Thalassemia comprises a group of inherited disorders characterized by impaired synthesis of globin chains, leading to increased erythrocyte fragility and hemolysis-induced unconjugated hyperbilirubinemia. In some patients, persistent hyperbilirubinemia occurs despite relatively stable hemolysis, potentially masking underlying comorbidities. A common cause of sustained hyperbilirubinemia is Gilbert's syndrome (GS), a benign condition caused by variants in the UGT1A1 gene that impair bilirubin conjugation. GS affects approximately 2–13% of the general population and typically requires no specific treatment. However, in individuals with thalassemia, coexisting GS is often underrecognized, resulting in frequent misdiagnoses and unnecessary treatment interventions. This study aims to investigate the prevalence and clinical characteristics of UGT1A1 variants in thalassemia patients, and to identify potential biomarkers and diagnostic thresholds for early recognition, thereby optimizing clinical management strategies.

We conducted a single-center cohort study at The First Affiliated Hospital of Zhejiang Chinese Medical University, Department of Hematology between December 2020 and February 2025. A total of 22 thalassemia patients with elevated unconjugated hyperbilirubinemia (>18.6 μmol/L, 1.5× the upper limit of normal) were enrolled, 14 (63.6%) were females. Among them, 15 individuals (68.18%) harbored UGT1A1 variants, including five distinct mutations: p.G71R in exon 1, p.P364L in exon 4, p.Y468D in exon 5, c.-3279T>G in the PBREM region, and UGT1A1*28 in the TATA box. Based on the genetic profiles, the 22 patients were divided into two groups: those with UGT1A1 variants (n=15) and those without (n=7). Laboratory parameters reflecting hemolysis severity, including RBC, HB, RET and LDH, were compared between the two groups, with no statistically significant differences observed (P=0.422, 0.797, 0.056 and 0.413, respectively). Notably, patients with UGT1A1 variants had significantly higher levels of total bilirubin (79.50 [49.50-119.40] vs. 40.60 [31.00-55.50] μmol/L, P = 0.002) and unconjugated bilirubin (71.60 [43.60-107.20] vs. 29.60 [20.80-43.10] μmol/L, P = 0.001). About half of patients with UGT1A1 variants were found to be on long-term bilirubin-lowering medications, which is inconsistent with current understanding and highlights the need for more accurate diagnostic strategies. ROC analysis for unconjugated bilirubin yielded an optimal cutoff value of 59.8 μmol/L for predicting GS, producing 100% sensitivity, 73% specificity, and 82% accuracy (AUC = 0.90, P = 0.003). Additionally, 46.7% of variant carriers had coexisting gallstones, compared to only one patient in the control group. Although the difference did not reach statistical significance due to the limited sample size, a trend towards a higher prevalence was observed among variant carriers (P = 0.193, OR = 5.25).

In summary, this study highlights the impact of UGT1A1 variants on bilirubin metabolism in thalassemia patients and identifies potential markers for the early detection of coexisting Gilbert's syndrome. To avoid misdiagnosis and overtreatment, we recommend that thalassemia patients with markedly elevated unconjugated bilirubin levels, especially those exceeding 59.8 μmol/L, undergo genetic screening for UGT1A1 variants.

This content is only available as a PDF.
2025
Sign in via your Institution