Jaundice pathophysiology: Difference between revisions
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**[[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 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> | *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 | **'''[[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]] | **'''[[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. | ***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]] | **'''[[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]]. | ||
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***The [[unconjugated bilirubin]] is reabsorbed back into [[Blood|the blood]] and to the liver through the [[enterohepatic circulation]] of [[bilirubin]]. | ***The [[unconjugated bilirubin]] is reabsorbed back into [[Blood|the blood]] and to the liver through the [[enterohepatic circulation]] of [[bilirubin]]. | ||
***A small amount of [[bilirubin]] is cleared into the [[urine]] as [[urobilinogen]]. | ***A small amount of [[bilirubin]] is cleared into the [[urine]] as [[urobilinogen]]. | ||
===Pathogenesis=== | ===Pathogenesis of Neonatal jaundice=== | ||
*Neonatal jaundice may be a result of [[physiological]] or [[pathological]] mechanisms. The different mechanisms for development of jaundice may be concluded into either an increase in the [[bilirubin]] production, increase the [[enterohepatic circulation]], or decrease bilirubin [[Elimination reaction|elimination]].<ref name="pmid27398328">{{cite journal| author=Ullah S, Rahman K, Hedayati M| title=Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article. | journal=Iran J Public Health | year= 2016 | volume= 45 | issue= 5 | pages= 558-68 | pmid=27398328 | doi= | pmc=4935699 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27398328 }}</ref> | *Neonatal jaundice may be a result of [[physiological]] or [[pathological]] mechanisms. The different mechanisms for development of jaundice may be concluded into either an increase in the [[bilirubin]] production, increase the [[enterohepatic circulation]], or decrease bilirubin [[Elimination reaction|elimination]].<ref name="pmid27398328">{{cite journal| author=Ullah S, Rahman K, Hedayati M| title=Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article. | journal=Iran J Public Health | year= 2016 | volume= 45 | issue= 5 | pages= 558-68 | pmid=27398328 | doi= | pmc=4935699 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27398328 }}</ref> | ||
*'''Physiological jaundice | *'''Physiological jaundice'''<ref name="pmid11207355">{{cite journal| author=Dennery PA, Seidman DS, Stevenson DK| title=Neonatal hyperbilirubinemia. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 8 | pages= 581-90 | pmid=11207355 | doi=10.1056/NEJM200102223440807 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11207355 }}</ref><ref name="pmid4479604">{{cite journal| author=Brouillard RP| title=Measurement of red blood cell life-span. | journal=JAMA | year= 1974 | volume= 230 | issue= 9 | pages= 1304-5 | pmid=4479604 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4479604 }}</ref> | ||
**The children have [[red blood cells]] twice or more than twice the number compared with the adults have and with shorter [[lifespan]]. | **The children have [[red blood cells]] twice or more than twice the number compared with the adults have and with shorter [[lifespan]]. | ||
**Increased rate of the red blood cells destruction produces elevated levels of [[bilirubin]] which ends up in [[jaundice]]. | **Increased rate of the red blood cells destruction produces elevated levels of [[bilirubin]] which ends up in [[jaundice]]. | ||
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**Unconjugated [[hyperbilirubinemia]] is the predominant form of [[physiological]] jaundice. | **Unconjugated [[hyperbilirubinemia]] is the predominant form of [[physiological]] jaundice. | ||
**Physiological jaundice is benign and resolves within 10 to 14 days of life. | **Physiological jaundice is benign and resolves within 10 to 14 days of life. | ||
*'''Pathological jaundice | *'''Pathological jaundice'''<ref name="pmid273983282">{{cite journal| author=Ullah S, Rahman K, Hedayati M| title=Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article. | journal=Iran J Public Health | year= 2016 | volume= 45 | issue= 5 | pages= 558-68 | pmid=27398328 | doi= | pmc=4935699 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27398328 }}</ref> | ||
**The majority of neonatal jaundice is due to pathological conditions. Pathological neonatal jaundice is due to acquired or [[inherited]] conditions. | **The majority of neonatal jaundice is due to pathological conditions. Pathological neonatal jaundice is due to acquired or [[inherited]] conditions. | ||
**Pathological jaundice is the result of an increase in the level of [[unconjugated bilirubin]] which is named as "Indirect [[hyperbilirubinemia]]". | **Pathological jaundice is the result of an increase in the level of [[unconjugated bilirubin]] which is named as "Indirect [[hyperbilirubinemia]]". | ||
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|- | |- | ||
