Minimal Hypothalamic-Pituitary-Thyroid Feedback Model

models/hpt_feedback_axis/

A minimal two-state (TSH, free T4) ODE model of the hypothalamic-pituitary-thyroid negative-feedback loop, authored for dismech-perturb (analogous to the hand-authored CKD-MBD Antimony component; not a BioModels deposit). Pituitary TSH output is suppressed by free T4; the thyroid secretes T4 in proportion to TSH scaled by secretory capacity S_thy. Calibrated to a euthyroid steady state (TSH ~1.5 mU/L, free T4 ~15 pmol/L). Reducing S_thy reproduces primary congenital hypothyroidism (dysgenesis / dyshormonogenesis) with the compensatory TSH rise; reducing pituitary capacity reproduces central hypothyroidism (low free T4 with inappropriately normal TSH); and the exogenous levothyroxine term (LT4) restores euthyroidism, with over-replacement driving iatrogenic thyrotoxicosis.

Runs through dismech-perturb kinetic
Home / Models / hpt_feedback_axis

Where this model is curated

The entry card says what the model is for: which mechanism nodes it links to, how faithfully, and what it found. This page holds the model itself.

Committed run

From exports/model_runs/hpt_feedback_axis.json, regenerated by just gen-model-results. Scenario roots link to the mechanism node they drive on the entry page.

Simulation results — 15 scenarios run with dismech-perturb (tellurium / libRoadRunner CVODE) over 2000 h; baseline S_thy = 1.0
Scenario FT4 (pmol/L) TSH (mU/L) Activated phenotypes
Healthy baseline
S_thy = 1.0
 15.023105 1.482311 reference
Subclinical primary hypothyroidism (S_thy=0.3)
drives Defective Thyroid Hormone Biosynthesis
12.244755
0.82× baseline
 4.014918
2.71× baseline
 Elevated circulating thyroid-stimulating hormone concentration · mild Hypothyroidism · mild
Overt primary hypothyroidism (S_thy=0.1)
drives Defective Thyroid Hormone Biosynthesis
10.095095
0.67× baseline
 9.895095
6.68× baseline
 Elevated circulating thyroid-stimulating hormone concentration · mild Hypothyroidism · moderate
Athyreosis / severe hypothyroidism (S_thy=0.03)
drives Thyroid Gland Dysgenesis
8.000092
0.53× baseline
 26.000307
17.54× baseline
 Elevated circulating thyroid-stimulating hormone concentration · severe Hypothyroidism · severe
Central (pituitary) hypothyroidism (P_pit low)
drives Impaired Hypothalamic-Pituitary TSH Drive
10.853411
0.72× baseline
 1.065341
0.72× baseline
 Hypothyroidism · mild
TPO loss-of-function (dyshormonogenesis)
drives Defective Thyroid Hormone Biosynthesis
10.095095
0.67× baseline
 9.895095
6.68× baseline
 Elevated circulating thyroid-stimulating hormone concentration · mild Hypothyroidism · moderate
TG loss-of-function (dyshormonogenesis)
drives Defective Thyroid Hormone Biosynthesis
10.095095
0.67× baseline
 9.895095
6.68× baseline
 Elevated circulating thyroid-stimulating hormone concentration · mild Hypothyroidism · moderate
DUOX2 loss-of-function (dyshormonogenesis)
drives Defective Thyroid Hormone Biosynthesis
10.853411
0.72× baseline
 7.102274
4.79× baseline
 Elevated circulating thyroid-stimulating hormone concentration · mild Hypothyroidism · mild
SLC5A5/NIS loss-of-function (iodide transport defect)
drives Defective Thyroid Hormone Biosynthesis
10.095095
0.67× baseline
 9.895095
6.68× baseline
 Elevated circulating thyroid-stimulating hormone concentration · mild Hypothyroidism · moderate
TSHR loss-of-function (TSH resistance)
drives Thyroid Gland Dysgenesis
10.853411
0.72× baseline
 7.102274
4.79× baseline
 Elevated circulating thyroid-stimulating hormone concentration · mild Hypothyroidism · mild
PAX8 loss-of-function (thyroid dysgenesis)
drives Thyroid Gland Dysgenesis
8.869514
0.59× baseline
 17.339029
11.70× baseline
 Elevated circulating thyroid-stimulating hormone concentration · moderate Hypothyroidism · moderate
NKX2-1 loss-of-function (thyroid dysgenesis)
drives Thyroid Gland Dysgenesis
8.869514
0.59× baseline
 17.339029
11.70× baseline
 Elevated circulating thyroid-stimulating hormone concentration · moderate Hypothyroidism · moderate
FOXE1 loss-of-function (thyroid agenesis)
drives Thyroid Gland Dysgenesis
8.869514
0.59× baseline
 17.339029
11.70× baseline
 Elevated circulating thyroid-stimulating hormone concentration · moderate Hypothyroidism · moderate
Levothyroxine, under-dosed (residual hypothyroidism)
drives Defective Thyroid Hormone Biosynthesis
11.57508
0.77× baseline
 5.250267
3.54× baseline
 Elevated circulating thyroid-stimulating hormone concentration · mild Hypothyroidism · mild
Levothyroxine, full replacement (euthyroid restored)
drives Defective Thyroid Hormone Biosynthesis
14.524937
0.97× baseline
 1.749789
1.18× baseline
 none
Levothyroxine, over-replacement (iatrogenic thyrotoxicosis)
drives Defective Thyroid Hormone Biosynthesis
24.042932
1.60× baseline
 0.143108
0.10× baseline
 Hyperthyroidism · moderate
Derived artifact, regenerated by just gen-model-results — not curated evidence. Values rounded to 6 decimals. Config 9d52d1d81903, model.xml 0b426f0a5a26. Phenotypes activate per the curated variable thresholds.

