]
****Gilbert syndrome
****[[Crigler-Najjar syndrome]]
****Crigler-Najjar syndrome
****[[Lucey-Driscoll syndrome]]
****Lucey-Driscoll syndrome
****[[Breast milk jaundice]]
****Breast milk jaundice
***Defective [[excretion]] of [[bilirubin]] into the [[bile]] and this syndrome called [[Dubin-Johnson syndrome]]
***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.
***Defective [[reuptake]] of the [[conjugated bilirubin]] through the [[enterohepatic circulation]]. This syndrome called Rotor syndrome.
====Acquired pathological neonatal jaundice====
====Acquired pathological neonatal jaundice====
*The following table contains the different hemolytic mechanisms which lead to neonatal jaundice:<ref name="pmid97130362">{{cite journal| author=McDonnell M, Hannam S, Devane SP| title=Hydrops fetalis due to ABO incompatibility. | journal=Arch Dis Child Fetal Neonatal Ed | year= 1998 | volume= 78 | issue= 3 | pages= F220-1 | pmid=9713036 | doi= | pmc=1720779 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9713036  }}</ref><ref name="pmid156862672">{{cite journal| author=Kaplan M, Hammerman C| title=Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus. | journal=Semin Perinatol | year= 2004 | volume= 28 | issue= 5 | pages= 356-64 | pmid=15686267 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15686267  }}</ref>
*The following table contains the different hemolytic mechanisms which lead to neonatal jaundice:<ref name="pmid9713036">{{cite journal| author=McDonnell M, Hannam S, Devane SP| title=Hydrops fetalis due to ABO incompatibility. | journal=Arch Dis Child Fetal Neonatal Ed | year= 1998 | volume= 78 | issue= 3 | pages= F220-1 | pmid=9713036 | doi= | pmc=1720779 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9713036  }}</ref><ref name="pmid15686267">{{cite journal| author=Kaplan M, Hammerman C| title=Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus. | journal=Semin Perinatol | year= 2004 | volume= 28 | issue= 5 | pages= 356-64 | pmid=15686267 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15686267  }}</ref>
{| class="wikitable"
{|
!Hemolytic disease
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hemolytic disease
!Pathogenesis
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Pathogenesis
|-
|-
|[[Rh disease|Rhesus factor (Rh) hemolytic disease]]
| align="center" style="background:#DCDCDC;" + |'''[[Rh disease|Rhesus factor (Rh) hemolytic disease]]'''
|
| style="background:#F5F5F5;" + |
*It is known as the Rh hemolytic disease of the newborns (RHDN).
*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]].
*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 disease|Rh]] [[antigen]] and the first birth is not affected.
*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 disease|Rh]] [[antigen]] but the first born 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]].
*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 incompatibility (patient information)|ABO blood group incompatibility]]
| align="center" style="background:#DCDCDC;" + |'''[[ABO incompatibility (patient information)|ABO blood group incompatibility]]'''
|
| style="background:#F5F5F5;" + |
*[[ABO blood group system|ABO blood group]] incompatibility is another form of the [[alloimmunization]] of the maternal blood cells against the fetal [[erythrocytes]].
*[[ABO blood group system|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]] in a [[fetus]] with [[Blood group|A or B blood group]].
*ABO incompatibility occurs when the mother has O group of the [[blood]] and [[pregnant]] with a [[fetus]] with [[Blood group|A or B blood group]].
*The maternal [[Blood cell|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 increase the [[unconjugated bilirubin]] and [[jaundice]].
*The maternal [[Blood cell|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.
*This condition, unlike RHDN, develops in the first newborn.
|-
|-
|[[Glucose-6-phosphate dehydrogenase deficiency|G6PD deficiency]]
| align="center" style="background:#DCDCDC;" + |'''[[Glucose-6-phosphate dehydrogenase deficiency|G6PD deficiency]]'''
|
| style="background:#F5F5F5;" + |
*[[Glucose-6-phosphate dehydrogenase|G6PD]] is an important [[enzyme]] found in the [[Red blood cell|red blood cells]] and incorporated in the [[Pentose phosphate pathway|hexose monophosphate pathway]]. G6PD collaborates in the production of [[NADPH]] and reduction of [[glutathione]] thus, helping in decrease the [[oxidative stress]] around the [[RBCs]].