| rowspan="5" align="center" style="background:#DCDCDC;" + |'''Disorder of bilirubin conjugation''' | | rowspan="5" align="center" style="background:#DCDCDC;" + |'''Disorder of bilirubin conjugation''' | ||
| align="center" style="background:#DCDCDC;" + |'''Gilbert syndrome''' | | align="center" style="background:#DCDCDC;" + |'''Gilbert syndrome'''<ref name="pmid7565971">{{cite journal| author=Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA et al.| title=The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 18 | pages= 1171-5 | pmid=7565971 | doi=10.1056/NEJM199511023331802 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7565971 }}</ref> | ||
| style="background:#F5F5F5;" + | | | style="background:#F5F5F5;" + | | ||
*Gilbert syndrome, the most common inherited neonatal jaundice syndrome, is an [[autosomal recessive]] disease which is one of the causes of neonatal jaundice due to a defect (not total absence) in the [[UGT1A1|Uridine diphosphate Glucuronsyl Transferase (UGT) enzyme]]. | *Gilbert syndrome, the most common inherited neonatal jaundice syndrome, is an [[autosomal recessive]] disease which is one of the causes of neonatal jaundice due to a defect (not total absence) in the [[UGT1A1|Uridine diphosphate Glucuronsyl Transferase (UGT) enzyme]]. | ||
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*The most common gene mutation occurs in the TA sequence of the TATAA box of the [[promoter region]] of [[UGT1A1]] gene. | *The most common gene mutation occurs in the TA sequence of the TATAA box of the [[promoter region]] of [[UGT1A1]] gene. | ||
|- | |- | ||
| align="center" style="background:#DCDCDC;" + |'''Crigler-Najjar syndrome type I | | align="center" style="background:#DCDCDC;" + |'''Crigler-Najjar syndrome type I'''<ref name="pmid9497253">{{cite journal| author=Gantla S, Bakker CT, Deocharan B, Thummala NR, Zweiner J, Sinaasappel M et al.| title=Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1. | journal=Am J Hum Genet | year= 1998 | volume= 62 | issue= 3 | pages= 585-92 | pmid=9497253 | doi=10.1086/301756 | pmc=1376950 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9497253 }}</ref><ref name="pmid23403257">{{cite journal| author=Canu G, Minucci A, Zuppi C, Capoluongo E| title=Gilbert and Crigler Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database. | journal=Blood Cells Mol Dis | year= 2013 | volume= 50 | issue= 4 | pages= 273-80 | pmid=23403257 | doi=10.1016/j.bcmd.2013.01.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23403257 }}</ref> | ||
| style="background:#F5F5F5;" + | | | style="background:#F5F5F5;" + | | ||
*Crigler-Najjar syndrome type I is characterized by a total absence of the [[UGT1A1]] enzyme, unlike Gilbert syndrome. | *Crigler-Najjar syndrome type I is characterized by a total absence of the [[UGT1A1]] enzyme, unlike Gilbert syndrome. | ||
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*[[Genetic mutations]] in the [[introns]] may also lead to [[Frameshift mutation|frameshift]] of the [[Amino acid sequence|amino acid sequences]] or create prematu1e [[Stop codon|stop codons]] which result in cessation of the [[enzyme]] formation. | *[[Genetic mutations]] in the [[introns]] may also lead to [[Frameshift mutation|frameshift]] of the [[Amino acid sequence|amino acid sequences]] or create prematu1e [[Stop codon|stop codons]] which result in cessation of the [[enzyme]] formation. | ||
|- | |- | ||
| align="center" style="background:#DCDCDC;" + |'''Crigler-Najjar syndrome type II (Arias syndrome) | | align="center" style="background:#DCDCDC;" + |'''Crigler-Najjar syndrome type II (Arias syndrome)'''<ref name="pmid7989595">{{cite journal| author=Seppen J, Bosma PJ, Goldhoorn BG, Bakker CT, Chowdhury JR, Chowdhury NR et al.| title=Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. | journal=J Clin Invest | year= 1994 | volume= 94 | issue= 6 | pages= 2385-91 | pmid=7989595 | doi=10.1172/JCI117604 | pmc=330068 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7989595 }}</ref> | ||
| style="background:#F5F5F5;" + | | | style="background:#F5F5F5;" + | | ||
*Crigler-Najjar syndrome type II has a reduced activity of the [[UGT1A1|UGT1A1 enzyme]] (not completely inactive). | *Crigler-Najjar syndrome type II has a reduced activity of the [[UGT1A1|UGT1A1 enzyme]] (not completely inactive). | ||
*The [[gene mutation]] in the UGT1A1 gene is [[point mutation]] which results in [[amino acid]] substitution not [[stop codon]]. Hereby, reduction in the [[UGT1A1|UGT enzyme]] activity occurs. | *The [[gene mutation]] in the UGT1A1 gene is [[point mutation]] which results in [[amino acid]] substitution not [[stop codon]]. Hereby, reduction in the [[UGT1A1|UGT enzyme]] activity occurs. | ||
|- | |- | ||
| align="center" style="background:#DCDCDC;" + |'''Lucey-Driscoll syndrome | | align="center" style="background:#DCDCDC;" + |'''Lucey-Driscoll syndrome'''<ref name="pmid14332157">{{cite journal| author=ARIAS IM, WOLFSON S, LUCEY JF, MCKAY RJ| title=TRANSIENT FAMILIAL NEONATAL HYPERBILIRUBINEMIA. | journal=J Clin Invest | year= 1965 | volume= 44 | issue= | pages= 1442-50 | pmid=14332157 | doi=10.1172/JCI105250 | pmc=292625 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14332157 }}</ref> | ||
