Jaundice pathophysiology: Difference between revisions

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{{Jaundice}}
{{Jaundice}}
{{CMG}}; {{AE}}{{AEL}}
{{CMG}}; {{AE}}{{EG}}, {{AEL}}


==Overview==
==Overview==
[[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>
====  Bilirubin formation and metabolism ====
*[[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>
*[[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>
**[[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
*[[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===
==== For more information about viral hepatitis pathophysiology [[Viral hepatitis|click here]] ====
*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>
 
*'''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>
==== For more information about cirrhosis pathophysiology [[Cirrhosis pathophysiology|click here]] ====
**The child has [[red blood cells]] twice or more than what 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]].
==== For more information about neonatal jaundice pathophysiology [[Neonatal jaundice pathophysiology|click here]] ====
**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]].
===Pathogenesis of Adult jaundice===
**Unconjugated [[hyperbilirubinemia]] is the predominant form of [[physiological]] jaundice.
* Jaundice in adult patients classified into two major types:
**Physiological jaundice is a benign case and resolves within a 10 to 14 days of life.
** [[Unconjugated bilirubin|Unconjugated]] [[hyperbilirubinemia]]
*'''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>
** [[Conjugated bilirubin|Conjugated]] [[hyperbilirubinemia]]
**The majority of jaundice is due to pathological conditions. Pathological jaundice is due to acquired or [[inherited]] conditions.
=== Unconjugated hyperbilirubinemia ===
**Pathological jaundice is the result of an increase in the level of [[unconjugated bilirubin]] which is named as "Indirect [[hyperbilirubinemia]]".
The primary [[pathophysiology]] of unconjugated hyperbilirubinemia include:<ref name="pmid16512459">{{cite journal |vauthors=Duseja A, Das A, Das R, Dhiman RK, Chawla Y, Bhansali A |title=Unconjugated hyperbilirubinemia in nonalcoholic steatohepatitis--is it Gilbert's syndrome? |journal=Trop Gastroenterol |volume=26 |issue=3 |pages=123–5 |date= 2005 |pmid=16512459 |doi= |url=}}</ref>
**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]].
* Overproduction of [[bilirubin]]
**[[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>
* Reduced [[bilirubin]] uptake
***[[Rhesus|Rhesus (Rh)]] [[hemolytic disease]]
* Impaired [[bilirubin]] [[conjugation]]
***[[ABO incompatibility (patient information)|ABO blood group incompatibility]]
** The combination of progestational and estrogenic steroids may result in increased [[UDP glucuronosyltransferase 1 family, polypeptide A1|UDP-glucuronyl transferase]] activity
***[[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>
=== Conjugated hyperbilirubinemia ===
***Defective [[hepatic]] uptake and storage of the [[bilirubin]]
 
