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{{Jaundice}}
{{Jaundice}}
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{{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==
====  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]].
*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="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]].
***[[Hepatocytes|The hepatocytes]] then reuptake the [[bilirubin]] and prepare it for excretion.
**'''[[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 with [[glucuronic acid]] producing [[bilirubin diglucuronide]] which is [[water]] soluble.
***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]].
**'''[[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]].
***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.
***The sterile tract ends up with a small amount of [[Bile|excreted bile]].
***The remaining conjugated bilirubin is unconjugated by the [[Beta-glucuronidase|beta-glucuronidase enzyme]] in the [[neonatal]] [[intestine]].
***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]].
==== For more information about viral hepatitis pathophysiology [[Viral hepatitis|click here]] ====
==== For more information about cirrhosis pathophysiology [[Cirrhosis pathophysiology|click here]] ====
==== For more information about neonatal jaundice pathophysiology [[Neonatal jaundice pathophysiology|click here]] ====
===Pathogenesis of Adult jaundice===
* Jaundice in adult patients classified into two major types:
** [[Unconjugated bilirubin|Unconjugated]] [[hyperbilirubinemia]]
** [[Conjugated bilirubin|Conjugated]] [[hyperbilirubinemia]]
=== Unconjugated 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>
* Overproduction of [[bilirubin]]
* Reduced [[bilirubin]] uptake
* Impaired [[bilirubin]] [[conjugation]]
** The combination of progestational and estrogenic steroids may result in increased [[UDP glucuronosyltransferase 1 family, polypeptide A1|UDP-glucuronyl transferase]] activity


==Pathophysiology==
=== Conjugated hyperbilirubinemia ===
=== 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="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 the liver and spleen through two steps which include the following:<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 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
** 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="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="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 the liver.
*** The hepatocytes then reuptake the bilirubin and prepare it for excretion. 
** 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 with glucuronic acid producing bilirubin diglucuronide which is water soluble. 
*** Being water soluble, hence, the conjugated bilirubin can be excreted into bile. 
*** The conjugation process occurs by the glucuronosyltransferase enzyme in the liver cells.
** Clearance and excretion:<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 the liver, it is secreted into the bile then into the gastrointestinal tract.
*** In the GIT, the conjugated bilirubin is metabolized by the gut enzymes into urobilinogen which is oxidized into urobilin.
*** Metabolism of the conjugated bilirubin occurs properly in the adults. However, the newborns have sterile gastrointestinal canal which impedes the catalyzation of the conjugated bilirubin.
*** The sterile tract will end up with a small amount of excreted bile.
*** The remaining conjugated bilirubin will be unconjugated by the beta-glucuronidase enzyme in the neonatal intestine.
*** The unconjugated bilirubin can be reabsorbed back into the blood and to the liver through the enterohepatic circulation of bilirubin.
*** A small amount of bilirubin is cleared into the urine as urobilinogen. 