| style="background:#F5F5F5;" + | | | style="background:#F5F5F5;" + | | ||
*Also known as the transient [[familial]] neonatal [[hyperbilirubinemia]] as it is a rare familial disease which results in severe [[hyperbilirubinemia]] in the first 24 hours of life. | *Also known as the transient [[familial]] neonatal [[hyperbilirubinemia]] as it is a rare familial disease which results in severe [[hyperbilirubinemia]] in the first 24 hours of life. | ||
*It is believed that Lucey-Driscoll syndrome is associated with an inhibitor of the [[UGT1A1|UGT1A1 enzyme]] and this inhibitor is unidentified until the moment. | *It is believed that Lucey-Driscoll syndrome is associated with an inhibitor of the [[UGT1A1|UGT1A1 enzyme]] and this inhibitor is unidentified until the moment. | ||
|- | |- | ||
| align="center" style="background:#DCDCDC;" + |'''Breast milk jaundice | | align="center" style="background:#DCDCDC;" + |'''Breast milk jaundice'''<ref name="pmid2869347">{{cite journal| author=Gourley GR, Arend RA| title=beta-Glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies. | journal=Lancet | year= 1986 | volume= 1 | issue= 8482 | pages= 644-6 | pmid=2869347 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2869347 }}</ref> | ||
| style="background:#F5F5F5;" + | | | style="background:#F5F5F5;" + | | ||
*[[Breast milk jaundice]] is one of the benign causes of neonatal jaundice with no specific pathogenesis. It is considered as the continuation of physiologic jaundice beyond one week. | *[[Breast milk jaundice]] is one of the benign causes of neonatal jaundice with no specific pathogenesis. It is considered as the continuation of physiologic jaundice beyond one week. | ||
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| align="center" style="background:#DCDCDC;" + |'''Disorders of excretion into Bile''' | | align="center" style="background:#DCDCDC;" + |'''Disorders of excretion into Bile''' | ||
| align="center" style="background:#DCDCDC;" + |'''Dubin-Johnson syndrome | | align="center" style="background:#DCDCDC;" + |'''Dubin-Johnson syndrome'''<ref name="pmid9185779">{{cite journal| author=Paulusma CC, Kool M, Bosma PJ, Scheffer GL, ter Borg F, Scheper RJ et al.| title=A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. | journal=Hepatology | year= 1997 | volume= 25 | issue= 6 | pages= 1539-42 | pmid=9185779 | doi=10.1002/hep.510250635 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9185779 }}</ref> | ||
| style="background:#F5F5F5;" + | | | style="background:#F5F5F5;" + | | ||
* Dubin-Johnson syndrome is a result of a genetic mutation in the ''ABCC2''/MRP2 transporter resulting in absence of the transporter expression. | * Dubin-Johnson syndrome is a result of a genetic mutation in the ''ABCC2''/MRP2 transporter resulting in absence of the transporter expression. | ||
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|- | |- | ||
| align="center" style="background:#DCDCDC;" + |'''Disorders of reuptake''' | | align="center" style="background:#DCDCDC;" + |'''Disorders of reuptake''' | ||
| align="center" style="background:#DCDCDC;" + |'''Rotor syndrome (RS) | | align="center" style="background:#DCDCDC;" + |'''Rotor syndrome (RS)'''<ref name="pmid22232210">{{cite journal| author=van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E et al.| title=Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. | journal=J Clin Invest | year= 2012 | volume= 122 | issue= 2 | pages= 519-28 | pmid=22232210 | doi=10.1172/JCI59526 | pmc=3266790 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22232210 }}</ref> | ||
| style="background:#F5F5F5;" + | | | style="background:#F5F5F5;" + | | ||
*Rotor syndrome is an [[autosomal recessive]] disease which results in a defect of the [[hepatic]] reuptake of the [[bilirubin]]. | *Rotor syndrome is an [[autosomal recessive]] disease which results in a defect of the [[hepatic]] reuptake of the [[bilirubin]]. | ||
*Genetic mutation of ''SLCO1B1''/OATP1B1 and ''SLCO1B3''/OATP1B3 leads to absence of the OATP1B1 and OATP1B3 transporters of bilirubin. | *Genetic mutation of ''SLCO1B1''/OATP1B1 and ''SLCO1B3''/OATP1B3 leads to absence of the OATP1B1 and OATP1B3 transporters of bilirubin. | ||
|} | |} | ||
== Pathogenesis of Adult jaundice == | |||
* Jaundice in adult patients classified into two major types: | |||
** [[Unconjugated bilirubin|Unconjugated]] [[hyperbilirubinemia]] | |||
** [[Conjugated bilirubin|Conjugated]] [[hyperbilirubinemia]] | |||
<br> | |||
<small> | |||
{{family tree/start}} | |||
{{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]]}} | |||
{{family tree| | |`|-|-|-|^|-|-|-|^|-|-|v|^|-|-|-|^|-|-|-|'| | | |`|-|-|-|+|-|-|-|^|-|-|-|'| | | | | | | | | | |}} | |||
{{family tree| | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | |}} | |||
{{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> | |||
