Home Precision medicine in hypothyroidism: an engineering approach to individualized levothyroxine dosing
Article
Licensed
Unlicensed Requires Authentication

Precision medicine in hypothyroidism: an engineering approach to individualized levothyroxine dosing

  • Davide Manca ORCID logo EMAIL logo
Published/Copyright: April 2, 2025
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Physical Sciences Reviews
From the journal Physical Sciences Reviews Volume 10 Issue 4

Abstract

This chapter presents an innovative engineering approach to precision medicine in the treatment of hypothyroidism. By leveraging mathematical modeling of the hypothalamic-pituitary-thyroid (HPT) axis, a novel algorithm, PzeroT, is developed for individualized optimization of levothyroxine dosing. The chapter explores the HPT axis physiology and pathology and the current state-of-the-art in hypothyroidism treatment. The core contribution lies in implementing a compartmental model of the HPT axis, which is the foundation for the PzeroT algorithm. This model-based approach enables the prediction of the optimal levothyroxine dose tailored to individual patient characteristics. The chapter further validates the PzeroT algorithm using real patient case studies, demonstrating its potential to improve hypothyroidism management by reducing treatment times and enhancing dose accuracy compared to standard clinical practices. This work, at the intersection of chemical engineering and medicine, exemplifies how engineering principles can advance precision medicine and paves the way for more personalized and effective treatment of thyroid disorders.

Keywords: thyroid disorders; endocrine system modeling; hormone replacement therapy; dose optimization algorithm; multi-compartmental approach; patient-specific treatment
Corresponding author: Davide Manca, PSE-Lab, Process Systems Engineering Laboratory, Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy, E-mail:

Acknowledgments

The author acknowledges the valuable contribution of Federico Appiani and Giovanni Colombo, master’s degree students in Chemical Engineering at Politecnico di Milano, who worked with outstanding commitment and dedication to the discovery of thyroid pathologies and the modeling of the HPT axis, with particular attention to the condition of hypothyroidism and the identification of the optimal dose of levothyroxine.

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: The author has accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: The author states no conflict of interest.

  6. Research funding: None declared.

  7. Data availability: Data available on request from the author.

References

1. Hall, JE, Guyton, AC. Guyton and Hall Textbook of medical physiology. Saunders/Elsevier; 2011. Available from: https://books.google.it/books?id=X491kgEACAAJ.Search in Google Scholar

2. Singer, C. A short history of anatomy from the Greeks to Harvey. Dover Publications; 1957. Available from: https://books.google.it/books?id=w7MtTIVPML0C.Search in Google Scholar

3. Abbiati, RA, Savoca, A, Manca, D. Chapter 2 – an engineering oriented approach to physiologically based pharmacokinetic and pharmacodynamic modeling. In: Manca, D, editor. Computer Aided Chemical Engineering. Amsterdam, Netherlands: Elsevier; 2018, vol 42:37–63 pp.10.1016/B978-0-444-63964-6.00002-7Search in Google Scholar

4. Di Muria, M, Lamberti, G, Titomanlio, G. Physiologically based pharmacokinetics: a simple, all purpose model. Ind Eng Chem Res 2010;49:2969–78. https://doi.org/10.1021/ie9015717.Search in Google Scholar

5. Standring, S, Borley, NR. Gray’s anatomy: the anatomical basis of clinical practice. Churchill Livingstone/Elsevier; 2008. Available from: https://books.google.it/books?id=kvhkPQAACAAJ.Search in Google Scholar

6. Rivolta, CM, Targovnik, HM. Molecular advances in thyroglobulin disorders. Clinica Chimica Acta; J Int Fed Clin Chem 2006;374:8–24. https://doi.org/10.1016/J.CCA.2006.05.043.Search in Google Scholar PubMed

7. Silverthorn, J, Bruce, R, Ober, WC, Ober, CE, Impagliazzo, A. Human physiology: an integrated approach, 8th ed. Indianapolis, IN: Pearson Education, Inc.; 2019.Search in Google Scholar

