Bilirubin
68344
222603202
2008-06-30T05:46:42Z
124.181.164.23
/* Interpretation */
{{NatOrganicBox
| image= [[Image:Bilirubin.svg|270px|The structure of bilirubin]]
|height =no
| name= 3-[2-[(3-(2-carboxyethyl)-5-[(3-ethenyl-<br />4-methyl-5-oxo-pyrrol-2-ylidene)methyl]-<br />4-methyl-1H-pyrrol-2-yl]methyl)-5-[(4-ethenyl-<br />3-methyl-5-oxo-pyrrol-2-ylidene)methyl]-<br />4-methyl-1H-pyrrol-3-yl] propanoic acid
| C=33 | H=36 | N=4 | O=6
| mass=584.662
| PubChem=250
}}
'''Bilirubin''' (formerly referred to as '''hematoidin''') is the yellow breakdown product of normal [[heme]] [[catabolism]]. Heme is formed from hemoglobin, a principle component of [[red blood cell]]s. Bilirubin is excreted in [[bile]], and its levels are elevated in certain diseases. It is responsible for the yellow colour of [[bruise]]s and the yellow discolouration in [[jaundice]]. Bilirubin reduction in the gut leads to a product called [[urobilinogen]] which is then oxidized to [[urobilin]] which is excreted in the urine.
==Chemistry==
Bilirubin consists of an open chain of four [[pyrrole]]-like rings (''tetrapyrrole''). In [[heme]], by contrast, these four rings are connected into a larger ring, called a [[porphyrin]] ring.
Bilirubin is very similar to the [[pigment]] [[phycobilin]] used by certain algae to capture light energy, and to the pigment [[phytochrome]] used by plants to sense light. All of these contain an open chain of four pyrrolic rings.
Like these other pigments, bilirubin changes its conformation when exposed to light. This is used in the [[phototherapy]] of jaundiced newborns: the [[Cis-trans isomerism|isomer]] of bilirubin formed upon light exposure is more soluble than the unilluminated isomer.
Several textbooks and research articles show incorrect chemical structures for the two [[isoform]]s of bilirubin.<ref>{{cite web |url=http://www3.nsta.org/main/news/stories/college_science.php?news_story_ID=48991 |title=Bilirubin's Chemical Formula |accessdate=2007-08-14 |format= |work=}}</ref>
==Function==
Bilirubin is created by the activity of [[biliverdin reductase]] on [[biliverdin]]. Bilirubin, when oxidized, reverts to become biliverdin once again. This cycle, in addition to the demonstration of the potent antioxidant activity of bilirubin, has led to the hypothesis that bilirubin's main physiologic role is as a cellular antioxidant.<ref name="pmid12456881">{{cite journal |author=Baranano DE, Rao M, Ferris CD, Snyder SH |title=Biliverdin reductase: a major physiologic cytoprotectant |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue=25 |pages=16093–8 |year=2002 |pmid=12456881 |doi=10.1073/pnas.252626999}}</ref>
==Metabolism==
[[Erythrocytes]] (red blood cells) generated in the [[bone marrow]] are destroyed in the [[spleen]] when they get old or damaged. This releases [[hemoglobin]], which is broken down to [[heme]], as the globin parts are turned into [[amino acids]]. The heme is then turned into unconjugated bilirubin in the [[macrophage]]s of the spleen. This unconjugated bilirubin is not water soluble. It is then bound to [[serum albumin|albumin]] and sent to the [[liver]].
In the liver it is conjugated with [[glucuronic acid]], making it soluble in water. Much of it goes into the bile and thus out into the small intestine. Some of the conjugated bilirubin remains in the large intestine and is metabolised by colonic bacteria to [[urobilinogen]], which is further metabolized to [[stercobilinogen]], and finally oxidised to [[stercobilin]]. This stercobilin is what gives feces its brown color. Some of the urobilinogen is reabsorbed, and excreted in the urine along with an oxidized form, [[urobilin]].
Normally, a tiny amount of bilirubin is excreted in the urine, accounting for the light yellow colour. If the liver’s function is impaired or when biliary drainage is blocked, some of the conjugated bilirubin leaks out of the hepatocytes and appears in the urine, turning it dark amber. The presence of this conjugated bilirubin in the urine can be tested for clinically, and is reported as an increase in urine bilirubin. However, in the disorder [[hemolytic anemia]], an increased number of red blood cells are broken down, causing an increase in the amount of unconjugated bilirubin in the blood. As stated above, the unconjugated bilirubin is not water soluble, and thus one will not see an increase in bilirubin in the urine. Because there is no problem with the liver or bile systems, this excess unconjugated bilirubin will go through all of the normal processing mechanisms that occur (e.g., conjugation, excretion in bile, metabolism to urobilinogen, reabsorption) and will show up as an increase in urine urobilinogen. This difference between increased urine bilirubin and increased urine urobilinogen is an important one, as it allows clinicians to determine what disorders a patient likely has.
==Toxicity==
Unconjugated hyperbilirubinaemia in the neonate can lead to accumulation of bilirubin in certain brain regions, a phenomenon known as [[kernicterus]], with consequent irreversible damage to these areas manifesting as various neurological deficits, [[seizure]]s, abnormal [[reflexes]] and eye movements. The neurotoxicity of neonatal hyperbilirubinemia manifests because the [[blood-brain barrier]] has yet to develop fully, 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 [[hyperbilirubinaemia]], 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 [[glucuronidase|β-glucuronidase]] and a large proportion is reabsorbed through the [[enterohepatic circulation]].
