UGT1A1-related disorders in Bahrain: A genetic and clinical overview of Crigler-Najjar and Gilbert syndromes

Abstract

BACKGROUND

UGT1A1-related disorders, including Crigler-Najjar syndrome (CNS) type I, type II, and Gilbert syndrome (GS), disrupt bilirubin metabolism, resulting in unconjugated hyperbilirubinemia.

AIM

To evaluate the prevalence of UGT1A1-related disorders and compare clinical features, genetic variations, management, and outcomes across the three phenotypes.

METHODS

We conducted a retrospective cohort study at the Department of Pediatrics, Salmaniya Medical Complex, Government Hospitals, Bahrain, between 2004 and 2024. This hospital is the only national referral center for genetic services in Bahrain. Of 55 suspected cases, 35 patients (63.6%) were genetically confirmed to have UGT1A1-related disorders. The three phenotypes were compared regarding clinical characteristics, biochemical parameters, genetic variations, treatment, and outcomes. Fisher’s exact test, Student’s t-test, the Mann–Whitney U test, and paired t-test were used for comparison.

RESULTS

The estimated national disease prevalence was 2.2 per 100000 individuals. GS was the most common phenotype (n = 27, 77.1%), followed by CNS-II (n = 7, 20.0%) and CNS-I (n = 1, 2.9%). Parental consanguinity was reported in 40.0% of cases. CNS-I was diagnosed earlier, at 6 months of age, than CNS-II [11.3 (0.3-16.8) years] and GS [13.4 (11.9-16.9) years]. Glucose-6-phosphate dehydrogenase deficiency was the most common coexisting condition (48.6%). Total bilirubin level at presentation was higher in CNS-I (409 μmol/L) than CNS-II (105.3 ± 46.2 μmol/L) and GS (88.2 ± 53.8 μmol/L). Homozygous (TA)7/7 polymorphism in the UGT1A1 promoter was the most common variant (91.4%). CNS-I required continuous phototherapy then liver transplantation, achieving sustained bilirubin normalization over 16.7 years of follow-up. Among patients with CNS-II, 85.7% were treated with phenobarbital, whereas 48.1% of patients with GS received phenobarbital before diagnosis, with poor adherence in 78.9% of cases. In CNS-II, there was no significant difference between indirect bilirubin level at presentation and at follow-up (92.3 ± 47.6 μmol/L vs 90.9 ± 58.0 μmol/L, P = 0.969).

CONCLUSION

Although rare, UGT1A1-related disorders represent important causes of unconjugated hyperbilirubinemia in Bahrain, with GS being the most prevalent phenotype. Genetic testing is essential for accurate diagnosis and appropriate management, particularly in patients with coexisting hematological conditions.

Keywords: Indirect hyperbilirubinemia; UGT1A1-related disorders; Crigler-Najjar syndrome; Gilbert syndrome; Bahrain

Core Tip: This first study from Bahrain demonstrated that UGT1A1-related disorders represent important causes of persistent unconjugated hyperbilirubinemia, affecting 2.2 per 100000 individuals. Gilbert syndrome (GS) was the most common phenotype, followed by Crigler–Najjar syndrome (CNS) type I and type II. Early genetic testing is crucial for diagnosis, particularly in patients with parental consanguinity and those with associated hematological disorders, mainly glucose-6-phosphate dehydrogenase deficiency. Homozygous (TA)7/7 was the most common variant. CNS-I requires lifelong phototherapy or liver transplantation, whereas CNS-II is treated with phenobarbital; however, treatment adherence remains challenging. No treatment is required for GS.