# Thyroid Function Tests for USMLE: TSH, Free T4

> How do you interpret thyroid function tests on USMLE?

Sixteen TSH, free T4 and T3 patterns, what a reflex order can miss, the uptake scan, and current ATA and FDA guidance on thyroid drugs, storm and eye disease.

Read TSH first, then free T4. High TSH with low free T4 means primary hypothyroidism; low TSH with high free T4 or T3 means thyrotoxicosis, usually hyperthyroidism. An abnormal TSH with normal free T4 and T3 is subclinical disease. Low free T4 with a low or inappropriately normal TSH points to central hypothyroidism, which a TSH-only screen can miss.

## How do you interpret thyroid function tests on USMLE?

TSH comes first because its log-linear relationship with free T4 makes it leave the reference range before free T4 does; the American Thyroid Association calls it the best initial test. Then read free T4 and ask whether the two moved in opposite directions or the same one.

- **Opposite directions:** primary gland disease.
- **Same direction:** both low suggests pituitary or hypothalamic failure or severe illness; both high suggests a TSH-secreting adenoma, resistance to thyroid hormone or assay interference.
- **Only TSH abnormal:** subclinical disease, once T3 toxicosis, early pregnancy and recovery from illness are excluded.

Free hormone reflects thyroid status because T4 and T3 circulate almost entirely protein-bound: pregnancy, estrogen and combined oral contraceptives raise thyroxine-binding globulin (TBG) and total T4 while free T4 and TSH stay normal. The [Endocrinology](/topics/endocrinology) hub collects related guides.

## Thyroid function test patterns: TSH, free T4 and T3

Sixteen patterns cover nearly every thyroid lab stem; the last column gives the clue or next step.

| Pattern | TSH | Free T4 | T3 | Clue or next step |
| --- | --- | --- | --- | --- |
| Primary hypothyroidism | ↑ | ↓ | Normal or ↓ | Usually Hashimoto; T3 adds little |
| Subclinical hypothyroidism | ↑ | Normal | Normal | Treat when TSH is above 10 mIU/L |
| Central hypothyroidism | ↓ or inappropriately normal | ↓ | Normal or ↓ | Pituitary or hypothalamic disease; follow free T4 |
| Primary hyperthyroidism | ↓ | ↑ | ↑ | Uptake scan or TSH-receptor antibodies |
| T3 toxicosis | ↓ | Normal | ↑ | Order T3 when TSH is low and free T4 normal |
| Subclinical hyperthyroidism | ↓ | Normal | Normal | Atrial fibrillation and bone loss risk |
| TSH-secreting pituitary adenoma | Normal or ↑ | ↑ | ↑ | Raised alpha-subunit; pituitary mass |
| Resistance to thyroid hormone | Normal or ↑ | ↑ | ↑ | THRB mutation; no pituitary mass |
| Nonthyroidal illness (sick euthyroid) | Normal or ↓; mildly ↑ in recovery | Normal, ↓ if severe | ↓, reverse T3 ↑ | Treat the illness, not the thyroid |
| Excess levothyroxine or factitious T4 | ↓ | ↑ | ↑ or normal | Low thyroglobulin, near-absent uptake |
| Liothyronine (T3) use | Normal or ↓ | ↓ | ↑ | Low free T4 is not hypothyroidism here |
| Estrogen, oral contraceptives, pregnancy (↑ TBG) | Normal | Normal | Total T3 ↑ | Total T4 rises too; trust free T4 |
| First trimester (hCG) | Low-normal or mildly ↓ | Normal | Normal | hCG weakly stimulates the TSH receptor |
| Biotin megadoses | Falsely ↓ | Falsely ↑ | Falsely ↑ | Mimics hyperthyroidism; stop biotin 2 days, retest |
| Amiodarone | ↑ or ↓ | ↓ or ↑ | Varies | Hypothyroidism nearly twice as common as thyrotoxicosis |
| Lithium | ↑ | ↓ or normal | Normal or ↓ | Blocks synthesis and release; test once or twice a year |

> **10-second read:** opposite-moving TSH and free T4 = primary gland disease. Low free T4 with a TSH that is not high = central disease or severe illness. High free T4 with a TSH that is not suppressed = TSH-secreting adenoma, hormone resistance or assay interference. Low TSH with normal free T4 = check T3 before calling it subclinical.

