# Thyroid Function Tests (USMLE Guide)

> How do you interpret thyroid function tests on USMLE?

TSH and free T4, read as a pair, settle almost every thyroid vignette. Here are the lab patterns, the causes behind each one, and the drug choices worth memorizing.

Order TSH first. A high TSH with low free T4 means primary hypothyroidism; a low TSH with high free T4 or T3 means primary hyperthyroidism. Normal free T4 with an abnormal TSH is subclinical disease, and a low or inappropriately normal TSH alongside low free T4 points to central pituitary or hypothalamic failure.

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

**TSH is the most sensitive first-line test**: the pituitary responds logarithmically to free T4, so TSH moves before free T4 leaves the reference range. Order it first, then free T4.

**Read the pair, never either value alone.** Opposite movement means primary gland disease. Same-direction movement means central disease -- pituitary or hypothalamic failure if free T4 is low, a TSH-secreting adenoma if it is high.

**Free hormone beats total hormone when binding proteins shift.** Estrogen raises thyroxine-binding globulin, so total T4 rises while free T4 and TSH stay normal. Suppressed TSH with a normal free T4 is subclinical hyperthyroidism or **T3 toxicosis** -- order free T3. The [Endocrinology](/topics/endocrinology) hub covers the wider axis.

## Hypothyroidism and hyperthyroidism compared

The two syndromes oppose each other on every axis below.

| Feature | Hypothyroidism | Hyperthyroidism |
| --- | --- | --- |
| **Symptoms and signs** | Cold intolerance, weight gain, constipation, dry skin, delayed reflex relaxation | Heat intolerance, weight loss, diarrhea, tremor, lid lag, atrial fibrillation |
| **TSH** | ↑ (primary) | ↓ (primary) |
| **Free T4** | ↓ | ↑ |
| **Free T3** | ↓ or low-normal | ↑, often before T4 |
| **Causes** | Hashimoto, iodine deficiency, thyroidectomy, amiodarone, lithium | Graves, toxic multinodular goiter, toxic adenoma, thyroiditis |
| **Treatment** | Levothyroxine, retitrated to TSH at 6 weeks | Beta-blocker plus methimazole; radioiodine or surgery |

## Hashimoto thyroiditis leads the causes of hypothyroidism

**Hashimoto thyroiditis is the most common cause where iodine intake is sufficient.** Look for **anti-thyroid peroxidase (anti-TPO)** and **anti-thyroglobulin** antibodies, a firm nontender goiter, and a **lymphocytic infiltrate with germinal centers** plus **Hurthle cells** -- follicular cells with granular eosinophilic cytoplasm. Hashimoto raises **B-cell non-Hodgkin (MALT) lymphoma** risk, so a rapidly enlarging gland is lymphoma until biopsied.

**Iodine deficiency remains the leading cause worldwide**, causing goiter and, untreated in infancy, cretinism. The rest: **post-thyroidectomy or post-radioiodine** disease, **amiodarone**, **lithium**, and **congenital hypothyroidism** from thyroid dysgenesis -- a sluggish newborn with macroglossia and umbilical hernia, screened at birth to prevent intellectual disability.

## Graves disease leads the causes of hyperthyroidism

**Graves disease is autoimmune stimulation of the TSH receptor by thyroid-stimulating immunoglobulin**, an IgG that mimics TSH, so the whole gland grows and secretes. Two findings are antibody-driven and unique to Graves: **exophthalmos**, from glycosaminoglycan deposition behind the orbit, and **pretibial myxedema**.

**Toxic multinodular goiter** and **toxic adenoma** are autonomous, often from activating TSH-receptor mutations, without eye disease. **Subacute granulomatous (de Quervain) thyroiditis** follows a viral illness with a **painful, tender** gland and high ESR, releasing preformed hormone before a hypothyroid phase. **Factitious thyrotoxicosis** gives thyrotoxic labs with **no goiter and low thyroglobulin**. **Thyroid storm** is decompensated thyrotoxicosis -- fever, delirium, tachyarrhythmia -- triggered by surgery or infection.

## Seven thyroid function test patterns to memorize

Seven patterns cover almost every thyroid lab stem.

| Scenario | TSH | Free T4 | Free T3 |
| --- | --- | --- | --- |
| **Primary hypothyroidism** | ↑ | ↓ | ↓ or normal |
| **Subclinical hypothyroidism** | ↑ | Normal | Normal |
| **Central (secondary) hypothyroidism** | ↓ or inappropriately normal | ↓ | ↓ or normal |
| **Primary hyperthyroidism** | ↓ | ↑ | ↑ |
| **Subclinical hyperthyroidism** | ↓ | Normal | Normal |
| **Sick euthyroid syndrome** | Normal or ↓ | Normal, ↓ if severe | ↓ |
| **Normal pregnancy** | Low-normal, first trimester | Normal | Normal |

> **10-second exam strategy:** TSH sets the direction. Opposite-moving TSH and free T4 = primary disease; same-direction movement = central disease; abnormal TSH with normal free hormone = subclinical; isolated low T3 in the ICU = sick euthyroid.

## Radioactive iodine uptake separates the thyrotoxic causes

**Radioactive iodine uptake (RAIU) shows whether a thyrotoxic gland is making hormone or leaking it.** High uptake means synthesis; low uptake means preformed hormone released or swallowed.

- **Diffusely increased uptake** -> Graves disease.
- **Patchy hot nodules, suppressed background** -> toxic multinodular goiter.
- **One hot nodule, rest suppressed** -> toxic adenoma.
- **Low uptake, painful tender gland, high ESR** -> de Quervain thyroiditis.
- **Low uptake, painless gland, postpartum** -> postpartum thyroiditis.
- **Low uptake, no goiter, low thyroglobulin** -> factitious thyrotoxicosis.

