SimThyr

Last updated
Original author(s) Johannes W. Dietrich, Ulla Mitzdorf, Renate Pickardt, Rudolf Hoermann, John E. M. Midgley
Developer(s) Ruhr University Bochum
Initial release2002(21 years ago) (2002)
Stable release
4.0.6 / April 23, 2022;19 months ago (2022-04-23)
Repository
Written in Pascal and Object Pascal
Operating system macOS, Windows and Linux
Platform PowerPC, IA-32, x86-64 and ARM,
m68k (legacy versions only)
Available inBritish English, German (SimThyr 2.0 or older only)
Type Free scientific application software for physiological simulations
License BSD-style
Website simthyr.sourceforge.net   OOjs UI icon edit-ltr-progressive.svg

SimThyr is a free continuous dynamic simulation program for the pituitary-thyroid feedback control system. [1] The open-source program is based on a nonlinear model of thyroid homeostasis. [2] [3] [4] In addition to simulations in the time domain the software supports various methods of sensitivity analysis. Its simulation engine is multi-threaded and supports multiple processor cores. SimThyr provides a GUI, which allows for visualising time series, modifying constant structure parameters of the feedback loop (e.g. for simulation of certain diseases), storing parameter sets as XML files (referred to as "scenarios" in the software) and exporting results of simulations in various formats that are suitable for statistical software. SimThyr is intended for both educational purposes and in-silico research. [4] [5]

Contents

Mathematical model

The underlying model of thyroid homeostasis is based on fundamental biochemical, physiological and pharmacological principles, e.g. Michaelis-Menten kinetics, non-competitive inhibition and empirically justified kinetic parameters. [1] The model has been validated in healthy controls and in cohorts of patients with hypothyroidism and thyrotoxicosis. [6]

Scientific uses

SimThyr used for educational purposes in a computer resource centre SimThyr in computer resource centre.jpg
SimThyr used for educational purposes in a computer resource centre

Multiple studies have employed SimThyr for in silico research on the control of thyroid function. [7] [8]

The original version was developed to check hypotheses about the generation of pulsatile TSH release. [9] Later and expanded versions of the software were used to develop the hypothesis of the TSH-T3 shunt in the hypothalamus-pituitary-thyroid axis, [10] to assess the validity of calculated parameters of thyroid homeostasis (including SPINA-GT and SPINA-GD) [11] [12] and to study allostatic mechanisms leading to non-thyroidal illness syndrome. [13] [14]

SimThyr was also used to show that the release rate of thyrotropin is controlled by multiple factors other than T4 and that the relation between free T4 and TSH may be different in euthyroidism, hypothyroidism and thyrotoxicosis. [15]

Public perception, reception and discussion of the software

SimThyr is free and open-source software. This ensures the source code to be available, which facilitates scientific discussion and reviewing of the underlying model. [16] [17] Additionally, the fact that it is freely available may result in economical benefits. [18] [19]

The software provides an editor that enables users to modify most structure parameters of the information processing structure. [20] This functionality fosters simulation of several functional diseases of the thyroid and the pituitary gland. Parameter sets may be stored as MIRIAM- and MIASE-compliant XML files.

On the other hand, the complexity of the user interface and the lack of the ability to model treatment effects have been criticized. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Hypothyroidism</span> Endocrine disease

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Levothyroxine</span> Thyroid hormone

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken orally (by mouth) or given by intravenous injection. Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism, or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.

Allostasis (/ˌɑːloʊˈsteɪsɪs/) is a physiological mechanism of regulation in which the human body anticipates and adjusts its energy use according to environmental demands. First proposed by Peter Sterling and Joseph Eyer in 1988, the concept of allostasis shifts the focus away from the body maintaining a rigid internal set-point, as in homeostasis, to the brain's ability and role to interpret environmental stress and coordinate changes in the body using neurotransmitters, hormones, and other signaling mechanisms. Allostasis is believed to be not only involved in the body's stress response and adaptation to chronic stress; it may also have a role in the regulation of the immune system as well as in the development of chronic diseases such as hypertension and diabetes.

<span class="mw-page-title-main">Allostatic load</span> Wear and tear on the body due to stress

Allostatic load is "the wear and tear on the body" which accumulates as an individual is exposed to repeated or chronic stress. The term was coined by Bruce McEwen and Eliot Stellar in 1993. It represents the physiological consequences of chronic exposure to fluctuating or heightened neural or neuroendocrine response which results from repeated or prolonged chronic stress.

<span class="mw-page-title-main">Thyrotropin receptor</span> Mammalian protein found in Homo sapiens

The thyrotropin receptor is a receptor that responds to thyroid-stimulating hormone and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily of integral membrane proteins and is coupled to the Gs protein.