## TSH with reflex to free T4 (and free T3): what the order does

A reflex order measures TSH alone and adds free T4 only when TSH crosses the laboratory's preset cut-offs, which vary: below 0.3 or above 5.0 mIU/L in one hospital catalog, below 0.45 or above 4.5 in another. Some panels also add free T3 when TSH is low but free T4 is not high. An ATA-commissioned testing review describes the same practice. The cascade works because primary disease always moves TSH, and it fails in predictable places:

- **Central hypothyroidism:** TSH can stay in range while free T4 is low, so the reflex never fires. When pituitary disease is suspected, order free T4 directly.
- **T3 toxicosis:** a low TSH with normal free T4 needs a T3 before it is called subclinical. In suspected hypothyroidism, T3 rarely helps.
- **Biotin:** hair and nail supplements with 5,000 to 10,000 mcg can falsely lower TSH and raise T4 and T3; the ATA advises stopping biotin at least 2 days before testing.

## Why the thyroid axis produces these patterns

Hypothalamic TRH drives pituitary TSH, TSH drives a gland that secretes mostly T4, and tissues convert T4 to active T3 or inactive reverse T3 while free hormone feeds back on the pituitary. Gland failure removes feedback, so TSH is always elevated in primary hypothyroidism. Pituitary failure removes the drive, so free T4 falls while TSH is low, or normal but less bioactive. Severe illness slows T4-to-T3 conversion and reverse T3 clearance; cortisol is then often high, whereas it is low or low-normal in central hypothyroidism from pituitary disease. The TSH upper limit also rises with age, so a mildly high TSH in an older adult is not automatically disease.

## Radioactive iodine uptake separates the causes of thyrotoxicosis

Radioactive iodine uptake (RAIU) asks whether the gland is making new hormone: normal or high uptake means synthesis, and near-absent uptake means leakage from damaged follicles or hormone from elsewhere. A recent iodine load, such as contrast, also drives uptake toward zero. The grouping follows the 2016 ATA hyperthyroidism guideline, still the ATA's current version.

| Cause | Uptake | Distinguishing clue | First step |
| --- | --- | --- | --- |
| Graves disease | High, diffuse | TSH-receptor antibodies, orbitopathy, pretibial myxedema | Beta-blocker plus methimazole; radioiodine or surgery |
| Toxic multinodular goiter | Normal or high, patchy | Several autonomous nodules | Beta-blocker; radioiodine or surgery |
| Toxic adenoma | Normal or high, one focus | Single hot nodule, rest of gland suppressed | Beta-blocker; radioiodine or surgery |
| TSH-secreting adenoma | Normal or high | Unsuppressed TSH, raised alpha-subunit | Pituitary evaluation |
| hCG-mediated: hyperemesis, molar pregnancy, choriocarcinoma | Normal or high; not scanned in pregnancy | Very high hCG; resolves as hCG falls | Transient in hyperemesis; evacuate a mole, treat a tumor |
| Subacute granulomatous (de Quervain) thyroiditis | Near-absent | Painful, tender gland, fever, high ESR after a viral illness | NSAID or aspirin, prednisone if severe; beta-blocker |
| Painless and postpartum thyroiditis | Near-absent | Painless, anti-TPO positive; postpartum onset within 12 to 16 weeks | Beta-blocker only |
| Amiodarone | Type 2: near-absent | Type 1: iodine-fueled synthesis; type 2: destructive thyroiditis | Type 1: thionamide; type 2: glucocorticoid |
| Iodine-induced (Jod-Basedow) | Low | Iodine load, such as contrast, often with pre-existing thyroid disease | Beta-blocker for symptoms |
| Factitious or excess thyroid hormone | Near-absent | Low or low-normal thyroglobulin | Stop or reduce the hormone |
| Struma ovarii | Low in neck, pelvic uptake | Ovarian teratoma with thyroid tissue | Remove the tumor |

Thyroglobulin settles a near-absent uptake: it is low or low-normal in factitious thyrotoxicosis, unlike every other cause.

