Bilirubin

Bilirubin

Names
Other names
Pheophytin
Identifiers
CAS Registry Number 635-65-4
ChEBI

CHEBI:16990

ChEMBL

ChEMBL501680

ChemSpider

4444055

InChI[show]

Jmol-3D images

Image
Image

PubChem

5280352

SMILES[show]
UNII

RFM9X3LJ49

Properties
Molecular formula

C33H36N4O6

Molar mass

584.66 gmol1

Supplementary data page

Structure and
properties

Refractive index (n),

Dielectric constant (r), etc.

Thermodynamic
data

Phase behaviour
solidliquidgas

Spectral data

UV, IR, NMR, MS

Except where noted otherwise, data is given for

materials in their standard state (at 25 C (77 F),
100 kPa)
verify (what is: / ?)
Infobox references

Bilirubin (formerly referred to as haematoidin) is the yellow breakdown product of

normal heme catabolism, caused by the body's clearance of agedred blood cells which
contain hemoglobin.
Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases. It is
responsible for the yellow color of bruises and the yellow discoloration in jaundice. It is also
responsible for the brown color of feces (via its conversion to stercobilin), and the background
straw-yellow color of urine via its breakdown product, urobilin, contributing to urine color along

with thiochrome, a breakdown product of thiamine which produces the more obvious but
variable bright yellow color of urine.
It has also been found in plants.[1]
Contents
[hide]

1 Chemistry

2 Function

3 Metabolism
o 3.1 Unconjugated ("indirect")
o 3.2 Conjugated ("direct")
o 3.3 Urine

4 Toxicity

5 Associated health benefits

6 Blood tests
o 6.1 Measurement methods

7 Blood levels
o 7.1 Hyperbilirubinemia
o 7.2 Jaundice

8 Urine tests

9 See also

10 References

11 External links

Chemistry[edit]
Bilirubin consists of an open chain of four pyrrole-like rings (tetrapyrrole). Inheme, these four
rings are connected into a larger ring, called a porphyrinring.

Bilirubin can be "conjugated" with a molecule of glucuronic acid which makes it soluble in water
(see below). This is an example of glucuronidation.
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, some of the double-bonds in bilirubin isomerize when exposed to
light. This is used in thephototherapy of jaundiced newborns: the E,Z-isomers of bilirubin
formed upon light exposure are more soluble than the unilluminated Z,Z-isomer, as the
possibility of intramolecular hydrogen bonding is removed.[2] This allows the excretion of
unconjugated bilirubin in bile.
Some textbooks and research articles show the incorrect geometric isomer of bilirubin.[3] The
naturally occurring isomer is the Z,Z-isomer.
Function[edit]
Bilirubin is created by the activity of biliverdin reductase on biliverdin, a green tetrapyrrolic bile
pigment that is also a product of heme catabolism. Bilirubin, when oxidized, reverts to become
biliverdin once again. This cycle, in addition to the demonstration of the potent antioxidant
activity of bilirubin,[4] has led to the hypothesis that bilirubin's main physiologic role is as a
cellular antioxidant.[5][6][7]
Metabolism[edit]

Heme metabolism

Unconjugated ("indirect")[edit]
Erythrocytes (red blood cells) generated in the bone marrow are disposed of 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
monocyte macrophages system of the spleen. This unconjugated bilirubin is not soluble in water,
due to intramolecular hydrogen bonding. It is then bound to albumin and sent to theliver.
The measurement of direct bilirubin depends on its reaction with diazosulfanilic acid to
create azobilirubin. However, unconjugated bilirubin also reacts slowly with diazosulfanilic acid,
so that the measured indirect bilirubin is an underestimate of the true unconjugated
concentration.
Conjugated ("direct")[edit]
In the liver, bilirubin is conjugated with glucuronic acid by the enzymeglucuronyltransferase,
making it soluble in water: the conjugated version is also often called "direct" bilirubin. Much of
it goes into the bile and thus out into the small intestine. Though most bile acid is resorbed in
the terminal ileum to participate in enterohepatic circulation, conjugated bilirubin is not absorbed
and instead passes into the colon.[8]
There, colonic bacteria deconjugate and metabolize the bilirubin into colorless urobilinogen,
which can be oxidized to formurobilin and stercobilin: these give stool its characteristic brown
color. A trace (~1%) of the urobilinogen is resorbed into theenterohepatic circulation to be reexcreted in the bile: some of this is instead processed by the kidneys, coloring the urine yellow.[9]
Although the terms direct and indirect bilirubin are used equivalently with conjugated and
unconjugated bilirubin, this is not quantitatively correct, because the direct fraction includes both
conjugated bilirubin and bilirubin (bilirubin covalently bound to albumin, which appears in
serum when hepatic excretion of conjugated bilirubin is impaired in patients with hepatobiliary
disease).[10] Furthermore, direct bilirubin tends to overestimate conjugated bilirubin levels due to
unconjugated bilirubin that has reacted with diazosulfanilic acid, leading to increased
azobilirubin levels (and increased direct bilirubin).
Urine[edit]
Under normal circumstances, a tiny amount of urobilinogen, if any, is excreted in the urine. 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. However, in
disorders involving hemolytic anemia, an increased number of red blood cells are broken down,
causing an increase in the amount of unconjugated bilirubin in the blood. Because the
unconjugated bilirubin is not water-soluble, 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
helps to distinguish between various disorders in those systems.
Toxicity[edit]
Unconjugated hyperbilirubinaemia 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, seizures, 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 bloodbrain barrier has yet to develop fully[dubious discuss], 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 (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.
Associated health benefits[edit]
Research has indicated that in the absence of liver disease, individuals with high levels of total
bilirubin may experience various health benefits exceeding those with lower levels of bilirubin.
[11]
Studies have found higher levels of bilirubin in elderly individuals are associated with higher
functional independence.[12] Studies have also revealed that levels of serum bilirubin are
inversely related to risk of certain heart diseases.[13][14]
Blood tests[edit]
Bilirubin is degraded by light. Blood collection tubes containing blood or (especially) serum to
be used in bilirubin assays should be protected from illumination. For adults, blood is typically
collected by needle from a vein in the arm. In newborns, blood is often collected from a
heelstick, a technique that uses a small, sharp blade to cut the skin on the infant's heel and collect
a few drops of blood into a small tube. Non-invasive technology is available in some health care
facilities that will measure bilirubin by using an instrument placed on the skin (transcutaneous
bilirubin meter)
Bilirubin (in blood) is in one of two forms:
Abb. Name(s)

