Article: Bilirubin

The structure of Bilirubin

Bilirubin is a yellow breakdown product of normal heme catabolism. Its levels are elevated in certain diseases and it is responsible for the yellow color of bruises.

Physiology and metabolism

Bilirubin is formed when red blood cells die and their hemoglobin is broken down within the macrophages to heme and globins. The heme is further degraded to Fe²⁺, carbon monoxide and bilirubin via the intermediate compound biliverdin. Since bilirubin is poorly soluble in water, it is carried to the liver and bound to albumin. Bilirubin is made water-soluble in the liver by conjugation with glucuronic acid. Conjugated bilirubin, or bilirubinglucuronide, moves into the bile canaliculi of the liver and then to the gall bladder. When stimulated by eating, bile (including the conjugated bilirubin) is excreted into the small intestine. In the later portions of the small intestine (ileum) and the colon, about half of the bilirubinglucuronide is converted into urobilinogen. Urobilinogen is either reabsorbed or converted by the presence of oxygen to stercobilin. The stercobilin and remaining bilirubinglucuronide are excreted in the feces. These two metabolites of bilirubin are what give feces their characteristic brown color. Small amounts of urobilinogen remaining in the blood are filtered by the kidneys, ending up in the urine as urobilin. This bilirubin metabolite gives urine its characteristic yellow color.

In diseases where too much hemoglobin 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 form, conjugated bilirubin (also direct bilirubin), or bound to albumin form unconjugated bilirubin (also indirect bilirubin). 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 measure just total 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 ALT, AST, GGT, 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.

Interpretation

The reference range for total bilirubin is 2 - 14 μmol/L or 0.3 - 1.9 mg/dL. For direct bilirubin, it is 0 - 4 μmol/L or 0 - 0.3 mg/dL.

Mild rises in bilirubin may be caused by

• Hemolysis or increased breakdown of blood.
• 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

• 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.
• Crigler-Najjar syndrome
• Dubin-Johnson 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 above 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

Bilirubin 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, seizures, abnormal reflexes and eye movements. 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 billirubin in the feces (this is largely why the feces of a neonate are paler than those of an adult). Instead the conjugated billirubin is converted back into the unconjugated form by the enzyme b-glucoronidase and a large proportion is reabsorbed through the enterohepatic circulation.

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 contrast, the heme molecule is a ring of four pyrroles, called porphyrin.

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]

Trivia

Bilirubin was used as a wordplay in Silence of the Lambs, Lecter gives the name of the killer as Billy Rubin; after he escaped a sheet of paper with the formula for bilirubin is found in his cell.

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