TY - JOUR

T1 - Optimal Hormone Replacement Therapy in Hypothyroidism

T2 - A Model Predictive Control Approach

AU - Wolff, Tobias M.

AU - Dietrich, Johannes W.

AU - Müller, Matthias A.

N1 - Funding Information: This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 948679).

PY - 2022/6/24

Y1 - 2022/6/24

N2 - In this paper, we address the problem of optimal thyroid hormone replacement strategy development for hypothyroid patients. This is challenging for the following reasons. First, it is difficult to determine the correct dosage leading to normalized serum thyroid hormone concentrations of a patient. Second, it remains unclear whether a levothyroxine L-T 4) monotherapy or a liothyronine/levothyroxine (L-T 3/L-T 4) combined therapy is more suitable to treat hypothyroidism. Third, the optimal intake frequency of L-T 3/L-T 4 is unclear. We address these issues by extending a mathematical model of the pituitary-thyroid feedback loop to be able to consider an oral intake of L-T 3/L-T 4. A model predictive controller (MPC) is employed to determine optimal dosages with respect to the thyroid hormone concentrations for each type of therapy. The results indicate that the L-T 3/L-T 4 combined therapy is slightly better (in terms of the achieved hormone concentrations) to treat hypothyroidism than the L-T 4 monotherapy. In case of a specific genetic variant, namely genotype CC in polymorphism rs2235544 of gene DIO1, the simulation results suggest that the L-T 4 monotherapy is better to treat hypothyroidism. In turn, when genotype AA is considered, the L-T 3/L-T 4 combined therapy is better to treat hypothyroidism. Furthermore, when genotype CC of polymorphism rs225014 (also referred to as c.274A>G or p.Thr92Ala) in the DIO2 gene is considered, the outcome of the L-T 3/L-T 4 combined therapy is better in terms of the steady-state hormone concentrations (for a triiodothyronine setpoint at the upper limit of the reference range of healthy individuals). Finally, the results suggest that two daily intakes of L-T 3 could be the best trade-off between stable hormone concentrations and inconveniences for the patient.

AB - In this paper, we address the problem of optimal thyroid hormone replacement strategy development for hypothyroid patients. This is challenging for the following reasons. First, it is difficult to determine the correct dosage leading to normalized serum thyroid hormone concentrations of a patient. Second, it remains unclear whether a levothyroxine L-T 4) monotherapy or a liothyronine/levothyroxine (L-T 3/L-T 4) combined therapy is more suitable to treat hypothyroidism. Third, the optimal intake frequency of L-T 3/L-T 4 is unclear. We address these issues by extending a mathematical model of the pituitary-thyroid feedback loop to be able to consider an oral intake of L-T 3/L-T 4. A model predictive controller (MPC) is employed to determine optimal dosages with respect to the thyroid hormone concentrations for each type of therapy. The results indicate that the L-T 3/L-T 4 combined therapy is slightly better (in terms of the achieved hormone concentrations) to treat hypothyroidism than the L-T 4 monotherapy. In case of a specific genetic variant, namely genotype CC in polymorphism rs2235544 of gene DIO1, the simulation results suggest that the L-T 4 monotherapy is better to treat hypothyroidism. In turn, when genotype AA is considered, the L-T 3/L-T 4 combined therapy is better to treat hypothyroidism. Furthermore, when genotype CC of polymorphism rs225014 (also referred to as c.274A>G or p.Thr92Ala) in the DIO2 gene is considered, the outcome of the L-T 3/L-T 4 combined therapy is better in terms of the steady-state hormone concentrations (for a triiodothyronine setpoint at the upper limit of the reference range of healthy individuals). Finally, the results suggest that two daily intakes of L-T 3 could be the best trade-off between stable hormone concentrations and inconveniences for the patient.

KW - automatic control

KW - combined therapy

KW - mathematical modeling

KW - model predictive control

KW - monotherapy

KW - thyroid homeostasis

UR - http://www.scopus.com/inward/record.url?scp=85134055484&partnerID=8YFLogxK

U2 - 10.3389/fendo.2022.884018

DO - 10.3389/fendo.2022.884018

M3 - Article

VL - 13

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

SN - 1664-2392

M1 - 884018

ER -