8. Benvenga, S, Robbins, J. Altered thyroid hormone binding to plasma lipoproteins in hypothyroidism. Thyroid 1996;6:595–600. https://doi.org/10.1089/thy.1996.6.595.Search in Google Scholar PubMed

9. Schussler, GC. The thyroxine-binding proteins. Thyroid 2000;10:141–9. https://doi.org/10.1089/thy.2000.10.141.Search in Google Scholar PubMed

10. Nillni, EA. Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs. Front Neuroendocrinol 2010;31:134–56. https://doi.org/10.1016/j.yfrne.2010.01.001.Search in Google Scholar PubMed PubMed Central

11. Reichlin, S, Utiger, RD. Regulation of the pituitary-thyroid axis in man: relationship of TSH concentration to concentration of free and total thyroxine in plasma. J Clin Endocrinol Metab 1967;27:251–5. https://doi.org/10.1210/jcem-27-2-251.Search in Google Scholar PubMed

12. Treier, M, Rosenfeld, MG. The hypothalamic-pituitary axis; co-development of two organs. Curr Opin Cell Biol 1996;8:833–43. https://doi.org/10.1016/s0955-0674(96)80085-8.Search in Google Scholar PubMed

13. Werner, SC, Ingbar, SH, Braverman, LE, Utiger, RD. Werner & Ingbar’s the thyroid a fundamental and clinical text, 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. Available from: http://lib.ugent.be/catalog/ebk01:1000000000753717.Search in Google Scholar

14. Greenspan, SL, Klibansk, A, Schqenfeld, D, Ridgway, EC. Pulsatile secretion of thyrotropin in man. J Clin Endocrinol Metab 1986;63:661–8. https://doi.org/10.1210/jcem-63-3-661.Search in Google Scholar PubMed

15. Garmendia Madariaga, A, Santos Palacios, S, Guillén-Grima, F, Galofré, JC, Ledesma, F. Incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab 2014;99:923–31. https://doi.org/10.1210/jc.2013-2409.Search in Google Scholar PubMed

16. Vanderpump, MPJ. The epidemiology of thyroid disease. Br Med Bull 2011;99:39–51. https://doi.org/10.1093/bmb/ldr030.Search in Google Scholar PubMed

17. Taylor, PN, Albrecht, D, Scholz, A, Gutierrez-Buey, G, Lazarus, JH, Dayan, CM, et al.. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol 2018;14:301–16. https://doi.org/10.1038/nrendo.2018.18.Search in Google Scholar PubMed

18. Cooper, DS, Sipos, J. Medical management of thyroid disease. Boca Raton: CRC Press; 2018.10.1201/9781351267489Search in Google Scholar

19. Flynn, RWV, MacDonald, TM, Morris, AD, Jung, RT, Leese, GP. The thyroid epidemiology, audit, and research study: thyroid dysfunction in the general population. J Clin Endocrinol Metab 2004;89:3879–84. https://doi.org/10.1210/jc.2003-032089.Search in Google Scholar PubMed

20. Vanderpump, MPJ, Tunbrldge, WMG, French, J, Appleton, D, Bates, D, Clark, F, et al.. The incidence of thyroid disorders in the community: a twenty‐year follow‐up of the Whickham Survey. Clin Endocrinol 1995;43:55–68. https://doi.org/10.1111/j.1365-2265.1995.tb01894.x.Search in Google Scholar PubMed

21. Samuels, MH, Ridgway, EC. Central hypothyroidism. Endocrinol Metab Clin N Am 1992;21:903–19. https://doi.org/10.1016/s0889-8529(18)30194-4.Search in Google Scholar

22. Staub, JJ, Althaus, BU, Engler, H, Ryff, AS, Trabucco, P, Marquardt, K, et al.. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med 1992;92:631–42. https://doi.org/10.1016/0002-9343(92)90782-7.Search in Google Scholar PubMed

23. Roberts, CG, Ladenson, PW. Hypothyroidism. Lancet 2004;363. https://doi.org/10.1016/s0140-6736(04)15696-1.Search in Google Scholar PubMed