=== Unconjugated hyperbilirubinemia === | |||
The main pathophysiology of unconjugated hyperbilirubinemia consists of three main processes: | |||
* Overproduction of bilirubin | |||
** Extravascular hemolysis | |||
** Intravascular hemolysis | |||
** Extravasation | |||
** Dyserythropoiesis | |||
* Reduced bilirubin uptake | |||
** reduce hepatic blood flow and the delivery of bilirubin to hepatocytes: Congestive heart failure or portosystemic shunts: | |||
** capillarization of the sinusoidal endothelial cells (loss of fenestrae): Cirrhosis | |||
** impaired uptake of bilirubin at the sinusoidal surface of hepatocytes: Gilbert | |||
** drug-induced defect: rifamycin antibiotics, probenecid, flavaspidic acid, and bunamiodyl, a cholecystographic agent | |||
* Impaired bilirubin conjugation | |||
** decreased or absent UDP-glucuronosyltransferase activity: Crigler-Najjar syndrome, type I and II and Gilbert syndrome | |||
** inhibit bilirubin glucuronidation and UGT activity: Hyperthyroidism and ethinyl estradiol | |||
*** the combination of progestational and estrogenic steroids results in increased enzyme activity | |||
** Bilirubin glucuronidation can also be inhibited by certain antibiotics: novobiocin or gentamicin | |||
** Bilirubin glucuronidation can also be inhibited by certain diseases: chronic persistent hepatitis, advanced cirrhosis, and Wilson's disease | |||
==== Conjugated hyperbilirubinemia ==== | |||
* Biliary obstruction | |||
** both conjugated and unconjugated bilirubin accumulate in serum | |||
** Bilirubin may be transported back to the plasma via an MRP group of ATP-consuming pumps | |||
** The serum concentrations of conjugated bilirubin and alkaline phosphatase can be used as markers for hepatobiliary obstruction | |||
** Obstruction of biliary flow causes retention of conjugated bilirubin within the hepatocytes, where reversal of glucuronidation may take place. The unconjugated bilirubin formed by this process may diffuse or be transported back into the plasma. | |||
*** adults: cholelithiasis, intrinsic and extrinsic tumors, primary sclerosing cholangitis (PSC), parasitic infections, lymphoma, AIDS cholangiopathy, acute and chronic pancreatitis, and strictures after invasive procedures | |||
*** children, choledochal cysts and cholelithiasis are most common. Extrinsic compression from tumors or other anomalies are seen in all pediatric age groups as well as in adults | |||
*** neonates and young infants, important obstructive processes include biliary atresia and choledochal cysts | |||
** Mirizzi syndrome, a distended gallbladder caused by an impacted cystic duct stone may lead to compression of the extrahepatic bile ducts | |||
** intrahepatic and extrahepatic portions of the bile ducts can be affected in both PSC and cholangiocarcinoma | |||
** Parasites: | |||
*** Adult ''Ascaris lumbricoides'' | |||
*** Eggs of certain liver flukes (eg, ''Clonorchis sinensis'', ''Fasciola hepatica'') | |||
** AIDS cholangiopathy | |||
*** ''Cryptosporidium'' sp | |||
*** cytomegalovirus | |||
*** HIV itself | |||
**** viral hepatitis (hepatitis viruses, herpes simplex virus, Epstein-Barr virus) | |||
**** ''Mycobacterium'' tuberculosis and atypical mycobacteria (especially ''Mycobacterium avium'' intracellulare) | |||
**** fungal infections (''Cryptococcus neoformans'', ''Histoplasma capsulatum'', ''Candida albicans'', ''Coccidioides immitis'') | |||
**** parasites (''Pneumocystis carinii''), tumor infiltration (lymphoma, Kaposi sarcoma) | |||
**** drug-induced liver disease | |||
* Intrahepatic causes: A number of intrahepatic disorders can lead to jaundice and an elevated serum alkaline phosphatase (in relation to serum aminotransferases). This presentation mimics that of biliary obstruction but the bile ducts are patent | |||
** predominantly cholestatic syndrome with marked pruritus: Viral hepatitis | |||
** Cholestasis with fever and leukocytosis & ratio of serum AST to ALT exceeds 2.0 with the values being below 500 international unit/L: Alcoholic hepatitis | |||
** diabetes mellitus, morbid obesity, certain stomach and small bowel operations, and drugs : Nonalcoholic steatohepatitis | |||
** cholestatic picture, though evidence of hepatocellular injury also exists: Primary biliary cholangitis | |||
** toxicity | |||
*** dose-related fashion (eg, alkylated steroids such as methyltestosterone and ethinyl estradiol) | |||
*** an idiosyncratic or allergic reaction in a minority of subjects (eg, chlorpromazine, halothane). | |||
*** contain pyrrolizidine alkaloids which may cause veno-occlusive disease of the liver: natural" medicines (eg, Jamaican bush tea | |||
*** also can cause cholestasis: Arsenic | |||
** Sepsis and low perfusion states | |||
*** Multiple factors including hypotension, drugs, and bacterial endotoxins are responsible for the jaundice | |||
*** On the other hand, hyperbilirubinemia can promote bacterial sepsis by increasing intestinal wall permeability and altering mucosal immunity | |||
** Paraneoplastic syndromes