Gilbert syndrome

Gilberts

Which transporter are affected

What occurs physiologically?

How this induced in people of different ancestry?

Common disease

Slightly decreased expression of UGT1A1 and low activity of OATP (SLCO1B) (more minor) 

Mild intermittent jaundice

Mildly elevated free bilirubin

In people with European ancestry, the variant is a *28 with a (TA)n dinucleotide repeat at the promoter region which decrease efficiency of enzyme transcription. It appears as a common autosomal recessive syndrome. 

In people with Asian ancestry, *6 is common, but it is a point mutation in exon 1

Mild neonatal jaundice is due to…

What can b a solution for this 

Liver UGT enzyme not fully mature (this can takes up to 3 months to reach adult level)

Gilberts syndrome is a contribution 

Component in breast milk that competes with bilirubin for glucuronidation 

UV light converts bilirubin to maleimide fragments that are easily eliminated in the urine

Incomplete penetrance of Gilberts syndrome

The syndrome may not be recognised for years, jaundice is only evident when one of the triggers for bilirubin level (eg infection (malaria), dehydration, fasting,..)  is induced

A lower than normal erythrocytes (anemia) will decrease the amount of ciculating bilirubin following breakdown of old cells 

What is G6PD deficiency and how is this related to the incomplete penetrance of UGT1A1 variants

In G6PD deficiency, RBCS are more susceptible to ROS damage, it is highly prevalent in malaria endemic regions as provide protection. An individual with G6PD has predisposing factor for hyperbilirunemia and if has UGT1A1 result in even higher bilirubin level

Crigler-Najjar syndrome type 1

Rare

Complete lack of UGT1A1 enzyme

Highly elevated free bilirubin level

Cause permanent neurological damage and can be fatal, at birth requires urgent daily phototherapy and plasmapheresis

Liver transplant required

Very severe, continuous jaundice, kernicterus

(bilirubin is lipid soluble, so can gets through BBB and penetrate into neuronal and glial cell membrane)

Allelic heterogeneity

• Numerous mutations within coding regions of exons 2,3,4 of the UGT1A gene locus are found

• Consanguinity and founders effect

Crigler-Najjar type II

Rare

Characterised by partial enzyme activity of UGT1A1 and milder symptoms than type I 

Point mutations in the coding exons that alter the functions of the protein

Can be treated with phenobarbital (PB) that enhances UGT1A1 gene transcription 

Severe continuous jaundice & kernicterus 

Very elevated free bilirubin 

Not as bad as type 1 

Dubin Johnson syndrome

Rare

A mild fluctuating jaundice due to slightly elevated conjugated-bilirubin . Typically observed in adolescence and patients have normal life expectancy.

Conjugated bilirubin is more water soluble so are less likely to damage tissues

Lack of MRP2 efflux protein to pump out as a part of bile salt