Bilirubin
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Bilirubin is a yellow breakdown product of haem (heme in American English). Haem is a special ring shaped molecule that is found in haemoglobin and is essential to the oxygen carrying capacity of blood.
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Physiology
Bilirubin is essentially a waste product, formed when red blood cells die and haemoglobin is broken down. It is not soluble in water and is carried to the liver bound onto albumin. Bilirubin is made water soluble in the liver by conjugation with uridine diphosphoglucuronic acid or UDPGA. As part of bile, the soluble bilirubin then passes through the common bile duct and is either temporarily stored in the gallbladder or passes right away into the gut. Some of the excreted bilirubin may be reabsorbed (entero-hepatic circulation). Bacteria in the intestines modify bilirubin, causing the brown color of feces. The yellow colour of urine is a result of products derived from bilirubin. The name of this metabolite is urobilinogen.
In diseases where too much haemoglobin is broken down or the removal of bilirubin does not function properly, the accumulating bilirubin in the body causes jaundice.
Bilirubin blood tests
Bilirubin is broken down by light, and blood collection tubes (especially serum tubes) should therefore be protected from such exposure.
Bilirubin is found in blood either in the soluble, conjugated form ("direct"), or bound to albumin ("indirect"). The terms "direct" and "indirect" refer to the fact that soluble bilirubin can be measured directly, whereas insoluble, or indirect, bilirubin must be solubilised before measurement.
Although both direct and indirect bilirubin can be measured separately, it is more common to just measure total bilirubin. When we try to further elucidate the causes of jaundice or increased bilirubin it is usually simpler to look at other liver function tests (especially the enzymes ALT, AST, GGT, Alk Phos), blood film examination (haemolysis etc.) or evidence of infective hepatitis (e.g. Hepatitis A, B, C, delta E etc).
Bilirubin is basically an excretion product and the body does not control levels. Bilirubin levels reflect the balance between production and excretion. Thus strictly speaking there is not a normal level of bilirubin.
Interpretation
The reference range for total bilirubin is 2 - 14 μmol/L. For direct bilirubin, it is 0 - 4 μmol/L.
Mild rises in bilirubin may be caused by:
- Haemolysis or increased breakdown of blood.
- Gilbert's syndrome - slightly increased bilirubin due to an inherited enzyme deficiency. This has no clinical significance.
Moderate rise in bilirubin may be caused by:
- Drugs (especially anti-psychotic, some sex hormones, and a wide range of other drugs).
- Hepatitis (levels may be moderate or high).
Very high levels of bilirubin may be caused by:
- 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.
- Criggler-Najjar syndrome
Cirrhosis may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis.
Jaundice
Jaundice may be noticeable in the sclera (white) of the eyes at levels over 30 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
Bilirubin toxicity
Unconjugated hyperbilirubinaemia in the neonate can lead to kernicterus in which there is damage to certain brain regions. The newborn has abnormal reflexes and unusual eye movements.
Bilirubin benefits
Reasonable levels of bilirubin can be beneficial to the organism. Evidence is accumulating that suggests bilirubin can protect tissues against oxidative damage caused by free radicals and other reactive oxygen species.
Chemistry
Bilirubin consists of an open chain of four pyrroles (tetrapyrrole); by constrast, the haem molecule is a ring of four pyrroles.
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 pyrroles.
Like these other pigments, bilirubin changes its conformation when exposed to light. This is used in the phototherapy of jaundiced newborns: the illuminated version of bilirubin is more soluble than the unilluminated version.
Several textbooks and research articles show incorrect chemical structures for the two isoforms of bilirubin. [1] (http://www.nsta.org/main/news/stories/college_science.php?news_story_ID=48991)