## Methimazole is first-line except in two situations

**Methimazole and propylthiouracil (PTU) both block thyroid peroxidase**, stopping organification and coupling. Methimazole is preferred, but **PTU wins in the first trimester** -- methimazole causes aplasia cutis and choanal atresia -- and **in thyroid storm**, where PTU also blocks peripheral T4-to-T3 conversion. Both cause **agranulocytosis** -- fever and sore throat on a thionamide demand an immediate white count -- and **hepatotoxicity**, fulminant with PTU, cholestatic with methimazole: another [high-yield drug side effect](/blog/high-yield-drug-side-effects-usmle) to drill.

**Propranolol controls adrenergic symptoms immediately** and at high dose inhibits T4-to-T3 conversion. Storm adds glucocorticoids and iodine, given **at least an hour after** the thionamide. **Radioactive iodine** cures Graves and toxic nodules but is contraindicated in pregnancy and can worsen ophthalmopathy. **Thyroidectomy** suits compressive goiter or drug intolerance, risking **recurrent laryngeal nerve injury** and **hypoparathyroidism**.

## Three associations show up repeatedly on stems

**Amiodarone is 37% iodine by weight and causes thyroid disease in both directions.** Type 1 amiodarone-induced thyrotoxicosis is iodine-driven overproduction in a nodular gland, treated with thionamides; type 2 is destructive thyroiditis treated with glucocorticoids. Amiodarone *hypo*thyroidism reflects failure to escape the Wolff-Chaikoff effect.

**Lithium blocks hormone release, causing goiter and hypothyroidism**, so monitor TSH and add levothyroxine rather than stopping lithium. **Postpartum thyroiditis** appears within a year of delivery, painless and anti-TPO positive, running a thyrotoxic phase into a hypothyroid phase before usually recovering. Autoimmune thyroid disease clusters with [type 1 diabetes](/blog/diabetes-type-1-vs-type-2-usmle), so check those patients' TSH too.

## How this is tested on the exam

- **Fatigue, firm goiter, high TSH, low free T4, anti-TPO positive** -> Hashimoto; give levothyroxine.
- **Weight loss, tremor, proptosis, undetectable TSH, diffuse increased RAIU** -> Graves disease.
- **Septic ICU patient, low T3, normal TSH, high reverse T3** -> sick euthyroid; retest later.

## Common wrong-answer traps

- **Trap: treating a high total T4 in pregnancy.** Rising TBG lifts total T4 while free T4 and TSH stay normal.
- **Trap: giving a thionamide for thyroiditis.** Destructive thyroiditis releases preformed hormone, so blocking synthesis does nothing -- beta-block instead.
- **Trap: methimazole in the first trimester or in storm.** PTU is correct in both.
- **Trap: calling a low TSH with low free T4 hyperthyroidism.** That is central hypothyroidism; image the pituitary.

## Sources

- [American Thyroid Association guidelines](https://www.thyroid.org/professionals/ata-professional-guidelines/)
- [NBME exam resources](https://www.nbme.org/)

Thyroid vignettes reward one habit: read TSH and free T4 as a pair first. [Practice thyroid disorder questions on StepGenie](https://dashboard.stepgenie.app/sign-up) and drill these patterns until TSH alone points at the answer.

## Frequently asked questions

### Which thyroid test should you order first?

Order TSH first. Because the pituitary responds logarithmically to free T4, TSH shifts outside its reference range before free T4 does, making it the most sensitive single screen for thyroid dysfunction. Add free T4 to confirm the direction and grade severity, and add free T3 only when TSH is suppressed but free T4 is normal, which suggests T3 toxicosis.

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

Compare the direction of TSH and free T4. In primary hypothyroidism the gland fails and the intact pituitary drives TSH up while free T4 falls, so the two move in opposite directions. In central hypothyroidism the pituitary or hypothalamus fails, so free T4 is low while TSH is low or inappropriately normal. Same-direction movement should prompt pituitary imaging and evaluation of the other pituitary axes.

### When is propylthiouracil preferred over methimazole?

Propylthiouracil is preferred in two situations: the first trimester of pregnancy, because methimazole is associated with aplasia cutis and choanal or esophageal atresia, and thyroid storm, because propylthiouracil also blocks peripheral conversion of T4 to T3. Methimazole is otherwise first-line. Both drugs can cause agranulocytosis, so fever and sore throat require an urgent white blood cell count, and both can injure the liver.

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

Low uptake means the gland is not synthesizing hormone, so the excess hormone is either leaking from damaged follicles or coming from outside the thyroid. Think subacute granulomatous thyroiditis when the gland is painful and tender with a high ESR, postpartum or silent thyroiditis when it is painless, and factitious thyrotoxicosis when there is no goiter and thyroglobulin is low. Treat thyroiditis with a beta-blocker, not a thionamide.

### Should sick euthyroid syndrome be treated with levothyroxine?

No. Sick euthyroid syndrome is an adaptive response to severe illness, with reduced peripheral conversion of T4 to T3, a low free T3, a high reverse T3, and a normal or low TSH. Thyroid hormone replacement has not been shown to help these patients. The correct step is to treat the underlying illness and repeat thyroid function tests once the patient has recovered.

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Canonical page: [Thyroid Function Tests (USMLE Guide)](https://www.stepgenie.app/blog/thyroid-disorders-usmle)
Topic hub: [Endocrinology](https://www.stepgenie.app/topics/endocrinology)