Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
Division of Endocrinology, Georgetown University, Washington, DC, United States.
Front Endocrinol (Lausanne). 2022 Jul 14;13:888429. doi: 10.3389/fendo.2022.888429. eCollection 2022.
A personalized simulation tool, p-THYROSIM, was developed (1) to better optimize replacement LT4 and LT4+LT3 dosing for hypothyroid patients, based on individual hormone levels, BMIs, and gender; and (2) to better understand how gender and BMI impact thyroid dynamical regulation over time in these patients.
p-THYROSIM was developed by (1) modifying and refining THYROSIM, an established physiologically based mechanistic model of the system regulating serum T3, T4, and TSH level dynamics; (2) incorporating sex and BMI of individual patients into the model; and (3) quantifying it with 3 experimental datasets and validating it with a fourth containing data from distinct male and female patients across a wide range of BMIs. For validation, we compared our optimized predictions with previously published results on optimized LT4 monotherapies. We also optimized combination T3+T4 dosing and computed unmeasured residual thyroid function (RTF) across a wide range of BMIs from male and female patient data.
Compared with 3 other dosing methods, the accuracy of p-THYROSIM optimized dosages for LT4 monotherapy was better overall (53% vs. 44%, 43%, and 38%) and for extreme BMI patients (63% vs. ~51% low BMI, 48% vs. ~36% and 22% for high BMI). Optimal dosing for combination LT4+LT3 therapy and unmeasured RTFs was predictively computed with p-THYROSIM for male and female patients in low, normal, and high BMI ranges, yielding daily T3 doses of 5 to 7.5 μg of LT3 combined with 62.5-100 μg of LT4 for women or 75-125 μg of LT4 for men. Also, graphs of steady-state serum T3, T4, and TSH concentrations vs. RTF (range 0%-50%) for untreated patients showed that neither BMI nor gender had any effect on RTF predictions for our patient cohort data. Notably, the graphs provide a means for estimating unmeasurable RTFs for individual patients from their hormone measurements before treatment.
p-THYROSIM can provide accurate monotherapies for male and female hypothyroid patients, personalized with their BMIs. Where combination therapy is warranted, our results predict that not much LT3 is needed in addition to LT4 to restore euthyroid levels, suggesting opportunities for further research exploring combination therapy with lower T3 doses and slow-releasing T3 formulations.
开发了个性化模拟工具 p-THYROSIM，用于根据个体激素水平、BMI 和性别更好地优化甲状腺功能减退患者的替代 LT4 和 LT4+LT3 剂量；（2）更好地了解性别和 BMI 如何影响这些患者随时间推移的甲状腺动态调节。
p-THYROSIM 通过以下方式开发：（1）修改和完善 THYROSIM，这是一种成熟的基于生理的甲状腺调节系统的机制模型，用于调节血清 T3、T4 和 TSH 水平的动态；（2）将个体患者的性别和 BMI 纳入模型；（3）用 3 个实验数据集进行量化，并使用包含来自不同 BMI 范围的男性和女性患者数据的第四个数据集进行验证。为了验证，我们将优化后的预测与先前关于优化 LT4 单疗法的发表结果进行了比较。我们还优化了 T3+T4 联合治疗的剂量，并计算了从男性和女性患者数据中不同 BMI 范围的未测量残余甲状腺功能（RTF）。
与其他 3 种剂量方法相比，p-THYROSIM 优化的 LT4 单疗法剂量总体上更为准确（53% 比 44%、43% 和 38%），且对于极端 BMI 患者更为准确（63% 比低 BMI 约 51%、48% 比高 BMI 约 36% 和 22%）。对于男性和女性患者在低、正常和高 BMI 范围内的 LT4+LT3 联合治疗的最佳剂量和未测量的 RTF，使用 p-THYROSIM 进行了预测计算，得出女性每日 LT3 剂量为 5 至 7.5μg，LT4 剂量为 62.5-100μg，男性 LT4 剂量为 75-125μg。此外，未治疗患者的稳态血清 T3、T4 和 TSH 浓度与 RTF（0%-50%）的关系图表明，BMI 和性别对我们患者队列数据的 RTF 预测均无影响。值得注意的是，这些图表提供了一种从治疗前的激素测量值估算个体患者不可测量的 RTF 的方法。
p-THYROSIM 可以为男性和女性甲状腺功能减退患者提供个体化的 BMI 优化单疗法。对于需要联合治疗的患者，我们的结果表明，除了 LT4 之外，LT3 的需求量不大即可恢复甲状腺功能正常水平，这表明有机会进一步研究探索使用低剂量 T3 和缓慢释放 T3 制剂的联合治疗。
