2.3 Thyroid Function Testing & Hypothyroidism

Thyroid disorders encompass common functional disturbances, life-threatening endocrine emergencies, and structural lesions. This section builds the interpretive framework — how to read a thyroid-stimulating hormone and free thyroxine pair, when that pair is lying, and how to manage hypothyroidism and myxedema coma. Thyrotoxicosis, thyroid storm, thyroiditis, and thyroid nodules and carcinoma are developed in the section that follows.

1. Interpretation of Thyroid Function Test Patterns

Serum TSH (Thyroid-Stimulating Hormone) (normal range: 0.4–4.5 mIU/L) paired with Free T4 (normal range: 0.8–1.8 ng/dL) and Free T3 (normal range: 2.3–4.2 pg/mL) provides the foundation for diagnosis.

2. Hypothyroidism & Myxedema Coma

Primary Hypothyroidism Etiology & Management

• Etiology: Hashimoto thyroiditis (chronic lymphocytic thyroiditis) is the most common cause in iodine-sufficient areas; characterized by circulating anti-thyroperoxidase (anti-TPO) antibodies (>90%) and anti-thyroglobulin (anti-Tg) antibodies. Other causes include prior radioiodine ablation, total/subtotal thyroidectomy, external neck irradiation, and medications (Amiodarone, Lithium, Sunitinib, Pembrolizumab/Nivolumab checkpoint inhibitors).
• Levothyroxine (T4) Dosing:
  • Young, Healthy Adults: Full replacement dose of 1.6 mcg/kg/day ideal body weight.
  • Elderly (>=65 yo) or Known Coronary Artery Disease (CAD): Start low at 25–50 mcg/day and titrate gradually by 12.5–25 mcg every 6–8 weeks (avoids precipitating myocardial ischemia, angina, or tachyarrhythmias).
  • Administration Instructions: Take on an empty stomach with plain water 30–60 minutes before breakfast or at bedtime (>=3–4 hours after dinner). Separate by at least 4 hours from interfering medications: calcium carbonate, ferrous sulfate, aluminum hydroxide antacids, proton pump inhibitors, sucralfate, cholestyramine, and raloxifene.
  • Monitoring: Recheck serum TSH 6–8 weeks after initiating or changing dose. Once euthyroid, monitor annually.
  • Pregnancy Requirements: Thyroid binding globulin (TBG) surges in pregnancy. Hypothyroid women must increase levothyroxine by 25–30% (e.g., take 2 extra tablets weekly) immediately upon confirming pregnancy; target trimester-specific TSH (1st trimester < 2.5 mIU/L).

Subclinical Hypothyroidism Indications for Treatment

Treatment with levothyroxine is indicated if:

1. Serum TSH is >= 10 mIU/L (reduces progression to overt disease, adverse lipid profiles, and cardiovascular mortality).
2. Patient is pregnant or actively attempting pregnancy.
3. Serum TSH is between 4.5–9.9 mIU/L WITH positive anti-TPO antibodies, symptomatic overt fatigue/depression, or prominent goiter.

Myxedema Coma: Life-Threatening Decompensation

• Clinical Presentation: Severe decompensated hypothyroidism triggered by sepsis, cold exposure, stroke, myocardial infarction, or sedative medications. Classic pentad: Hypothermia (temperature often <35°C / 95°F), Severe Bradycardia, Altered Mental Status / Coma, Hypoventilation (respiratory failure with hypercapnia), and Hyponatremia / Hypoglycemia.
• Emergency ICU Protocol:
  1. Stress-Dose Glucocorticoids FIRST: Administer Hydrocortisone 100 mg IV every 8 hours (or Dexamethasone 4 mg IV) immediately BEFORE or concurrently with levothyroxine until secondary adrenal insufficiency is excluded (thyroid hormone replacement accelerates hepatic cortisol clearance, precipitating fatal adrenal crisis if adrenal reserve is compromised).
  2. Intravenous Thyroid Hormone Replacement: IV Levothyroxine (T4) loading dose of 200–400 mcg IV, followed by 50–100 mcg IV daily, plus consideration of IV Liothyronine (T3) 5–20 mcg loading then 2.5–10 mcg q8h (due to impaired peripheral T4-to-T3 conversion in critical illness).
  3. Supportive Care: Mechanical ventilation, passive external rewarming with warm blankets (avoid aggressive active warming which causes vasodilation and circulatory collapse), and cautious IV isotonic crystalloids/hypertonic saline for severe hyponatremia.

