ORIGINAL ARTICLE 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 Oshan Shrestha 1 & Alka Rani Khadwal 2 & Manphool Singhal 3 & Amita Trehan 4 & Deepak Bansal 4 & Richa Jain 4 & Arnab Pal 5 & Jasbir Kaur Hira 6 & Sanjeev Chhabra 6 & Pankaj Malhotra 2 & Reena Das 6 & Prashant Sharma 6 Received: 24 May 2020 /Accepted: 9 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020 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 syn- drome (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. Keywords Bilirubin . Gallstones . Gilbert syndrome . Jaundice . Liver disease . Thalassemia Introduction Thalassemias represent the commonest autosomal recessive disorders worldwide. They are characterized by reduced biosynthesis of one or more globin chain subunits of the he- moglobin tetramer, resulting in severe anemia in homozygous/compound heterozygous states. Classified ac- cording to the specific globin chain affected into α, β, δβ, Prior presentation: As a poster at the 109 th Annual Meeting of the United States and Canadian Academy of Pathologists (USCAP) at Los Angeles on March 3, 2020. * Prashant Sharma sharma.prashant@pgimer.edu.in; prashant.sh@gmail.com 1 Pathology Group of Departments, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India 2 Department of Internal Medicine, Adult Clinical Hematology Unit, PGIMER, Chandigarh, India 3 Department of Radiodiagnosis and Imaging, PGIMER, Chandigarh, India 4 Department of Pediatric Medicine, Pediatric Hematology/Oncology Unit, PGIMER, Chandigarh, India 5 Department of Biochemistry, PGIMER, Chandigarh, India 6 Department of Hematology, PGIMER, Level 5, Research Block A, Sector 12, Chandigarh 160012, India Annals of Hematology https://doi.org/10.1007/s00277-020-04176-2