24. Baloch, Z, Carayon, P, Conte-Devolx, B, Demers, LM, Feldt-Rasmussen, U, Henry, J-F, et al.. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid: Off J Am Thyroid Assoc 2003;13:3–126. https://doi.org/10.1089/105072503321086962.Search in Google Scholar PubMed

25. Means, JH. Relative frequency of the several symptoms and signs of myxedema. The Thyroid and its Disease, 2nd ed. Philadelphia, PA: JB Lippencott; 1948:232–4 pp.Search in Google Scholar

26. Zulewski, H, Müller, B, Exer, P, Miserez, AR, Staub, J-J. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82:771–6.10.1210/jc.82.3.771Search in Google Scholar

27. Hollowell, JG, Staehling, NW, Flanders, WD, Hannon, WH, Gunter, EW, Spencer, CA, et al.. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): national health and nutrition examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489–99. https://doi.org/10.1210/jcem.87.2.8182.Search in Google Scholar PubMed

28. Ho, PY, Lisowski, FP. Brief history of Chinese medicine and its influence, A. Singapore: World Scientific Publishing Company; 1997.10.1142/9789812830074Search in Google Scholar

29. Murray, GR. Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. Br Med J 1891;2:796. https://doi.org/10.1136/bmj.2.1606.796.Search in Google Scholar PubMed PubMed Central

30. Kendall, EC. The isolation in crystalline form of the compound containing iodine which occurs in the thyroid: its chemical nature and physiological activity. Trans Assoc Am Phys 1915;30:420–49.10.1001/jama.1915.02570510018005Search in Google Scholar

31. Chalmers, JR, Dickson, GT, Elks, J, Hems, BA. 715. The synthesis of thyroxine and related substances. Part V. A synthesis of L-thyroxine from L-tyrosine. J Chem Soc (Resumed) 1949:3424–33. https://doi.org/10.1039/jr9490003424.Search in Google Scholar

32. Colucci, P, Yue, CS, Ducharme, M, Benvenga, S. A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. Eur Endocrinol 2013;9:40. https://doi.org/10.17925/ee.2013.09.01.40.Search in Google Scholar

33. Izumi, M, Larsen, PR. Triiodothyronine, thyroxine, and iodine in purified thyroglobulin from patients with Graves’ disease. J Clin Investig 1977;59:1105–12. https://doi.org/10.1172/jci108734.Search in Google Scholar PubMed PubMed Central

34. Carr, D, McLeod, DT, Parry, G, Thornes, HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol 1988;28:325–33. https://doi.org/10.1111/j.1365-2265.1988.tb01219.x.Search in Google Scholar PubMed

35. Gottwald-Hostalek, U, Razvi, S. Getting the levothyroxine (LT4) dose right for adults with hypothyroidism: opportunities and challenges in the use of modern LT4 preparations. Curr Med Res Opin 2022;38:1865–70. https://doi.org/10.1080/03007995.2022.2071059.Search in Google Scholar PubMed

36. Roos, A, Linn-Rasker, SP, van Domburg, RT, Tijssen, JP, Berghout, A. The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med 2005;165:1714–20. https://doi.org/10.1001/archinte.165.15.1714.Search in Google Scholar PubMed

37. Lebbink, CA, Links, TP, Czarniecka, A, Dias, RP, Elisei, R, Izatt, L, et al.. 2022 European Thyroid Association Guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma. Eur Thyroid J 2022;11. https://doi.org/10.1530/etj-22-0146.Search in Google Scholar

38. Burmeister, LA, Goumaz, MO, Mariash, CN, Oppenheimer, JH. Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab 1992;75:344–50. https://doi.org/10.1210/jcem.75.2.1639933.Search in Google Scholar PubMed

39. Santini, F, Pinchera, A, Marsili, A, Ceccarini, G, Castagna, MG, Valeriano, R, et al.. Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases. J Clin Endocrinol Metab 2005;90:124–7. https://doi.org/10.1210/jc.2004-1306.Search in Google Scholar PubMed