## Hashimoto thyroiditis and the other causes of hypothyroidism

Hashimoto thyroiditis is the most common cause of hypothyroidism in the United States. More than 90% of patients have anti-thyroid peroxidase (anti-TPO) antibodies and 50% to 80% have anti-thyroglobulin antibodies; histology shows lymphocytes with germinal centers, Hurthle (Askanazy) cells and fibrosis. Early destruction can leak stored hormone, a transient "hashitoxicosis". Hashimoto is linked to primary thyroid lymphoma, coexists with celiac disease, and appears in autoimmune polyglandular syndromes with [type 1 diabetes](/blog/diabetes-type-1-vs-type-2-usmle).

- **After radioiodine or surgery:** the second most common cause; 25% to 50% of patients are hypothyroid a year after radioiodine.
- **Drugs:** lithium (blocks synthesis and release), amiodarone, interferon-alfa, immune checkpoint inhibitors and tyrosine kinase inhibitors.
- **Iodine deficiency:** endemic goiter and, where deficiency is severe, congenital hypothyroidism.

Subclinical hypothyroidism is treated when TSH exceeds 10 mIU/L, even without symptoms; between about 4.5 and 10, a trial is reasonable if symptoms suggest early disease.

## Levothyroxine dosing basics

The FDA label puts full replacement at about 1.6 mcg/kg/day. Older patients and those with heart disease start lower, often at 25 mcg a day, and TSH is rechecked 6 to 8 weeks after each change. The tablet goes on an empty stomach 30 to 60 minutes before breakfast, at least 4 hours apart from calcium, iron and bile acid sequestrants. Two label rules are testable: in central hypothyroidism, free T4 in the upper half of normal guides the dose, and adrenal insufficiency is treated with glucocorticoids first, because thyroid hormone speeds cortisol clearance and can precipitate adrenal crisis. A boxed warning bars thyroid hormone for obesity or weight loss.

## Treating hyperthyroidism: drugs, radioiodine and surgery

Beta-blockers come first: the 2016 ATA guideline recommends them in symptomatic thyrotoxicosis, especially for older patients, a resting heart rate above 90 or cardiovascular disease. Methimazole and propylthiouracil (PTU) block thyroid peroxidase, cutting iodide organification and coupling.

| Feature | Methimazole | Propylthiouracil |
| --- | --- | --- |
| Use | First-line for most patients | First trimester, thyroid storm, minor methimazole reaction when radioiodine and surgery are declined |
| Peripheral T4-to-T3 block | No | Yes, at high doses |
| Liver | Acute liver failure reported, less often than PTU | Boxed warning: severe liver injury, acute liver failure |
| Pregnancy | First-trimester aplasia cutis, choanal or esophageal atresia, omphalocele | Defects rarer and milder; label says methimazole may be preferable after the first trimester |
| Blood and vessels | Agranulocytosis; ANCA-positive vasculitis | Agranulocytosis; ANCA-positive vasculitis |

Agranulocytosis is rare, about 0.1% to 0.5%, and usually appears within the first 3 months, so the ATA asks for a baseline blood count and liver profile and a differential count with any fever or sore throat. After agranulocytosis the other thionamide is not an option. The same toxicity appears in [high-yield drug side effects](/blog/high-yield-drug-side-effects-usmle), and the [methimazole vs PTU flowchart](/blog/2026-06-08-step-by-step-flowchart-antithyroid-drugs-methimazole-ptu) walks through the choice. A Graves course usually runs 12 to 18 months.

