Thyroid Function Tests and Thyroid Disorders (USMLE Step 1)

★ High-yield tip #1

Hashimoto with normal thyroid tests

Classically in hypothyroidism, T3 and T4 fall and TSH rises because of the loss of negative feedback. So normal TSH, T3 and T4 seem strange for Hashimoto thyroiditis, but it is what the exam wants. Not every patient with thyroid disease has abnormal thyroid function tests, so keep that in mind.

★ High-yield tip #2

Other hypothyroid findings

Hypothyroidism can also cause a myopathy with proximal muscle weakness and raised creatine kinase, as well as depression and bradycardia, around 55 to 60. These are high yield, especially on Step 2 CK.

★ High-yield tip #3

No nodularity as an important negative

When a question lists no nodularity as an important negative, it is implying that this is not thyroid cancer. Anaplastic and medullary thyroid carcinoma usually present as a thyroid nodule or a neck mass, so a question that tells you outright there is no nodularity is steering you away from them.

★ High-yield tip #4

Anaplastic carcinoma

Anaplastic thyroid carcinoma is very rare. It typically affects older adults, and it can invade nearby structures such as the esophagus, causing dysphagia. Across the many thousands of NBME questions for Step 1 and Step 2, it has very rarely been the correct answer, so it is low yield.

★ High-yield tip #5

Medullary carcinoma

Medullary thyroid carcinoma is very high yield. It is part of MEN 2A and MEN 2B, often from a RET proto-oncogene mutation, and it can also run in families without the rest of the MEN picture. A question might simply say the patient, her brother and her father all had thyroid cancer, with nothing else. The answer is medullary thyroid carcinoma.

★ High-yield tip #6

Medullary carcinoma findings

For medullary thyroid carcinoma, raised serum calcitonin is classic. On biopsy, a Congo red stain shows apple-green birefringence because of amyloid, which is made of beta-pleated sheets.

★ High-yield tip #7

Graves disease

Graves disease causes hyperthyroidism, with classic findings such as a fast heart rate or heat intolerance. Activating antibodies bind the TSH receptor. They are called thyroid-stimulating immunoglobulins, or TSI, and this is a type II hypersensitivity reaction, which is very high yield.

★ High-yield tip #8

Do not pick the obscure option

Hürthle cell carcinoma is a deliberate distractor. When students don’t know an answer, they tend to pick the strange-sounding option. If you are unsure, don’t choose an answer just because it sounds obscure.

★ High-yield tip #9

De Quervain thyroiditis

Subacute granulomatous thyroiditis is also called subacute thyroiditis, or de Quervain thyroiditis. The question will always give you a tender or painful thyroid. Classically, a viral upper respiratory infection comes first, such as a runny nose for four days. But on harder Step 2 CK questions, the viral illness may not be mentioned, because not every patient reports one. Many do, 2 to 8 weeks before.

★ High-yield tip #10

Iodine uptake scans

The other high-yield point for de Quervain is that a radioactive iodine uptake scan is low, even if the patient is hyperthyroid. In a hyperthyroid patient, diffusely increased uptake fits Graves disease, a single focal area fits a toxic adenoma, and several nodules fit a toxic multinodular goiter. Hyperthyroidism with low uptake means thyroiditis: drug-induced, postpartum, or de Quervain, the painful one.

★ High-yield tip #1

Why T3 falls

Several mechanisms have been proposed, but cortisol is thought to play a role by shutting off the peripheral conversion of T₄ to T₃. T₄ does not rise, because it is diverted to reverse T₃. It is unusual, but you just need to know the pattern: normal T₄, normal TSH, low T₃, and high reverse T₃.

★ High-yield tip #2

How the exam presents it

The exam can describe a patient who cannot be weaned from a ventilator, which is what appears on the NBME. Or it can simply describe a patient with an illness of some kind. Either way, with this lab pattern, the answer is euthyroid sick syndrome.

★ High-yield tip #3

Drug-induced thyroiditis

Drug-induced thyroiditis mostly refers to amiodarone and lithium, two of the most important drugs that cause it. It can cause hypothyroidism or hyperthyroidism, but the exam likes to present it as hyperthyroidism. The highest-yield point is that the radioactive iodine uptake scan is low, even if the patient is hyperthyroid. So expect high T₃ and T₄, low TSH, and low uptake.

★ High-yield tip #4

Why uptake is low in thyroiditis

If uptake is increased instead, think Graves disease, a toxic adenoma, or a toxic multinodular goiter. In thyroiditis, inflammation damages the thyroid follicles, so stored, preformed thyroid hormone leaks out into the blood. The gland is not making extra hormone, so it takes up little iodine. That is why low uptake points to destructive thyroiditis.

★ High-yield tip #5

Lymphocytic thyroiditis

Lymphocytic thyroiditis here means chronic lymphocytic thyroiditis, another name for Hashimoto thyroiditis. Step 2 CK forms have used that wording. If you biopsy the thyroid in Hashimoto, you see lymphocytes, and they do ask about that detail. In Hashimoto, expect low T₃ and T₄ with a high TSH.

★ High-yield tip #6

Hypothyroid findings

Buzzy findings like weight gain, cold intolerance, brittle hair, and dry skin are often left out because they are too easy. Know the others: carpal tunnel syndrome, menstrual irregularities, depression, and raised transaminases, ALT and AST, which seems odd but shows up on Step 2 CK forms. Also raised creatine kinase from hypothyroid myopathy, bradycardia, and raised total cholesterol.

★ High-yield tip #7

De Quervain thyroiditis

Subacute thyroiditis is another name for subacute granulomatous, or de Quervain, thyroiditis. As with drug-induced thyroiditis, uptake is low even when the patient is hyperthyroid. In fact, postpartum, drug-induced and de Quervain thyroiditis all show low uptake, even in hyperthyroidism. De Quervain classically follows a viral infection and gives a tender, painful thyroid.

★ High-yield tip #8

The missing virus

The viral infection does not have to be mentioned. On Step 2 CK, conditions that usually follow a virus are often described without it, such as immune thrombocytopenia, or transient synovitis in children. So any tender, painful thyroid points to de Quervain thyroiditis.

★ High-yield tip #9

Subclinical hypothyroidism

Subclinical hypothyroidism means a raised TSH with normal T₄, and it is more common in women and older adults. Most of the time it is monitored rather than treated. It is often caused by Hashimoto thyroiditis, and it can progress to overt hypothyroidism.

★ High-yield tip #10

When to treat subclinical hypothyroidism

For Step 3, know when treatment is recommended: in pregnancy or when trying to conceive; when TSH is above 10, against a normal range of roughly 0.4 to 4.8; or when anti-thyroid peroxidase antibodies, also called anti-microsomal antibodies, are positive.

★ High-yield tip #1

Hypothyroidism beyond the buzzwords

You already know the classic findings: weight gain, cold intolerance, brittle hair, and dry skin. Those are almost too easy, so questions often leave them out, especially on Step 2 CK. Know the less obvious clues instead, such as menstrual irregularities. An elevated creatine kinase reflects hypothyroid myopathy.

★ High-yield tip #2

Bradycardia and hyponatremia

Bradycardia fits hypothyroidism. A rate in the 50s could be normal, but questions often give a rate between 50 and 60 as a clue. Hyponatremia seems odd, but you may see a sodium around 130 mEq/L, where normal is 135 to 145. The proposed mechanism: lower cardiac output in hypothyroidism triggers baroreceptor-mediated ADH release, so the body retains free water.

★ High-yield tip #3

More hypothyroid findings

Hypercholesterolemia is also seen in hypothyroidism, and so is depression. In Hashimoto thyroiditis, the thyroid shows a lymphocytic infiltrate. That is the answer to one NBME question, and it almost became the answer to this one.

★ High-yield tip #4

Gallstone risk factors

Cholelithiasis means gallstones. Remember the classic risk profile: fat, forty, female and fertile. That is the typical patient with cholesterol stones, and the risk also goes up in pregnancy, because of the hormone changes of pregnancy.

★ High-yield tip #5

Gallstones in pregnancy

In pregnancy, progesterone relaxes smooth muscle, and the gallbladder is more likely to fail to empty. As a side note, progesterone also reduces ureteral tone and peristalsis, which helps explain the higher risk of upper urinary tract infection, or pyelonephritis. Meanwhile, the extra estrogen of pregnancy makes gallstones more likely. Together, these hormone changes make pregnancy a gallstone risk factor.

★ High-yield tip #6

Hereditary spherocytosis and pigment stones

Also know that patients with hereditary spherocytosis get pigment stones. That shows up on NBME exams. In more severe hereditary spherocytosis, splenectomy is used, and it improves the anemia caused by red cell destruction in the spleen. That same red cell turnover releases bilirubin, which forms pigment stones, so if the patient has symptomatic gallstones, the gallbladder is removed at the same operation.

★ High-yield tip #7

Cubital tunnel syndrome

B, cubital tunnel syndrome, is not high-yield for Step 1, but it shows up all over Step 2 CK. It is compression of the ulnar nerve at the elbow. Patients get tingling and sensory changes that can run down the medial forearm and into the fourth and fifth fingers.

★ High-yield tip #8

Guyon canal and splinting

If the tingling and sensory changes start only at the wrist and run into the hand, think of Guyon canal syndrome instead. For cubital tunnel syndrome, the exam wants more than the diagnosis. It also wants the treatment: an elbow splint worn overnight, which keeps the elbow from staying bent while the patient sleeps.

★ High-yield tip #9

Giant cell arteritis and polymyalgia rheumatica

C, giant cell arteritis, also called temporal arteritis, usually affects patients over 50. Pain in the shoulders and legs can suggest polymyalgia rheumatica, which goes along with giant cell arteritis. But PMR patients are also usually over 50, and an elevated creatine kinase tells you it is not PMR.

★ High-yield tip #10

Polymyositis versus PMR

Polymyositis has an elevated creatine kinase, weakness on physical exam, or both. Polymyalgia rheumatica does not, and PMR is the one linked to giant cell arteritis. One more point on giant cell arteritis: start steroids right away, before the biopsy, to prevent blindness. IV methylprednisolone is used when vision is threatened.

★ High-yield tip #11

Granulomas

D, granulomas, can point to many diagnoses on the USMLE: Crohn disease, sarcoidosis, tuberculosis, which forms caseating granulomas, and berylliosis. When it comes to thyroid disease, also remember subacute granulomatous thyroiditis.

★ High-yield tip #12

Expect transaminitis on Step 2 CK

If transaminitis still seems strange, expect it anyway. When you reach the Step 2 CK Clinical Mastery Series forms, you will meet a question with a hypothyroid patient whose transaminases are elevated.

★ High-yield tip #1

Uptake in thyroiditis

Thyroiditis can present as hypothyroid or hyperthyroid, but exams like to give it to you hyperthyroid. The reason is that radioiodine uptake in thyroiditis is low. If the patient were hypothyroid, low uptake would be no surprise. A hyperthyroid picture tests whether you know uptake stays low even when hormone levels are high.