40. Devdhar, M, Drooger, R, Pehlivanova, M, Singh, G, Jonklaas, J. Levothyroxine replacement doses are affected by gender and weight, but not age. Thyroid 2011;21:821–7. https://doi.org/10.1089/thy.2011.0029.Search in Google Scholar PubMed PubMed Central

41. Raverot, V, Bonjour, M, Abeillon du Payrat, J, Perrin, P, Roucher-Boulez, F, Lasolle, H, et al.. Age-and sex-specific TSH upper-limit reference intervals in the general French population: there is a need to adjust our actual practices. J Clin Med 2020;9:792. https://doi.org/10.3390/jcm9030792.Search in Google Scholar PubMed PubMed Central

42. Rosenbaum, RL, Barzel, US. Levothyroxine replacement dose for primary hypothyroidism decreases with age. Ann Intern Med 1982;96:53–5. https://doi.org/10.7326/0003-4819-96-1-53.Search in Google Scholar PubMed

43. Walsh, JP. Thyroid function across the lifespan: do age-related changes matter? Endocrinol Metabol 2022;37:208. https://doi.org/10.3803/enm.2022.1463.Search in Google Scholar

44. Eligar, V, Taylor, PN, Okosieme, OE, Leese, GP, Dayan, CM. Thyroxine replacement: a clinical endocrinologist’s viewpoint. Ann Clin Biochem 2016;53:421–33. https://doi.org/10.1177/0004563216642255.Search in Google Scholar PubMed

45. Hays, MT. Localization of human thyroxine absorption. Thyroid 1991;1:241–8. https://doi.org/10.1089/thy.1991.1.241.Search in Google Scholar PubMed

46. Wenzel, KW, Kirschsieper, HE. Aspects of the absorption of oral L-thyroxine in normal man. Metabolism 1977;26:1–8. https://doi.org/10.1016/0026-0495(77)90121-4.Search in Google Scholar PubMed

47. Verhaert, N, Poorten, VV, Delaere, P, Bex, M, Debruyne, F. Levothyroxine replacement therapy after thyroid surgery. B ENT 2006;3:129.Search in Google Scholar

48. Mandel, SJ, Brent, GA, Larsen, PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993;119:492–502. https://doi.org/10.7326/0003-4819-119-6-199309150-00009.Search in Google Scholar PubMed

49. Cruz-Loya, M, Chu, B, Jonklaas, J, Schneider, D, DiStefano, JJ. Optimized replacement T4 and T4+T3 dosing in male and female hypothyroid patients with different BMIs using a personalized mechanistic model of thyroid hormone regulation dynamics. Front Endocrinol 2022;13. https://doi.org/10.3389/fendo.2022.888429.Search in Google Scholar PubMed PubMed Central

50. Hoermann, R, Midgley, JEM, Larisch, R, Dietrich, JWC. Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine. PLoS One 2017;12:e0187232. https://doi.org/10.1371/journal.pone.0187232.Search in Google Scholar PubMed PubMed Central

51. DiStefano, JJ, Mak, PH. On model and data requirements for determining the bioavailability of oral therapeutic agents: application to gut absorption of thyroid hormones. Am J Physiol Regul Integr Comp Physiol 1979;236:R137–41. https://doi.org/10.1152/ajpregu.1979.236.3.r137.Search in Google Scholar PubMed

52. DiStefano, JJ. A model of the normal thyroid hormone glandular secretion mechanism. J Theor Biol 1969;22:412–17. https://doi.org/10.1016/0022-5193(69)90013-7.Search in Google Scholar PubMed

53. DiStefano, JJ, Jonklaas, J. Predicting optimal combination LT4+ LT3 therapy for hypothyroidism based on residual thyroid function. Front Endocrinol 2019;10:746. https://doi.org/10.3389/fendo.2019.00746.Search in Google Scholar PubMed PubMed Central

54. DiStefano, JJ, Stear, EB. Neuroendocrine control of thyroid secretion in living systems: a feedback control system model. Bull Math Biophys 1968;30:3–26. https://doi.org/10.1007/bf02476936.Search in Google Scholar PubMed