Radioiodine is contraindicated in pregnancy, breastfeeding and suspected thyroid cancer; it needs a pregnancy test within 48 hours beforehand, and conception waits until thyroid function is stable, typically 4 to 6 months or longer. Radioiodine can worsen active orbitopathy, so it is avoided in moderate-to-severe disease; patients with mild orbitopathy who receive it get prednisone 0.4 to 0.5 mg/kg/day, started 1 to 3 days afterward and continued for a month. Thyroidectomy suits large or compressive goiters and moderate-to-severe orbitopathy; Graves patients take potassium iodide for about 10 days beforehand, and in high-volume hands permanent hypoparathyroidism affects under 2% and permanent recurrent laryngeal nerve injury under 1%.

## Thyroid storm and myxedema coma

Thyroid storm is decompensated thyrotoxicosis: fever of 104 to 106 °F, heart rate above 140, heart failure and delirium, often after stopping antithyroid drugs, surgery, trauma or acute illness. A Burch-Wartofsky score of 45 or more is highly suggestive, and 25 to 44 suggests impending storm. Treat in order: propranolol; PTU, preferred here; iodine at least 1 hour after the thionamide, so the iodine cannot feed new synthesis; IV hydrocortisone; acetaminophen and cooling, never aspirin, which can raise free hormone. Mortality is still 8% to 25%; the [thyroid storm question breakdown](/blog/2026-06-08-q-bank-breakdown-thyroid-storm-why-every-answer-choice-matters) drills the order.

Myxedema coma is decompensated hypothyroidism, mostly in older women in winter; infection is the most common trigger, and cold and sedatives are others. Expect confusion, hypothermia, bradycardia, hypoventilation, hyponatremia and hypoglycemia. Give IV levothyroxine and, first, hydrocortisone, because levothyroxine speeds cortisol metabolism and hypothyroidism can mask adrenal insufficiency; add IV liothyronine if there is no response in 24 hours. Rewarm passively, since active rewarming can cause vasodilatory shock, and correct sodium slowly.

## Thyroid eye disease and teprotumumab

Graves orbitopathy develops when TSH-receptor antibodies activate orbital fibroblasts, which deposit hydrophilic glycosaminoglycans and expand retro-orbital fat and muscle; similar fibroblast stimulation in skin causes pretibial myxedema, and stopping smoking is part of every plan. The 2022 ATA/ETA consensus prefers teprotumumab for active moderate-to-severe disease with significant proptosis or diplopia, and IV methylprednisolone (4.5 g over about 12 weeks) when inflammation dominates.

Teprotumumab blocks the IGF-1 receptor and is given as 8 infusions 3 weeks apart. Its current label (revised November 2025) has no boxed warning and covers the disease regardless of activity or duration. It warns of infusion reactions, inflammatory bowel disease (flares and new cases), hyperglycemia and hearing impairment that may be permanent, so hearing is checked before, during and after treatment, and it advises contraception until 6 months after the last dose.

## Pregnancy changes the reference points

The ATA's 2026 preconception, pregnancy and postpartum guideline, published online on 31 May 2026, succeeds the 2017 version.

- **TSH range:** without a local range, a first-trimester interval of 0.1 to 4.0 mU/L is reasonable.
- **Drugs:** PTU is preferred if one is needed in the first trimester (ATA patient guidance: until week 16); both drugs carry birth-defect risk, PTU's rarer and milder. Radioiodine is contraindicated.
- **Graves antibodies:** maternal thyroid-stimulating immunoglobulins cause fetal or neonatal hyperthyroidism in about 1% to 5% of pregnant women with Graves disease.
- **Levothyroxine:** requirements usually rise from early pregnancy, so the guideline suggests TSH at confirmation, about every 4 weeks through the first half and at least once in the third trimester. Treat with levothyroxine alone; before conception, aim for a TSH of 0.5 to 2.5 mU/L.
- **Postpartum thyroiditis:** about 5% of women, onset within 12 to 16 weeks of delivery, anti-TPO positive, and it tends to recur.

