Editing Bilirubin (section)

== Toxicity ==
=== Hyperbilirubinemia ===
[[Jaundice|Hyperbilirubinemia]] is a higher-than-normal level of bilirubin in the blood. Hyperbilirubinemia may refer to increased levels of conjugated, unconjugated or both conjugated and unconjugated bilirubin. The causes of hyperbilirubinemia can also be classified into prehepatic, intrahepatic, and posthepatic. <ref name=":5">{{Cite journal |last1=Roche |first1=Sean P. |last2=Kobos |first2=Rebecca |date=2004-01-15 |title=Jaundice in the Adult Patient |url=https://www.aafp.org/pubs/afp/issues/2004/0115/p299.html |journal=American Family Physician |language=en-US |volume=69 |issue=2 |pages=299–304|pmid=14765767 }}</ref>

Prehepatic causes are associated mostly with an increase of unconjugated (indirect) bilirubin.<ref name=":5" /> They include:
* [[Hemolysis]] or increased breakdown of red blood cells (for example hematoma resorption)

Intrahepatic causes can be associated with elevated levels of conjugated bilirubin, unconjugated bilirubin or both.<ref name=":5" /> They include:<ref name=":5" />
* [[Neonatal jaundice|Neonatal hyperbilirubinemia]], where the newborn's liver is not able to properly process the bilirubin causing [[jaundice]]
* Hepatocellular disease
** Viral infections (hepatitis A, B, and C)
** Chronic alcohol use
** Autoimmune disorders
* Genetic syndromes:
** [[Gilbert's syndrome]] – a genetic disorder of bilirubin metabolism that can result in mild jaundice, found in about 5% of the population
** [[Rotor syndrome]]: non-itching jaundice, with rise of bilirubin in the patient's serum, mainly of the conjugated type
** [[Dubin–Johnson syndrome]]
** [[Crigler–Najjar syndrome]]
* [[Pharmaceutical drug]]s (especially [[antipsychotic]], some [[sex hormone]]s, and a wide range of other drugs)
** [[Sulfonamide (medicine)|Sulfonamide]]s are contraindicated in infants less than 2 months old (exception when used with [[pyrimethamine]] in treating [[toxoplasmosis]]) as they increase unconjugated bilirubin leading to [[kernicterus]].<ref>{{cite web |title=Sulfonamides: Bacteria and Antibacterial Drugs: Merck Manual Professional |url=http://www.merck.com/mmpe/sec14/ch170/ch170n.html?qt=kernicterus&alt=sh#sec14-ch170-ch170n-404f|archive-url=https://archive.today/20120904003305/http://www.merck.com/mmpe/sec14/ch170/ch170n.html?qt=kernicterus&alt=sh%23sec14-ch170-ch170n-404f|url-status=dead|archive-date=4 September 2012}}</ref>
** Drugs such as [[Protease inhibitor (pharmacology)|protease inhibitor]]s like [[Indinavir]] can also cause disorders of bilirubin metabolism by competitively inhibiting the [[UGT1A1]] enzyme.<ref name="Ramakrishnan Jialal 2019">{{cite journal |last1=Ramakrishnan |first1=N. |last2=Bittar |first2=K. |last3=Jialal |first3=I. |date=2019-03-08 |title=Impaired Bilirubin Conjugation |url=https://www.ncbi.nlm.nih.gov/books/NBK482483/ |pmid=29494090 |access-date=2019-05-03 |website=NCBI Bookshelf}}</ref>

Post-hepatic causes are associated with elevated levels of conjugated bilirubin. <ref name=":5" /> These include:<ref name=":5" />
* Unusually large bile duct obstruction, e.g. gallstone in common bile duct (which is the most common post-hepatic cause)
* Biliary stricture (benign or malignant)
* Cholangitis
* Severe liver failure with [[cirrhosis]] (e.g. [[primary biliary cirrhosis]])
* Pancreatitis

Cirrhosis may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis.

