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A high frequency of Gilbert syndrome (UGT1A1*28/*28) and associated hyperbilirubinemia but not cholelithiasis in adolescent and adult north Indian patients with transfusion-dependent β-thalassemia

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Abstract

Hyperbilirubinemia and pigment gallstones are frequent complications in transfusion-dependent β-thalassemia (TDβT) patients. Bilirubin production and clearance are determined by genetic as well as environmental variables like ineffective erythropoiesis, hemolysis, infection-induced hepatic injury, and drug- or iron-related toxicities. We studied the frequency of the Gilbert syndrome (GS), a common hereditary cause of hyperbilirubinemia in 102 TDβT patients aged 13–43 years (median 26 years). Total and unconjugated hyperbilirubinemia were frequent (81.4% and 84.3% patients respectively). Twenty (19.6%) patients showed total bilirubin > 3.0 mg/dL; 53 (51.9%) had an elevation of either alanine or aspartate aminotransferase, or alkaline phosphatase liver enzymes. Nineteen (18.6% of the 92 tested) were positive for hepatitis B or C, or HIV. The mean total and unconjugated bilirubin levels and AST, ALT, and ALP levels in patients positive for hepatitis B or C were not significantly different from negative cases. Eighteen patients (17.7%) had GS: homozygous (TA)7/7 UGT1A1 promoter motif (the *28/*28 genotype), 48 (47.1%) were heterozygous (TA)6/7. Total + unconjugated bilirubin rose significantly with the (TA)7 allele dose. Fourteen (13.7%) patients had gallstones. There was no significant difference in total/unconjugated bilirubin in patients with/without gallstones and no significant differences in frequencies of gallstones within the three UGT1A1 genotypes. This largest study in Indian TDβT patients suggests that GS should be excluded in TDβT cases where jaundice remains unexplained after treatable causes like infections, chelator toxicity, or transfusion-related hemolysis are excluded. GS was not associated with gallstones, possibly due to a lower incidence of cholelithiasis overall, a younger age cohort, or other environmental factors.

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Acknowledgments

The authors acknowledge the nursing and administrative staff of the Thalassemia Day Care Centre, Pediatric Hematology/Oncology Unit, Advanced Pediatric Centre and the Thalassemia/Hemoglobinopathy Pediatric-to-Adult Crossover Clinic, Adult Clinical Hematology Unit, Department of Internal Medicine, PGIMER, Chandigarh.

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Funding

Parts of this work were supported by the Medical Education and Research Cell, PGIMER, Chandigarh, and the Department of Biotechnology, Government of India (grant no. BT/PR26461/MED/12/821/2018).

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Authors and Affiliations

  1. Pathology Group of Departments, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

    Oshan Shrestha

  2. Department of Internal Medicine, Adult Clinical Hematology Unit, PGIMER, Chandigarh, India

    Alka Rani Khadwal & Pankaj Malhotra

  3. Department of Radiodiagnosis and Imaging, PGIMER, Chandigarh, India

    Manphool Singhal

  4. Department of Pediatric Medicine, Pediatric Hematology/Oncology Unit, PGIMER, Chandigarh, India

    Amita Trehan, Deepak Bansal & Richa Jain

  5. Department of Biochemistry, PGIMER, Chandigarh, India

    Arnab Pal

  6. Department of Hematology, PGIMER, Level 5, Research Block A, Sector 12, Chandigarh, 160012, India

    Jasbir Kaur Hira, Sanjeev Chhabra, Reena Das & Prashant Sharma

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  1. Oshan Shrestha
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  2. Alka Rani Khadwal
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Correspondence to Prashant Sharma.

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This research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013). It was approved by the authors’ Institutional Review Board.

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Prior presentation: As a poster at the 109th Annual Meeting of the United States and Canadian Academy of Pathologists (USCAP) at Los Angeles on March 3, 2020.

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Shrestha, O., Khadwal, A.R., Singhal, M. et al. A high frequency of Gilbert syndrome (UGT1A1*28/*28) and associated hyperbilirubinemia but not cholelithiasis in adolescent and adult north Indian patients with transfusion-dependent β-thalassemia. Ann Hematol 99, 2019–2026 (2020). https://doi.org/10.1007/s00277-020-04176-2

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