***Defective [[bilirubin]] [[conjugation]] to [[glucuronic acid]] and it includes the following syndromes:
==== Biliary tract obstruction<ref name="pmid18345288">{{cite journal| author=Abdallah AA, Krige JE, Bornman PC| title=Biliary tract obstruction in chronic pancreatitis. | journal=HPB (Oxford) | year= 2007 | volume= 9 | issue= 6 | pages= 421-8 | pmid=18345288 | doi=10.1080/13651820701774883 | pmc=2215354 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18345288 }}</ref> ====
****[[Gilbert syndrome]]
* [[Biliary obstruction|Biliary tract obstruction]] leads to both conjugated and unconjugated bilirubinemia.
****[[Crigler-Najjar syndrome]]
* [[Bilirubin]] is transported back to the plasma by ATP-consuming pumps.
****[[Lucey-Driscoll syndrome]]
* The markers are serum concentrations of [[bilirubin]] and [[alkaline phosphatase]].  
****[[Breast milk jaundice]]
* Biliary retention secondary to obstruction may reverse the glucuronidation.
***Defective [[excretion]] of [[bilirubin]] into the [[bile]] and this syndrome called [[Dubin-Johnson syndrome]]
* Produced unconjugated [[bilirubin]] will diffuse or be transported back into the [[plasma]].
***Defective [[reuptake]] of the [[conjugated bilirubin]] through the [[enterohepatic circulation]]. This syndrome called Rotor syndrome.
* [[Mirizzi syndrome]]<ref name="pmid23002333">{{cite journal| author=Beltrán MA| title=Mirizzi syndrome: history, current knowledge and proposal of a simplified classification. | journal=World J Gastroenterol | year= 2012 | volume= 18 | issue= 34 | pages= 4639-50 | pmid=23002333 | doi=10.3748/wjg.v18.i34.4639 | pmc=3442202 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23002333 }}</ref>
====Acquired pathological neonatal jaundice====
** [[Extrahepatic bile ducts]] compression by a distended [[gallbladder]] due to [[cholelithiasis]].
*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>
* [[Primary sclerosing cholangitis]] and cholangiocarcinoma
{| class="wikitable"
** [[Intrahepatic bile ducts|Intrahepatic]] and [[Extrahepatic bile ducts|extrahepatic]] portions of the bile ducts are affected.
!Hemolytic disease
* [[Parasites]]
!Pathogenesis
** Adult ''[[Ascaris lumbricoides]]''
|-
** Eggs of certain [[liver flukes]] (e.g., ''[[Clonorchis sinensis]]'', ''[[Fasciola hepatica]]'')
|[[Rh disease|Rhesus factor (Rh) hemolytic disease]]
* [[AIDS]] cholangiopathy<ref name="pmid15010025">{{cite journal |vauthors=Yusuf TE, Baron TH |title=AIDS Cholangiopathy |journal=Curr Treat Options Gastroenterol |volume=7 |issue=2 |pages=111–117 |date=April 2004 |pmid=15010025 |doi= |url=}}</ref>
|
** ''[[Cryptosporidium]]'' species
*It is known as the Rh hemolytic disease of the newborns (RHDN).
** [[Cytomegalovirus]]
*RHDN is the result of [[alloimmunization]] of the maternal [[red blood cells]] when the mother is pregnant with a Rh-positive [[fetus]].
** [[HIV]]  
*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.
*** [[Viral hepatitis]] ([[Hepatitis|hepatitis viruses]], [[herpes simplex virus]], [[Epstein-Barr virus]])
*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]].
*** [[Mycobacterium tuberculosis|''Mycobacterium'' tuberculosis]] and [[atypical mycobacteria]] (especially [[Mycobacterium avium intracellulare|''Mycobacterium avium'' intracellulare]])
|-
*** [[Fungal infections]] (''[[Cryptococcus neoformans]]'', ''[[Histoplasma capsulatum]]'', ''[[Candida albicans]]'', ''[[Coccidioides immitis]]'')
|[[ABO incompatibility (patient information)|ABO blood group incompatibility]]
*** [[Parasites]] (''[[Pneumocystis carinii]]'')
|
*** Tumor infiltration ([[lymphoma]], [[Kaposi sarcoma]])
*[[ABO blood group system|ABO blood group]] incompatibility is another form of the [[alloimmunization]] of the maternal blood cells against the fetal [[erythrocytes]].
*** Drug-induced liver disease
*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]].
 