Water-soluble Reaction

"BC
"

"BU
"

"Conjugated" or
"direct bilirubin"

"Unconjugated" or
"indirect bilirubin"

Yes (bound to Reacts quickly when dyes (diazo reagent) are

glucuronic
added to the blood specimen to
acid)
produce azobilirubin "Direct bilirubin"

No

Reacts more slowly, still produces azobilirubin,

Ethanol makes all bilirubin react promptly, then:
indirect bilirubin = total bilirubin direct
bilirubin

Total bilirubin (TBIL) 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.
Indirect bilirubin is fat-soluble and direct bilirubin is water-soluble.
Measurement methods[edit]
Originally, the Van den Bergh reaction was used for a qualitative estimate of bilirubin.
This test is performed routinely in most medical laboratories and can be measured by a variety of
methods.[15]
Total bilirubin is now often measured by the 2,5-dichlorophenyldiazonium (DPD) method, and
direct bilirubin is often measured by the method of Jendrassik and Grof.[16]
Blood levels[edit]
The bilirubin level found in the body reflects the balance between production and excretion.
Blood test results should always be interpreted using the reference range provided by the
laboratory that performed the test, but typical [0.3 to 1.9 mg/dL]s for adults and [340 mol/L] for
new borns:

total bilirubin

direct bilirubin

mol/l = micromole/litre

mg/dl = milligram/ decilitre

<21 [17]

<1.23

1.05.1[18]

00.3,[19]
0.10.3,[18]
0.10.4[20]

Reference ranges for blood tests, comparing blood content of bilirubin (shown in blue near
center) with other constituents[21]
Hyperbilirubinemia[edit]
Hyperbilirubinemia results from a higher-than-normal level of bilirubin in the blood. For adults,
this is any level above 17 mol/l and for newborns 340 mol/l and critical hyperbilirubinemia
425 mol/l.
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 that can result in mild
jaundice, found in about 5% of the population

Rotor syndrome: nonitching jaundice, with rise of bilirubin in the patient's serum, mainly
of the conjugated type

Moderate[clarification needed] rise in bilirubin may be caused by:

Pharmaceutical drugs (especially antipsychotic, some sex hormones, and a wide range of
other drugs)

Sulfonamides are contraindicated in infants less than 2 months old (exception when used
with pyrimethamine in treatingtoxoplasmosis) as they increase unconjugated bilirubin leading
to kernicterus.[22]

Hepatitis (levels may be moderate or high)

Chemotherapy

Biliary stricture (benign or malignant)

Very high[clarification needed] levels of bilirubin may be caused by:

Neonatal hyperbilirubinaemia, where the newborn's liver is not able to properly process
the bilirubin causing jaundice

Unusually large bile duct obstruction, e.g. stone in common bile duct, tumour obstructing
common bile duct etc.

Severe liver failure with cirrhosis (e.g. primary biliary cirrhosis)

CriglerNajjar syndrome

DubinJohnson syndrome

Choledocholithiasis (chronic or acute).

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.).
Jaundice[edit]
Jaundice may be noticeable in the conjunctiva of the eyes at levels of about 2 to 3 mg/dl (34 to
51 mol/l),[23] and in the skin at higher levels. For conversion, 1 mg/dl = 17.1 mol/l.[24]
Jaundice is classified depending upon whether the bilirubin is free or conjugated to glucuronic
acid into conjugated jaundice or unconjugated jaundice.[citation needed].

Urine tests[edit]
Urine bilirubin may also be clinically significant.[25] Bilirubin is not normally detectable in the
urine of healthy people. If the blood level of conjugated bilirubin becomes elevated, e.g. due to
liver disease, excess conjugated bilirubin is excreted in the urine, indicating a pathological
process.[26] Unconjugated bilirubin is not water-soluble and so is not excreted in the urine.
Testing urine for both bilirubin and urobilinogen can help differentiate obstructive liver disease
from other causes of jaundice.
See also[edit]

Biliary atresia

Bilirubin diglucuronide

Biliverdin

CriglerNajjar syndrome

Gilbert's syndrome, a genetic disorder of bilirubin metabolism that can result in mild
jaundice, found in about 5% of the population.

Hy's Law

Primary biliary cirrhosis

Primary sclerosing cholangitis

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