3. When the Thyroid Function Tests Are Misleading

Most thyroid items on the exam are decided before any disease is named, at the moment the thyroid-stimulating hormone (TSH) and free thyroxine (free T4) pair is interpreted. A discordant or clinically implausible pair should trigger a search for interference or for non-thyroidal illness before a patient is started on, or taken off, thyroid hormone.

Assay Interference and Binding-Protein Artifact

Euthyroid Sick Syndrome: the Three-Phase Trap

Non-thyroidal illness follows a predictable sequence in a critically ill patient, and each phase can be misread:

1. Early: peripheral 5'-deiodinase is inhibited, so T3 falls first and reverse T3 rises, while TSH and free T4 remain normal.
2. Severe illness: TSH falls and free T4 may fall, superficially resembling central hypothyroidism.
3. Recovery: TSH rebounds transiently above the reference range — the phase most often misdiagnosed as new primary hypothyroidism, prompting unnecessary lifelong levothyroxine.

The management rule is deliberately conservative: do not screen thyroid function in the intensive care unit without a specific clinical suspicion, do not treat the low T3 with levothyroxine or liothyronine, and repeat testing about 6 weeks after recovery if the abnormality needs explaining. A markedly elevated TSH above 20 mIU/L, a goiter, or a clear precipitant argues for genuine thyroid disease rather than non-thyroidal illness.

A Persistently Elevated TSH Despite Levothyroxine

Work this common scenario in order of frequency rather than reaching for a dose increase:

1. Non-adherence is by far the most common cause. The tell-tale pattern is a high TSH with a normal or even high free T4 in a patient who took the pill only before the appointment; supervised weekly dosing confirms it.
2. Administration error: taken with food, coffee, or too close to breakfast.
3. Chelation by co-medications separated by less than 4 hours — calcium carbonate, ferrous sulfate, aluminum or magnesium antacids, proton pump inhibitors, sucralfate, bile acid sequestrants, and raloxifene.
4. Malabsorption: celiac disease, atrophic gastritis, Helicobacter pylori infection, or prior bariatric surgery. A liquid or soft-gel formulation bypasses some of these.
5. Increased requirement: pregnancy, oral estrogen, substantial weight gain, or nephrotic syndrome.
6. Accelerated clearance: phenytoin, carbamazepine, phenobarbital, rifampin, and sertraline.
7. Assay artifact: macro-TSH or heterophile antibody, as above.

Amiodarone and Checkpoint Inhibitor Thyroid Disease

• Amiodarone is roughly 37% iodine by weight and has a 45-60 day half-life. In the first weeks the iodine load produces a transient Wolff-Chaikoff effect with a modest TSH rise in a large fraction of patients, which usually self-corrects by 3 months and should not be treated. True amiodarone-induced hypothyroidism is common in iodine-replete regions and in patients with positive anti-thyroperoxidase antibodies; the important management point is that it is treated with levothyroxine while amiodarone is continued when the drug is needed for arrhythmia control, because thyroid failure is easily replaced whereas the arrhythmia may not be easily controlled otherwise.
• Immune checkpoint inhibitors (pembrolizumab, nivolumab, ipilimumab) most often cause a destructive thyroiditis with a brief thyrotoxic phase followed by permanent hypothyroidism; monitor TSH before each cycle and replace when overt. Distinguish this from checkpoint-induced hypophysitis, which produces central hypothyroidism — a low or inappropriately normal TSH with a low free T4 — accompanied by secondary adrenal insufficiency. Always check an 8 a.m. cortisol and replace glucocorticoid before levothyroxine in that setting.

Central Hypothyroidism

Central hypothyroidism inverts the usual monitoring rule: TSH is uninformative and must not be used to titrate the dose. Titrate instead to a free T4 in the upper half of the reference range, evaluate the entire anterior pituitary axis (cortisol, gonadotropins, prolactin, insulin-like growth factor 1), and image the sella. As in myxedema coma, glucocorticoid replacement precedes thyroid hormone whenever adrenal insufficiency has not yet been excluded, because thyroid hormone accelerates hepatic cortisol clearance and can precipitate adrenal crisis.