What is the role of conjugated bilirubin retention in the pathophysiology of cholestasis?

Updated: Aug 09, 2017
  • Author: Hisham Nazer, MBBCh, FRCP, DTM&H; Chief Editor: Carmen Cuffari, MD  more...
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Excretion of conjugated bilirubin is the rate-limiting step of bilirubin clearance. During cholestasis, conjugation of bilirubin continues but excretion is reduced. The mechanism by which conjugated bilirubin regurgitates into serum is unclear, but it may differ according to the disease etiology. In hepatocellular cholestasis, where bile formation is reduced, conjugated bilirubin is likely to efflux directly from the hepatocyte via diffusion or vesicular exocytosis. On the other hand, in obstructive cholestasis, conjugated bilirubin possibly enters the canalicular space and effluxes back through a weakened tight junction.

The presence of elevated serum concentration of conjugated bilirubin is a principal sign of cholestasis. It results in jaundice, which can be detected by scleral icterus at a concentration as low as 2 mg/dL, and by dark urine. The concentration of conjugated bilirubin is affected by the rate of production of bilirubin, the degree of cholestasis, and alternate pathways of elimination, principally renal excretion. The magnitude of elevation is not diagnostically important because it does not reflect the type or degree of cholestasis. For example, whereas other investigations clearly indicate that patients with neonatal giant cell hepatitis typically have more bile flow than patients with biliary atresia, the serum conjugated bilirubin concentration is usually higher in neonatal giant cell hepatitis. This probably reflects an increase in bilirubin production.

Alternate elimination pathways, principally by way of the kidneys, limit the absolute elevation of conjugated bilirubin. Conjugated bilirubin concentration rarely exceeds 30 mg/dL, although such elevated levels can occur. Because conjugated bilirubin is relatively weakly bound to albumin, it can dissociate relatively easily and be filtered into the urine. The parents of children with cholestasis frequently report dark urine or a stained diaper, and examination of the urine is a useful starting point in the evaluation of an infant with jaundice.

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