=== Pathogenesis ===
==== 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> ====
*Neonatal jaundice may be a result of physiologic or pathological mechanisms. The different mechanisms of developing jaundice are concluded into either an increase in the bilirubin production, or increase the enterohepatic circulation, or decrease bilirubin elimination.<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>
* [[Biliary obstruction|Biliary tract obstruction]] leads to both conjugated and unconjugated bilirubinemia.
*'''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>
* [[Bilirubin]] is transported back to the plasma by ATP-consuming pumps.
**The child has red blood cells twice or more than what the adults have and with shorter lifespan.  
* The markers are serum concentrations of [[bilirubin]] and [[alkaline phosphatase]].  
**Increase rate of the red blood cells destruction produces more levels of bilirubin which end up with jaundice.
* Biliary retention secondary to obstruction may reverse the glucuronidation.
**The newborn gastrointestinal gut is considered sterile so, a little amount of the unconjugated is converted to conjugated and excreted. Most of the unconjugated is recirculated through the enterohepatic circulation. 
* Produced unconjugated [[bilirubin]] will diffuse or be transported back into the [[plasma]].
**Unconjugated hyperbilirubinemia is the predominant form of physiological jaundice.
* [[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>
**Physiologic jaundice is a benign case and resolves within a 10 to 14 days of life.
** [[Extrahepatic bile ducts]] compression by a distended [[gallbladder]] due to [[cholelithiasis]].
*'''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>
* [[Primary sclerosing cholangitis]] and cholangiocarcinoma
**The majority of neonatal jaundice is due to pathological conditions. Pathological neonatal jaundice is due to acquired or inherited conditions.
** [[Intrahepatic bile ducts|Intrahepatic]] and [[Extrahepatic bile ducts|extrahepatic]] portions of the bile ducts are affected.  
**Pathological jaundice is the result of an increase in the level of unconjugated bilirubin which is named as "Indirect hyperbilirubinemia".  
* [[Parasites]]
**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.
** Adult ''[[Ascaris lumbricoides]]''
**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>
** Eggs of certain [[liver flukes]] (e.g., ''[[Clonorchis sinensis]]'', ''[[Fasciola hepatica]]'')
***Rhesus (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>
***ABO blood group incompatibility
** ''[[Cryptosporidium]]'' species
***Glucose 6 phosphate dehydrogenase enzyme deficiency (G6PD deficiency)  
** [[Cytomegalovirus]]
**Inhereted pathological neonatal jaundice occurs due to a defect in the bilirubin metabolism process and it includes the following:<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>
** [[HIV]]
***Defective hepatic uptake and storage of the bilirubin
*** [[Viral hepatitis]] ([[Hepatitis|hepatitis viruses]], [[herpes simplex virus]], [[Epstein-Barr virus]])
***Defective bilirubin conjugation to glucuronic acid and it includes the following syndromes:
*** [[Mycobacterium tuberculosis|''Mycobacterium'' tuberculosis]] and [[atypical mycobacteria]] (especially [[Mycobacterium avium intracellulare|''Mycobacterium avium'' intracellulare]])
****Gilbert syndrome
*** [[Fungal infections]] (''[[Cryptococcus neoformans]]'', ''[[Histoplasma capsulatum]]'', ''[[Candida albicans]]'', ''[[Coccidioides immitis]]'')
****Crigler-Najjar syndrome
*** [[Parasites]] (''[[Pneumocystis carinii]]'')
****Lucey-Driscoll syndrome
*** Tumor infiltration ([[lymphoma]], [[Kaposi sarcoma]])
****Breast milk jaundice
*** Drug-induced liver disease
***Defective excretion of bilirubin into the bile and this syndrome called Dubin-Johnson syndrome
***Defective reuptake of the conjugated bilirubin through the enterohepatic ciruclation. This syndrome called Rottor syndrome.