associated with malignancy: | |||
*** renal cell carcinoma, | |||
*** malignant lymphoproliferative diseases | |||
*** gynecologic malignancies | |||
*** prostate cancer | |||
** Infiltrative processes of the liver | |||
*** amyloidosis | |||
*** lymphoma | |||
*** sarcoidosis | |||
*** tuberculosis | |||
** Steatosis, lipidosis, and cholestasis are frequently encountered in patients receiving total parenteral nutrition(TPN). | |||
*** at least two to three weeks of therapy for the development of cholestasis | |||
*** TPN promotes bacterial overgrowth in the small intestine | |||
*** induce cholestasis | |||
**** translocation of intestinal endotoxins into the portal system | |||
**** bacterial sepsis | |||
**** formation of secondary bile acids (eg, lithocholic acid) | |||
**** biliary sludge, which occurs in all patients after six weeks of TPN, | |||
**** hepatotoxic factors such as tryptophan degradation products and aluminum contaminants | |||
** Sickle cell disease | |||
*** hemolysis | |||
*** mild hepatic dysfunction | |||
*** Both unconjugated and conjugated bilirubin accumulate in the plasma | |||
*** may contribute in selected patients | |||
**** Viral hepatitis, particularly hepatitis C virus | |||
** Intrahepatic cholestasis of pregnancy | |||
*** usually occurring in the third trimester of pregnancy but sometimes earlier, | |||
*** typically heralds cholestasis which may evolve into frank jaundice | |||
*** may be associated with an increased frequency of stillbirths and prematurity | |||
*** All the pathologic changes disappear following delivery | |||
* Hepatocellular injury | |||
** These conditions cannot always be separated clearly from the cholestatic syndromes because of the variability in presentation of these diseases | |||
** release of intracellular proteins and small molecules into the plasma | |||
** elevations in the serum concentrations of hepatocellular enzymes, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} |
Revision as of 19:48, 23 February 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]
Overview
Bilirubin is the catabolic product of the heme which is the main component of the red blood cells. Bilirubin is formed in the liver and spleen then it passes through several process in order to be metabolized. Metabolism processes include hepatic uptake, conjugation, clearance and excretion of the bilirubin in the bile. Jaundice develops due to increase the level of bilirubin and deposition under the skin and cause the yellow discoloration of the skin. Pathogenesis of neonatal jaundice includes physiologic process of bilirubin accumulation or pathological mechanism. The pathological jaundice may be acquired or inherited. Acquired neonatal jaundice include Rh hemolytic disease, ABO incompatibility disease, and hemolytic disease due to G6PD enzyme deficiency. Inherited neonatal jaundice is due to defect of one of the processes of bilirubin metabolism and it concludes some inherited syndromes. Inherited neonatal jaundice include Gilbert's syndrome, Crigler-Najjar syndrome type I and II, Lucey-Driscoll syndrome, Dubin-Johnson syndrome, and Rotor syndrome.
Pathophysiology
For more information about viral hepatitis pathophysiology click here
For more information about cirrhosis pathophysiology click here
Bilirubin formation and metabolism
- Bilirubin is the final catabolic product of the heme. The heme is a component of various biological molecules and enzymes but, it is mainly incorporated in the hemoglobin which is the primary component of the red blood cells.[1][2]
- Bilirubin is formed mainly in the liver and spleen through two steps which include:[3][4]
- Heme oxygenase enzyme degrades the porphyrin ring of the heme and breaks it down. A green compound called biliverdin is then formed as a result of the previous reaction. Carbon monoxide is released as a result of the reaction.
- Biliverdin reductase enzyme catalyzes the formation of bilirubin from biliverdin.
- Bilirubin is a toxic metabolite so, the body has physiologic processes to eliminate the bilirubin. Bilirubin elimination process includes:[5]
- Hepatic uptake[6]
- 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[7][8]
- 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[9]
- After conjugation of the bilirubin in the liver, it is secreted into the bile then into the gastrointestinal tract.
- In the GIT, the conjugated bilirubin is metabolized by the gut enzymes into urobilinogen which is oxidized into urobilin.
- Metabolism of the conjugated bilirubin occurs properly in the adults. However, the newborns have sterile gastrointestinal canal which impedes the catalyzation of the conjugated bilirubin.
- The sterile tract ends up with a small amount of excreted bile.
- The remaining conjugated bilirubin is unconjugated by the beta-glucuronidase enzyme in the neonatal intestine.
- The unconjugated bilirubin is reabsorbed back into the blood and to the liver through the enterohepatic circulation of bilirubin.
- A small amount of bilirubin is cleared into the urine as urobilinogen.