★ High-yield tip #2

Any thyroiditis

The same rule covers every type of thyroiditis: viral, as in de Quervain, postpartum thyroiditis, or drug-induced thyroiditis from lithium or amiodarone. If the patient is hyperthyroid from thyroiditis, uptake is decreased. Any thyroiditis means release of preformed thyroid hormone.

★ High-yield tip #3

Flow murmurs

A soft systolic ejection murmur in a high-flow state is most likely a functional flow murmur, and you will see it in many vignettes: hyperthyroidism, pediatric vignettes, especially with fever or illness, and obstetrics vignettes, where blood volume is increased. These innocent murmurs are harmless and do not need specific cardiac treatment.

★ High-yield tip #4

Toxic adenoma uptake

A toxic adenoma also causes hyperthyroidism, but its uptake is increased and focal: a single nodule taking up the tracer. That is the opposite of thyroiditis, where uptake is decreased. This is easy, pass-level material that shows up all over Step 2 CK.

★ High-yield tip #5

Hashimoto thyroiditis

B describes Hashimoto thyroiditis, also called chronic lymphocytic thyroiditis. If you know that other name, you know the histology is a lymphocytic infiltrate. It sounds like a Step 1 fact, but Step 2 CK asks it too, sometimes as an easy family medicine vignette where the answer is simply lymphocytic infiltrate.

★ High-yield tip #6

Hashimoto labs

Anti-microsomal antibodies are the same thing as anti-thyroid peroxidase, or anti-TPO, antibodies. You can also see anti-thyroglobulin antibodies. But Hashimoto causes hypothyroidism: a high TSH with a low T₄, while T₃ is often still normal.

★ High-yield tip #7

Surreptitious thyrotoxicosis

D, surreptitious thyrotoxicosis, means the patient is secretly taking thyroid hormone. That would cause hyperthyroidism with decreased uptake. But it does not cause a tender, painful, enlarged gland. In fact, the thyroid may be small, because the high hormone levels suppress TSH over time, so the gland is not being stimulated.

★ High-yield tip #8

Taking T4 versus T3

For Step 1: taking T₄ causes high T₄, high T₃, and low TSH, because T₄ is converted to T₃ in the tissues. Taking T₃ causes high T₃ and low TSH, but low T₄. That is because the suppressed TSH shuts off the body’s own T₄ production. NBME exams ask this for Step 1.

★ High-yield tip #9

Graves disease

E, thyroid-stimulating immunoglobulin, or TSI, points to Graves disease. It is the antibody that activates the TSH receptor. Graves causes high T₃ and T₄ with increased, diffuse uptake. It is a type II hypersensitivity reaction.

★ High-yield tip #10

Practice thyroid patterns

Telling these high-yield thyroid conditions apart is pass-level material, especially for Step 2 CK. For Step 1, the wording of the answer choices makes this a medium-difficulty question, so practice thyroid hormone questions until the patterns feel automatic.

★ High-yield tip #1

C-cell hyperplasia

NBME questions may even describe parafollicular C-cell hyperplasia on the biopsy. That points to medullary thyroid carcinoma too, because the parafollicular C cells of the thyroid are the cells that make calcitonin.

★ High-yield tip #2

Amyloid and Congo red

Apple-green birefringence with Congo red under polarized light means amyloid, which is misfolded protein deposited in tissue. You can see the same staining elsewhere, such as in renal and cardiac amyloidosis linked to multiple myeloma. In principle, any amyloid can give apple-green birefringence.

★ High-yield tip #3

Calcitonin is not the opposite of PTH

Students often think calcitonin is simply the opposite of PTH. It isn’t. PTH acts on osteoblasts, which express RANKL. RANKL binds the RANK receptor on osteoclasts and drives bone resorption, so calcium leaches out of bone into the blood and serum calcium rises.

★ High-yield tip #4

What calcitonin does

Calcitonin is not a reverse PTH. It acts directly on osteoclasts and inhibits them, so less calcium is released from bone. In humans, its effect on blood calcium is small. That is why patients with medullary carcinoma usually have normal calcium even when calcitonin is very high. The osteoclast effect is what the USMLE really wants you to know.

★ High-yield tip #5

Bisphosphonates

The exam also wants you to know that bisphosphonates, such as alendronate and pamidronate, inhibit osteoclasts too, as drugs. For osteoporosis, weight-bearing exercise matters, and brisk walking beats swimming for bone density. Adequate calcium and vitamin D are also part of care. For drug therapy, a bisphosphonate such as alendronate is the usual first-choice drug.

★ High-yield tip #6

Other bisphosphonate uses

Pamidronate is used for hypercalcemia of malignancy, along with vigorous saline hydration. In family medicine especially, bisphosphonates are also given to patients on long-term corticosteroids to prevent osteoporosis.

★ High-yield tip #7

MEN 2A and urinary stones

Urolithiasis means urinary stones that have moved out of the kidney into the rest of the urinary tract, such as the ureter. Medullary thyroid carcinoma can be part of MEN 2A, along with hyperparathyroidism from a parathyroid adenoma or hyperplasia, which can cause kidney stones. Uric acid stones, by contrast, are linked to low urine pH, gout and chronic diarrhea.

★ High-yield tip #8

Psammoma bodies

Students get anxious about psammoma bodies as if they were high-yield. They do show up on NBME exams, but they aren’t high-yield. Psammoma bodies are laminated, ring-like calcium deposits seen in papillary thyroid carcinoma, mesothelioma, meningioma, and serous cystadenocarcinoma of the ovary.

★ High-yield tip #9

Hyperparathyroidism and Paget disease

Increased bone turnover could fit hyperparathyroidism, where excess PTH drives osteoclastic bone resorption, and a raised calcium from primary hyperparathyroidism could go with a decreased serum phosphate. Bone turnover is also a very generic answer choice. As a side note, Paget disease of bone has mixed osteoclastic and osteoblastic activity with an isolated rise in serum alkaline phosphatase, and exams like this descriptor for it.

★ High-yield tip #1

The names of de Quervain thyroiditis

De Quervain thyroiditis is also called subacute granulomatous thyroiditis, or simply subacute thyroiditis. The exam may write just subacute thyroiditis as the answer, and that confuses students who don’t know it by that name.

★ High-yield tip #2

The classic picture

The textbook story is a viral infection, followed weeks later by a painful, tender thyroid gland. But the exam doesn’t have to mention the viral infection. If a question leaves it out, it’s still de Quervain, because the thyroid gland is tender and painful.

★ High-yield tip #3

Uptake is low even when hyper

What you need to know is that uptake is low, even when the patient is hyperthyroid. That’s why the exam likes to show de Quervain in the hyperthyroid phase. If they gave it to you in the hypothyroid phase, choosing decreased uptake would be too easy. They want to see that you know uptake is low even when the patient is hyper.

★ High-yield tip #4

Graves disease

Diffusely increased I¹³¹ uptake refers to Graves disease. In Graves, you get high T3 and T4, suppressed TSH, and diffusely increased uptake. The mechanism is thyroid-stimulating immunoglobulin, an activating antibody against the TSH receptor. That makes Graves a type II hypersensitivity reaction.

★ High-yield tip #5

Hyperthyroidism with a nodule

On Step 2 CK, if a patient has hyperthyroidism and a thyroid nodule, get an iodine uptake scan. Uptake in a single nodule means toxic adenoma. Diffuse uptake, even if you feel a nodule, means Graves disease. Uptake in multiple nodules means toxic multinodular goiter.

★ High-yield tip #6

Overt versus subclinical disease

When a patient has overt hypo- or hyperthyroidism, free T4 is out of the normal range. In subclinical disease, TSH is abnormal but free T4 stays normal, and symptoms are often mild or nonspecific.

★ High-yield tip #7

Which thyroid test

For Step 2 CK, the best initial test of thyroid function is TSH, keeping in mind that its normal range is different in pregnancy. Free T4, checked along with TSH, then more accurately reflects how the gland is functioning, which is why it confirms whether the patient is truly hypo- or hyperthyroid.

★ High-yield tip #8

TSH in primary and secondary disease

In primary hyperthyroidism, where the problem is in the thyroid gland itself, the extra thyroid hormone feeds back on the pituitary, so TSH is suppressed. TSH can be high in secondary hyperthyroidism, for example from a TSH-secreting tumor of the anterior pituitary. On the flip side, one offline NBME question gives decreased TSH with decreased T4, and the answer is secondary hypothyroidism, such as Sheehan syndrome.

★ High-yield tip #9

Hashimoto thyroiditis

Microsomal antibodies, also called anti-thyroid peroxidase antibodies, point to Hashimoto thyroiditis, where you can also see anti-thyroglobulin antibodies. Hashimoto has a lymphocytic infiltrate in the thyroid gland, so it’s also called chronic lymphocytic thyroiditis. Expect a decreased T4 and an increased TSH, while T3 is often still normal. That’s textbook hypothyroidism.

★ High-yield tip #1

De Quervain across the spectrum

In de Quervain, or subacute granulomatous thyroiditis, uptake is low, even if the patient is hyperthyroid. It can present across the spectrum: hypo, eu or hyperthyroid. The exam tends to give it to you hyperthyroid, to check that you know iodine uptake is decreased in thyroiditis. In the hypothyroid phase, choosing decreased uptake would be obvious.

★ High-yield tip #2

Why uptake is low

Uptake is low because the gland isn’t making new thyroid hormone, unlike Graves, toxic adenoma or toxic multinodular goiter, where uptake is increased. In de Quervain, inflammation damages the gland, so stored thyroid hormone leaks out into the blood. With TSH suppressed, new hormone production is actually turned down.

★ High-yield tip #3

The viral clue

De Quervain often follows a viral infection, but in truth only about a third of questions will tell you that. The exam does this in general. It doesn’t have to mention a viral infection before low platelets in ITP, or before transient synovitis, which is a painful hip in children. Also, the exam can give you de Quervain as hypo- or hyperthyroid.

★ High-yield tip #4

Hashimoto thyroiditis

Anti-microsomal antibody, also known as anti-thyroid peroxidase, is for Hashimoto thyroiditis. You can also see anti-thyroglobulin antibodies. Hashimoto is the classic primary hypothyroidism, with autoimmune destruction of the thyroid gland. T4 is low, and TSH goes up to compensate, while T3 is often still normal.

★ High-yield tip #5

Hot nodules

A hot nodule is a thyroid adenoma that secretes hormone on its own, also called a toxic adenoma. This is more Step 2 CK level, across family medicine, internal medicine and surgery. The exam loves to test whether you know how to evaluate cold versus hot nodules.