*[[Glucose-6-phosphate dehydrogenase]] (G6PD) is an important [[enzyme]] found in the [[Red blood cell|red blood cells]] and incorporated in the [[Pentose phosphate pathway|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 [[Glucose-6-phosphate dehydrogenase|G6PD]] occurs due to a [[genetic defect]] which will lead to increase the [[oxidative stress]] on the [[Red blood cell|RBCs]] and the [[hemolysis]] of the fetal [[blood cells]].
*A deficiency in the [[Glucose-6-phosphate dehydrogenase|G6PD]] occurs due to a [[genetic defect]] which leads to increased [[oxidative stress]] in the [[Red blood cell|RBCs]] and the [[hemolysis]] of the fetal [[blood cells]].
|}
|}
====Inherited pathological neonatal jaundice====
====Inherited pathological neonatal jaundice====
*The following table includes the different causes of inherited neonatal jaundice:
*The following table includes the different causes of inherited neonatal jaundice:
{| class="wikitable"
{|
!Defective mechanism
! colspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Defective mechanism
!Pathogenesis
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Pathogenesis
|-
|-
|Defective [[bilirubin]] [[hepatic]] [[reuptake]] and storage<ref name="pmid173186212">{{cite journal| author=Muslu N, Dogruer ZN, Eskandari G, Atici A, Kul S, Atik U| title=Are glutathione S-transferase gene polymorphisms linked to neonatal jaundice? | journal=Eur J Pediatr | year= 2008 | volume= 167 | issue= 1 | pages= 57-61 | pmid=17318621 | doi=10.1007/s00431-007-0425-z | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17318621  }}</ref>
| colspan="2" align="center" style="background:#DCDCDC;" + |'''Defective [[bilirubin]] [[hepatic]] [[reuptake]] and storage<ref name="pmid17318621">{{cite journal| author=Muslu N, Dogruer ZN, Eskandari G, Atici A, Kul S, Atik U| title=Are glutathione S-transferase gene polymorphisms linked to neonatal jaundice? | journal=Eur J Pediatr | year= 2008 | volume= 167 | issue= 1 | pages= 57-61 | pmid=17318621 | doi=10.1007/s00431-007-0425-z | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17318621  }}</ref>'''
|
| style="background:#F5F5F5;" + |
*Defective of [[bilirubin]] hepatic uptake and storage is not well understood. There are recent studies that revealed the correlation between mutations in the [[GSTA1|GST gene]] and neonatal jaundice.
*Defective [[hepatic]] uptake and storage of [[bilirubin]] are not well understood. There are recent studies that revealed the correlation between mutations in the [[GSTA1|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
*The gene deletion in GST-M [[gene]] class is believed to cause the dysfunction of the GSTM1 [[enzyme]] and defective [[hepatic]] uptake of bilirubin
|-
|-
| rowspan="5" |Disorder of bilirubin conjugation
| rowspan="5" align="center" style="background:#DCDCDC;" + |'''Disorder of bilirubin conjugation'''
|'''Gilbert syndrome''':<ref name="pmid75659712">{{cite journal| author=Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA et al.| title=The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 18 | pages= 1171-5 | pmid=7565971 | doi=10.1056/NEJM199511023331802 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7565971  }}</ref>
| align="center" style="background:#DCDCDC;" + |'''Gilbert syndrome''':<ref name="pmid7565971">{{cite journal| author=Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA et al.| title=The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 18 | pages= 1171-5 | pmid=7565971 | doi=10.1056/NEJM199511023331802 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7565971  }}</ref>
| style="background:#F5F5F5;" + |
*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 [[UGT1A1|Uridine diphosphate Glucuronsyl Transferase (UGT) enzyme]].
*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 [[UGT1A1|Uridine diphosphate Glucuronsyl Transferase (UGT) enzyme]].
*It is accompanied by several [[Gene mutation|gene mutations]] (about 100 different mutations).
*It is accompanied by several [[Gene mutation|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.
