Long-standing unconjugated hyperbilirubinaemia disproportionate to β-thalassaemia trait: unmasking coexisting homozygous UGT1A1*28 Gilbert syndrome through stepwise diagnostic reasoning

Gagan Harnathka; Swati Saini; Rahul Prasad Sah; Prakash Tendulkar; Ravi Kant

doi:10.18203/2320-6012.ijrms20264209

Authors

Gagan Harnathka Department of Internal Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India https://orcid.org/0009-0000-3382-8152
Swati Saini Department of Internal Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India https://orcid.org/0009-0006-2546-3505
Rahul Prasad Sah Department of Internal Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India https://orcid.org/0009-0007-9444-6140
Prakash Tendulkar Department of Internal Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India
Ravi Kant Department of Internal Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India https://orcid.org/0000-0003-1144-4478

DOI:

https://doi.org/10.18203/2320-6012.ijrms20264209

Keywords:

Unconjugated hyperbilirubinaemia, Gilbert syndrome, β-thalassaemia trait, Diagnostic reasoning

Abstract

A man in his late twenties presented with a 13-year history of icterus and dark urine, together with a short history of abdominal pain for 2.5 months. Biochemical evaluation demonstrated a total serum bilirubin of 9.46 mg/dL with an unconjugated fraction of 9.04 mg/dl, normal hepatocellular enzymes, and splenomegaly on abdominal ultrasonography. The peripheral blood film showed a microcytic, hypochromic picture with anisopoikilocytosis and mild red-cell fragmentation. Whole-exome sequencing identified a heterozygous pathogenic HBB c.92+5G>C splice-donor variant (IVS-I-5 G>C), confirming β-thalassaemia carrier status. The magnitude of unconjugated hyperbilirubinaemia was, however, disproportionate to trait alone, prompting a targeted search for a coexisting inherited disorder of bilirubin conjugation. UGT1A1 promoter fragment analysis revealed a homozygous (TA)7/(TA)7 (*28/*28) genotype, confirming Gilbert syndrome. Recognising the coexistence of the two disorders, rather than accepting a single incomplete diagnosis, altered counselling, drug-safety advice and reproductive planning. This case underscores that when unconjugated hyperbilirubinaemia is disproportionate to the demonstrable degree of haemolysis, a second inherited disorder of bilirubin metabolism should be actively sought.

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