★ High-yield tip #6

Working up a thyroid nodule

If you’re evaluating for thyroid cancer and both are listed, the first step is palpating the thyroid gland, not TSH. If a nodule is palpated, the next best step is TSH. A high or normal TSH, meaning the patient is hypo- or euthyroid, keeps malignancy on the table, because a higher TSH is linked to a higher cancer risk, and hyperfunctioning, or hot, nodules rarely harbor malignancy.

★ High-yield tip #7

Cold versus hot nodules

For a nodule with high or normal TSH, do an ultrasound followed by fine needle aspiration. If ultrasound is listed, choose it. If it isn’t, choose FNA. If TSH is suppressed, the nodule may be hot, meaning a toxic adenoma, and the next best step is a radioactive iodine uptake scan. A hot nodule rarely harbors malignancy.

★ High-yield tip #8

Graves disease

Exophthalmos, or proptosis, is a protrusion of the eyes, and it points to Graves disease. Graves is autoimmunity of the thyroid gland driven by thyroid-stimulating immunoglobulin. TSI binds to and activates the TSH receptor, a type II hypersensitivity reaction. You get increased T3 and T4 with a suppressed TSH.

★ High-yield tip #9

Graves-specific findings

Exophthalmos and pretibial myxedema are classic extrathyroidal signs of Graves disease, and de Quervain lacks them. Many Graves patients don’t have eye findings, but if a vignette describes hyperthyroidism and goes out of its way to say there’s no exophthalmos, the exam is steering you away from Graves.

★ High-yield tip #1

Psammoma bodies

A psammoma body is a ring-like, layered accumulation of calcium seen in some cancers. They’re not extremely high yield, but students report seeing them on the real exam. You can see them in papillary thyroid carcinoma, serous cystadenocarcinoma of the ovary, mesothelioma and meningioma.

★ High-yield tip #2

Hot nodules

If a patient has a nodule and is hyperthyroid, TSH is suppressed. In a way, that’s good news, because it means the nodule is very unlikely to be malignant. A hot nodule is known as a toxic adenoma.

★ High-yield tip #3

Thyroid nodule workup

This is more Step 2 CK, but quickly: if a patient has a thyroid nodule, measure serum TSH next. If it’s normal or elevated, the next best step is ultrasound if it’s listed. If ultrasound isn’t listed, choose fine needle aspiration. If TSH is decreased, the next best step is a radionuclide uptake scan, preferably with ¹²³I.

★ High-yield tip #4

Hypoparathyroidism after thyroidectomy

For primary hypoparathyroidism, know two high-yield points. Number one, it can happen after thyroidectomy, because the parathyroids can be removed along with the thyroid. Then calcium and PTH are both low.

★ High-yield tip #5

Signs of hypocalcemia

After thyroid surgery, look for signs of low calcium. Chvostek sign is twitching of the facial muscles when you tap the facial nerve in front of the ear. Trousseau sign is carpal spasm when a blood pressure cuff is inflated on the arm. Both point to hypocalcemia.

★ High-yield tip #6

DiGeorge syndrome

The other important point is DiGeorge syndrome, where the third and fourth pharyngeal pouches fail to develop. The third pouches give the two inferior parathyroids and the thymus. The fourth pouches give the superior parathyroids. So again, PTH is low and calcium is low.

★ High-yield tip #7

Calcitonin

Calcitonin is increased in medullary thyroid carcinoma, not papillary thyroid carcinoma. You can also get C-cell hyperplasia, which has appeared on an NBME question. Know the mechanism: calcitonin inhibits osteoclast activity. Bisphosphonates such as alendronate also inhibit osteoclasts, so think of them as the outside drug that does what calcitonin does inside the body.

★ High-yield tip #8

Medullary thyroid carcinoma and MEN2

Medullary thyroid carcinoma shows amyloid on biopsy, with apple-green birefringence on Congo red stain. It can also be part of MEN2, both 2A and 2B. Both come from the RET proto-oncogene and include pheochromocytoma and medullary thyroid cancer. MEN2A adds parathyroid adenoma or diffuse four-gland hyperplasia. MEN2B adds mucosal neuromas and a marfanoid body habitus.

★ High-yield tip #9

RET on the exam

As just mentioned, RET is for MEN2, both 2A and 2B. A bonus point: when MEN2 shows up on the exam, they don’t need to give you the whole constellation, because real patients don’t develop every finding at once. An NBME question can simply say the patient has medullary thyroid cancer and ask which gene is mutated. The answer is RET.

★ High-yield tip #10

Signet ring cells

Signet ring cells contain mucin and are classic for gastric cancer, which can give a leather-bottle appearance of the stomach called linitis plastica. Gastric cancer can spread to both ovaries, and those metastases are called Krukenberg tumors.

★ High-yield tip #1

Where students slip

This is where students slip: with exogenous T₃, T₄ is decreased, not increased. Memorize this: T₄ is the thyroid’s main product, and it is converted to T₃ in the tissues. The FDA label even notes that serum T₄ can’t be used to monitor liothyronine.

★ High-yield tip #2

Exogenous levothyroxine

Choice B would be correct if we gave exogenous levothyroxine, which is T₄. T₄ would go up, and it would be converted to T₃ in the periphery, so T₃ would also be high. That would cause negative feedback, so TSH would be low.

★ High-yield tip #3

The two patterns to remember

So the two patterns to remember: exogenous T₃ gives you ↑ T₃, ↓ T₄ and ↓ TSH. Exogenous T₄, or levothyroxine, gives you ↑ T₃, ↑ T₄ and ↓ TSH.

★ High-yield tip #4

Subtle hypothyroid findings

Irregular menses are extremely important in hypothyroidism, and low mood, dysthymia or depression can be seen too. A heart rate of 55 to 60 can be normal in a healthy person, but NBME exams like to use it, and it can support hypothyroidism when you are not sure. The patient does not have to be obese; an overweight BMI can still fit.

★ High-yield tip #5

Hypothyroid lab clues

Hypothyroidism can raise total cholesterol, which should be under 200. A raised AST can look strange, but thyroid dysfunction can cause transaminitis, with a raised AST, ALT, or both. And creatine kinase can rise from hypothyroid myopathy, even when the question never mentions proximal muscle weakness or pain.

★ High-yield tip #6

Hypothyroid clues recap

Beyond the buzzy findings like constipation, brittle hair, dry skin and cold intolerance, know these hypothyroid clues: menstrual irregularities, dysthymia or depression, apathy, bradycardia, increased total cholesterol, transaminitis, and hypothyroid myopathy with an increased CK.

★ High-yield tip #1

Menses and BMI in hypothyroidism

A BMI doesn’t have to be high to fit hypothyroidism; 25 is right at the cutoff where overweight begins. Menstrual irregularities are extremely high yield for hypothyroidism on the USMLE, alongside fatigue and weight gain.

★ High-yield tip #2

Why the menses are irregular

The mechanism behind the irregular menses is a little unusual. Low thyroid hormone can raise TRH, and TRH can stimulate prolactin release. Raised prolactin inhibits GnRH release, which can disturb the menstrual cycle. Don’t lean on that mechanism, because it can cost you questions. The main control of prolactin is dopamine, which inhibits its release. Questions are far more likely to describe a cut pituitary stalk, where loss of dopamine inhibition lets prolactin rise.

★ High-yield tip #3

Heart rate and mood

A heart rate of 55 is a sneaky clue USMLE likes to use. A heart rate of 72 doesn’t exclude hypothyroidism, and healthy people can have a rate of 55. But if you already suspect hypothyroidism, a rate of 55 or 60 supports it. Short, quiet answers suggest low mood, and hypothyroidism is a cause of dysthymia and depression.

★ High-yield tip #4

Cholesterol

So questions can give you increased serum cholesterol in hypothyroidism. Vignettes, especially at the Step 2 CK level, may simply say the total cholesterol is 300. Just know that dyslipidemia can be seen with hypothyroidism.

★ High-yield tip #5

Creatine kinase

In hypothyroidism, creatine kinase goes up, not down, because of hypothyroid myopathy. There can be proximal muscle weakness or pain, with breakdown of some skeletal muscle that raises serum CK.

★ High-yield tip #6

Transaminases

The USMLE can give you an elevated ALT, AST, or both in hypothyroidism. On NBME exams, you may see a hypothyroid vignette with only the AST elevated and nothing said about the ALT. It seems odd, but thyroid dysfunction can cause transaminitis.

★ High-yield tip #7

Amyloid and the thyroid

Apple green birefringence with Congo red stain means amyloid, made of beta-pleated sheets. You can find dozens of causes of amyloidosis, but the highest-yield thyroid link for USMLE is medullary thyroid carcinoma. Renal amyloidosis, cardiac amyloidosis, or amyloid with autoimmune disease are not impossible, but none is the most likely answer here.

★ High-yield tip #8

Hypothyroid recap

Look beyond cold intolerance, constipation, weight gain, brittle hair and dry skin, which are often left out because they are too easy. Know menstrual irregularities, increased CK from hypothyroid myopathy, hypercholesterolemia, transaminitis, dysthymia or depression, and bradycardia.

★ High-yield tip #1

Autoimmune diseases go together

Autoimmune diseases go together. You don’t need to memorize strict HLA associations. The vignette can tell you that the patient or a family member has another autoimmune disease, such as vitiligo, rheumatoid arthritis or lupus. The implication is simply that autoimmunity is in play.

★ High-yield tip #2

Another example: pernicious anemia

To reinforce the point with another example: a question may say a patient has vitamin B₁₂ deficiency and also has vitiligo. The implication is that the B₁₂ deficiency is due to pernicious anemia, because autoimmune diseases go together.

★ High-yield tip #3

Treating Graves’ disease

Graves’ disease is treated with thionamides, such as propylthiouracil and methimazole. Both inhibit thyroid peroxidase. PTU also blocks the peripheral conversion of T₄ to T₃. Both can cause agranulocytosis, a severe form of neutropenia.

★ High-yield tip #4

Thyroid storm

In thyroid storm, PTU is classically chosen over methimazole because it also blocks peripheral T₄ to T₃ conversion. Steroids are given too; they also lower T₄ to T₃ conversion, and steroids are used for the eye disease, the proptosis or exophthalmos. Potassium iodide, given after the thionamide, blocks thyroid hormone release, and propranolol treats the tachycardia and also blocks T₄ to T₃ conversion.

★ High-yield tip #5

Hashimoto thyroiditis

Anti-microsomal antibodies point to Hashimoto thyroiditis. Hashimoto causes hypothyroidism, not hyperthyroidism, so you’d see ↓ T₄ with ↑ TSH. On histology, USMLE wants you to know there is a lymphocytic infiltrate within the thyroid gland.

★ High-yield tip #6

Hashimoto findings beyond the buzzwords

Beyond the buzzy findings, cold intolerance, constipation, dry skin and brittle hair, know the others: menstrual irregularities, dysthymia or depression, transaminitis with an increased ALT, AST or both, and hypothyroid myopathy with an increased creatine kinase. These are very important findings.