55. Eisenberg, M, Samuels, M, DiStefano III, JJ. L-T4 bioequivalence and hormone replacement studies via feedback control simulations. Thyroid 2006;16:1279–92. https://doi.org/10.1089/thy.2006.0144.Search in Google Scholar PubMed

56. Goutelle, S, Maurin, M, Rougier, F, Barbaut, X, Bourguignon, L, Ducher, M, et al.. The Hill equation: a review of its capabilities in pharmacological modelling. Fund Clin Pharmacol 2008;22:633–48. https://doi.org/10.1111/j.1472-8206.2008.00633.x.Search in Google Scholar PubMed

57. Caron, P, Grunenwald, S, Persani, L, Borson-Chazot, F, Leroy, R, Duntas, L. Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults. Rev Endocr Metab Disord 2021:1–21. https://doi.org/10.1007/s11154-021-09691-9.Search in Google Scholar PubMed PubMed Central

58. Eisenberg, M, Santini, F, Marsili, A, Pinchera, A, DiStefano III, JJ. TSH regulation dynamics in central and extreme primary hypothyroidism. Thyroid 2010;20:1215–28. https://doi.org/10.1089/thy.2009.0349.Search in Google Scholar PubMed PubMed Central

59. Eisenberg, M, Samuels, M, DiStefanoIIIJJ. Extensions, validation, and clinical applications of a feedback control system simulator of the hypothalamo-pituitary-thyroid axis. Thyroid 2008;18:1071–85. https://doi.org/10.1089/thy.2007.0388.Search in Google Scholar PubMed PubMed Central

60. Manca, D, Appiani, F, Colombo, G. Optimal dosing of thyroid hormones in hypothyroid patients with an individualized compartmental model. Comput Aided Chem Eng 2023;52:2643–8. https://doi.org/10.1016/b978-0-443-15274-0.50420-0.Search in Google Scholar

61. Van Deventer, HE, Mendu, DR, Remaley, AT, Soldin, SJ. Inverse log-linear relationship between thyroid-stimulating hormone and free thyroxine measured by direct analog immunoassay and tandem mass spectrometry. Clin Chem 2011;57:122–7. https://doi.org/10.1373/clinchem.2010.154088.Search in Google Scholar PubMed

62. McNeil, AR, Stanford, PE. Reporting thyroid function tests in pregnancy. Clin Biochem Rev 2015;36:109.Search in Google Scholar
Received: 2024-10-15
Accepted: 2025-02-19
Published Online: 2025-04-02

© 2025 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Inhaled aerosols as carriers of pulmonary medicines and the limitations of in vitro–in vivo correlation (IVIVC) methods
  4. Analysis of an automated solar panel cleaning robot on photovoltaics (PV) module frames with composites materials
  5. Mechanical and thermal properties of graphene reinforced poly (lactic acid) composites for battery casing in electric vehicles
  6. Precision medicine in hypothyroidism: an engineering approach to individualized levothyroxine dosing
  7. Advancements in composite materials for energy harvesting
  8. Model-based dose selection for gene therapy for haemophilia B
https://doi.org/10.1515/psr-2024-0060
Keywords for this article
thyroid disorders; endocrine system modeling; hormone replacement therapy; dose optimization algorithm; multi-compartmental approach; patient-specific treatment

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Inhaled aerosols as carriers of pulmonary medicines and the limitations of in vitro–in vivo correlation (IVIVC) methods
  4. Analysis of an automated solar panel cleaning robot on photovoltaics (PV) module frames with composites materials
  5. Mechanical and thermal properties of graphene reinforced poly (lactic acid) composites for battery casing in electric vehicles
  6. Precision medicine in hypothyroidism: an engineering approach to individualized levothyroxine dosing
  7. Advancements in composite materials for energy harvesting
  8. Model-based dose selection for gene therapy for haemophilia B
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 19.11.2025 from https://www.degruyterbrill.com/document/doi/10.1515/psr-2024-0060/pdf
Scroll to top button