AIMTo evaluate the impact of genetic polymorphisms in uridine 5′-glucuronosylytansferases UGT1A1 and UGT1A3 and iodothyronine-deiodinases types 1 and 2 on levothyroxine (T4; 3,5,3′,5′-triiodo-L-thyronine) dose requirement for suppression of thyrotropin (TSH) secretion in patients with differentiated thyroid cancer (DTC). METHODSPatients (n = 268) submitted to total thyroidectomy and ablation by 131 I, under T4 therapy for at least 6 months were recruited in three public institutions in Brazil. Multivariate regression modelling was applied to assess the association of T4 dosing with polymorphisms in UGT1A1 (rs8175347), UGT1A3 (rs3806596 and rs1983023), DIO1 (rs11206244 and rs2235544) and DIO2 (rs225014 and rs12885300), demographic and clinical variables. RESULTSA regression model including UGT1A haplotypes, age, gender, body weight and serum TSH concentration accounted for 39% of the inter-individual variation in the T4 dosage. The association of T4 dose with UGT1A haplotype is attributed to reduced UGT1A1 expression and T4 glucuronidation in liver of carriers of low expression UGT1A1 rs8175347 alleles. The DIO1 and DIO2 genotypes had no influence of T4 dosage. CONCLUSIONUGT1A haplotypes associate with T4 dosage in DTC patients, but the effect accounts for only 2% of the total variability and recommendation of pre-emptive UGT1A genotyping is not warranted. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Inter-individual variation in L-thyroxine (T4) doses required for suppression of thyrotropin (TSH) in patients with differentiated thyroid cancer (DTC) is considerable and multifactorial. Age, gender and body weight explain part of this variability.• To exert its inhibitory control of TSH secretion, T4 must be deiodinated to T3 (3,5,3′-triiodo-L-thyronine) by iodothyronine-deiodinases types 1 (D1) and 2 (D2). Genetic polymorphisms in D1 and D2 have been associated with circulating levels of T3 and T4 and/or TSH, with controversial results. • T4 is metabolized in human liver by UDP-glucuronyltransferases, especially UGT1A1 and UGT1A3 and readily excreted into bile as thyroxine glucuronide. A common polymorphism in UGT1A1 (-53(TA)n, rs8175347) has been associated with the T4 dose required for TSH suppression in DTC patients. WHAT THIS STUDY ADDS• Multivariate regression modelling was applied to assess the association of T4 dosing in 268 Brazilian DTC patients with polymorphisms in DIO1 (rs11206244 and rs2235544), DIO2 (rs225014 and rs12885300), UGT1A1 (rs8175347) and UGT1A3 (rs3806596 and rs1983023), in addition to demographic and clinical variables. • A regression model including UGT1A haplotypes, age, gender, body weight and serum TSH concentration accounted for 39% of the inter-individual variation in the T4 dosage. The association of T4 dose with UGT1A haplotype is attributed to reduced UGT1A1 expression and T4 glucuronidation in liver of carriers of low expression UGT1A1 rs8175347 alleles. The DIO1 and DIO2 genotypes had no influence of T4 dosage.• UGT1A haplotypes associate with T4 dosage in DTC patients, but the ef...

There is a considerable interindividual variation in L-thyroxine [3,5,3',5'-tetraiodo-l-thyronine (T4)] dose required for thyrotropin (thyroid-stimulating hormone) suppression in patients with differentiated thyroid cancer. To investigate whether uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)-mediated T4 glucuronidation in liver affects T4 dose, we genotyped 101 patients for the common UGT1A1-53(TA)n polymorphism and compared T4 doses among patients having zero (5/6 and 6/6 genotypes), one (6/7 genotype), or two (7/7 and 7/8 genotypes) copies of the low-expression (TA)7 and (TA)8 alleles. A significant trend for decreasing T4 dose with increasing number of copies of (TA)7 and (TA)8 (P=0.037) and significant difference in T4 dose across the UGT1A1-53(TA)n genotypes (P=0.048) were observed, despite considerable overlap of T4 doses among different genotypes. These results are consistent with reduced T4 glucuronidation in patients with low-expression (TA)7 and (TA)8 alleles and provide the first evidence for association between UGT1A1-53(TA)n and T4-dose requirement for thyroid-stimulating hormone suppression in a natural clinical setting.