★ High-yield tip #7

Primary biliary cholangitis

Anti-mitochondrial antibodies are for PBC, primary biliary cholangitis, formerly called primary biliary cirrhosis. Picture a middle-aged woman with generalized itching, high cholesterol, increased alkaline phosphatase, and jaundice with a rising bilirubin as the disease advances. The vignette may say a family member has an autoimmune disease, because autoimmune diseases go together.

★ High-yield tip #8

A gallstone in a PBC question

The question may also show a stone in the gallbladder. That confuses students, who start weighing other biliary diagnoses, such as cholelithiasis, against PBC. Gallstones are very common and often silent, so a stone can simply be an incidental finding. Ursodiol, or ursodeoxycholic acid, is a treatment for PBC.

★ High-yield tip #9

The three Hashimoto antibody names

Anti-thyroperoxidase is the same thing as anti-microsomal, and both are for Hashimoto. Anti-TPO, also called anti-microsomal, and anti-thyroglobulin: these are the three antibody names you need to know for Hashimoto thyroiditis.

★ High-yield tip #1

Know all three names

The diagnosis is de Quervain thyroiditis, also called subacute granulomatous thyroiditis, or simply subacute thyroiditis. Know all three names. A question can give you this same easy one or two line vignette, and the answer is just ‘subacute thyroiditis’. Students get confused because they are looking for de Quervain or subacute granulomatous.

★ High-yield tip #2

TSH in hyperthyroidism

In primary hyperthyroidism, such as thyroiditis, TSH is suppressed. You would only see a high TSH with hyperthyroidism if there were a central cause, like a TSH-secreting tumor of the anterior pituitary, which is rare and essentially never the answer on the USMLE.

★ High-yield tip #3

The triphasic course of thyroiditis

De Quervain thyroiditis, drug-induced thyroiditis, for example from amiodarone or lithium, and postpartum thyroiditis, which is silent or painless thyroiditis occurring after delivery, can all follow a triphasic course: a hyperthyroid phase, then a hypothyroid phase, then recovery.

★ High-yield tip #4

Why exams show the hyperthyroid phase

For de Quervain and postpartum thyroiditis, the USMLE usually gives you the hyperthyroid state. Why? If they gave you de Quervain in the hypothyroid state, low uptake would be the obvious, logical choice even if you didn’t know the physiology. They want to test that you know uptake is low even when the patient is hyperthyroid.

★ High-yield tip #5

Lithium and amiodarone

Drug-induced thyroiditis is the exception to that exam pattern. NBME questions often just say the patient is on lithium or amiodarone and ask which thyroid problem you’d expect, and the answer is hypothyroidism. When they play with the uptake arrows, it tends to be de Quervain, the highest-yield diagnosis here.

★ High-yield tip #6

Recap of low uptake

To recap: choose decreased uptake in the hyperthyroid state not only for de Quervain, but also for drug-induced thyroiditis from amiodarone or lithium, and for silent thyroiditis, including postpartum thyroiditis, even though the patient is hyperthyroid.

★ High-yield tip #7

When uptake is increased

If you chose increased uptake in this hyperthyroid setting, you would pick E: ↓ TSH, ↑ T₄, ↑ uptake. It is wrong here, but it would be correct for Graves’ disease, toxic adenoma, and toxic multinodular goiter.

★ High-yield tip #1

Hashimoto antibodies and the gut

Besides anti-microsomal, or anti-thyroid peroxidase, antibodies, you can also see anti-thyroglobulin antibodies in Hashimoto thyroiditis. Thyroid dysfunction also affects the gut: hypothyroidism causes constipation, and hyperthyroidism causes diarrhea.

★ High-yield tip #2

Menstrual changes

Abnormal menses can occur with both hypothyroidism and hyperthyroidism. In hypothyroidism, free T₄ is low, so the hypothalamus raises TRH to compensate. TRH also stimulates prolactin. When prolactin goes up, it inhibits GnRH release, and that can cause abnormal menses.

★ High-yield tip #3

Biopsy questions

When a question asks what a biopsy will show, you don’t have to be a histopathologist to answer it. You just have to know the diagnoses well, and then infer the answer.

★ High-yield tip #4

The Step exams overlap

On histology questions you can often eliminate your way to the answer, but knowing that Hashimoto is also called chronic lymphocytic thyroiditis is the shortcut. It sounds like a Step 1 fact, but a Step 2 CK form asked exactly this, and the answer was lymphocytic infiltration. The Step exams overlap a lot.

★ High-yield tip #5

Germinal centers

Germinal centers form inside lymphoid follicles. There, B cells activated by antigen, with help from T cells, proliferate and become plasma cells or memory B cells. Lymphocytic infiltration with germinal center formation is what you see in Hashimoto thyroiditis.

★ High-yield tip #6

Granulomas in de Quervain

Multinucleated giant cells and disrupted follicles point to de Quervain thyroiditis, also called subacute granulomatous thyroiditis. Granulomas are collections of activated macrophages, also called epithelioid macrophages or histiocytes. These macrophages fuse and become multinucleated. As an aside, sarcoidosis gives non-caseating granulomas in the lungs, built from the same epithelioid macrophages.

★ High-yield tip #7

When de Quervain is the answer

De Quervain thyroiditis is the answer when the thyroid is painful or tender. Only about half the time will the question tell you that a viral infection came first. The same is true for ITP: the exam mentions the preceding viral infection only about half the time.

★ High-yield tip #8

De Quervain uptake

Know that radioiodine uptake is low in de Quervain thyroiditis, even if the patient is hyperthyroid. It can present as hypothyroid or hyperthyroid. In the hyperthyroid version, uptake is still low, not increased, because the gland isn’t making more hormone. Inflammation simply lets stored thyroid hormone leak into the blood.

★ High-yield tip #9

Medullary thyroid carcinoma

Amyloid derived from calcitonin is the buzzword for medullary thyroid carcinoma. It’s the highest-yield thyroid cancer on USMLE because there’s so much to ask about. The amyloid shows apple-green birefringence with Congo red stain, and the tumor is associated with the RET gene.

★ High-yield tip #10

Familial medullary cancer

RET doesn’t require all the features of MEN2A or MEN2B. A family can have medullary thyroid cancer alone. Say a 20-year-old man has medullary thyroid cancer, and his brother and father had it too. The answer is RET. You may think other findings are needed, but medullary thyroid cancer alone is enough.

★ High-yield tip #11

Calcitonin

Calcitonin is classically increased in medullary thyroid carcinoma. Know its mechanism: calcitonin inhibits osteoclast activity, and they will ask that. Bisphosphonates, given as drugs, have the same end effect. They also inhibit osteoclasts.

★ High-yield tip #12

Papillary thyroid carcinoma

Branching papillae with nuclear grooves and inclusions describe papillary thyroid carcinoma. Besides the papillary structure, it has psammoma bodies, which are whorled, round calcifications. Psammoma bodies show up in papillary thyroid carcinoma, serous cystadenocarcinoma of the ovary, meningioma and mesothelioma. Orphan Annie eye nuclei are also seen, but they are lower yield.

★ High-yield tip #13

Reasoning out Graves disease

Say you still weren’t sure, and scalloped colloid means nothing to you. Hyperplastic follicles point to Graves disease. In Hashimoto, a hypothyroid condition, would the follicles be hyperplastic? That doesn’t make sense, since these follicular cells are not overproducing thyroid hormone. In Graves disease, by contrast, you have increased T₃ and T₄ and a suppressed TSH. Look for proptosis, also called exophthalmos, and pretibial myxedema.

★ High-yield tip #1

Autoimmune diseases cluster

Autoimmune diseases go together: one in the patient or the family raises the risk of others. You don’t need strict HLA associations. Instead of a sister with lupus, the question could have said vitiligo, pernicious anemia, or a sister with celiac disease.

★ High-yield tip #2

Other uptake patterns

A single round area of uptake would fit a toxic adenoma. Multiple spots in an elderly patient would fit toxic multinodular goiter. No uptake at all could mean exogenous thyroid hormone. And it’s not de Quervain thyroiditis, which has a tender or painful gland and decreased uptake, even when the patient is hyperthyroid.

★ High-yield tip #3

Graves findings

Graves can cause diarrhea and menstrual irregularities, and you can still get muscle weakness. But the two findings specific to Graves disease that USMLE wants you to know are pretibial myxedema and proptosis, also called exophthalmos or ophthalmopathy.

★ High-yield tip #4

Treating Graves

For Graves, you give PTU or methimazole, and they want you to know these can cause agranulocytosis. For the ophthalmopathy, give steroids. For the tachycardia, give a beta blocker, propranolol, which also inhibits peripheral conversion of T₄ to T₃. Potassium iodide can be used in some cases.

★ High-yield tip #5

Anti-Smith and lupus

Anti-Smith antibodies point to SLE. The Smith antigen is a component of the nucleus, and anti-Smith is more specific for lupus than anti-dsDNA. USMLE wants you to know that besides the malar rash, a type III hypersensitivity from immune complex deposition, the blood is commonly affected, for example with thrombocytopenia.

★ High-yield tip #6

Lupus on the USMLE

Musculoskeletal involvement such as arthritis affects about 80 to 90 percent of patients with SLE, and you’ll see it in nearly every USMLE lupus vignette. So if a 34-year-old woman has arthritis and low platelets, and nothing else, that’s an easy diagnosis: SLE. They also like discoid lupus, skin findings, and mouth ulcers.

★ High-yield tip #7

Primary biliary cholangitis

Anti-mitochondrial antibodies mean primary biliary cholangitis, formerly called primary biliary cirrhosis. Expect a woman in her 40s or 50s with high cholesterol, raised alkaline phosphatase and bilirubin, and generalized itching. They may mention another autoimmune disease, such as Hashimoto thyroiditis, but not IBD, so you don’t confuse it with primary sclerosing cholangitis.

★ High-yield tip #8

The incidental gallstone

They can also show an incidental gallbladder stone on ultrasound, which confuses students. Gallstones are very common and most are silent, so a stone can simply be an incidental finding. She can still have a stone, and it does not change the diagnosis: the underlying condition in that vignette is still primary biliary cholangitis.

★ High-yield tip #9

Hashimoto antibodies

An enzyme targeting tyrosine residues sounds obscure, but it is thyroid peroxidase, and anti-thyroid peroxidase antibodies, also called anti-microsomal antibodies, mean Hashimoto thyroiditis. In thyroid hormone synthesis, tyrosine residues on thyroglobulin are iodinated, and thyroid peroxidase is the enzyme responsible for that iodination. Antibodies against thyroglobulin, the precursor of thyroid hormone, also mean Hashimoto thyroiditis.