*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:'''<ref name="pmid94972532">{{cite journal| author=Gantla S, Bakker CT, Deocharan B, Thummala NR, Zweiner J, Sinaasappel M et al.| title=Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1. | journal=Am J Hum Genet | year= 1998 | volume= 62 | issue= 3 | pages= 585-92 | pmid=9497253 | doi=10.1086/301756 | pmc=1376950 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9497253  }}</ref><ref name="pmid234032572">{{cite journal| author=Canu G, Minucci A, Zuppi C, Capoluongo E| title=Gilbert and Crigler Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database. | journal=Blood Cells Mol Dis | year= 2013 | volume= 50 | issue= 4 | pages= 273-80 | pmid=23403257 | doi=10.1016/j.bcmd.2013.01.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23403257  }}</ref>
| align="center" style="background:#DCDCDC;" + |'''Crigler-Najjar syndrome type I:'''<ref name="pmid9497253">{{cite journal| author=Gantla S, Bakker CT, Deocharan B, Thummala NR, Zweiner J, Sinaasappel M et al.| title=Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1. | journal=Am J Hum Genet | year= 1998 | volume= 62 | issue= 3 | pages= 585-92 | pmid=9497253 | doi=10.1086/301756 | pmc=1376950 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9497253  }}</ref><ref name="pmid23403257">{{cite journal| author=Canu G, Minucci A, Zuppi C, Capoluongo E| title=Gilbert and Crigler Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database. | journal=Blood Cells Mol Dis | year= 2013 | volume= 50 | issue= 4 | pages= 273-80 | pmid=23403257 | doi=10.1016/j.bcmd.2013.01.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23403257  }}</ref>
*Crigler Najjar syndrome type I is characterized by a total absence of the UGT1A1 enzyme, unlike Gilbert syndrome.
| style="background:#F5F5F5;" + |
*Gene mutation of the [[UGT1A1|UGT1A1 enzyme]] occurs due to [[deletion]] of the [[Amino acid sequence|amino acid sequences]] of the [[exons]] of the UGT1A1 enzyme.
*Crigler-Najjar syndrome type I is characterized by a total absence of the [[UGT1A1]] enzyme, unlike Gilbert syndrome.
*[[Genetic mutations]] in the [[introns]] also can lead to [[Frameshift mutation|frameshift]] of the [[Amino acid sequence|amino acid sequences]] or create premature [[Stop codon|stop codons]] which result in cessation of the enzyme formation.
*Gene mutation of the [[UGT1A1|UGT1A1 enzyme]] occurs due to [[deletion]] of the [[Amino acid sequence|amino acid sequences]] of the [[exons]] of the [[UGT1A1]] enzyme.
*[[Genetic mutations]] in the [[introns]] may also lead to [[Frameshift mutation|frameshift]] of the [[Amino acid sequence|amino acid sequences]] or create prematu1e [[Stop codon|stop codons]] which result in cessation of the [[enzyme]] formation.
|-
|-
|'''Crigler-Najjar syndrome type II (Arias syndrome):'''<ref name="pmid79895952">{{cite journal| author=Seppen J, Bosma PJ, Goldhoorn BG, Bakker CT, Chowdhury JR, Chowdhury NR et al.| title=Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. | journal=J Clin Invest | year= 1994 | volume= 94 | issue= 6 | pages= 2385-91 | pmid=7989595 | doi=10.1172/JCI117604 | pmc=330068 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7989595  }}</ref>
| align="center" style="background:#DCDCDC;" + |'''Crigler-Najjar syndrome type II (Arias syndrome):'''<ref name="pmid7989595">{{cite journal| author=Seppen J, Bosma PJ, Goldhoorn BG, Bakker CT, Chowdhury JR, Chowdhury NR et al.| title=Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. | journal=J Clin Invest | year= 1994 | volume= 94 | issue= 6 | pages= 2385-91 | pmid=7989595 | doi=10.1172/JCI117604 | pmc=330068 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7989595  }}</ref>
*Crigler Najjar syndrome type II has a reduced activity of the [[UGT1A1|UGT1A1 enzyme]] (not completely inactive).
| style="background:#F5F5F5;" + |
*The [[gene mutation]] in the UGT1A1 gene is [[point mutation]] which results in [[amino acid]] substitution not [[stop codon]]. Hereby, a decrease in the [[UGT1A1|UGT enzyme]] occurs.
*Crigler-Najjar syndrome type II has a reduced activity of the [[UGT1A1|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 [[UGT1A1|UGT enzyme]] activity  occurs.
|-
|-
|'''Lucey-Driscoll syndrome:'''<ref name="pmid143321572">{{cite journal| author=ARIAS IM, WOLFSON S, LUCEY JF, MCKAY RJ| title=TRANSIENT FAMILIAL NEONATAL HYPERBILIRUBINEMIA. | journal=J Clin Invest | year= 1965 | volume= 44 | issue=  | pages= 1442-50 | pmid=14332157 | doi=10.1172/JCI105250 | pmc=292625 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14332157  }}</ref>
| align="center" style="background:#DCDCDC;" + |'''Lucey-Driscoll syndrome:'''<ref name="pmid14332157">{{cite journal| author=ARIAS IM, WOLFSON S, LUCEY JF, MCKAY RJ| title=TRANSIENT FAMILIAL NEONATAL HYPERBILIRUBINEMIA. | journal=J Clin Invest | year= 1965 | volume= 44 | issue=  | pages= 1442-50 | pmid=14332157 | doi=10.1172/JCI105250 | pmc=292625 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14332157  }}</ref>