Phenotype thresholds

PhenotypeVariableDirectionThresholdReading
Elevated circulating thyroid-stimulating hormone concentration TSH above 4.0 absolute
Hypothyroidism FT4 below 0.85 ratio of baseline
Hyperthyroidism FT4 above 20.0 absolute

Gene effects

How config.yaml turns a gene perturbation into a model parameter change: the multiplier applied for a loss- or gain-of-function.

GeneParameterEffectRationale
TPO S_thy LoF ×0.1 Thyroid peroxidase catalyzes iodide organification and coupling; biallelic loss causes dyshormonogenetic congenital hypothyroidism with goiter. Modeled as reduced thyroid secretory capacity S_thy.
TG S_thy LoF ×0.1 Thyroglobulin is the scaffold for thyroid hormone synthesis; loss-of- function causes dyshormonogenesis. Modeled as reduced S_thy.
DUOX2 S_thy LoF ×0.15 DUOX2 generates the H2O2 required for organification; loss-of-function causes (often transient) dyshormonogenetic hypothyroidism. Modeled as reduced S_thy.
SLC5A5 S_thy LoF ×0.1 SLC5A5 (NIS) is the sodium-iodide symporter; loss-of-function causes an iodide-transport defect. Modeled as reduced S_thy.
TSHR S_thy LoF ×0.15 TSH receptor loss-of-function causes TSH resistance / thyroid hypoplasia, so the gland cannot respond to TSH drive. Modeled as reduced S_thy.
PAX8 S_thy LoF ×0.05 PAX8 is a thyroid-development transcription factor; loss-of-function causes thyroid dysgenesis (hypoplasia/agenesis). Modeled as severely reduced S_thy.
NKX2-1 S_thy LoF ×0.05 NKX2-1 (TTF-1) governs thyroid (and lung/brain) development; loss-of- function causes thyroid dysgenesis. Modeled as severely reduced S_thy.
FOXE1 S_thy LoF ×0.05 FOXE1 (TTF-2) is required for thyroid migration; loss-of-function causes thyroid agenesis (Bamforth-Lazarus). Modeled as severely reduced S_thy.

Run it locally

uv run python -m dismech.perturb kb/disorders/Congenital_Hypothyroidism.yaml --alljust gen-model-results --id hpt_feedback_axis

Files

config.yamlmodel.antmodel.xml

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