★ High-yield tip #10

Hypothyroidism review

As a quick review, hypothyroidism gives cold intolerance, constipation, brittle hair, dry skin, menstrual irregularities, high cholesterol and bradycardia. You can see raised transaminases, and raised creatine kinase from hypothyroid myopathy. Mood changes include depression.

★ High-yield tip #1

De Quervain and the viral clue

De Quervain thyroiditis, also called subacute thyroiditis or subacute granulomatous thyroiditis, is the USMLE answer for a tender or painful thyroid. Questions mention a preceding viral infection in only about half of vignettes. An easier version would say she recently recovered from a viral upper respiratory infection and now has a painful thyroid. You must know that.

★ High-yield tip #2

Why uptake is low in de Quervain

In de Quervain thyroiditis, iodine uptake by the thyroid is decreased, even if the patient is hyperthyroid. The disease moves through hyperthyroid, euthyroid and hypothyroid phases, and in the hyperthyroid phase uptake is low because the gland isn’t making new hormone. Inflammation disrupts the follicles, so preformed hormone is released into the blood. They can also ask the mechanism: release of preformed thyroid hormone.

★ High-yield tip #3

Uptake patterns in hyperthyroidism

Low uptake separates de Quervain from Graves disease, which has diffusely increased uptake because the gland is making new hormone. Toxic multinodular goiter, a condition of the elderly, shows multifocal uptake. A toxic adenoma, a single nodule, shows one focal area of uptake. Those causes of hyperthyroidism have high or normal uptake. De Quervain has decreased uptake.

★ High-yield tip #4

Hashimoto thyroiditis

Anti-microsomal antibodies, also called anti-thyroid peroxidase antibodies, mean Hashimoto thyroiditis, where you can also see anti-thyroglobulin antibodies. That is hypothyroidism, not hyperthyroidism: increased TSH and decreased T₄. You’d expect cold intolerance, not heat intolerance, and bradycardia, not tachycardia.

★ High-yield tip #5

Hashimoto and a tender thyroid

Hashimoto thyroiditis is virtually never linked to a tender thyroid on the exam. In maybe one out of 15 questions there’s mild tenderness, but don’t read between the lines. Students also ask about the transient hyperthyroid phase of Hashimoto. That’s getting too nitpicky, and it will cost you questions.

★ High-yield tip #6

Thyrotropin and Graves disease

This is important: thyrotropin is another name for thyroid-stimulating hormone. USMLE wants you to know it. The mechanism of Graves disease is antibodies against the TSH receptor, which you can call thyrotropin receptor antibodies. They’re called thyroid-stimulating immunoglobulin, or TSI. Graves gives increased T₃ and T₄ and decreased TSH.

★ High-yield tip #7

The Jod-Basedow phenomenon

The Jod-Basedow phenomenon is unlikely to show up on USMLE. It happens in someone with a pre-existing thyroid disorder, such as Graves disease, who is exposed to an excessive amount of iodine and becomes hyperthyroid as a result.

★ High-yield tip #8

The Wolff-Chaikoff effect

Contrast the Jod-Basedow phenomenon with the Wolff-Chaikoff effect. A person with a healthy thyroid is exposed to excessive iodine, and the gland transiently shuts off hormone production. Think of it as a safety mechanism, a natural negative feedback against too much iodine. People with thyroid disorders like Graves lack this protection, so they make more thyroid hormone instead.

★ High-yield tip #1

Triiodothyronine versus levothyroxine

If you’ve worked through high-yield thyroid arrow questions before, this type won’t feel hard, but many students get tripped up. Know the two drugs apart: triiodothyronine is exogenous T₃, and levothyroxine, in contrast, is exogenous T₄. Both suppress TSH, but they give different T₃ and T₄ arrows.

★ High-yield tip #2

The sentence to memorize

Here is the sentence to memorize: T₄ is converted to T₃ in the tissues, but giving T₃ does not raise T₄. So with exogenous T₃, T₄ is a down arrow, not an up arrow, because the suppressed thyroid stops making it.

★ High-yield tip #3

If it were levothyroxine

Now compare levothyroxine, exogenous T₄. TSH is suppressed by the same negative feedback, and the thyroid’s own production of T₃ and T₄ drops. But T₄ is high, because you’re giving it, and that T₄ is converted peripherally into T₃, so T₃ is high too. If the question had said levothyroxine, the answer would be E: decreased TSH, increased T₃ and T₄.

★ High-yield tip #4

Don’t overthink T3

Exam tip: don’t overthink the obvious arrow. When a patient is receiving T₃, some students suspect a trick question and pick a low T₃. It isn’t a trick. The hormone you give is the hormone that goes up, so T₃ is up.

★ High-yield tip #1

Thyrotropin means TSH

Thyrotropin is another way of writing TSH, thyroid-stimulating hormone. That’s not being fancy. You have to know it, and students get it wrong because they didn’t know it meant TSH.

★ High-yield tip #2

Graves mechanism and labs

The mechanism is activating antibodies against the TSH receptor, also called the thyrotropin receptor. So the gland takes up more iodine and makes more thyroid hormone. T₃ and T₄ go up, and TSH is suppressed: primary hyperthyroidism. Contrast Hashimoto, a primary hypothyroidism, where T₄ is down and TSH is up.

★ High-yield tip #3

Eyes and skin in Graves

Graves can cause proptosis, also called exophthalmos, a protrusion of the eyes from glycosaminoglycan deposition, and pretibial myxedema. That’s because orbital and dermal fibroblasts also have TSH receptors. The antibodies activate them, and they secrete GAGs. Know this mechanism.

★ High-yield tip #4

Only Graves causes them

Among the causes of hyperthyroidism, you’ll only see exophthalmos and pretibial myxedema in Graves disease. Toxic adenoma, toxic multinodular goiter, and de Quervain subacute granulomatous thyroiditis don’t cause them. They are specific for Graves on USMLE because of the mechanism we just described.

★ High-yield tip #5

Hashimoto uptake and histology

Anti-microsomal antibodies, also called anti-thyroid peroxidase antibodies, point to Hashimoto thyroiditis, where you can also see anti-thyroglobulin antibodies. That’s hypothyroidism, so uptake is usually decreased, though it can vary, sometimes described as patchy: not necessarily zero, just less than a normal scan. Besides the antibodies, know that Hashimoto shows a lymphocytic infiltrate, since they can ask you for the histology.

★ High-yield tip #6

Calcium distractors

On the exam’s reference range, normal calcium is 8.4 to 10.2 mg/dL. Low and high calcium are here as distractors, for students who mix up the parathyroid and the thyroid. There are four parathyroid glands on the back of the thyroid. Hypoparathyroidism, for example after thyroidectomy removes the parathyroids, causes low calcium.

★ High-yield tip #7

DiGeorge syndrome

You can also get low calcium in DiGeorge syndrome, with aplasia of the third and fourth pharyngeal pouches. Those pouches form the parathyroid glands and the thymus, so the result is hypocalcemia.

★ High-yield tip #8

High and low calcium in hyperparathyroidism

Hypercalcemia could be primary hyperparathyroidism, from a parathyroid adenoma or multigland hyperplasia. Note that in secondary hyperparathyroidism, such as from renal failure, calcium is actually low. That could also be what choice C refers to.

★ High-yield tip #9

Spotting de Quervain

A post-viral state points to de Quervain thyroiditis. The viral infection is mentioned in only about half of vignettes. They can just say a 32-year-old woman has a painful, tender thyroid gland, with no other information, and that’s de Quervain until proven otherwise. She can be hyperthyroid, with tachycardia and heat intolerance.

★ High-yield tip #10

Uptake in de Quervain

In de Quervain thyroiditis, uptake is low. The gland isn’t making new thyroid hormone; inflammation lets preformed hormone leak into the blood. Uptake stays low even when the patient is hyperthyroid, and students get that wrong.

★ High-yield tip #1

Steroid hormones and estrogen

Most steroid hormones, such as testosterone, progesterone, cortisol and aldosterone, are taught to bind receptors in the cytosol, which then move into the nucleus. Estrogen is the odd one out. It is a steroid hormone, but it mostly binds receptors in the nucleus.

★ High-yield tip #2

Peptide hormones

Nearly every other hormone you can think of, such as prolactin, growth hormone, insulin, TSH, ACTH, LH and FSH, is a peptide hormone. Peptide hormones cannot cross the cell membrane, so they bind receptors on the cell membrane.

★ High-yield tip #3

The insulin receptor

Insulin is a peptide hormone too, so it binds a cell membrane receptor, and that receptor is a tyrosine kinase. Insulin directly increases tyrosine kinase activity and indirectly increases serine-threonine kinase activity. It also decreases protein breakdown, because insulin is a fed-state hormone, not a fasting-state hormone.

★ High-yield tip #4

The reverse question

Expect a twist on this question. A researcher finds that a hormone binds a cell membrane receptor, and you are asked which hormone it is. Four options are steroid hormones and one, such as prolactin, growth hormone or ACTH, is not. Even if you don’t remember the binding, pick the odd one out, or simply recall that peptide hormones bind membrane receptors.

★ High-yield tip #5

Recap

To recap: vitamin A, vitamin D and thyroid hormone bind intranuclear receptors through zinc finger motifs and upregulate transcription. Most steroid hormones bind receptors in the cytosol. Estrogen, although a steroid, mainly binds intranuclear receptors. Peptide hormones, which means nearly all other hormones, bind cell membrane receptors.

★ High-yield tip #1

Why T4 falls when you take T3

The key rule: T4 can be converted peripherally to T3, but extra T3 does not make T4. So when someone takes T3 alone, TSH is suppressed, the thyroid makes less of its own T3 and T4, the T3 being taken keeps T3 high, and nothing replaces the missing T4. T4 goes down, not up.

★ High-yield tip #2

Levothyroxine gives a different pattern

Compare a patient taking levothyroxine, which is exogenous T4. TSH would still be suppressed, but T3 and T4 would both rise, because the T4 she takes is converted peripherally to T3. That pattern, ↓ TSH with ↑ T3 and ↑ T4, is choice E.

★ High-yield tip #3

Untreated Hashimoto thyroiditis

Now compare hypothyroidism that is not being treated with T3 or T4, for example Hashimoto thyroiditis on its own. TSH would be high and T4 low; T3 falls less often. Among these options, the closest pattern is choice D, ↑ TSH with ↓ T3 and ↓ T4.

★ High-yield tip #1

De Quervain thyroiditis

A tender, painful thyroid is de Quervain thyroiditis until proven otherwise. Know its other names: subacute granulomatous thyroiditis, or simply subacute thyroiditis. Many patients have had a viral upper respiratory infection 2 to 8 weeks before, but not all, so the question may leave it out, so do not rely on it as a crutch.

★ High-yield tip #2

Increased uptake means new hormone

Increased uptake means the gland is making new thyroid hormone. Graves’ disease, from antibodies against the TSH receptor, shows diffusely increased uptake. A toxic adenoma, described here wordily as toxic adenomatous autonomous secretion, shows increased uptake in one focal area, the nodule. Both cause hyperthyroidism with a suppressed TSH.