Orosomucoid (ORM) or alpha-1-acid glycoprotein is an acute phase protein found in plasma. It is an alpha-globulin glycoprotein and is modulated by two polymorphic genes. It is synthesized primarily in hepatocytes and has a normal plasma concentration between 0.6–1.2 mg/mL. Plasma levels are affected by pregnancy, burns, certain drugs, and certain diseases, particularly HIV.

<span class="mw-page-title-main">Hypothalamic–pituitary–thyroid axis</span> Part of the neuroendocrine system

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

<span class="mw-page-title-main">Reverse triiodothyronine</span> Chemical compound

Reverse triiodothyronine (3,3′,5′-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3′ triiodothyronine, T3).

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences, and impaired assay characteristics in critical illness.

Myxedema coma is an extreme or decompensated form of hypothyroidism and while uncommon, is potentially lethal. A person may have laboratory values identical to a "normal" hypothyroid state, but a stressful event precipitates the myxedema coma state, usually in the elderly. Primary symptoms of myxedema coma are altered mental status and low body temperature. Low blood sugar, low blood pressure, hyponatremia, hypercapnia, hypoxia, slowed heart rate, and hypoventilation may also occur. Myxedema, although included in the name, is not necessarily seen in myxedema coma. Coma is also not necessarily seen in myxedema coma, as patients may be obtunded without being comatose.

Hypothalamic disease is a disorder presenting primarily in the hypothalamus, which may be caused by damage resulting from malnutrition, including anorexia and bulimia eating disorders, genetic disorders, radiation, surgery, head trauma, lesion, tumour or other physical injury to the hypothalamus. The hypothalamus is the control center for several endocrine functions. Endocrine systems controlled by the hypothalamus are regulated by antidiuretic hormone (ADH), corticotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, oxytocin, all of which are secreted by the hypothalamus. Damage to the hypothalamus may impact any of these hormones and the related endocrine systems. Many of these hypothalamic hormones act on the pituitary gland. Hypothalamic disease therefore affects the functioning of the pituitary and the target organs controlled by the pituitary, including the adrenal glands, ovaries and testes, and the thyroid gland.

<span class="mw-page-title-main">Thyroid's secretory capacity</span>

Thyroid's secretory capacity is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit.

The sum activity of peripheral deiodinases is the maximum amount of triiodothyronine produced per time-unit under conditions of substrate saturation. It is assumed to reflect the activity of deiodinases outside the central nervous system and other isolated compartments. GD is therefore expected to reflect predominantly the activity of type I deiodinase.

Pulsatile secretion is a biochemical phenomenon observed in a wide variety of cell and tissue types, in which chemical products are secreted in a regular temporal pattern. The most common cellular products observed to be released in this manner are intercellular signaling molecules such as hormones or neurotransmitters. Examples of hormones that are secreted pulsatilely include insulin, thyrotropin, TRH, gonadotropin-releasing hormone (GnRH) and growth hormone (GH). In the nervous system, pulsatility is observed in oscillatory activity from central pattern generators. In the heart, pacemakers are able to work and secrete in a pulsatile manner. A pulsatile secretion pattern is critical to the function of many hormones in order to maintain the delicate homeostatic balance necessary for essential life processes, such as development and reproduction. Variations of the concentration in a certain frequency can be critical to hormone function, as evidenced by the case of GnRH agonists, which cause functional inhibition of the receptor for GnRH due to profound downregulation in response to constant (tonic) stimulation. Pulsatility may function to sensitize target tissues to the hormone of interest and upregulate receptors, leading to improved responses. This heightened response may have served to improve the animal's fitness in its environment and promote its evolutionary retention.

<span class="mw-page-title-main">3,5-Diiodothyronine</span> Chemical compound

3,5-Diiodothyronine (3,5-T2) is an active thyroid hormone within the class of iodothyronines. It has two iodine atoms at positions 3 and 5 of its inner ring.

<span class="mw-page-title-main">Jostel's TSH index</span>

Jostel's TSH index, also referred to as Jostel's thyrotropin index or Thyroid Function index (TFI), is a method for estimating the thyrotropic function of the anterior pituitary lobe in a quantitative way. The equation has been derived from the logarithmic standard model of thyroid homeostasis. In a paper from 2014 further study was suggested to show if it is useful, but the 2018 guideline by the European Thyroid Association for the diagnosis of uncertain cases of central hypothyroidism regarded it as beneficial. It is also recommended for purposes of differential diagnosis in the sociomedical expert assessment.

The Thyrotroph Thyroid Hormone Sensitivity Index is a calculated structure parameter of thyroid homeostasis. It was originally developed to deliver a method for fast screening for resistance to thyroid hormone. Today it is also used to get an estimate for the set point of thyroid homeostasis, especially to assess dynamic thyrotropic adaptation of the anterior pituitary gland, including non-thyroidal illnesses.

The Thyroid Feedback Quantile-based Index (TFQI) is a calculated parameter for thyrotropic pituitary function. It was defined to be more robust to distorted data than established markers including Jostel's TSH index (JTI) and the thyrotroph thyroid hormone sensitivity index (TTSI).