*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]].
==== Liver infrastructure damage ====
*This condition, unlike RHDN, develops in the first newborn.
* [[Viral hepatitis]]: For more information about viral hepatitis [[Viral hepatitis X (non-A,-B,-C,-D,-E)|click here]]
|-
* [[Alcoholic hepatitis]]: For more information about viral hepatitis [[Alcoholic hepatitis pathophysiology|click here]]
|[[Glucose-6-phosphate dehydrogenase deficiency|G6PD deficiency]]
* [[Nonalcoholic steatohepatitis]]: For more information about viral hepatitis [[Non-alcoholic fatty liver disease|click here]]
|
* [[Primary biliary cholangitis]]: For more information about viral hepatitis [[Primary biliary cirrhosis pathophysiology|click here]]
*[[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]].
* [[Toxicity]]<ref name="pmid171822">{{cite journal |vauthors=Schaffner F |title=Hepatic drug metabolism and adverse hepatic drug reactions |journal=Vet. Pathol. |volume=12 |issue=2 |pages=145–56 |date= 1975 |pmid=171822 |doi=10.1177/030098587501200206 |url=}}</ref>
*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]].
** Dose-related fashion (e.g., alkylated steroids such as [[methyltestosterone]] and [[ethinyl estradiol]])
|}
** [[Idiosyncratic reaction|Idiosyncratic]] or [[allergic reaction]] (e.g., [[chlorpromazine]], [[halothane]]).
====Inherited pathological neonatal jaundice====
** [[Pyrrolizidine alkaloid|Pyrrolizidine alkaloids]] which may cause [[veno-occlusive disease]] of the [[liver]] (e.g., Jamaican bush tea)
*The following table includes the different causes of inherited neonatal jaundice:
* [[Sepsis]] and low perfusion states<ref name="pmid12919846">{{cite journal |vauthors=Famularo G, De Simone C, Nicotra GC |title=Jaundice and the sepsis syndrome: a neglected link |journal=Eur. J. Intern. Med. |volume=14 |issue=4 |pages=269–271 |date=July 2003 |pmid=12919846 |doi= |url=}}</ref>
{| class="wikitable"
** [[Hypotension]]
!Defective mechanism
** [[Drugs]]
!Pathogenesis
** [[Bacterial endotoxins]]
|-
* [[Paraneoplastic syndromes]]
|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>
** [[Renal cell carcinoma]]
|
** [[Lymphoproliferative disease|Malignant lymphoproliferative diseases]]
*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.
** [[Gynecologic cancer|Gynecologic malignancies]]
*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
** [[Prostate cancer]]
|-
* [[Infiltrative and Metabolic Diseases Affecting the Liver|Infiltrative diseases of the liver]]
| rowspan="5" |Disorder of bilirubin conjugation
** [[Amyloidosis]]
|'''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>
** [[Lymphoma]]
*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]].
** [[Sarcoidosis]]
*It is accompanied by several [[Gene mutation|gene mutations]] (about 100 different mutations).
** [[Tuberculosis]]
*The most common gene mutation occurs in the TA sequence of the TATAA box of the [[promoter region]] of [[UGT1A1]] gene.
* [[Total parenteral nutrition|Total parenteral nutrition (TPN)]]<ref name="pmid8468653">{{cite journal |vauthors=Moss RL, Das JB, Ansari G, Raffensperger JG |title=Hepatobiliary dysfunction during total parenteral nutrition is caused by infusate, not the route of administration |journal=J. Pediatr. Surg. |volume=28 |issue=3 |pages=391–6; discussion 396–7 |date=March 1993 |pmid=8468653 |doi= |url=}}</ref>
|-
** At least two to three weeks of [[Total parenteral nutrition|TPN]] may lead to development of [[cholestasis]].
|'''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>
*** Intestinal [[endotoxins]] transfer into the [[portal system]]
*Crigler Najjar syndrome type I  is characterized by a total absence of the UGT1A1 enzyme, unlike Gilbert syndrome.
*** Bacterial [[sepsis]]
*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.
*** Formation of secondary [[Bile acid|bile acids]] (e.g., lithocholic acid)
*[[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.
*** Biliary sludge after six weeks of [[Total parenteral nutrition|TPN]]
|-
*** Hepatotoxic factors, such as [[tryptophan]] degradation metabolites and [[Aluminium|aluminum]] contaminants
|'''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>
*** [[Small bowel bacterial overgrowth syndrome|Bacterial overgrowth in the small intestine]]
*Crigler Najjar syndrome type II has a reduced activity of the [[UGT1A1|UGT1A1 enzyme]] (not completely inactive).
* [[Sickle cell disease]]<ref name="pmid3186339">{{cite journal |vauthors=Mallouh AA, Asha MI |title=Acute cholestatic jaundice in children with sickle cell disease: hepatic crises or hepatitis? |journal=Pediatr. Infect. Dis. J. |volume=7 |issue=10 |pages=689–92 |date=October 1988 |pmid=3186339 |doi= |url=}}</ref>
*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.
** [[Hemolysis]]  
|-
** Mild [[hepatic dysfunction]]  
|'''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>
** Both [[Unconjugated bilirubin|unconjugated]] and [[conjugated bilirubin]] accumulate in the [[plasma]]
*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.
* [[Intrahepatic cholestasis of pregnancy]]<ref name="pmid19418576">{{cite journal| author=Geenes V, Williamson C| title=Intrahepatic cholestasis of pregnancy. | journal=World J Gastroenterol | year= 2009 | volume= 15 | issue= 17 | pages= 2049-66 | pmid=19418576 | doi= | pmc=2678574 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19418576  }}</ref>
*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.
** Usually in the third trimester but sometimes earlier
|-
** Heralds [[cholestasis]] and then frank jaundice
|'''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>
** May be associated with increased [[stillbirths]] and [[prematurity]]  
*[[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
** All the pathologic changes would disappear after [[delivery]]
*It is believed that a combination of [[genetic mutation]] and environmental ([[breast milk]] components) factors lead to the [[jaundice]] development.
 