★ High-yield tip #3

Hashimoto thyroiditis

B, anti-microsomal antibodies, points to Hashimoto thyroiditis. These are also called anti-thyroid peroxidase antibodies, and anti-thyroglobulin antibodies can be present too. Hashimoto causes hypothyroidism, so TSH should be elevated. Uptake into the gland can be reduced as well, so it is the high TSH that separates it from de Quervain.

★ High-yield tip #4

Factitious thyrotoxicosis

Taking thyroid hormone, such as levothyroxine, is called factitious thyrotoxicosis. It suppresses TSH and reduces uptake into the thyroid gland, just like thyroiditis, so it is a tempting choice. But neck tenderness is not classic for it, so when the thyroid is tender, look for a better answer.

★ High-yield tip #5

Know the normal TSH range

You may not be given normal ranges, especially on Step 2 CK, so know that a normal TSH is roughly 0.4 to 4.8 mIU/L, varying slightly by lab. A value below that range, with symptoms such as palpitations and restlessness, points to hyperthyroidism.

★ High-yield tip #1

The Graves mechanism

In Graves’ disease, antibodies called thyroid-stimulating immunoglobulins (TSI) bind to and activate the TSH receptor. The result is diffuse activation of the whole thyroid gland. Endogenous TSH is suppressed, while T3 and T4 are high.

★ High-yield tip #2

Bullous pemphigoid versus pemphigus vulgaris

Bullous pemphigoid has autoantibodies against hemidesmosomes, specifically the bullous pemphigoid antigen, in the basement membrane of the skin. In contrast, pemphigus vulgaris has antibodies against desmosomes, specifically the desmoglein proteins within the epidermis. Knowing both is pass level. This question is a little trickier because it asks you to integrate them with Graves’ disease through the type of hypersensitivity.

★ High-yield tip #3

Other type 2 reactions

Other high-yield type II hypersensitivities to know are pernicious anemia, idiopathic thrombocytopenic purpura, and heparin-induced thrombocytopenia. Like Graves’ disease and bullous pemphigoid, each is driven by antibodies directed against the body’s own cells or proteins.

★ High-yield tip #4

Anaphylaxis

A, anaphylaxis, is a type I hypersensitivity. An antigen, such as a bee sting or peanut protein, binds IgE that is already attached to the surface of mast cells and basophils. The bound IgE molecules cross-link, the cells degranulate and release histamine, and the result is hypotension and swelling.

★ High-yield tip #5

The Arthus reaction

B, the Arthus reaction, is a type III hypersensitivity caused by immune complexes. It follows an injection, such as a vaccine, with local swelling, redness and pain at the injection site. It is not immediate like type I, but appears within a few hours and usually peaks within 24 hours. Avoid calling it delayed, a word that suggests the T cell response of type IV.

★ High-yield tip #6

Contact dermatitis

D, contact dermatitis, is a type IV hypersensitivity, a T cell response. Classic triggers are nickel from the back of a watch, sunscreen, and latex. A vignette might describe a woman working in an anatomy lab, or a nurse in a new facility, with diffuse redness on her hands. The PPD test for tuberculosis is also type IV.

★ High-yield tip #7

Type 4 timing

Poison ivy, oak and sumac are also high-yield, with linear rows of vesicles. Type IV reactions are delayed, meaning they do not occur immediately. The rash takes at least a day, and often a few days, to appear after contact.

★ High-yield tip #8

Serum sickness

E, serum sickness, is type III, the same as the Arthus reaction, so it is driven by immune complexes. Classically a drug or foreign protein is given, and fever, rash and joint pain follow, usually one to two weeks after a first exposure, or within a week if the patient was exposed before. Type III reactions can also follow infections, such as hepatitis B and C.

★ High-yield tip #1

TBG in pregnancy

In pregnancy, estrogen makes the liver produce more TBG. The extra TBG binds up free T₄ in the blood. The pituitary senses the dip in free T₄ and briefly raises TSH. Total T₄ climbs until free T₄ returns to normal, and then TSH settles back to normal too. Separately, high hCG late in the first trimester can briefly lower TSH.

★ High-yield tip #2

The pregnancy pattern on the exam

For the exam, just remember the end result: in pregnancy, TSH and free T4 are normal and total T4 is increased, because estrogen increases TBG. This is very high yield. A pediatric question like this one is really testing whether you know the pregnancy pattern, because the concept is the same, just in reverse.

★ High-yield tip #3

Thyrotropin and Graves

Thyrotropin is simply another name for TSH, thyroid-stimulating hormone. You may see the term in a tricky Graves disease question. There, the autoantibody that activates the TSH receptor is called thyroid-stimulating immunoglobulin, or TSI. A question might call it a thyrotropin receptor antibody, which means the same thing as a TSH receptor antibody.

★ High-yield tip #4

Sick euthyroid syndrome

Sick euthyroid syndrome is high yield. During acute stress, such as acute illness, recent surgery or trauma, less T4 is converted into T3. One proposed reason is the acute rise in cortisol. T3 falls, and T4 is shunted toward an inactive form called reverse T3, which rises. TSH and T4 usually stay normal.

★ High-yield tip #5

The sick euthyroid pattern

The sick euthyroid pattern is decreased T3, increased reverse T3, and usually normal TSH and T4. Students often miss this diagnosis, but it does appear on practice exams.

★ High-yield tip #6

Recap

To recap: in pregnancy, TBG goes up, TSH and free T4 are normal, and total T4 is increased. So in a child with a normal TSH, a normal free T4 and a decreased total T4, think thyroxine-binding globulin deficiency.

★ High-yield tip #1

Thyroid tests in pregnancy

Why is total T4 increased in pregnancy? Estrogen makes the liver produce more thyroxine-binding globulin, or TBG. More TBG means more bound T4, so total T4 rises while TSH and free T4 stay normal. This combination of findings in pregnancy is extremely high yield.

★ High-yield tip #2

Cretinism

Cretinism is congenital hypothyroidism. Endemic cretinism comes from iodine deficiency in areas where iodine is scarce, while in countries with enough iodine the most common cause is a thyroid gland that did not develop fully. Expect a child, usually in the first year of life, with intellectual disability, a pot belly, a large tongue and poor bone growth.

★ High-yield tip #3

Why cretinism harms the brain

Why the intellectual disability? Thyroid hormone is needed for normal brain development, including myelination, so untreated congenital hypothyroidism harms the developing brain. It is also needed for bone growth.

★ High-yield tip #4

Subclinical hypothyroidism

Congenital subclinical hypothyroidism is a made-up distractor. Subclinical hypothyroidism in general, not congenital, is classically an adult with an elevated TSH but normal T3 and T4. If a vignette describes an asymptomatic person with that pattern, it is subclinical hypothyroidism. Most cases are monitored rather than treated.

★ High-yield tip #5

Euthyroid sick syndrome

Euthyroid sick syndrome is an underrated, high-yield diagnosis. Think of it in a patient who has had surgery, recent trauma, or is being weaned off a ventilator. TSH and T4 show no change, T3 is decreased, and reverse T3 is increased.

★ High-yield tip #6

Why euthyroid sick happens

Several mechanisms are proposed. One is that cortisol rises acutely during stress, and less T4 is converted into T3. So T3 goes down, and T4 is shunted to an inactive form called reverse T3, which goes up. TSH and T4 stay normal. Students often skip this diagnosis because it seems odd, and then it shows up on the exam.

★ High-yield tip #7

Silent thyroiditis

Silent thyroiditis is tested less often. It is a painless autoimmune thyroiditis, and its postpartum form looks like Hashimoto thyroiditis under the microscope. Picture a woman with no previous thyroid problems who, within a year of giving birth, develops hyperthyroid and then hypothyroid values with a nontender thyroid. For example, she gave birth four months ago and now has hypothyroid labs.

★ High-yield tip #8

Reason from pregnancy

You do not need to memorize a list of rare conditions. Pregnancy values are so high yield that you can reason from them: TBG goes up in pregnancy, so the reverse pattern, a low total T4 with normal TSH and free T4, means TBG is down. Thyroid-binding globulin deficiency does appear in Step 2 CK pediatrics questions.

★ High-yield tip #1

Embryologic origin of thyroid cells

Embryologic origin is high yield. The follicular cells, which make the actual thyroid hormones T3 and T4, come from endoderm. The parafollicular C cells that produce calcitonin are classically taught as neural crest in origin. So for medullary thyroid carcinoma, know the neural crest link.

★ High-yield tip #2

Medullary carcinoma buzzwords

Buzzwords for medullary thyroid carcinoma: neural crest cells, parafollicular C cells, calcitonin, amyloid, Congo red stain and apple-green birefringence. Calcitonin is often elevated in the serum, because the tumor is made of calcitonin-producing C cells.

★ High-yield tip #3

Calcitonin is not just the opposite of PTH

Calcitonin works by inhibiting osteoclast activity. A common mistake is to think calcitonin is simply the opposite of PTH. PTH raises blood calcium partly by driving bone resorption, through osteoclasts. Calcitonin is released when serum calcium is high, and it lowers calcium mainly by inhibiting osteoclasts, so less calcium leaches out of bone, and by increasing calcium excretion in the urine.

★ High-yield tip #4

Bisphosphonates

A related point: bisphosphonates also inhibit osteoclast activity. Examples are alendronate for osteoporosis, and intravenous drugs such as zoledronic acid for hypercalcemia of malignancy. They work through a different mechanism than calcitonin, but the end effect on bone resorption is similar.

★ High-yield tip #5

Hereditary medullary carcinoma

Medullary thyroid carcinoma can be hereditary. If a question only says the patient’s father and brother had thyroid cancer and asks for the likely type, choose medullary thyroid carcinoma. Hereditary cases come from RET gene mutations on chromosome 10. Some families have only medullary thyroid cancer, a form now considered a variant of MEN 2A.

★ High-yield tip #6

MEN 2

It also occurs in multiple endocrine neoplasia type 2. Both MEN 2A and MEN 2B have medullary thyroid carcinoma and pheochromocytoma. MEN 2A adds parathyroid hyperplasia or adenoma. MEN 2B adds mucosal neuromas and marfanoid body habitus.

★ High-yield tip #7

Cretinism

In cretinism, or congenital hypothyroidism, poor myelin development causes intellectual disability. Endemic cretinism comes from iodine deficiency in areas where iodine is scarce. Thyroid hormone is needed for myelination, bone development and general metabolism.

★ High-yield tip #8

Leydig and Sertoli cells

Choice D, stimulation of Leydig cells, describes luteinizing hormone, LH. Leydig cells are in males, and the female equivalent is the theca cells. Choice E, stimulation of Sertoli cells in males, describes follicle-stimulating hormone, FSH. The female equivalent is the granulosa cells.