- Hepatic uptake[6]
Pathogenesis of Neonatal jaundice
- Neonatal jaundice may be a result of physiological or pathological mechanisms. The different mechanisms for development of jaundice may be concluded into either an increase in the bilirubin production, increase the enterohepatic circulation, or decrease bilirubin elimination.[10]
- Physiological jaundice[11][12]
- The children have red blood cells twice or more than twice the number compared with the adults have and with shorter lifespan.
- Increased rate of the red blood cells destruction produces elevated levels of bilirubin which ends up in jaundice.
- The newborn gastrointestinal gut is considered sterile so, a small amount of the unconjugated bilirubin is converted to conjugated and excreted. Most of the unconjugated bilirubin is recirculated through the enterohepatic circulation.
- Unconjugated hyperbilirubinemia is the predominant form of physiological jaundice.
- Physiological jaundice is benign and resolves within 10 to 14 days of life.
- Pathological jaundice[13]
- The majority of neonatal jaundice is due to pathological conditions. Pathological neonatal jaundice is due to acquired or inherited conditions.
- Pathological jaundice is the result of an increase in the level of unconjugated bilirubin which is named as "Indirect hyperbilirubinemia".
- It includes some features like the appearance of jaundice within the first day of life, persistent jaundice manifestations more than two weeks, and dark urine.
- Acquired pathological neonatal jaundice develops mainly due to hemolysis of the red blood cells via three main diseases:[14]
- Inherited pathological neonatal jaundice occurs due to a defect in the bilirubin metabolism and it include:[15]
- Defective hepatic uptake and storage of the bilirubin
- Defective bilirubin conjugation to glucuronic acid and it include:
- Gilbert syndrome
- Crigler-Najjar syndrome
- Lucey-Driscoll syndrome
- Breast milk jaundice
- Defective excretion of bilirubin into the bile and this syndrome called Dubin-Johnson syndrome
- Defective reuptake of the conjugated bilirubin through the enterohepatic circulation. This syndrome called Rotor syndrome.
Acquired pathological neonatal jaundice
- The following table contains the different hemolytic mechanisms which lead to neonatal jaundice:[16][17]
Hemolytic disease | Pathogenesis |
---|---|
Rhesus factor (Rh) hemolytic disease |
|
ABO blood group incompatibility |
|
G6PD deficiency |
|
Inherited pathological neonatal jaundice
- The following table includes the different causes of inherited neonatal jaundice:
Defective mechanism | Pathogenesis | |
---|---|---|
Defective bilirubin hepatic reuptake and storage[18] |
| |
Disorder of bilirubin conjugation | Gilbert syndrome[19] |
|
Crigler-Najjar syndrome type I[20][21] |
| |
Crigler-Najjar syndrome type II (Arias syndrome)[22] |
| |
Lucey-Driscoll syndrome[23] |
| |
Breast milk jaundice[24] |
| |
Disorders of excretion into Bile | Dubin-Johnson syndrome[25] |
|
Disorders of reuptake | Rotor syndrome (RS)[26] |
|
Pathogenesis of Adult jaundice
- Jaundice in adult patients classified into two major types:
Unconjugated hyperbilirubinemia
The main pathophysiology of unconjugated hyperbilirubinemia consists of three main processes:
- Overproduction of bilirubin
- Extravascular hemolysis
- Intravascular hemolysis
- Extravasation
- Dyserythropoiesis
- Reduced bilirubin uptake
- reduce hepatic blood flow and the delivery of bilirubin to hepatocytes: Congestive heart failure or portosystemic shunts:
- capillarization of the sinusoidal endothelial cells (loss of fenestrae): Cirrhosis
- impaired uptake of bilirubin at the sinusoidal surface of hepatocytes: Gilbert
- drug-induced defect: rifamycin antibiotics, probenecid, flavaspidic acid, and bunamiodyl, a cholecystographic agent
- Impaired bilirubin conjugation
- decreased or absent UDP-glucuronosyltransferase activity: Crigler-Najjar syndrome, type I and II and Gilbert syndrome
- inhibit bilirubin glucuronidation and UGT activity: Hyperthyroidism and ethinyl estradiol
- the combination of progestational and estrogenic steroids results in increased enzyme activity
- Bilirubin glucuronidation can also be inhibited by certain antibiotics: novobiocin or gentamicin
- Bilirubin glucuronidation can also be inhibited by certain diseases: chronic persistent hepatitis, advanced cirrhosis, and Wilson's disease
Conjugated hyperbilirubinemia
- Biliary obstruction
- both conjugated and unconjugated bilirubin accumulate in serum
- Bilirubin may be transported back to the plasma via an MRP group of ATP-consuming pumps
- The serum concentrations of conjugated bilirubin and alkaline phosphatase can be used as markers for hepatobiliary obstruction
- Obstruction of biliary flow causes retention of conjugated bilirubin within the hepatocytes, where reversal of glucuronidation may take place. The unconjugated bilirubin formed by this process may diffuse or be transported back into the plasma.