To further elucidate the causes of jaundice or increased bilirubin, it is usually simpler to look at other [[liver function tests]] (especially the enzymes [[alanine transaminase]], [[aspartate transaminase]], [[gamma-glutamyl transpeptidase]], [[alkaline phosphatase]]), [[blood film]] examination ([[hemolysis]], etc.) or evidence of infective hepatitis (e.g., hepatitis A, B, C, delta, E, etc.).{{cn|date=July 2024}}

==== Jaundice ====
{{main|Jaundice}}

Hemoglobin acts to transport oxygen which the body receives to all body tissue via blood vessels. Over time, when red blood cells need to be replenished, the hemoglobin is broken down in the spleen; it breaks down into two parts: heme group consisting of iron and bile, and protein fraction. While protein and iron are utilized to renew red blood cells, pigments that make up the red color in blood are deposited into the bile to form bilirubin.<ref>{{cite journal |vauthors=Point WW |date=April 1958 |title=Jaundice |journal=The American Journal of Nursing |volume=58 |issue=4 |pages=556–7 |pmid=13508735}}</ref> Jaundice leads to raised bilirubin levels<ref>[https://kdl.ru/analizy-i-tseny/bilirubin-obshiy Blood testing Bilirubin level] Last full review/revision July 2023 by KDL</ref>  that in turn negatively remove [[elastin]]-rich tissues.<ref>{{cite journal |vauthors=Greenberg DA |date=December 2002 |title=The jaundice of the cell |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=99 |issue=25 |pages=15837–9 |bibcode=2002PNAS...9915837G |doi=10.1073/pnas.012685199 |pmc=138521 |pmid=12461187 |s2cid=30298986 |doi-access=free}}</ref> [[Jaundice]] may be noticeable in the [[sclera]] of the eyes at levels of about 2 to 3&nbsp;mg/dl (34 to 51 μmol/L),<ref>[http://www.merck.com/mmpe/sec03/ch022/ch022d.html Merck Manual Jaundice] Last full review/revision July 2009 by Steven K. Herrine</ref> and in the skin at higher levels.<ref group="note">For conversion, 1&nbsp;mg/dl = 17.1 μmol/L.</ref>

Jaundice is classified, depending upon whether the bilirubin is free or conjugated to [[glucuronic acid]], into conjugated jaundice or unconjugated jaundice.{{Citation needed|date=November 2008}}<!-- not according to [[jaundice]]-->

==== Kernicterus ====
{{main|Kernicterus}}
Unbound bilirubin (Bf) levels can be used to predict the risk of  neurodevelopmental handicaps within infants.<ref name="SciFinder">{{cite journal|last1=Hegyi|first1=T.|last2=Chefitz|first2=D.|last3=Weller|first3=A.|last4=Huber|first4=A|last5=Carayannopoulos|first5=M.|last6=Kleinfeld|first6=A.|date=2020|title=Unbound bilirubin measurements in term and late-preterm infants|journal=Journal of Maternal-Fetal & Neonatal Medicine|volume=35 |issue=8 |pages=1532–1538|doi=10.1080/14767058.2020.1761318|pmid=32366186|pmc=7609464}}</ref> Unconjugated [[Hyperbilirubinaemia|hyperbilirubinemia]] in a newborn can lead to accumulation of bilirubin in certain brain regions (particularly the [[basal nuclei]]) with consequent irreversible damage to these areas manifesting as various neurological deficits, [[seizure]]s, abnormal [[reflexes]] and eye movements. This type of neurological injury is known as kernicterus. The spectrum of clinical effect is called [[bilirubin encephalopathy]]. The neurotoxicity of neonatal hyperbilirubinemia manifests because the [[blood–brain barrier]] has yet to develop fully,{{Dubious|Toxicity_.26_the_blood-brain_barrier|date=September 2014}} and bilirubin can freely pass into the brain interstitium, whereas more developed individuals with increased bilirubin in the blood are protected. Aside from specific chronic medical conditions that may lead to hyperbilirubinemia, neonates in general are at increased risk since they lack the intestinal bacteria that facilitate the breakdown and excretion of conjugated bilirubin in the feces (this is largely why the feces of a neonate are paler than those of an adult). Instead the conjugated bilirubin is converted back into the unconjugated form by the enzyme [[Beta-glucuronidase|β-glucuronidase]] (in the gut, this enzyme is located in the brush border of the lining intestinal cells) and a large proportion is reabsorbed through the [[enterohepatic circulation]]. In addition, recent studies point towards high total bilirubin levels  as a cause for gallstones regardless of gender or age.<ref>{{cite journal|last1=Zeng|first1=D.|last2=Wu|first2=H.|last3=Huang|first3=Q.|last4=Zeng|first4=A.|last5=Yu|first5=Z.|last6=Zhong|first6=Z.|date=2021|title=High levels of serum triglyceride, low-density lipoprotein cholesterol, total bile acid, and total bilirubin are risk factors for gallstones|url=https://pubmed.ncbi.nlm.nih.gov/34383399/|journal=Clinical Laboratory|volume=67|issue=8|pages=1905–1913|doi=10.7754/Clin.Lab.2021.201228|pmid=34383399|s2cid=234775572|access-date=November 11, 2021|via=PubMed}}</ref>