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Richard Thompson



These include health benefits of high normal levels of bilirubin, and discussion of the genetic basis of Gilbert’s syndrome.

Updated on 29 May 2014. The previous version of this content can be found here.
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date: 30 March 2017

Physiology of bilirubin

All haem molecules are degraded in macrophages by haem oxygenase to biliverdin, and thence by biliverdin reductase to bilirubin, which is selectively removed by hepatocytes from sinusoidal blood and then conjugated, mainly by one of the two specific isoforms of the microsomal enzyme UDP-glucuronyl (glucuronate-glucuronosyl) transferase, chiefly with two glucuronic acid moieties. Conjugated bilirubin is excreted into the bile by the anionic conjugate transporter protein (MRP2), but in many liver diseases it refluxes back into blood and—since it is water soluble and less firmly bound to albumin than unconjugated bilirubin—about 1% is filtered across the glomerular membrane and darkens the urine (choluria). In the distal intestine conjugated bilirubin is deconjugated and reduced to a series of uro- and stercobilinogens that give the normal colour to faeces. Some colourless urobilinogen is normally absorbed from the colon and undergoes an enterohepatic circulation, with a small amount being excreted in urine. If this biliary excretion is impaired in liver disease, or increased in haemolysis, then excess urobilinogen is excreted in urine, where it is easily detected by routine clinical ‘stix’.

Clinical approach

Jaundice is the clinical sign of hyperbilirubinaemia and usually, but not always, indicates disease of the liver or biliary tree. Dark urine and, less commonly, pale stools indicate cholestasis. Stigmata of chronic liver disease are important, but do not define the cause of jaundice.

Unconjugated hyperbilirubinaemia—should be sought by testing whether serum bilirubin levels are raised and other liver-related blood tests normal. Causes include (1) haemolysis, which if severe enough to raise bilirubin levels is likely to cause an elevated reticulocyte count and reduction in plasma haptoglobin levels; (2) benign constitutional unconjugated hyperbilirubinaemia (Gilbert’s syndrome)—a common recessive condition affecting at least 3% of the normal adult population, and due to homozygous polymorphisms in the promoter region of the specific glucuronyl transferase gene. It is recognized by a fluctuating, elevated serum bilirubin concentration that rises excessively on fasting; patients require reassurance that the results do not indicate liver disease.

Conjugated hyperbilirubinaemia—routine liver-related blood tests cannot differentiate between intra- or extrahepatic causes of jaundice, unless the transferases are very high, in which case hepatitis (e.g. viral, alcoholic) is certain. Cholestasis should be sought by abdominal ultrasonography to detect a dilated intra- and/or extrahepatic biliary tree (and often also reveal its cause, e.g. gallstones, tumour). Further investigation depends on the clinical context: (1) likely biliary disease—endoscopic retrograde cholangiopancreatography (ECRP), magnetic resonance cholangiography (MRC), endoscopic ultrasound; (2) likely intrahepatic cholestasis—viral hepatitis C serology, autoantibodies, serum caeruloplasmin/copper, plasma α‎1-antitrypsin concentration; liver biopsy.

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