Hypothyroidism

Etiology and Clinical Context

Chronic autoimmune thyroiditis (Hashimoto disease) is a major cause of primary hypothyroidism in iodine-sufficient populations. Thyroidectomy, radioiodine, medication effects, iodine deficiency or excess, and inflammatory thyroid disease are other causes. Pituitary or hypothalamic dysfunction produces central hypothyroidism. Risk increases with autoimmune disease, prior thyroid treatment, and select medication exposures (Esfandiari & McPhee, 2019).

Autoimmune and treatment-related disease: Hashimoto thyroiditis involves lymphocytic injury and thyroid autoantibodies, commonly anti-thyroid peroxidase, although an antibody result alone does not establish thyroid functional failure. Thyroidectomy, radioiodine, iodine excess or deficiency, lithium, amiodarone, and inflammatory thyroiditis can also lower hormone production. Transient thyroiditis may follow an initial thyrotoxic phase; the trajectory affects monitoring and treatment decisions.

Pathophysiology

Thyroid hormone normally supports mitochondrial energy use, thermogenesis, cardiac chronotropy and contractility, gastrointestinal motility, and lipid metabolism. Deficiency slows these processes, causing cold intolerance, bradycardia, constipation, reduced exercise tolerance, and elevated LDL cholesterol. Deposition of glycosaminoglycans in interstitial tissue contributes to nonpitting edema and characteristic facial or periorbital changes.

In primary gland failure, falling free T4 removes pituitary negative feedback, so TSH increases. In central disease, TSH secretion or biologic activity is insufficient relative to circulating hormone, so TSH may be low, normal, or mildly elevated despite inadequate free T4.

Clinical Manifestations

Fatigue, weight gain that is often modest, cold intolerance, dry skin, coarse hair, constipation, slowed cognition, depressed mood, menstrual changes, myalgias, and delayed reflex relaxation may occur. Presentation may be subtle or nonspecific. Severe cases can have pericardial effusion, hyponatremia, hypoventilation, and decreased consciousness.

Diagnostic Evaluation

TSH is a useful initial screen for primary thyroid disease; free T4 distinguishes overt from subclinical hypothyroidism and is essential when central disease is possible. Positive thyroid peroxidase antibodies support autoimmune thyroiditis but are not required to establish biochemical hypothyroidism. Low T3 alone is an unreliable diagnostic marker in illness.

Read TSH relative to free T4, not in isolation. Elevated TSH with low free T4 indicates overt primary gland failure; elevated TSH with free T4 in range describes subclinical primary dysfunction, which may warrant repeat confirmation and risk-based treatment decisions rather than automatic replacement. Low free T4 with a non-elevated TSH raises central hypothyroidism, especially with headaches, visual changes, or other pituitary deficits. A falsely reassuring TSH can therefore mask substantial hormone deficiency.

Unexpected thyroid results require a second question: is the number biologically plausible? Severe illness can distort pituitary–thyroid signaling; medications and recent replacement changes alter the time course; binding-protein changes and assay interference may affect interpretation. Thyroid peroxidase antibodies identify autoimmune risk or etiology but do not measure functional severity. When central disease is possible, assess cortisol reserve before initiating thyroid hormone if clinically feasible, because unrecognized adrenal insufficiency can deteriorate after replacement.

Management Principles

The general approach is levothyroxine replacement with monitoring appropriate to etiology, age, cardiovascular risk, and pregnancy. TSH ordinarily guides adjustment in primary disease; free T4 rather than TSH alone guides central hypothyroidism. Steady-state response generally takes several weeks. Absorption may be impaired by iron, calcium, and some gastrointestinal medicines, making dosing conditions important. If central thyroid failure is suspected, assess coexisting adrenal insufficiency before replacement because thyroid hormone can precipitate adrenal decompensation in cortisol deficiency (Fleseriu et al., 2016; Jonklaas et al., 2014; Katz, 2026).

Complications and Red Flags

Myxedema crisis represents severe physiologic failure and may occur without coma. Infection, cold exposure, sedatives, and other physiologic stressors can precipitate hypothermia, bradycardia, hypoventilation, hypotension, and altered mental status. It demands emergency supportive care and endocrine management.

A normal TSH cannot exclude central hypothyroidism when free T4 is low or low-normal in the appropriate clinical setting. In primary hypothyroidism, TSH generally guides levothyroxine replacement, but free T4 and clinical context are central in pituitary disease. When pituitary failure is possible, assess adrenal sufficiency before escalating thyroid hormone because thyroid replacement may unmask adrenal crisis. Pregnancy requires separate trimester- and assay-appropriate interpretation and individualized replacement management (Fleseriu et al., 2016; Jonklaas et al., 2014; Korevaar et al., 2026).

Clinical Reasoning Priorities

Case discrimination: A fatigued patient has low free T4 with TSH reported ‘normal.’ In a healthy feedback loop, TSH should rise as free T4 falls; repeat and contextualize the measurements and assess for pituitary dysfunction rather than closing the workup. If pituitary disease and possible cortisol deficiency coexist, evaluation or coverage of adrenal insufficiency precedes routine thyroid replacement. By contrast, an isolated mildly elevated TSH with normal free T4 is not the same biochemical or therapeutic problem.

High-Yield Distinctions

• Primary failure: TSH rises as free T4 falls. Central failure: TSH is inappropriately low for the free T4.
• TSH is not a reliable sole monitoring marker in central hypothyroidism.
• Adrenal status matters before thyroid replacement when multiple pituitary hormone deficiencies are possible.

Related YourDNP Guides

• Back to Pathophysiology

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References

Esfandiari, N. H., & McPhee, S. J. (2019). Thyroid disease. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed., Chapter 20). McGraw-Hill Education.

Fleseriu, M., Hashim, I. A., Karavitaki, N., Melmed, S., Murad, M. H., Salvatori, R., & Samuels, M. H. (2016). Hormonal replacement in hypopituitarism in adults: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 101(11), 3888–3921. https://doi.org/10.1210/jc.2016-2118

Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., & Sawka, A. M. (2014). Guidelines for the treatment of hypothyroidism: Prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid, 24(12), 1670–1751. https://doi.org/10.1089/thy.2014.0028

Katz, M. D. (2026). Thyroid disorders. In M. A. Chisholm-Burns, J. M. Kolesar, P. M. Malone, K. C. Lee, B. P. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed., Chapter 45). McGraw Hill.

Korevaar, T. I. M., Leung, A. M., Alexander, E. K., Bliddal, S., Boelaert, K., Brenta, G., Chou, R., Dhillon-Smith, R., Dosiou, C., Eaton, J. L., Guan, H., Kilpatrick, S. J., Lasserre, B. J., Lee, S. Y., Maraka, S., Meister, K. D., Morris-Wiseman, L. F., Nguyen, C. T., Pearce, E. N., & Shan, Z. (2026). American Thyroid Association 2026 guidelines for thyroid disease in preconception, pregnancy, and postpartum. Thyroid, 36(5), 481–544. https://doi.org/10.1177/10507256261445624

Penman, I. D., Ralston, S. H., Strachan, M. W. J., & Hobson, R. P. (Eds.). (2023). Davidson’s principles and practice of medicine (24th ed.). Elsevier.