==== Acquired pathological neonatal jaundice ====
==== Liver infrastructure damage ====
* 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>  
* [[Viral hepatitis]]: For more information about viral hepatitis [[Viral hepatitis X (non-A,-B,-C,-D,-E)|click here]]
{| class="wikitable"
* [[Alcoholic hepatitis]]: For more information about viral hepatitis [[Alcoholic hepatitis pathophysiology|click here]]
!Hemolytic disease
* [[Nonalcoholic steatohepatitis]]: For more information about viral hepatitis [[Non-alcoholic fatty liver disease|click here]]
!Pathogenesis
* [[Primary biliary cholangitis]]: For more information about viral hepatitis [[Primary biliary cirrhosis pathophysiology|click here]]
|-
* [[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>
|Rhesus factor (Rh) hemolytic disease
** Dose-related fashion (e.g., alkylated steroids such as [[methyltestosterone]] and [[ethinyl estradiol]])
|
** [[Idiosyncratic reaction|Idiosyncratic]] or [[allergic reaction]] (e.g., [[chlorpromazine]], [[halothane]]).
* It is known as the Rh hemolytic disease of the newborns (RHDN).
** [[Pyrrolizidine alkaloid|Pyrrolizidine alkaloids]] which may cause [[veno-occlusive disease]] of the [[liver]] (e.g., Jamaican bush tea)
* RHDN is the result of alloimmunization of the maternal red blood cells when the mother is pregnant with a Rh-positive fetus.
* [[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>
* In the first pregnancy, if the fetus is a Rh-positive, some of the fetal blood is mixed with the maternal blood during birth. The maternal body will form antibodies (IgG) against the fetal Rh antigen and the first birth is not affected.
** [[Hypotension]]
* 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.
** [[Drugs]]
|-
** [[Bacterial endotoxins]]
|ABO blood group incompatibility
* [[Paraneoplastic syndromes]]
|
** [[Renal cell carcinoma]]
* ABO blood group incompatibility is another form of the alloimmunization of the maternal blood cells against the fetal erythrocytes.
** [[Lymphoproliferative disease|Malignant lymphoproliferative diseases]]
* ABO incompatibility occurs when the mother has O group of the blood and pregnant in a fetus with A or B blood group.
** [[Gynecologic cancer|Gynecologic malignancies]]
* The maternal blood cells will form eitantibodieA 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. 
** [[Prostate cancer]]
* This condition, unlike RHDN, develops in the first newborn. 
* [[Infiltrative and Metabolic Diseases Affecting the Liver|Infiltrative diseases of the liver]]
|-
** [[Amyloidosis]]
|G6PD deficiency
** [[Lymphoma]]
|
** [[Sarcoidosis]]
* G6PD is an important enzyme found in the red blood cells and incorporated in the hexose monophosphate pathway. G6PD collaborates in the production of NADPH and reduction of glutathione thus, helping in decrease the oxidative stress around the RBCs.
** [[Tuberculosis]]
* A deficiency in the G6PD occurs due to a genetic defect which will lead to increas  the oxidative stress on the RBCs and the hemolysis of the fetal blood cells. 
* [[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]].
*** Intestinal [[endotoxins]] transfer into the [[portal system]]
*** Bacterial [[sepsis]]
*** Formation of secondary [[Bile acid|bile acids]] (e.g., lithocholic acid)
*** Biliary sludge after six weeks of [[Total parenteral nutrition|TPN]]
*** Hepatotoxic factors, such as [[tryptophan]] degradation metabolites and [[Aluminium|aluminum]] contaminants
*** [[Small bowel bacterial overgrowth syndrome|Bacterial overgrowth in the small intestine]]
* [[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>
** [[Hemolysis]]
** Mild [[hepatic dysfunction]]
** Both [[Unconjugated bilirubin|unconjugated]] and [[conjugated bilirubin]] accumulate in the [[plasma]]
* [[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>
** Usually in the third trimester but sometimes earlier
** Heralds [[cholestasis]] and then frank jaundice
** May be associated with increased [[stillbirths]] and [[prematurity]]
** All the pathologic changes would disappear after [[delivery]]