- adults: cholelithiasis, intrinsic and extrinsic tumors, primary sclerosing cholangitis (PSC), parasitic infections, lymphoma, AIDS cholangiopathy, acute and chronic pancreatitis, and strictures after invasive procedures
- children, choledochal cysts and cholelithiasis are most common. Extrinsic compression from tumors or other anomalies are seen in all pediatric age groups as well as in adults
- neonates and young infants, important obstructive processes include biliary atresia and choledochal cysts
- Mirizzi syndrome, a distended gallbladder caused by an impacted cystic duct stone may lead to compression of the extrahepatic bile ducts
- intrahepatic and extrahepatic portions of the bile ducts can be affected in both PSC and cholangiocarcinoma
- Parasites:
- Adult Ascaris lumbricoides
- Eggs of certain liver flukes (eg, Clonorchis sinensis, Fasciola hepatica)
- AIDS cholangiopathy
- Cryptosporidium sp
- cytomegalovirus
- HIV itself
- viral hepatitis (hepatitis viruses, herpes simplex virus, Epstein-Barr virus)
- Mycobacterium tuberculosis and atypical mycobacteria (especially Mycobacterium avium intracellulare)
- fungal infections (Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Coccidioides immitis)
- parasites (Pneumocystis carinii), tumor infiltration (lymphoma, Kaposi sarcoma)
- drug-induced liver disease
- Intrahepatic causes: A number of intrahepatic disorders can lead to jaundice and an elevated serum alkaline phosphatase (in relation to serum aminotransferases). This presentation mimics that of biliary obstruction but the bile ducts are patent
- predominantly cholestatic syndrome with marked pruritus: Viral hepatitis
- Cholestasis with fever and leukocytosis & ratio of serum AST to ALT exceeds 2.0 with the values being below 500 international unit/L: Alcoholic hepatitis
- diabetes mellitus, morbid obesity, certain stomach and small bowel operations, and drugs : Nonalcoholic steatohepatitis
- cholestatic picture, though evidence of hepatocellular injury also exists: Primary biliary cholangitis
- toxicity
- dose-related fashion (eg, alkylated steroids such as methyltestosterone and ethinyl estradiol)
- an idiosyncratic or allergic reaction in a minority of subjects (eg, chlorpromazine, halothane).
- contain pyrrolizidine alkaloids which may cause veno-occlusive disease of the liver: natural" medicines (eg, Jamaican bush tea
- also can cause cholestasis: Arsenic
- Sepsis and low perfusion states
- Multiple factors including hypotension, drugs, and bacterial endotoxins are responsible for the jaundice
- On the other hand, hyperbilirubinemia can promote bacterial sepsis by increasing intestinal wall permeability and altering mucosal immunity
- Paraneoplastic syndromes associated with malignancy:
- renal cell carcinoma,
- malignant lymphoproliferative diseases
- gynecologic malignancies
- prostate cancer
- Infiltrative processes of the liver
- amyloidosis
- lymphoma
- sarcoidosis
- tuberculosis
- Steatosis, lipidosis, and cholestasis are frequently encountered in patients receiving total parenteral nutrition(TPN).
- at least two to three weeks of therapy for the development of cholestasis
- TPN promotes bacterial overgrowth in the small intestine
- induce cholestasis
- translocation of intestinal endotoxins into the portal system
- bacterial sepsis
- formation of secondary bile acids (eg, lithocholic acid)
- biliary sludge, which occurs in all patients after six weeks of TPN,
- hepatotoxic factors such as tryptophan degradation products and aluminum contaminants
- Sickle cell disease
- hemolysis
- mild hepatic dysfunction
- Both unconjugated and conjugated bilirubin accumulate in the plasma
- may contribute in selected patients
- Viral hepatitis, particularly hepatitis C virus
- Intrahepatic cholestasis of pregnancy
- usually occurring in the third trimester of pregnancy but sometimes earlier,
- typically heralds cholestasis which may evolve into frank jaundice
- may be associated with an increased frequency of stillbirths and prematurity
- All the pathologic changes disappear following delivery
- Hepatocellular injury
- These conditions cannot always be separated clearly from the cholestatic syndromes because of the variability in presentation of these diseases
- release of intracellular proteins and small molecules into the plasma
- elevations in the serum concentrations of hepatocellular enzymes, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
References
- ↑ Berk PD, Howe RB, Bloomer JR, Berlin NI (1969). "Studies of bilirubin kinetics in normal adults". J Clin Invest. 48 (11): 2176–90. doi:10.1172/JCI106184. PMC 297471. PMID 5824077.
- ↑ LONDON IM, WEST R, SHEMIN D, RITTENBERG D (1950). "On the origin of bile pigment in normal man". J Biol Chem. 184 (1): 351–8. PMID 15422003.
- ↑ Knobloch E, Hodr R, Herzmann J, Houdková V (1986). "Kinetics of the formation of biliverdin during the photochemical oxidation of bilirubin monitored by column liquid chromatography". J Chromatogr. 375 (2): 245–53. PMID 3700551.
- ↑ Bissell DM, Hammaker L, Schmid R (1972). "Liver sinusoidal cells. Identification of a subpopulation for erythrocyte catabolism". J Cell Biol. 54 (1): 107–19. PMC 2108858. PMID 5038868.