*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.
| style="background:#F5F5F5;" + |
*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|UGT1A1 enzyme]] and this inhibitor is unidentified until the moment.
*It is believed that Lucey-Driscoll syndrome is associated with an inhibitor of the [[UGT1A1|UGT1A1 enzyme]] and this inhibitor is unidentified until the moment.
|-
|-
|'''Breast milk jaundice:'''<ref name="pmid28693472">{{cite journal| author=Gourley GR, Arend RA| title=beta-Glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies. | journal=Lancet | year= 1986 | volume= 1 | issue= 8482 | pages= 644-6 | pmid=2869347 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2869347  }}</ref>
| align="center" style="background:#DCDCDC;" + |'''Breast milk jaundice:'''<ref name="pmid2869347">{{cite journal| author=Gourley GR, Arend RA| title=beta-Glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies. | journal=Lancet | year= 1986 | volume= 1 | issue= 8482 | pages= 644-6 | pmid=2869347 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2869347  }}</ref>
*[[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
| style="background:#F5F5F5;" + |
*It is believed that a combination of [[genetic mutation]] and environmental ([[breast milk]] components) factors lead to the [[jaundice]] development.
*[[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|beta-glucuronidase enzyme]], one of the milk substances, may be one of the causes that increase the [[bilirubin]] and develop jaundice.
*The [[Beta-glucuronidase|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.
*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
| align="center" style="background:#DCDCDC;" + |'''Disorders of excretion into Bile'''
|'''Dubin-Johnson syndrome:'''<ref name="pmid91857792">{{cite journal| author=Paulusma CC, Kool M, Bosma PJ, Scheffer GL, ter Borg F, Scheper RJ et al.| title=A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. | journal=Hepatology | year= 1997 | volume= 25 | issue= 6 | pages= 1539-42 | pmid=9185779 | doi=10.1002/hep.510250635 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9185779  }}</ref>
| align="center" style="background:#DCDCDC;" + |'''Dubin-Johnson syndrome:'''<ref name="pmid9185779">{{cite journal| author=Paulusma CC, Kool M, Bosma PJ, Scheffer GL, ter Borg F, Scheper RJ et al.| title=A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. | journal=Hepatology | year= 1997 | volume= 25 | issue= 6 | pages= 1539-42 | pmid=9185779 | doi=10.1002/hep.510250635 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9185779  }}</ref>
* Dubin-Johnson syndrome is a result of a genetic mutation in the ''ABCC2''/MRP2 transporter result in absence of the transporter expression.
| style="background:#F5F5F5;" + |
* 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.
*Other mutations which may lead to Dubin-Johnson syndrome include base deletion, nonsense mutation, or exon skipping.
|-
|-
|Disorders of reuptake
| align="center" style="background:#DCDCDC;" + |'''Disorders of reuptake'''
|'''Rotor syndrome (RS):'''<ref name="pmid222322102">{{cite journal| author=van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E et al.| title=Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. | journal=J Clin Invest | year= 2012 | volume= 122 | issue= 2 | pages= 519-28 | pmid=22232210 | doi=10.1172/JCI59526 | pmc=3266790 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22232210  }}</ref>
| align="center" style="background:#DCDCDC;" + |'''Rotor syndrome (RS):'''<ref name="pmid22232210">{{cite journal| author=van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E et al.| title=Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. | journal=J Clin Invest | year= 2012 | volume= 122 | issue= 2 | pages= 519-28 | pmid=22232210 | doi=10.1172/JCI59526 | pmc=3266790 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22232210  }}</ref>
*Rotor syndrome is an autosomal recessive disease which results in a defect of the hepatic reuptake of the bilirubin.
| style="background:#F5F5F5;" + |
*Genetic mutation of  ''SLCO1B1''/OATP1B1 and''SLCO1B3''/OATP1B3 lead to absence of the OATP1B1 and OATP1B3 transporters of bilirubin.
*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==
==References==

