P1709 - Severe Unconjugated Hyperbilirubinemia With a Gilbert’s Genotype: An Unusual Presentation

Doa'a Alkhader, MD, Sulieman Abdal Raheem, MD
Cleveland Clinic Abu Dhabi, Abu Dhabi, Abu Dhabi, United Arab Emirates

Introduction: Hereditary unconjugated hyperbilirubinemias encompass a spectrum of disorders ranging from the benign Gilbert’s syndrome to the more severe Crigler-Najjar syndromes. Gilbert’s syndrome typically presents with mild, intermittent unconjugated hyperbilirubinemia, whereas Crigler-Najjar syndrome type 2 (CNS2) involves higher bilirubin levels and partial response to phenobarbital. We present a case of marked, lifelong unconjugated hyperbilirubinemia clinically resembling CNS2, but with genetic findings consistent solely with Gilbert’s syndrome, posing a diagnostic and therapeutic challenge.

Case Description/

Methods: A male patient with lifelong jaundice was evaluated for persistently elevated total bilirubin levels. Since childhood, his bilirubin had remained around 300 µmol/L and increased further to 400–500 µmol/L following an appendectomy. Laboratory workup revealed isolated unconjugated hyperbilirubinemia, with no evidence of hemolysis or hepatic dysfunction.
A therapeutic trial of phenobarbital 60 mg twice daily was initiated. While there was a modest reduction in bilirubin levels, the response was incomplete, and treatment was discontinued due to side effects.
Genetic testing for UGT1A1 revealed homozygosity for the A(TA)7TAA promoter polymorphism (UGT1A1*28), commonly associated with Gilbert’s syndrome. No pathogenic mutations were identified in the coding region of UGT1A1, ruling out Crigler-Najjar syndrome types 1 and 2.

Discussion: This case illustrates a striking phenotype-genotype discordance. The homozygous UGT1A1*28 allele typically causes only mild elevations in unconjugated bilirubin, yet this patient’s levels were significantly higher and more persistent than expected for Gilbert’s syndrome. Additionally, his partial response to phenobarbital paralleled that seen in CNS2, further complicating the diagnostic picture.
The absence of UGT1A1 coding mutations suggests the possibility of unidentified regulatory variants, modifier genes, or epigenetic factors that may contribute to enzyme deficiency beyond what is captured by current genetic assays.
Clinicians should be aware of the phenotypic overlap and diagnostic limitations in hereditary hyperbilirubinemia syndromes, especially in patients whose clinical course does not match genetic expectations.

Disclosures:
Doa'a Alkhader indicated no relevant financial relationships.
Sulieman Abdal Raheem indicated no relevant financial relationships.

Doa'a Alkhader, MD, Sulieman Abdal Raheem, MD. P1709 - Severe Unconjugated Hyperbilirubinemia With a Gilbert’s Genotype: An Unusual Presentation, ACG 2025 Annual Scientific Meeting Abstracts. Phoenix, AZ: American College of Gastroenterology.