*The [[Beta-glucuronidase|beta-glucuronidase enzyme]], one of the milk substances, may be one of the causes that increase the [[bilirubin]] and develop jaundice.
==== [[Hepatocellular Disease|Hepatocellular injury]]<ref name="pmid21532726">{{cite journal| author=Gowda S, Desai PB, Hull VV, Math AA, Vernekar SN, Kulkarni SS| title=A review on laboratory liver function tests. | journal=Pan Afr Med J | year= 2009 | volume= 3 | issue= | pages= 17 | pmid=21532726 | doi= | pmc=2984286 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21532726  }}</ref> ====
*In a Japanese study, a correlation between a genetic mutation in UGT1A1 gene and breast milk jaundice has been considered.
* Different presentations simulate [[Cholestatic liver diseases|cholestatic syndromes]].
|-
* Intracellular [[proteins]] and small molecules are released into the [[plasma]].
|Disorders of excretion into Bile
* Increased [[transaminases]], such as [[Aspartate aminotransferase|aspartate aminotransferase (AST)]] and [[Alanine aminotransferase|alanine aminotransferase (ALT)]].
|'''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>
<br>
* Dubin-Johnson syndrome is a result of a genetic mutation in the ''ABCC2''/MRP2 transporter result in absence of the transporter expression.
<small>
*Other mutations which may lead to Dubin-Johnson syndrome include base deletion, nonsense mutation, or exon skipping.
 
