Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare, Chiba, Japan.
Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.
J Clin Endocrinol Metab. 2020 Feb 1;105(2). doi: 10.1210/clinem/dgz073.
Hashimoto's thyroiditis is the most common cause of hypothyroidism. Patients usually respond well to oral synthetic thyroxine (levothyroxine); however, for unknown reasons some individuals present with treatment-resistant Hashimoto thyroiditis. In cases of cancer and certain infectious diseases, the ATP binding cassette (ABC) transporters have been implicated in multidrug resistance, and we hypothesized and investigated a role of ABC transporters in drug-resistant Hashimoto's thyroiditis.
The patient whose case we report had a history of Hashimoto's thyroiditis, immune thrombocytopenia, and refractory hypertension, with varying treatment resistance to the oral medications prescribed for each condition. In order to establish or exclude a genetic basis for her illness, we examined the patient's gene expression profiles using peripheral blood leukocytes, and found that ABCG2/BCRPexpression was significantly high compared with healthy volunteers. Also, the increased daunomycin efflux capacity of our patient's lymphocytes was successfully inhibited by fumitremorgin C, a specific ABCG2/BCRP inhibitor, and the patient's level of thyroid-stimulating hormone increased by 248.6% after administration of intact levothyroxine tablets but decreased by 45.1% when tablets were crushed. Her average blood pressure decreased from 166.3/108.5 mmHg to 125.9/78.8 mmHg when switching from intact to crushed losartan tablets.
High expression and accelerated efflux transporter activity of ABCG2/BCRP in the small intestine are expected to contribute to the ineffectiveness of orally administered intact tablets in cases with treatment-resistant Hashimoto's thyroiditis, and crushed tablets can be more effective for some of these patients.
桥本甲状腺炎是甲状腺功能减退症最常见的原因。患者通常对口服合成甲状腺素（左旋甲状腺素）反应良好；然而，由于未知原因，一些个体表现出治疗抵抗性桥本甲状腺炎。在癌症和某些传染病的情况下，三磷酸腺苷结合盒（ABC）转运体已被牵连到多药耐药中，我们假设并研究了 ABC 转运体在治疗抵抗性桥本甲状腺炎中的作用。
我们报告的病例患者患有桥本甲状腺炎、免疫性血小板减少症和难治性高血压病史，每种疾病的口服药物治疗均存在不同程度的耐药性。为了确定或排除她疾病的遗传基础，我们使用外周血白细胞检查了患者的基因表达谱，发现与健康志愿者相比，ABCG2/BCRP 表达明显升高。此外，我们患者的淋巴细胞中增加的柔红霉素外排能力可被特定的 ABCG2/BCRP 抑制剂 fumitremorgin C 成功抑制，并且完整左甲状腺素片给药后患者的促甲状腺激素水平增加了 248.6%，而当片剂被压碎时，其水平降低了 45.1%。当从完整的转换为压碎的氯沙坦片剂时，她的平均血压从 166.3/108.5mmHg 降低到 125.9/78.8mmHg。
小肠中 ABCG2/BCRP 的高表达和加速外排转运体活性预计会导致治疗抵抗性桥本甲状腺炎患者口服完整片剂无效，而压碎片剂对其中一些患者可能更有效。
