What is Gilbert's syndrome?

Gilbert's syndrome 

Gilbert’s syndrome is the most common inherited disorder of bilirubin metabolism. It causes mild isolated hyperbilirubinemia while all the other LFTs are completely normal and there are no signs of liver disease. In this condition, almost 100% of the serum bilirubin is unconjugated. The prevalence is approximately 2-7% in the general population, with males predominating over females by a 2-7: 1 ratio.  

Mode of inheritance:

It is an autosomal recessive trait caused by a mutation in the gene's promoter region for UDP-glucuronyl transferase enzyme (UGT1A1), which leads to reduced enzyme expression. It can be inherited in a dominant fashion as well when there is a missense mutation in the gene. 

Normal biochemistry of conjugation of bilirubin with glucuronate:  

Bilirubin is nonpolar and would persist in cells (e.g. bound to lipids) if not converted to a more water-soluble form. Bilirubin is converted to a more polar molecule by conjugation with glucuronic acid. A bilirubin-specific UDP-glucosyl transferase (Bilirubin UDPGT) of the endoplasmic reticulum catalyzes stepwise transfer to bilirubin of two glucosyl moieties from UDP-glucuronate:

Bilirubin + UDP-glucuronate → bilirubin monoglucuronide + UDP

Bilirubin monoglucuronide + UDP-glucuronate → bilirubin diglucuronide + UDP

Pathology in Gilbert’s syndrome:

Gilbert's syndrome is marked by the impaired conjugation of bilirubin (to approximately one-third of normal) due to reduced bilirubin UDPGT activities. To be mentioned, it is seen that, if about 30% of the bilirubin UDP-glucuronosyl transferase activity is retained in Gibert syndrome, the condition is harmless. 

Features: 

• Unconjugated hyperbilirubinemia 
• It is often diagnosed incidentally during a routine per-employee check-up. 
• Jaundice may only be seen during an intercurrent illness. It may be exacerbated by periods of fasting, alcohol, estrogen, acute illness even sore throat, etc.

Investigations: 

• Establishing the diagnosis is necessary to provide reassurance and prevent unnecessary investigations. 
• The raised unconjugated bilirubin is diagnostic (serum levels almost always <103 μmol /L (6 mg/dL) and the rise in bilirubin can be provoked by prolonged fasting or IV nicotinic acids. 
• The reticulocyte count is normal, excluding hemolysis.

Management:

• No treatment is required.
• If severe jaundice (which is rare), phenobarbitone can rapidly decrease unconjugated serum bilirubin levels. 

Source: 

• Step Up to MRCP Review Notes for P1 & P2 By Dr Khaled El Magraby 1st ed 2015; page 281
• Kumar & Clark’s Clinical Medicine 9e (2016); page 448 (1098)
• Davidson Principles and Practice of Medicine 23 edition; pages 860 & 897
• Harrison’s Principles of Internal Medicine 2 volumes 19th Edition; page 282
• Harper's Illustrated Biochemistry, 30E (2015); page: 331, 333; Fig 31-15