==Benefits==
Reasonable levels of bilirubin can be beneficial to the organism. Evidence is accumulating{{Fact|date=March 2008}} that suggests bilirubin can protect tissues against oxidative damage caused by [[free radical]]s and other [[reactive oxygen species]].
Statistical analysis of people with high normal or slightly elevated bilirubin levels in blood shows that they have a lower risk of developing cardiovascular diseases. In infants it is not very common for the spleen to destroy red blood cells faster than the liver can conjugate the bilirubin. The effect of this would be more bilirubin in the blood plasma.
==Blood tests==
Bilirubin is in one of two forms:
{| class="wikitable"
| '''Abb.''' || '''Name''' || '''Soluble?''' || '''Reaction'''
|-
| "BC" || ''conjugated'' || Yes (bound to [[glucuronic acid]]) || Reacts quickly when dyes are added to the blood specimen. Product is Azobilirubin "Direct bilirubin"
|-
| "BU" || ''unconjugated'' || No || Reacts more slowly. Still produces Azobilirubin. Ethanol makes all bilirubin react promptly. Indirect bilirubin = Total bilirubin - Direct bilirubin
|}
Total bilirubin measures both BU and BC. Total and direct bilirubin levels can be measured from the blood, but indirect bilirubin is calculated from the total and direct bilirubin.
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|ALT]], [[aspartate transaminase|AST]], [[GGT]], [[alkaline phosphatase|Alk Phos]]), [[blood film]] examination ([[hemolysis]], etc.) or evidence of infective [[hepatitis]] (e.g., Hepatitis A, B, C, delta, E, etc).
Bilirubin is an excretion product, and the body does not control levels. Bilirubin levels reflect the balance between production and excretion. Thus, there is no "normal" level of bilirubin.
Bilirubin is broken down by light, and therefore blood collection tubes (especially serum tubes) should be protected from such exposure.
== Interpretation ==
Different sources provide [[Reference ranges for common blood tests|reference range]]s which are similar but not identical. Some examples for adults are provided below (different reference ranges are often used for newborns):
{| class="wikitable"
| || '''μmol/L''' || '''mg/dL'''
|-
| total bilirubin || 5.1–17.0 <ref name="WebMD">{{cite web |url=http://www.webmd.com/digestive-disorders/Bilirubin-15434?page=3 |title=Bilirubin |accessdate=2007-08-14 |format= |work=}}</ref> || 0.2-1.9,<ref name="MedlinePlus">{{MedlinePlus|003468}}</ref> 0.3–1.0,<ref name="WebMD"/> 0.1-1.2<ref name="LSUHSC">{{cite web |url=http://www.sh.lsuhsc.edu/fammed/OutpatientManual/content.html |title=Laboratory tests |accessdate=2007-08-14 |format= |work=}}</ref>
|-
| direct bilirubin || 1.0–5.1 <ref name="WebMD"/> || 0-0.3,<ref name="MedlinePlus"/> 0.1–0.3,<ref name="WebMD"/> 0.1-0.4<ref name="LSUHSC"/>
|}
'''Mild rises in bilirubin may be caused by'''
*[[Hemolysis]] or increased breakdown of red blood cells.
*[[Gilbert's syndrome]] - a genetic disorder of bilirubin metabolism which can result in mild jaundice, found in about 5% of the population.
'''Moderate rise in bilirubin may be caused by'''
* [[Recreational drug use|Drugs]] (especially [[anti-psychotic]], some [[sex hormone]]s, and a wide range of other drugs).
* [[Hepatitis]] (levels may be moderate or high).
* [[Chemotherapy]]
* Biliary stricture (benign or malignant)
'''Very high levels of bilirubin may be caused by'''
* [[Neonatal jaundice|Neonatal hyperbilirubinaemia]], where the newborn's liver is not able to properly [[conjugate]] the bilirubin (see [[jaundice]]).
* Unusually large bile duct obstruction, eg stone in common bile duct, tumour obstructing common bile duct etc.
* Severe liver failure with [[cirrhosis]].
* Severe hepatitis.
* [[Crigler-Najjar syndrome]]
* [[Dubin-Johnson syndrome]]
* [[Choledocholithiasis]] (chronic or acute)
[[Cirrhosis]] may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis
Indirect bilirubin is fat soluble and direct bilirubin is water soluble.
==Jaundice==
[[Jaundice]] may be noticeable in the [[sclera]] (white) of the eyes at levels of about 30-50 μmol/l, and in the skin at higher levels. Jaundice is classified depending upon whether the bilirubin is free or conjugated to [[glucuronic acid]] into:
* Conjugated jaundice
* Unconjugated jaundice
==See also==
* [[Primary sclerosing cholangitis]]
* [[Primary biliary cirrhosis]]
* [[Gilbert's syndrome]], a genetic disorder of bilirubin metabolism which can result in mild jaundice, found in about 5% of the population.
* [[Crigler-Najjar syndrome]]
* [[Biliary atresia]]
* [[Bilirubin diglucuronide]]
==References==
<references/>
{{Tetrapyrroles}}
[[Category:Chemical pathology]]
[[Category:Metabolism]]
[[Category:Pigments]]
[[Category:Tetrapyrroles]]
[[Category:Hepatology]]
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