★ High-yield tip #1

Palpate first

This is the classic thyroid nodule workup, very high yield across Step 2 CK surgery, family medicine and internal medicine. It may sound obvious, but if a patient comes to the clinic and you are asked for the first step in evaluating for thyroid cancer, the answer is palpation of the thyroid gland, not a serum TSH.

★ High-yield tip #2

TSH comes next

After you palpate the gland and find a nodule, then you order a serum TSH. Guidelines recommend measuring TSH during the initial evaluation of every patient with a thyroid nodule. The TSH result then decides the next best step for the nodule.

★ High-yield tip #3

Echocardiography versus thyroid ultrasound

Students get this wrong by choosing echocardiography, an ultrasound of the heart. It plays no role in a thyroid nodule workup. Do not confuse it with ultrasound of the thyroid itself. Guidelines recommend thyroid ultrasound for every patient with a nodule, and FNA is usually done under ultrasound guidance, so an answer like ultrasound-guided FNA can also be correct.

★ High-yield tip #4

Low TSH means a scan

In contrast, if the TSH is decreased, the nodule may be hot. Hot nodules secrete hormone and are very rarely cancers. So instead of FNA, the next step is a radioiodine uptake scan, which tells us more about what is going on.

★ High-yield tip #5

Uptake patterns

If the scan shows uptake in the single nodule alone, that is a toxic adenoma. Diffuse uptake throughout the gland is consistent with Graves disease. Uptake in multiple nodules is toxic multinodular goiter. Remember, order the radioiodine uptake scan only when the TSH is low.

★ High-yield tip #6

The nodule algorithm

To sum up: the first step is palpating the thyroid. If that is not listed, check a serum TSH. If TSH is normal or elevated, the answer is fine-needle aspiration, or ultrasound-guided FNA. Echocardiography is always wrong here. If TSH is decreased, the answer is a radioiodine uptake scan.

★ High-yield tip #1

When to treat, TSH above 10

Guidelines list a few situations where we do treat subclinical hypothyroidism with levothyroxine. This matters more for Step 3, but it is worth knowing. The first is a TSH above 10.

★ High-yield tip #2

Other reasons to treat

Other indications include a positive antibody screen for Hashimoto thyroiditis, meaning antibodies against thyroid peroxidase, also called anti-microsomal antibodies, as well as pregnancy and clear hypothyroid symptoms. Before treating, the TSH is first repeated in 2 to 3 months to confirm that it stays high.

★ High-yield tip #3

Subclinical hypothyroidism versus euthyroid sick syndrome

Students often confuse this pattern with euthyroid sick syndrome. In euthyroid sick syndrome, TSH and T4 are usually normal, T3 is low, and reverse T3 is high. In subclinical hypothyroidism, TSH is high, while T3 and T4 are normal. Keep these two sets of arrows apart.

★ High-yield tip #1

An underrated diagnosis

Euthyroid sick syndrome, also known as nonthyroidal illness syndrome, is one of the most underrated high-yield diagnoses for Steps 1, 2 and 3. Resources often cover Graves disease, Hashimoto thyroiditis and de Quervain thyroiditis, but rarely this one, so students don’t recognize it when it appears.

★ High-yield tip #2

When to suspect euthyroid sick syndrome

Think of this diagnosis when the patient has recently had surgery or trauma, or is critically ill, for example in intensive care. One Step 2 CK level question describes a patient being weaned off a ventilator.

★ High-yield tip #3

Why the values change

During stress, high cortisol and inflammatory signals slow the enzyme that converts T4 into active T3 in the tissues, so regular T3 falls. T4 does not build up, because more of it is turned into reverse T3, an inactive form, which is also cleared more slowly. That is why reverse T3 rises. The normal T4 also helps keep TSH normal.

★ High-yield tip #4

A helpful comparison

This picture is driven by the acute illness and the body’s inflammatory response, not by disease of the thyroid itself. A useful way to remember it: euthyroid sick syndrome is roughly the thyroid version of anemia of chronic disease, where the liver makes an acute-phase protein, hepcidin, that locks iron away.

★ High-yield tip #5

Not subclinical hypothyroidism

Don’t confuse these values with subclinical hypothyroidism, where TSH is increased but T3 and T4 are normal. Euthyroid sick syndrome and subclinical hypothyroidism are often mixed up, so learn both sets of arrows side by side.

★ High-yield tip #6

Know the arrows

Take home this combination of arrows: normal TSH and T4, low T3 and high reverse T3. Euthyroid sick syndrome catches a lot of students off guard on the USMLE, but if you know it, it is an easy point.

★ High-yield tip #1

Histology still counts

This is a high-yield histology point for both Step 1 and Step 2. You don’t need to read a histology textbook, but a few facts like this one matter. Even a Step 2 level NBME, full of clinical questions, has asked for lymphocytic infiltration as the finding on biopsy in Hashimoto thyroiditis.

★ High-yield tip #2

Age and BMI

Hashimoto thyroiditis can occur in teenagers, and it shows up in NBME questions, so don’t rule it out as too young. The patient also does not need to be overweight, so a normal BMI should not trip you up.

★ High-yield tip #3

Bradycardia

USMLE vignettes like to give sinus bradycardia, defined as a rate under 60 beats per minute, in hypothyroidism. A healthy person can have a rate of 48 with no disease at all, but when you are thinking of hypothyroidism, a rate under 60 is a supporting clue.

★ High-yield tip #4

Menses in hypothyroidism

Periods can be irregular in the first years after menarche, but once cycles are established, new longer and heavier periods are a clue to hypothyroidism. Hypothyroidism can also stop periods altogether, so either pattern is a high-yield clue.

★ High-yield tip #5

Low mood

Hypothyroidism can cause low mood or depression, so a vignette may say the patient is socializing less with friends. Treating the hypothyroidism with levothyroxine, a T4 analog, can improve it. The USMLE can also say the patient makes little eye contact or is quiet during the exam, which reflects the same low mood.

★ High-yield tip #6

Hypothyroid myopathy

Know hypothyroid myopathy: a raised creatine kinase or proximal muscle weakness. The patient may have trouble getting up from a chair without help, or keeping the arms raised to brush her hair.

★ High-yield tip #7

Less obvious hypothyroid findings

Vignettes also like high cholesterol and raised liver transaminases, an odd finding that appears especially in Step 2 CK questions. Brittle hair, constipation, dry skin and weight gain can show up too, but those are the easy clues. Be aware of the less obvious findings as well.

★ High-yield tip #8

Riedel thyroiditis

A, fibrotic stroma, fits Riedel thyroiditis. The gland feels woody on exam because its stroma has become fibrotic, and the disease can affect other organs too. Like anaplastic carcinoma, it can extend into nearby structures such as the esophagus. But it is not the answer here.

★ High-yield tip #9

Follicular hyperplasia

B, follicular hyperplasia, may sound strange. Are we talking about the ovaries? No, this is clearly the thyroid. Follicular hyperplasia points to Graves disease, which causes hyperthyroidism, so it does not fit this patient.

★ High-yield tip #10

De Quervain thyroiditis

C and D test the two kinds of granulomas. Non-caseating granulomas fit de Quervain thyroiditis, also called subacute granulomatous thyroiditis. Expect a tender, painful thyroid after a viral infection. The question may not mention the infection, since not every patient reports one, but a painful thyroid on the USMLE means de Quervain.

★ High-yield tip #11

Caseating granulomas

Caseating granulomas point to tuberculosis, for example in the lungs, or to systemic fungal infections. Mycobacteria and fungi only rarely infect the thyroid, mostly in immunocompromised patients, so caseating granulomas are not the classic finding in thyroiditis.

★ High-yield tip #12

Take-home

Remember that the other name for Hashimoto thyroiditis is chronic lymphocytic thyroiditis. Not just on Step 1 but also on Step 2, they want you to know that the biopsy shows a lymphocytic infiltrate.

★ High-yield tip #1

How the exam words it

The vignette doesn’t need to tell you he works as a pharmacist; that would make it too easy. Recognize the pattern instead: a low TSH, a small gland and low radioiodine uptake. The answer choice may be written as surreptitious or as factitious thyrotoxicosis.

★ High-yield tip #2

Graves versus factitious thyrotoxicosis

A, Graves disease, also causes hyperthyroidism with a suppressed TSH. But radioiodine uptake is increased and diffuse. A palpable goiter isn’t required in Graves, and a question could call the gland non-palpable, but it won’t go out of its way to call it small. The increased, diffuse uptake is the key difference.

★ High-yield tip #3

Findings specific to Graves

Two findings are specific to Graves disease. The first is exophthalmos, or proptosis, where the eyes bulge forward. Among causes of hyperthyroidism, such as toxic adenoma or toxic multinodular goiter, exophthalmos tells you right away that the cause is Graves. The second is pretibial myxedema, a buildup of glycosaminoglycans in the skin of the shins.

★ High-yield tip #4

Graves cause and treatment

Graves disease is caused by an activating autoantibody against the TSH receptor, called thyroid-stimulating immunoglobulin, or TSI. It can be treated with propylthiouracil or methimazole. So again, it is not the diagnosis here.

★ High-yield tip #5

Hashimoto thyroiditis

B, Hashimoto thyroiditis, causes hypothyroidism. It is the most common cause of hypothyroidism in iodine-sufficient countries such as the United States; worldwide, iodine deficiency is the most common cause. The TSH would be high, not low, the heart rate may be slow, around 55 to 60, and recent weight loss would be unlikely.

★ High-yield tip #6

Hashimoto treatment and biopsy

In Hashimoto thyroiditis the gland is sometimes enlarged, and a radioiodine scan is not usually needed. It is treated with levothyroxine, a T4 analog. Also know that a biopsy shows a lymphocytic infiltrate, which is why it is also called chronic lymphocytic thyroiditis. That fact is fair game for Step 1 and has appeared on a Step 2 CK NBME.

★ High-yield tip #7

Riedel thyroiditis

C, Riedel thyroiditis, is a rare, low-yield distractor. It is an idiopathic fibrosis of the thyroid that can also affect other organs. It counts as an inflammation, which is why it is called thyroiditis, but it leads to fibrosis, so the gland can feel woody on examination.

★ High-yield tip #8

Riedel versus anaplastic carcinoma

Riedel thyroiditis can look like anaplastic thyroid carcinoma, which can invade nearby structures such as the esophagus. So a woody thyroid together with signs of spread into the esophagus points to Riedel thyroiditis. Here it is just a distractor; when students aren’t sure, they tend to pick unusual answers.

★ High-yield tip #1

Hashimoto thyroiditis

Hashimoto thyroiditis is the most common cause of hypothyroidism where iodine intake is adequate, as in Western countries, while iodine deficiency is the most common cause worldwide. Hashimoto is caused by antibodies against thyroid peroxidase, also called antimicrosomal antibodies, and patients often have antibodies against thyroglobulin as well.