|-
{{family tree/start}}
|Disorders of reuptake
{{family tree| | A01 | | A02 | | A03 | | A04 | | A05 | | A06 | | A07 | | A08 | | A09 | | A10 | | | | | | | | | |A01=[[Sepsis]]|A02=[[Paraneoplastic syndrome]]|A03=[[Infiltrative and Metabolic Diseases Affecting the Liver|Infiltrative hepatic diseases]]|A04=[[Total parenteral nutrition]]|A05=[[Sickle cell disease]]|A06=[[Pregnancy]]|A07=[[hemolysis|Extravascular hemolysis]]|A08=[[hemolysis|Intravascular hemolysis]]|A09=[[Extravasation]]|A10=[[Dyserythropoiesis]]}}
|'''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>
{{family tree| | |`|-|-|-|^|-|-|-|^|-|-|v|^|-|-|-|^|-|-|-|'| | | |`|-|-|-|+|-|-|-|^|-|-|-|'| | | | | | | | | | |}}
*Rotor syndrome is an autosomal recessive disease which results in a defect of the hepatic reuptake of the bilirubin.
{{family tree| | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | |}}
*Genetic mutation of  ''SLCO1B1''/OATP1B1 and''SLCO1B3''/OATP1B3 lead to absence of the OATP1B1 and OATP1B3 transporters of bilirubin.
{{family tree|boxstyle=text-align: left; | | B01 | | B02 | | B03 | |!| | B04 | | B05 | | B06 | | B07 |!| B08 | | B09 | | B10 | | B11 | |B01=• [[Cholelithiasis]]<br>• [[Tumor]]<br>• [[Primary biliary cholangitis]]<br>• [[Parasites]]<br>• [[Pancreatitis]]<br>• [[Stricture]]|B02=• [[Choledochal cyst]]<br>• [[Cholelithiasis]]<br>• [[Tumor]]|B03=• [[Biliary atresia]]<br>• [[Choledochal cyst]]|B04=• Decreased [[hepatic]] [[blood flow]]<br>• Decreased delivery of [[bilirubin]]|B05=• Capillarization of the sinusoidal [[endothelial cells]] (loss of [[fenestrae]])|B06=• Impaired [[bilirubin]] uptake at the [[sinusoidal]] surface of [[hepatocytes]]|B07=• [[Rifamycin]] [[antibiotics]]<br>• [[Probenecid]]<br>• Flavaspidic acid<br>• Bunamiodyl (a cholecystographic agent)|B08=• [[Crigler-Najjar syndrome|Type I and II Crigler Najjar syndrome]]|B09=• [[Hyperthyroidism]]<br>• [[Ethinyl estradiol]]|B10=• [[Novobiocin]]<br>• [[Gentamicin]]|B11=• [[Chronic hepatitis|Chronic persistent hepatitis]]<br>• Advanced [[cirrhosis]]<br>• [[Wilson's disease]]}}
|}
{{family tree| | |!| | | |!| | | |!| | |!| | |!| | | |!| | | |!| | | |!| |!| |!| | | |`|-|-|-|+|-|-|-|'| | |}}
{{family tree| | B01 | | B02 | | B03 | |!| | B04 | | B05 | | B06 | | B07 |!| B08 | | | | | | B09 | | | | | |B01=Adult|B02=Children|B03=Neonates and infants|B04=[[Heart failure]]<br>[[Portocaval anastomoses|Portosystemic shunt]]|B05=[[Cirrhosis]]|B06=[[Gilbert's Syndrome]]|B07=[[Drug-induced]] defect|B08=↓ or No[[UDP-glucuronosyltransferase|UGT]] activity|B09=Inhibit [[UDP-glucuronosyltransferase|UGT]]}}
{{family tree| | |`|-|-|-|+|-|-|-|'| | |!| | |`|-|-|-|^|-|v|-|^|-|-|-|'| |!| |`|-|-|-|-|-|v|-|'| | | | | | |}}
{{family tree| | | | | | |!| | | | | | |!| | | | | | | | |!| | | | | | | |!| | | | | | | |!| | | | | | | | |}}
{{family tree| | C01 | | C02 | | | | | C03 | | | | | | | C04 | | | | | | C05 | | | | | | C06 | | | | | | | |C01=[[Hepatocellular Disease]]|C02=[[Biliary obstruction]]|C03=[[Intrahepatic cholestasis]]|C04=Reduced [[bilirubin]] uptake|C05=Overproduction of [[bilirubin]]|C06=Impaired [[conjugation|bilirubin conjugation]]}}
{{family tree| | |`|-|-|-|^|-|v|-|-|-|-|'| | | | | | | | |`|-|-|-|-|-|-|-|+|-|-|-|-|-|-|-|'| | | | | | | | |}}
{{family tree| | | | | | | | D01 | | | | | | | | | | | | | | | | | | | | D02 | | | | | | | | | | | | | | | |D01='''''Conjugated hyperbilirubinemia'''''|D02='''''Unconjugated hyperbilirubinemia'''''}}
{{family tree| | | | | | | | |`|-|-|-|-|-|-|-|-|-|-|v|-|-|-|-|-|-|-|-|-|-|'| | | | | | | | | | | | | | | | |}}
{{family tree| | | | | | | | | | | | | | | | | | | E01 | | | | | | | | | | | | | | | | | | | | | | | | | | |E01='''Jaundice'''}}
{{family tree/end}}
</small>
 
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{WH}}
{{WS}}


[[Category:Needs content]]
[[Category:Needs content]]
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[[Category:Disease]]
[[Category:Disease]]
[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
[[Category:Hepatology]]
[[Category:Hepatology]]
{{WH}}
{{WS}}

Latest revision as of 22:27, 29 July 2020

Jaundice Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2], Ahmed Elsaiey, MBBCH [3]

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

For more information about viral hepatitis pathophysiology click here

For more information about cirrhosis pathophysiology click here

For more information about neonatal jaundice pathophysiology click here

Pathogenesis of Adult jaundice

Unconjugated hyperbilirubinemia

The primary pathophysiology of unconjugated hyperbilirubinemia include:[10]

Conjugated hyperbilirubinemia

Biliary tract obstruction[11]

Liver infrastructure damage

Hepatocellular injury[19]