## Thyroid nodules and cancer in brief

About half of people have a thyroid nodule by age 60, and more than 90% of nodules are benign. Start with TSH and ultrasound: a low TSH calls for a radionuclide scan to find a hyperfunctioning nodule, ultrasound features select nodules for fine-needle aspiration, and molecular tests help with indeterminate cytology. Subtypes are compared in [thyroid cancer types, papillary to anaplastic](/blog/2026-06-08-visual-hack-thyroid-cancer-papillary-follicular-medullary-anaplastic-made-easy); adult differentiated cancer follows the 2025 ATA guideline.

## How USMLE tests thyroid disorders

Most thyroid stems hide one discriminating lab value or historical detail.

- **Goiter, high TSH, low free T4, anti-TPO positive:** Hashimoto thyroiditis; levothyroxine.
- **Proptosis, pretibial myxedema, suppressed TSH, diffuse high uptake:** Graves disease.
- **Tender thyroid after a viral illness, high ESR, near-absent uptake:** subacute thyroiditis; NSAID and beta-blocker.
- **Thyrotoxic labs, near-absent uptake, low thyroglobulin:** factitious thyrotoxicosis.
- **ICU patient with low T3, high reverse T3, normal TSH:** nonthyroidal illness; retest after recovery.

## Worked vignette: the normal TSH that misleads

A 46-year-old man had transsphenoidal surgery 3 months ago for a nonfunctioning pituitary macroadenoma. He now reports fatigue, cold intolerance and constipation, and his blood pressure is 102/64 mm Hg. TSH is 1.1 mU/L (normal) and free T4 is 0.5 ng/dL (low). Which is the most appropriate next step?

- A. Repeat TSH in 6 weeks
- B. Measure serum T3
- C. Measure a morning serum cortisol
- D. Start levothyroxine and titrate to a TSH of 1 to 2 mU/L
- E. Order a radioactive iodine uptake scan

**Answer: C.** Low free T4 with an in-range TSH after pituitary surgery is central hypothyroidism, the pattern a TSH-only or reflex order can miss. Adrenal function comes before levothyroxine: thyroid hormone increases glucocorticoid clearance, and the FDA label warns that starting it before glucocorticoid replacement can precipitate adrenal crisis, which his soft blood pressure hints at. Repeating TSH (A) cannot detect central disease, and T3 (B) rarely helps in hypothyroidism. Titrating levothyroxine to TSH (D) is wrong in central disease, where free T4 in the upper half of normal is the target. Uptake scanning (E) evaluates thyrotoxicosis.

## Common wrong-answer traps

- **Treating a high total T4 in pregnancy or on estrogen.** TBG raises total hormone; free T4 and TSH are normal.
- **Giving methimazole for thyroiditis.** In any thyroiditis nothing is being overproduced; use a beta-blocker.
- **Calling low TSH with low free T4 hyperthyroidism.** That pattern is central hypothyroidism or severe illness.
- **Giving iodine before the thionamide in storm.** Wait at least an hour.
- **Switching to PTU after methimazole agranulocytosis.** Move to radioiodine or surgery instead.

