AssessmentsHyperthyroidism: Clinical practice
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 30-year-old female comes to the office because of fatigue and generalized weakness for 2 months. She says she has also developed frequent palpitations and an increase in bowel movements. She is also concerned about her recent weight loss, even though her appetite has not changed. Examination shows her skin is excessively sweaty. Her conjunctiva is also clearly visible above and below the iris, with her eyes in a neutral position bilaterally. Which of the following is the most likely mechanism for this patients pathology?
Content Reviewers:Rishi Desai, MD, MPH
Contributors:Sam Gillespie, BSc
Thyroid hormone production is under the control of the hypothalamus and the pituitary.
The hypothalamus secretes thyrotropin releasing hormone, or TRH, which makes the anterior pituitary secrete thyroid-stimulating hormone, or TSH.
TSH then binds to TSH receptors, which makes the thyroid secrete thyroxine, or T4, and triiodothyronine, or T3, in the blood. But this is not a one-way street - there’s also negative feedback happening, meaning when thyroid hormone levels rise, that inhibits the production of TSH and TRH, halting further production of T3 and T4 - to keep everything in balance.
Normally, some thyroid hormones travel through the bloodstream bound to thyroxine-binding globulin, and some are in their free form.
And the thyroid actually makes more T4 than T3, and that T4 is converted to the more potent T3 in the periphery.
Thyroid hormones then increase the rate of metabolism in all cells, so they make us think, move, and talk faster, and they also increase heat generation. They also activate the sympathetic nervous system, the part of the nervous system responsible for our ‘fight-or-flight’ response, increasing cardiac output.
Thyroid hormones are important - and the occasional increase is like getting a boost to fight off a zombie or to stay warm during a snowstorm!
But with hyperthyroidism, it’s like the entire body is buzzing at twice the normal rate. So individuals with hyperthyroidism tend to be hyperactive and talk really fast, and present with tremor in the extremities - as if they’ve had too much coffee. Also, making so much internal heat makes them sweat a lot and uncomfortable in warm temperatures.
It can also cause anxiety, irritability, and mood swings, as well as difficulty sleeping - again, think too much coffee.
Hyperthyroidism can also cause an increased appetite, unexplained weight loss, and more frequent bowel movements.
On a physical examination, the skin is warm and moist and their hair is fine and brittle.
Classically, individuals have lid retraction, which makes a person look “wide-eyed” like the stare of a person who’s “frozen in fear”.
Sometimes, pretibial myxedema may be present, which is a waxy, discolored induration of the skin on the anterior aspect of the lower legs, with a bumpy feel - like an orange peel.
There may be muscle weakness, especially in the thighs and upper arms, as well as exaggerated deep tendon reflexes.
Females can have menstrual irregularities, and males can have gynecomastia - or swelling of the breast tissue.
First one’s easy - get serum levels of free T3, T4 and TSH.
In hyperthyroidism, either free T3 or free T4, or both are elevated, and they inhibit TSH, so the majority of the time, TSH is low.
Elucidating the cause is the fun part. Pathophysiologically, the causes of Hyperthyroidism can be divided into 4 categories.
The first is excessive TSH receptor stimulation, and an example is Graves’ disease, which is an autoimmune condition where thyroid stimulating immunoglobulins, or TSIs, bind to the TSH receptor and stimulate excess hormone production. Sometimes, this excessive stimulation makes the thyroid gland swell up, causing goiter - but the most characteristic finding in Graves’ disease is exophthalmos, which is where the eyes bulge out of their sockets.
Exophthalmos is pretty specific for Graves’ disease, and classically causes high thyroid hormone levels, low TSH, and a large thyroid without any discernible nodules on palpation.
Elevated TSI antibodies levels confirms Graves’ disease.
Finally, if the diagnosis of Graves is unclear or if there seems to be another cause of hyperthyroidism, the next step is getting a radioactive iodine uptake scan, or RAIU, for short.
In an RAIU scan - a person is given either a capsule or a liquid that contains the radioactive isotope of Iodine, typically Iodine-123.
Functional thyroid tissue loves Iodine, and gobbles it up to make thyroid hormones.
So to see how much thyroid tissue is actively making hormones we perform a scintigraphic scan. The principle is simple - the more active the thyroid is, the more iodine it takes in, and, as a result, the more radiation it emits. Then a gamma camera is used to pick up the emitted radioactive signal, and a computer translates this into pictures with a white background, where the dark areas represent radiation emitted by the functional thyroid tissue. A set of these scans is obtained 4 to 6 hours later, and then another set is obtained 24 hours later.
A normal thyroid gland looks like two grey wings.
With Graves’ disease, there’s a diffuse increase in the uptake of both lobes of the thyroid - so the thyroid appears darker and larger.
If Graves’ disease is confirmed, treatment should be initiated with antithyroid medication - enter the thionamides, methimazole and propyl-tio-uracil, or PTU.
Thionamides inhibit the enzyme thyroid peroxidase inside thyroid cells, and that stops thyroid hormone synthesis.
For both methimazole and PTU, a high initial dose is used, and then once euthyroid status is achieved, meaning free T3 and T4 levels go back to normal, then a lower daily maintenance dose is used.
If individuals have really large goiters, that compress nearby structures, like the trachea, and cause trouble breathing, or the recurrent laryngeal nerve, causing hoarseness, surgical removal of the thyroid gland - this is called a thyroidectomy - can be performed.
Alright then! Another cause of excessive TSH receptor stimulation is a TSH-secreting pituitary adenoma, which is when a tumor forms in the pituitary, and secretes TSH regardless of any negative feedback signals.
In this situation, there are high free T3 and T4 levels, with a diffuse increase in the uptake of both lobes, but with high TSH levels - the only exception to the high thyroid hormones, low TSH rule of hyperthyroidism. In this case, a CT or MRI scan of the head is done to identify the adenoma, and then the adenoma is surgically removed, through transsphenoidal adenomectomy. That’s where it’s surgically removed through the nose - talk about tight working quarters!
Another cause of excessive stimulation of the TSH receptor is high levels of human chorionic gonadotropin, or HCG.
HCG is structurally similar to TSH, so it can bind to the TSH receptor and stimulate it.
HCG levels rise normally during the first trimester of pregnancy, and this sometimes results in a transient state of hyperthyroidism that resolves on its own. But other causes of excess HCG are HCG-secreting germ cell tumors of the testicles or ovaries or a hydatidiform mole- which is an abnormal kind of pregnancy, where the placenta develops with very little fetal tissue, and secretes too much HCG, but the fetus isn’t viable.