 
Sepsis
 
Paraneoplastic syndrome
 
Infiltrative hepatic diseases
 
Total parenteral nutrition
 
Sickle cell disease
 
Pregnancy
 
Extravascular hemolysis
 
Intravascular hemolysis
 
Extravasation
 
Dyserythropoiesis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Cholelithiasis
• Tumor
• Primary biliary cholangitis
• Parasites
• Pancreatitis
• Stricture
 
• Choledochal cyst
• Cholelithiasis
• Tumor
 
• Biliary atresia
• Choledochal cyst
 
 
 
 
• Decreased hepatic blood flow
• Decreased delivery of bilirubin
 
• Capillarization of the sinusoidal endothelial cells (loss of fenestrae)
 
• Impaired bilirubin uptake at the sinusoidal surface of hepatocytes
 
• Rifamycin antibiotics
• Probenecid
• Flavaspidic acid
• Bunamiodyl (a cholecystographic agent)
 
 
• Type I and II Crigler Najjar syndrome
 
• Hyperthyroidism
• Ethinyl estradiol
 
• Novobiocin
• Gentamicin
 
• Chronic persistent hepatitis
• Advanced cirrhosis
• Wilson's disease
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adult
 
Children
 
Neonates and infants
 
 
 
 
Heart failure
Portosystemic shunt
 
Cirrhosis
 
Gilbert's Syndrome
 
Drug-induced defect
 
 
↓ or NoUGT activity
 
 
 
 
 
Inhibit UGT
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatocellular Disease
 
Biliary obstruction
 
 
 
 
Intrahepatic cholestasis
 
 
 
 
 
 
Reduced bilirubin uptake
 
 
 
 
 
Overproduction of bilirubin
 
 
 
 
 
Impaired bilirubin conjugation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conjugated hyperbilirubinemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unconjugated hyperbilirubinemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Jaundice
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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. ↑ Duseja A, Das A, Das R, Dhiman RK, Chawla Y, Bhansali A (2005). "Unconjugated hyperbilirubinemia in nonalcoholic steatohepatitis--is it Gilbert's syndrome?". Trop Gastroenterol. 26 (3): 123–5. PMID 16512459.
  11. ↑ Abdallah AA, Krige JE, Bornman PC (2007). "Biliary tract obstruction in chronic pancreatitis". HPB (Oxford). 9 (6): 421–8. doi:10.1080/13651820701774883. PMC 2215354. PMID 18345288.
  12. ↑ Beltrán MA (2012). "Mirizzi syndrome: history, current knowledge and proposal of a simplified classification". World J Gastroenterol. 18 (34): 4639–50. doi:10.3748/wjg.v18.i34.4639. PMC 3442202. PMID 23002333.
  13. ↑ Yusuf TE, Baron TH (April 2004). "AIDS Cholangiopathy". Curr Treat Options Gastroenterol. 7 (2): 111–117. PMID 15010025.
  14. ↑ Schaffner F (1975). "Hepatic drug metabolism and adverse hepatic drug reactions". Vet. Pathol. 12 (2): 145–56. doi:10.1177/030098587501200206. PMID 171822.
  15. ↑ Famularo G, De Simone C, Nicotra GC (July 2003). "Jaundice and the sepsis syndrome: a neglected link". Eur. J. Intern. Med. 14 (4): 269–271. PMID 12919846.
  16. ↑ Moss RL, Das JB, Ansari G, Raffensperger JG (March 1993). "Hepatobiliary dysfunction during total parenteral nutrition is caused by infusate, not the route of administration". J. Pediatr. Surg. 28 (3): 391–6, discussion 396–7. PMID 8468653.
  17. ↑ Mallouh AA, Asha MI (October 1988). "Acute cholestatic jaundice in children with sickle cell disease: hepatic crises or hepatitis?". Pediatr. Infect. Dis. J. 7 (10): 689–92. PMID 3186339.
  18. ↑ Geenes V, Williamson C (2009). "Intrahepatic cholestasis of pregnancy". World J Gastroenterol. 15 (17): 2049–66. PMC 2678574. PMID 19418576.
  19. ↑ Gowda S, Desai PB, Hull VV, Math AA, Vernekar SN, Kulkarni SS (2009). "A review on laboratory liver function tests". Pan Afr Med J. 3: 17. PMC 2984286. PMID 21532726.

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