References

  1. 1 2 Dietrich, JW; Landgrafe, G; Fotiadou, EH (2012). "TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis". Journal of Thyroid Research. 2012: 351864. doi: 10.1155/2012/351864 . PMC   3544290 . PMID   23365787.
  2. Hoermann, R; Midgley, JE; Larisch, R; Dietrich, JW (2015). "Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment". Frontiers in Endocrinology. 6: 177. doi: 10.3389/fendo.2015.00177 . PMC   4653296 . PMID   26635726.
  3. Berberich, Julian (13 September 2018). "Mathematical Modeling of the Pituitary-Thyroid Feedback Loop: Matlab/Simulink Files for Simulation and Sensitivity Analysis". doi:10.5281/zenodo.1415331.{{cite journal}}: Cite journal requires |journal= (help)
  4. 1 2 Dietrich, Johannes W. (2002). Der Hypophysen-Schilddrüsen-Regelkreis : Entwicklung und klinische Anwendung eines nichtlinearen Modells. Berlin: Logos-Verlag. ISBN   978-3897228504.
  5. Dietrich, Johannes W.; Midgley, John E. M.; Hoermann, Rudolf (2018). Homeostasis and Allostasis of Thyroid Function. Lausanne: Frontiers Media SA. ISBN   9782889455706.
  6. Hoermann, R; Pekker, MJ; Midgley, JEM; Larisch, R; Dietrich, JW (February 2020). "Triiodothyronine secretion in early thyroid failure: The adaptive response of central feedforward control". European Journal of Clinical Investigation. 50 (2): e13192. doi:10.1111/eci.13192. PMID   31815292. S2CID   208956920.
  7. Ramos, André; Chaves, Rafael; Favero, Elói (11 November 2019). "Simulação baseada em Dinâmica de Sistemas para o ensino da fisiologia do eixo Hipotálamo-hipófise-tireoide no contexto da graduação em medicina". Brazilian Symposium on Computers in Education (Simpósio Brasileiro de Informática Na Educação - SBIE) (in Portuguese). 30 (1): 962. doi: 10.5753/cbie.sbie.2019.962 . ISSN   2316-6533. S2CID   213401607.
  8. Ghosh, Devleena; Mandal, Chittaranjan (2020). "Clustering Based Parameter Estimation of Thyroid Hormone Pathway". IEEE/ACM Transactions on Computational Biology and Bioinformatics. PP (1): 343–354. doi:10.1109/TCBB.2020.2995589. PMID   32750849. S2CID   219479222.
  9. DIETRICH, J. W.; TESCHE, A.; PICKARDT, C. R.; MITZDORF, U. (2004). "Thyrotropic Feedback Control: Evidence for an Additional Ultrashort Feedback Loop from Fractal Analysis". Cybernetics and Systems. 35 (4): 315–331. doi:10.1080/01969720490443354. S2CID   13421388.
  10. Hoermann, R; Midgley, JE; Larisch, R; Dietrich, JW (2015). "Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects". Horm Metab Res. 47 (9): 674–80. doi:10.1055/s-0034-1398616. PMID   25750078. S2CID   9824656.
  11. Dietrich, JW; Landgrafe-Mende, G; Wiora, E; Chatzitomaris, A; Klein, HH; Midgley, JE; Hoermann, R (2016). "Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research". Frontiers in Endocrinology. 7: 57. doi: 10.3389/fendo.2016.00057 . PMC   4899439 . PMID   27375554.
  12. Hoermann, Rudolf; Midgley, John E. M.; Larisch, Rolf; Dietrich, Johannes W. (October 2018). "The role of functional thyroid capacity in pituitary thyroid feedback regulation". European Journal of Clinical Investigation. 48 (10): e13003. doi:10.1111/eci.13003. PMID   30022470. S2CID   51698223.
  13. Hoermann, R; Midgley, JE; Larisch, R; Dietrich, JW (February 2013). "Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment?". European Journal of Endocrinology. 168 (2): 271–80. doi: 10.1530/EJE-12-0819 . PMID   23184912. S2CID   34158774.
  14. Chatzitomaris, A; Hoermann, R; Midgley, JE; Hering, S; Urban, A; Dietrich, B; Abood, A; Klein, HH; Dietrich, JW (2017). "Thyroid Allostasis-Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming". Frontiers in Endocrinology. 8: 163. doi: 10.3389/fendo.2017.00163 . PMC   5517413 . PMID   28775711.
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  20. Dietrich, J. W. (2017). "SimThyr 4.0 Handbook and Reference". figshare. doi:10.6084/m9.figshare.4902098.{{cite journal}}: Cite journal requires |journal= (help)
  21. Han, Simon Xian He (2013). THYROSIM: A Web Application for Human Thyroid System Regulation Education and Research (Thesis). Los Angeles: UCLA.