Raised serum bilirubin (jaundice) – a review of inheritable causes

Bilirubin is a waste product of hemoglobin catabolism that is excreted via the liver in bile. 

Abnormal accumulation of this yellow pigment in blood results in jaundice. For adults and children, increased serum bilirubin and resulting jaundice is most commonly a signal of liver or biliary-tract disease; whilst for neonates it usually reflects part of the complex adaptation that naturally occurs during transition from a supported intrauterine environment to physiological independence at birth, referred to as ”physiological” jaundice. 

More rarely, increased serum bilirubin at any age can be the result of hematological conditions associated with increased red-cell destruction, so called hemolytic jaundice. If serum bilirubin is raised in the absence of liver/ biliary-tract disease, and both ”physiological” and ”hemolytic” jaundice can also be excluded, rarer causes of increased serum bilirubin must be considered. 

This wider consideration should include the five inheritable disorders of bilirubin elimination that are the subject of a recently published review article. 

By way of introduction to these inheritable conditions, the authors first outline current understanding and controversies surrounding the molecular mechanisms of the three sequential steps of bilirubin elimination: passage of bilirubin from blood into liver cells; conjugation (joining) of bilirubin with glucuronic acid within liver cells; and passage of conjugated bilirubin from liver cells to the biliary tract.

The five inheritable conditions discussed are: Rotor syndrome (RS); Gilbert’s syndrome (GS); Crigler-Najjar syndrome types 1 and 2 (CNS1 and CNS2); Dubin-Johnson syndrome (DJS) and transient familial neonatal hyperbilirubinemia (TFNH). All can be attributed to a genetic defect in one of the three steps of bilirubin elimination but they vary in both rarity and relative seriousness. 

So for example, GS is by far the most common inherited cause of increased serum bilirubin – affecting 8 % of the Caucasian population – but is entirely benign, apart from the fact that the finding of a raised bilirubin (it rarely exceeds 70 µmol/L in those with GS) might prompt needless further investigation. By contrast with GS, CNS is a very rare disorder (prevalence 0.6 per million), evident as severe life-threatening jaundice at birth.

For each of these five inherited disorders the authors describe the precise genetic defect, severity of serum bilirubin increase, and resulting clinical significance. An interesting aspect of recent research in this area is the emerging knowledge that bilirubin is not merely a waste product of hemoglobin catabolism but also has a protective anti-oxidant property. 

Recent research discussed in this paper suggests that the mildly increased serum unconjugated bilirubin that characterizes Gilbert’s syndrome may offer protection against cardiovascular disease.

In discussion of its main topic – inheritable causes of increased serum bilirubin – this excellent review provides much up-to-date detail of the way bilirubin is normally processed.