Revision as of 16:33, 22 February 2018

Jaundice Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Jaundice from other Conditions

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Chest X Ray

Electrocardiogram

CT

MRI

Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Jaundice pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Jaundice pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Jaundice pathophysiology

CDC on Jaundice pathophysiology

Jaundice pathophysiology in the news

Blogs on Jaundice pathophysiology

Directions to Hospitals Treating Jaundice

Risk calculators and risk factors for Jaundice pathophysiology

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

For more information about viral hepatitis pathophysiology click here

For more information about cirrhosis pathophysiology click here

 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 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
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 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:[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. 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:[25]
  •  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):[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 and SLCO1B3/OATP1B3 leads to absence of the OATP1B1 and OATP1B3 transporters of bilirubin.

References

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. Dennery PA, Seidman DS, Stevenson DK (2001). "Neonatal hyperbilirubinemia". N Engl J Med. 344 (8): 581–90. doi:10.1056/NEJM200102223440807. PMID 11207355.
  12. Brouillard RP (1974). "Measurement of red blood cell life-span". JAMA. 230 (9): 1304–5. PMID 4479604.
  13. 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.
  14. 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.
  15. 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.
  16. McDonnell M, Hannam S, Devane SP (1998). "Hydrops fetalis due to ABO incompatibility". Arch Dis Child Fetal Neonatal Ed. 78 (3): F220–1. PMC 1720779. PMID 9713036.
  17. Kaplan M, Hammerman C (2004). "Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus". Semin Perinatol. 28 (5): 356–64. PMID 15686267.
  18. Muslu N, Dogruer ZN, Eskandari G, Atici A, Kul S, Atik U (2008). "Are glutathione S-transferase gene polymorphisms linked to neonatal jaundice?". Eur J Pediatr. 167 (1): 57–61. doi:10.1007/s00431-007-0425-z. PMID 17318621.
  19. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA; et al. (1995). "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome". N Engl J Med. 333 (18): 1171–5. doi:10.1056/NEJM199511023331802. PMID 7565971.
  20. Gantla S, Bakker CT, Deocharan B, Thummala NR, Zweiner J, Sinaasappel M; et al. (1998). "Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1". Am J Hum Genet. 62 (3): 585–92. doi:10.1086/301756. PMC 1376950. PMID 9497253.
  21. Canu G, Minucci A, Zuppi C, Capoluongo E (2013). "Gilbert and Crigler Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database". Blood Cells Mol Dis. 50 (4): 273–80. doi:10.1016/j.bcmd.2013.01.003. PMID 23403257.
  22. Seppen J, Bosma PJ, Goldhoorn BG, Bakker CT, Chowdhury JR, Chowdhury NR; et al. (1994). "Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase". J Clin Invest. 94 (6): 2385–91. doi:10.1172/JCI117604. PMC 330068. PMID 7989595.
  23. ARIAS IM, WOLFSON S, LUCEY JF, MCKAY RJ (1965). "TRANSIENT FAMILIAL NEONATAL HYPERBILIRUBINEMIA". J Clin Invest. 44: 1442–50. doi:10.1172/JCI105250. PMC 292625. PMID 14332157.
  24. Gourley GR, Arend RA (1986). "beta-Glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies". Lancet. 1 (8482): 644–6. PMID 2869347.
  25. Paulusma CC, Kool M, Bosma PJ, Scheffer GL, ter Borg F, Scheper RJ; et al. (1997). "A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome". Hepatology. 25 (6): 1539–42. doi:10.1002/hep.510250635. PMID 9185779.
  26. van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E; et al. (2012). "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver". J Clin Invest. 122 (2): 519–28. doi:10.1172/JCI59526. PMC 3266790. PMID 22232210.


Template:WH Template:WS