==== Inherited pathological neonatal 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> ====
* The following table includes the different causes of inherited neonatal jaundice:
* Different presentations simulate [[Cholestatic liver diseases|cholestatic syndromes]].  
{| class="wikitable"
* Intracellular [[proteins]] and small molecules are released into the [[plasma]].
!Defective mechanism
* Increased [[transaminases]], such as [[Aspartate aminotransferase|aspartate aminotransferase (AST)]] and [[Alanine aminotransferase|alanine aminotransferase (ALT)]].
!Pathogenesis
<br>
|-
<small>
|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>
|
* Defective of bilirubin hepatic uptake and storage is not well understood. The recently held studies revealed the correlation between mutations in the GST gene and neonatal jaundice.
* The gene deletion in GST-M gene class is believed it leads to dysfunction of the GSTM1 enzyme and defective hepatic uptake of bilirubin
|-
| rowspan="5" |Disorder of bilirubin conjugation
|'''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>
* Gilbert syndrome, the most common inherited neonatal jaundice syndrome, is an autosomal recessive disease which is one of the causes of neonatal jaundice due to a defect (not total absence) in the Uridine diphosphate Glucuronsyl Transferase (UGT) enzyme.
* It is accompanied by several gene mutations (about 100 different mutations).
* The most common gene mutation occurs in the TA sequence of the TATAA box of the promoter region of UGT1A1 gene.
|-
|'''Crigler-Najjar syndrome type I:'''<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.  
* Gene mutation of the UGT1A1 enzyme occurs due to deletion of the amino acid sequences of the exons of the UGT1A1 enzyme.  
* Genetic mutations in the introns also can lead to frameshift of the amino acid sequences or create premature stop codons which result in cessation of the enzyme formation.
|-
|'''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 enzyme (not completely inactive).  
* The gene mutation in the UGT1A1 gene is point mutation which results in amino acid substitution not stop codon. Hereby, a decrease in the UGT enzyme occurs.
|-
|'''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.
* It is believed that Lucey-Driscoll syndrome is associated with an inhibitor of the UGT1A1 enzyme and this inhibitor is unidentified until the moment.


|-
{{family tree/start}}
|'''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>  
{{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]]}}
* 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
{{family tree| | |`|-|-|-|^|-|-|-|^|-|-|v|^|-|-|-|^|-|-|-|'| | | |`|-|-|-|+|-|-|-|^|-|-|-|'| | | | | | | | | | |}}
* It is believed that a combination of genetic mutation and environmental (breast milk components) factors lead to the jaundice development.
{{family tree| | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | |}}
* The beta-glucuronidase enzyme, one of the milk substances, may be one of the causes that increase the bilirubin and develop jaundice. 
{{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]]}}
* In a Japanese study, a correlation between a genetic mutation in UGT1A1 gene and breast milk jaundice has been considered. 
{{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]]}}
|Disorders of excretion into Bile
{{family tree| | |`|-|-|-|+|-|-|-|'| | |!| | |`|-|-|-|^|-|v|-|^|-|-|-|'| |!| |`|-|-|-|-|-|v|-|'| | | | | | |}}
|'''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>
{{family tree| | | | | | |!| | | | | | |!| | | | | | | | |!| | | | | | | |!| | | | | | | |!| | | | | | | | |}}
*  Dubin-Johnson syndrome is a result of a genetic mutation in the ''ABCC2''/MRP2 transporter result in absence of the transporter expression.
{{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]]}}
* Other mutations which may lead to Dubin-Johnson syndrome include base deletion, nonsense mutation, or exon skipping.
{{family tree| | |`|-|-|-|^|-|v|-|-|-|-|'| | | | | | | | |`|-|-|-|-|-|-|-|+|-|-|-|-|-|-|-|'| | | | | | | | |}}
|-
{{family tree| | | | | | | | D01 | | | | | | | | | | | | | | | | | | | | D02 | | | | | | | | | | | | | | | |D01='''''Conjugated hyperbilirubinemia'''''|D02='''''Unconjugated hyperbilirubinemia'''''}}
|Disorders of reuptake
{{family tree| | | | | | | | |`|-|-|-|-|-|-|-|-|-|-|v|-|-|-|-|-|-|-|-|-|-|'| | | | | | | | | | | | | | | | |}}
|'''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>
{{family tree| | | | | | | | | | | | | | | | | | | E01 | | | | | | | | | | | | | | | | | | | | | | | | | | |E01='''Jaundice'''}}
* Rotor syndrome is an autosomal recessive disease which results in a defect of the hepatic reuptake of the bilirubin.
{{family tree/end}}
* Genetic mutation of  ''SLCO1B1''/OATP1B1 and''SLCO1B3''/OATP1B3 lead to absence of the OATP1B1 and OATP1B3 transporters of bilirubin.
</small>
|}


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{WH}}
{{WS}}


[[Category:Needs content]]
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[[Category:Disease]]
[[Category:Gastroenterology]]
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[[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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