## Sources

- American Thyroid Association: [guidelines list](https://www.thyroid.org/professionals/ata-professional-guidelines/), [2026 pregnancy guideline announcement](https://www.thyroid.org/new-ata-guidelines-for-thyroid-disease-in-preconception-pregnancy-and-postpartum/), [thyroid function tests](https://www.thyroid.org/thyroid-function-tests/), [thyroiditis](https://www.thyroid.org/thyroiditis/), [hyperthyroidism in pregnancy](https://www.thyroid.org/hyperthyroidism-in-pregnancy/), [thyroid nodules](https://www.thyroid.org/thyroid-nodules/), [biotin and thyroid tests](https://www.thyroid.org/patient-thyroid-information/ct-for-patients/december-2018/vol-11-issue-12-p-3-4/), [amiodarone-induced thyrotoxicosis](https://www.thyroid.org/patient-thyroid-information/ct-for-patients/november-2023/vol-16-issue-11-p-3-4/)
- ATA/ETA: [thyroid eye disease consensus statement (2022)](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9807259/)
- StatPearls (NCBI Bookshelf): [hyperthyroidism](https://www.ncbi.nlm.nih.gov/books/NBK537053/), [Graves disease](https://www.ncbi.nlm.nih.gov/books/NBK448195/), [Hashimoto thyroiditis](https://www.ncbi.nlm.nih.gov/books/NBK459262/), [thyroid storm](https://www.ncbi.nlm.nih.gov/books/NBK448095/), [myxedema coma](https://www.ncbi.nlm.nih.gov/books/NBK545193/), [lithium](https://www.ncbi.nlm.nih.gov/books/NBK519062/), [amiodarone](https://www.ncbi.nlm.nih.gov/books/NBK482154/)
- NIDDK: [Hashimoto's disease](https://www.niddk.nih.gov/health-information/endocrine-diseases/hashimotos-disease)
- FDA labels on DailyMed, checked October 2026: methimazole, propylthiouracil, levothyroxine and teprotumumab.

Read TSH and free T4 as a pair until the pattern names the diagnosis: [Practice thyroid disorder questions on StepGenie](https://dashboard.stepgenie.app/sign-up).

## Frequently asked questions

### What does TSH with reflex to free T4 mean?

It is a single lab order in which TSH is measured first and free T4 is added automatically only when TSH crosses the laboratory's preset cut-offs, which vary by lab; some panels also add free T3 when TSH is low but free T4 is not high. Because primary thyroid disease always moves TSH, the cascade catches most cases with fewer tests. It can miss central hypothyroidism, where TSH may stay in range while free T4 is low, so suspected pituitary disease calls for ordering free T4 directly.

### How do you distinguish primary from central hypothyroidism?

Compare the direction of TSH and free T4. In primary hypothyroidism the failing gland removes feedback, so TSH is always high while free T4 is low. In central hypothyroidism the pituitary or hypothalamus fails, so free T4 is low while TSH is low or inappropriately normal and may be less bioactive. Central disease needs pituitary evaluation and an adrenal check before levothyroxine is started, and its treatment is monitored with free T4 rather than TSH.

### When is propylthiouracil preferred over methimazole?

The 2016 American Thyroid Association guideline prefers propylthiouracil in three settings: the first trimester of pregnancy, thyroid storm, and a minor reaction to methimazole in a patient who declines radioactive iodine or surgery. Otherwise methimazole is first-line, because propylthiouracil carries an FDA boxed warning for severe liver injury and acute liver failure. First-trimester methimazole is linked to aplasia cutis, choanal and esophageal atresia and omphalocele. Both drugs can cause agranulocytosis, so fever or sore throat calls for a differential white count.

### What does a low radioactive iodine uptake mean in a thyrotoxic patient?

Low or near-absent uptake usually means the gland is not making new hormone, so the excess is leaking from damaged follicles or coming from outside the thyroid; a recent iodine load, such as contrast, is the exception. A painful, tender gland with a high ESR suggests subacute thyroiditis; a painless gland, often postpartum and anti-TPO positive, suggests silent thyroiditis; low thyroglobulin points to factitious thyroid hormone use; and pelvic uptake points to struma ovarii. Thionamides do not help thyroiditis or factitious disease, so a beta-blocker treats the symptoms.

### How does biotin affect thyroid function tests?

High-dose biotin, such as the 5,000 to 10,000 mcg in many hair and nail supplements, interferes with laboratory immunoassays and can produce falsely low TSH with falsely high T4 and T3. The result looks like hyperthyroidism, or like an excessive levothyroxine dose in a treated patient. The American Thyroid Association advises stopping biotin for at least 2 days before blood is drawn, and repeating any results that do not fit the clinical picture.

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