★ High-yield tip #2

The labs and Step 2 vignettes

Expect a high TSH and a low T₄; T₃ is low less often. Spotting this from a long vignette is very high yield for Step 2. Step 2 questions classically give you a massive paragraph with lots of lab values, and you have to sift out these same findings to recognize hypothyroidism.

★ High-yield tip #3

The easy clues are rare

For Step 1 this can be harder. The easiest clues would be brittle hair, dry skin, constipation and cold intolerance, but you will rarely get those on the USMLE, because they make the question too easy. So the exam leans on subtler findings.

★ High-yield tip #4

Menstrual changes

Hypothyroidism is classically linked to heavier and longer periods, called menorrhagia. In a woman of reproductive age, a vignette may simply say that her periods are getting longer and heavier. That is a classic clue for hypothyroidism.

★ High-yield tip #5

Heart rate

A heart rate of 60 sits at the lower limit of normal, so on its own it is no big deal. But if you already suspect hypothyroidism, a slow heart rate supports it, and true sinus bradycardia, a rate below 60, is a classic finding. USMLE vignettes often give a heart rate of 55 to 60.

★ High-yield tip #6

BMI and cholesterol

A BMI of 25 is borderline overweight. A patient with hypothyroidism need not have a high BMI, such as 32; a BMI of 25 is fine. Total cholesterol is often high in hypothyroidism, mainly from a rise in LDL. This assumes HDL, the good cholesterol, is normal, since a high HDL alone can also raise the total.

★ High-yield tip #7

Creatine kinase

Creatine kinase can be raised from hypothyroid myopathy. Some patients have proximal muscle weakness, such as trouble getting out of a chair without help, brushing their hair or reaching overhead. But the patient does not need symptoms. A mildly raised creatine kinase on routine labs also supports hypothyroid myopathy.

★ High-yield tip #8

Liver enzymes

Hypothyroidism can sometimes raise liver enzymes such as AST. In Step 2 CK questions, where you check every lab value and wonder why the AST is up, remember it can simply be part of hypothyroidism, alongside a high cholesterol and a raised creatine kinase.

★ High-yield tip #9

Low mood

Hypothyroidism can cause low mood, called dysthymia, or more severely, depression. USMLE likes to show this as decreased eye contact or a patient who is notably quiet during the examination. The low mood should improve once the hypothyroidism is treated with levothyroxine, a T₄ analog.

★ High-yield tip #10

Next best step

Family medicine questions may give this same vignette and ask for the next best step in diagnosis. The answer is to check serum TSH, which will be high, usually with a low T₄. Don’t confuse this with Graves disease, where the answer can be to check antibodies against the TSH receptor. In Graves, these antibodies activate the receptor.

★ High-yield tip #11

Autoimmune hepatitis

Autoimmune hepatitis is typically a young or middle-aged woman with high transaminases. The vignette may mention autoimmune disease in her or her family, such as rheumatoid arthritis. Hashimoto also comes with other autoimmune diseases, but an autoimmune hepatitis question won’t give you all these extra features of hypothyroidism.

★ High-yield tip #12

The autoimmune hepatitis vignette

Expect something like a 28-year-old woman with high ALT and AST, maybe a sister with rheumatoid arthritis, and little else. The question may also mention positive anti-smooth muscle antibodies, the antibody of autoimmune hepatitis, or ask you to pick that antibody as the answer.

★ High-yield tip #13

NASH

Non-alcoholic steatohepatitis, or NASH, is a tricky diagnosis, mostly at the Step 2 CK level. Expect a patient with metabolic syndrome: obesity, high blood pressure, and usually a high fasting glucose, as in prediabetes or diabetes. The tricky detail is that transaminases are usually normal, even though the name says hepatitis.

★ High-yield tip #14

Fatty liver disease

Fatty liver disease starts with an obese patient whose liver, if biopsied, would show steatosis, meaning fat inside the liver cells. Over time, transaminases can rise, and the disease can progress to cirrhosis and, rarely, hepatocellular carcinoma. So if a Step 2 CK question gives an obese patient with normal or slightly raised transaminases, and you can rule out everything else, choose NASH.

★ High-yield tip #15

Polymyositis

Polymyositis has two classic findings: proximal muscle weakness on exam and a raised creatine kinase, sometimes with muscle pain. You would not see the other features of hypothyroidism. Anti-Jo-1 antibodies can be present, while anti-Mi-2 is more typical of dermatomyositis. Muscle biopsy, showing a CD8 T-cell infiltrate, helps establish the diagnosis.

★ High-yield tip #16

Polymyalgia rheumatica versus polymyositis

Contrast polymyositis with polymyalgia rheumatica, where pain and stiffness are the main symptoms. In polymyalgia rheumatica, strength is normal on exam and creatine kinase is not elevated. Polymyositis gives a high creatine kinase and proximal weakness on exam.

★ High-yield tip #17

Primary biliary cholangitis

Primary biliary cirrhosis, now called primary biliary cholangitis, usually affects a woman between 30 and 60. Expect high serum cholesterol, generalized itching, and raised alkaline phosphatase and bilirubin, mostly conjugated. For example, a 34-year-old woman with high cholesterol, itching, and high alkaline phosphatase and bilirubin. Anti-mitochondrial antibodies are characteristic, and a biopsy can help with staging.

★ High-yield tip #18

The bottom line

The bottom line: constipation, brittle hair, weight gain and cold intolerance make hypothyroidism too easy, so know the subtler clues. These include menorrhagia or longer periods, sometimes even missed periods in a younger woman, high serum cholesterol, a slow heart rate, a BMI that need not be high, a raised creatine kinase from myopathy, raised transaminases, and low mood or depression.

★ High-yield tip #1

De Quervain and the viral clue

Subacute thyroiditis, also called de Quervain thyroiditis or subacute granulomatous thyroiditis, is the USMLE answer if they mention a tender or painful thyroid. It is presumed to follow a viral infection, but the vignette need not mention cough, runny nose or conjunctivitis, because not every patient reports a recent viral illness.

★ High-yield tip #2

The course of de Quervain thyroiditis

De Quervain thyroiditis follows a phased course: hyperthyroid first, then hypothyroid, then back to normal, or euthyroid. Vignettes almost always give you the hyperthyroid phase. That phase is where the classic trap lies.

★ High-yield tip #3

Why uptake is decreased

Now the challenging part, and by far the highest-yield point: radioactive iodine uptake is decreased in de Quervain thyroiditis, even when the patient is hyperthyroid. How is that possible? The gland is not overproducing hormone, as it does in Graves disease. It is inflamed, so the follicles are damaged and stored thyroid hormone leaks out into the blood.

★ High-yield tip #4

The leak and the recovery

That leak is why the patient is hyperthyroid at first. But there is no actual overproduction of thyroid hormone, so the gland takes up little iodine and the uptake is decreased, not increased. Uptake only rises again later, as the gland recovers and starts making hormone again.

★ High-yield tip #5

Treatment

Treat this with aspirin or another NSAID for the pain. Students often choose steroids, but steroids are kept for severe pain or for cases where NSAIDs fail. So on a typical question, the treatment answer is aspirin, not steroids.

★ High-yield tip #6

Hyperthyroidism with increased uptake

Students often get this wrong. They assume hyperthyroidism must come with increased uptake. But E, decreased TSH, increased T₃ and T₄, and increased uptake, fits a gland that really is overproducing: Graves disease, a toxic adenoma, or a toxic multinodular goiter.

★ High-yield tip #7

Low-uptake hyperthyroidism

Uptake is also low in drug-induced thyroiditis, for example from amiodarone or lithium, even when the patient is hyperthyroid. So in de Quervain thyroiditis and in drug-induced thyroiditis, a hyperthyroid patient still has decreased uptake. That is the highest-yield point to take away from this question.

★ High-yield tip #1

The names of subacute thyroiditis

Most questions, perhaps 80 percent, say subacute granulomatous thyroiditis or de Quervain thyroiditis. About 20 percent of the time the answer is written simply as subacute thyroiditis, as it is here. That confuses students who are looking for the words de Quervain or granulomatous. It is the same thing.

★ High-yield tip #2

Hyper or hypo, and the viral trigger

Subacute thyroiditis can present as hypothyroid or hyperthyroid, and most stems give the hyperthyroid phase. It is thought to be caused by a viral infection, but vignettes usually don’t mention one. Not every patient reports a recent viral illness, so the stem need not describe cough, runny nose or conjunctivitis. A tender thyroid with either picture points straight to this diagnosis.

★ High-yield tip #3

Low uptake in subacute thyroiditis

A very high-yield fact this question doesn’t test directly: if they ask about radioactive iodine uptake, it is decreased in subacute thyroiditis, even when the patient is hyperthyroid. The gland is not producing extra hormone. It is inflamed, so the damaged follicular cells release stored hormone into the blood, with no new hormone being made.

★ High-yield tip #4

Two take-home points and treatment

So two take-home points. First, a tender or painful thyroid means subacute thyroiditis. Second, uptake is low in subacute thyroiditis, even if the patient is hyperthyroid; nearly everyone gets this wrong. Treatment is aspirin or another NSAID. Students often choose steroids, but those are kept for severe pain or for cases where NSAIDs fail.

★ High-yield tip #5

Uptake patterns

If a hyperthyroid gland is overproducing, uptake is increased. Diffuse uptake is usually Graves disease. Focal uptake in a single nodule fits a toxic adenoma. Uptake in many nodules fits a toxic multinodular goiter, which is seen in older adults. In subacute thyroiditis, uptake stays low through the active phase and rises only during recovery.

★ High-yield tip #6

Graves disease

Graves disease causes hyperthyroidism with diffusely increased uptake. The mechanism is activating antibodies against the TSH receptor, called thyroid-stimulating immunoglobulins, or TSI. Graves disease can be treated with antithyroid drugs such as propylthiouracil and methimazole.

★ High-yield tip #7

Hashimoto thyroiditis

B, Hashimoto thyroiditis, causes hypothyroidism. The mechanism is antibodies against thyroid peroxidase or thyroglobulin. The patient will have an increased TSH and a low T₄. It is usually treated with levothyroxine, a T₄ analog of thyroxine. Rarely, T₃, called triiodothyronine, is given.

★ High-yield tip #8

Suppurative thyroiditis

D, suppurative thyroiditis, is a distractor here and essentially never the correct answer in NBME material. Suppurative means pus, from a bacterial infection of the gland. For it to be the answer, the vignette would need signs of a bacterial infection, such as redness over the gland, or an ultrasound showing a fluid collection.

★ High-yield tip #9

Toxic multinodular goiter

E, toxic multinodular goiter, is the most common cause of hyperthyroidism in older adults. Graves disease can occur in older adults too. Students sometimes wonder whether a young adult could have a toxic multinodular goiter. That is unlikely: think of it in older patients.