Differentiating Gilbert Syndrome from Crigler Najjar Syndrome Type 2 by Phenobarbitone Test

Gilbert syndrome characterized by jaundice with intermittent elevations of indirect bilirubin, in the absence of haemolysis or underlying liver disease, has both autosomal dominant and recessive inheritance. Crigler-Najjar syndrome type II (CNS2) is a hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to reduced and inducible activity of hepatic bilirubin glucuronosyltransferase (GT). We report 20 children between age 5 to 15 years with unconjugated hyperbilirubenemia who were given seven days of oral phenobarbitone (5mg/kg/day) and decrease in level of bilirubin was noted. There was only 30-40% reduction of bilirubin in Crigler Najjar Syndrome Type 2 compared to Gilberts Syndrome in which bilirubin level normalised. This case series highlights the importance of simple test to differentiate these two conditions. This test is also very helpful in a place where enzyme level and mutational study cannot be done. J Nepal Paediatr Soc 2015;35(1):82-84


Introduction
G ilbert's syndrome is named a er Augus n Gilbert (1858-  1927), a French physician.It is defi ned as benign, familial, mild, unconjugated hyperbilirubinaemia not due to haemolysis and with normal rou ne tests of hepa c func on and liver histology.The Crigler-Najjar syndrome type II (CNS2) is a hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to reduced and inducible ac vity of hepa c bilirubin glucuronosyltransferase (GT).This study was conducted in a small town of Bhutan named Haa.The total popula on of Bhutan is around 7.5 lacs with Pediatric age group(1-15yrs) around 40%.The popula on of Haa is around 12000.We report 20 children between age 5 to 15 years with unconjugated hyperbilirubenemia who were given 7 days of oral phenobarbitone(5mg/kg/day) and decrease in level of bilirubin was noted.

Material and Methods
Twenty children of the age group 5-15 years were included in the study with a male to female ra o of 12:8.It was a prospec ve interven onal study and 55 children were screened.The study was conducted in a Government Hospital in Haa, Bhutan The en re panel of test for haemoly c disease, autoimmune disease and chronic liver disease were done and it was nega ve.Wri en informed consent of the parents were also taken.The permission of ethical commi ee was taken for the use of Phenobarbitone.The inclusion criteria were: Children between age group 5-15 years who have reported to our OPD from Oct 2012 to May 2014 with features of Jaundice and Unconjugated Hyperbilirubinemia (a er blood tes ng) were included in the study.Exclusion criteria: Children with haemoly c disease and Conjugated Hyperbilirubenemia Interven on: These 20 children were admi ed and their baseline Total bilirubin (both conjugated and uncongugated), Enzymes SGOT/SGPT/ALP were recorded.The other causes of jaundice were ruled out by performing few tests.The Direct and indirect Coombs tests were nega ve.Serum haptoglobin, thyroid s mula ng hormone, ceruloplasmin, ferri n, glucose-6-phosphate dehydrogenase, and alpha-1-an trypsin levels, as well as a re culocyte index were within normal limits.Serologic tests for hepa s B and hepa s C showed no evidence of previous or ac ve infec on.An nuclear an body and an mitochondrial an body tests were both nega ve.The detail clinical examina on was done before Phenobarbitone administra on.They were given oral Phenobarbitone 5mg/kg/day for 7 days and levels of bilirubin including enzymes were recorded a er 7 days and both reading were compared.

Results
It was Interven onal prospec ve study in which levels of bilirubin and liver enzymes was checked before and a er administra on of Phenobarbitone.All the pa ents had undergone detail clinical examina on before and a er the interven on.The clinical examina on was normal except for jaundice.

Discussion
Gilbert syndrome, found in 3% to 10% of the popula on, is the most common hereditary cause of increased bilirubin and is an autosomal recessive condi on that is characterized by intermi ent jaundice in the absence of hemolysis or underlying liver disease.Type 2 Crigler-Najjar syndrome (CNS2) is a hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to reduced and inducible ac vity of hepa c bilirubin glucuronosyltransferase (GT).CNS2 is a milder form of CNS than CNS1.Numerous muta ons in the UGT1A1 gene on 2q37 are linked to CNS2 and result in reduced bilirubin GT ac vity, with marked impairment of bilirubin conjuga on.
In our study 20 children were admi ed for unconjugated hyperbilirubenemia evalua on in the age group 5-15 years.The only presen ng feature was yellowish discoloura on of eyes.The detail physical examina on was done to rule out haemoly c/ chronic liver disease.There was scleral icterus in all the pa ent.The vital parameters were normal.There was no features of chronic liver disease.The liver span was  1) with mild eleva on of liver enzymes.Subsequent laboratory tes ng revealed normal ranges of hemoglobin, lactate dehydrogenase, and transaminases.The other causes of jaundice were ruled out by relevant laboratory test as men oned in the material and method sec on.The Ultrasonography revealed normal span with normal echotexture of liver in all the subjects.A er phenobarbitone therapy there was normalising of bilirubin in 12 pa ents and 30-40% reduc on in bilirubin in 8 pa ents.These 12 pa ents were likely to be suff ering from Gilberts Syndrome and other 8 pa ents from Crigler Najjar syndrome 2. This high incidence of unconjugated hyperbilirubenemia in a small town of Bhutan could be most probably due to gene c cause.
A diagnosis of GS usually is made during or a er puberty, possibly due to the inhibi on of bilirubin glucuronida on by endogenous steroid hormones.In older individuals, the diagnosis usually is made when unconjugated hyperbilirubinemia is noted on rou ne blood tests or unmasked by an overlying illness.In the past, fas ng; administra on of nico nic acid (IV), phenobarbital, or rifampin (rifampicin); and thin layer chromatography have been used to confi rm a GS diagnosis.More recently, polymerase chain reac on tes ng has been used.A liver biopsy also can be performed but usually is not necessary 4,5,6,7 .
In our study Phenobarbitone test was used to diff eren ate Gilbert Syndrome and Crigler Najjar Syndrome.There are only very few studies of similar type in the literature.It is one of the most simple and cost eff ec ve test to diff eren ate these two condi on.Also a larger study might be required to establish likely cause of unconjugated hyperbilirubinemia in this region.

Conclusion
This ar cle highlights the importance of very simple test to diff eren ate these two rare syndrome without any side eff ects.This is very cheap and cost eff ec ve.In a resource constrained place this simple test is of prime importance to diff eren ate these two condi ons.There is a need to conduct larger study to validate the higher incidence of unconjugated hyperbilirubinemia in paediatric age group.

Table 1 :
List of all pa ents and the inves ga on results