- ↑ Paludetto R, Mansi G, Raimondi F, Romano A, Crivaro V, Bussi M; et al. (2002). "Moderate hyperbilirubinemia induces a transient alteration of neonatal behavior". Pediatrics. 110 (4): e50. PMID 12359823.
- ↑ Weiss JS, Gautam A, Lauff JJ, Sundberg MW, Jatlow P, Boyer JL; et al. (1983). "The clinical importance of a protein-bound fraction of serum bilirubin in patients with hyperbilirubinemia". N Engl J Med. 309 (3): 147–50. doi:10.1056/NEJM198307213090305. PMID 6866015.
- ↑ Chowdhury JR, Chowdhury NR, Wu G, Shouval R, Arias IM (1981). "Bilirubin mono- and diglucuronide formation by human liver in vitro: assay by high-pressure liquid chromatography". Hepatology. 1 (6): 622–7. PMID 6796486.
- ↑ Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR; et al. (1994). "Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man". J Biol Chem. 269 (27): 17960–4. PMID 8027054.
- ↑ Vítek L, Zelenka J, Zadinová M, Malina J (2005). "The impact of intestinal microflora on serum bilirubin levels". J Hepatol. 42 (2): 238–43. doi:10.1016/j.jhep.2004.10.012. PMID 15664250.
- ↑ Ullah S, Rahman K, Hedayati M (2016). "Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article". Iran J Public Health. 45 (5): 558–68. PMC 4935699. PMID 27398328.
- ↑ Dennery PA, Seidman DS, Stevenson DK (2001). "Neonatal hyperbilirubinemia". N Engl J Med. 344 (8): 581–90. doi:10.1056/NEJM200102223440807. PMID 11207355.
- ↑ Brouillard RP (1974). "Measurement of red blood cell life-span". JAMA. 230 (9): 1304–5. PMID 4479604.
- ↑ Ullah S, Rahman K, Hedayati M (2016). "Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article". Iran J Public Health. 45 (5): 558–68. PMC 4935699. PMID 27398328.
- ↑ Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker MW, Spitzer AR; et al. (2009). "Complex multifactorial nature of significant hyperbilirubinemia in neonates". Pediatrics. 124 (5): e868–77. doi:10.1542/peds.2009-0460. PMID 19858149.
- ↑ Memon N, Weinberger BI, Hegyi T, Aleksunes LM (2016). "Inherited disorders of bilirubin clearance". Pediatr Res. 79 (3): 378–86. doi:10.1038/pr.2015.247. PMC 4821713. PMID 26595536.
- ↑ McDonnell M, Hannam S, Devane SP (1998). "Hydrops fetalis due to ABO incompatibility". Arch Dis Child Fetal Neonatal Ed. 78 (3): F220–1. PMC 1720779. PMID 9713036.
- ↑ Kaplan M, Hammerman C (2004). "Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus". Semin Perinatol. 28 (5): 356–64. PMID 15686267.
- ↑ Muslu N, Dogruer ZN, Eskandari G, Atici A, Kul S, Atik U (2008). "Are glutathione S-transferase gene polymorphisms linked to neonatal jaundice?". Eur J Pediatr. 167 (1): 57–61. doi:10.1007/s00431-007-0425-z. PMID 17318621.
- ↑ Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA; et al. (1995). "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome". N Engl J Med. 333 (18): 1171–5. doi:10.1056/NEJM199511023331802. PMID 7565971.
- ↑ Gantla S, Bakker CT, Deocharan B, Thummala NR, Zweiner J, Sinaasappel M; et al. (1998). "Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1". Am J Hum Genet. 62 (3): 585–92. doi:10.1086/301756. PMC 1376950. PMID 9497253.
- ↑ Canu G, Minucci A, Zuppi C, Capoluongo E (2013). "Gilbert and Crigler Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database". Blood Cells Mol Dis. 50 (4): 273–80. doi:10.1016/j.bcmd.2013.01.003. PMID 23403257.
- ↑ Seppen J, Bosma PJ, Goldhoorn BG, Bakker CT, Chowdhury JR, Chowdhury NR; et al. (1994). "Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase". J Clin Invest. 94 (6): 2385–91. doi:10.1172/JCI117604. PMC 330068. PMID 7989595.
- ↑ ARIAS IM, WOLFSON S, LUCEY JF, MCKAY RJ (1965). "TRANSIENT FAMILIAL NEONATAL HYPERBILIRUBINEMIA". J Clin Invest. 44: 1442–50. doi:10.1172/JCI105250. PMC 292625. PMID 14332157.
- ↑ Gourley GR, Arend RA (1986). "beta-Glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies". Lancet. 1 (8482): 644–6. PMID 2869347.
- ↑ Paulusma CC, Kool M, Bosma PJ, Scheffer GL, ter Borg F, Scheper RJ; et al. (1997). "A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome". Hepatology. 25 (6): 1539–42. doi:10.1002/hep.510250635. PMID 9185779.
- ↑ van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E; et al. (2012). "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver". J Clin Invest. 122 (2): 519–28. doi:10.1172/JCI59526. PMC 3266790. PMID 22232210.