USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 20-year-old woman, gravida 1, para 0, is brought to the obstetrics clinic for her first prenatal visit. Patient's medical history include diabetes mellitus type 1 and hypothyroidism controlled with levothyroxine. Levothyroxine is explained to the patient as a category A drug. Which of the following best describes a category A medication?
Now, as treatment for hypothyroidism, we can use thyroid hormone analogues as a replacement to supply the body with normal levels of thyroid hormones.
There are 2 different thyroid hormones; triiodothyronine or T3, and thyroxine or T4.
They’re two tyrosine-based, iodine-containing hormones that are secreted by the thyroid gland, which is located anteriorly in the neck and consists of two lobes that look like two thumbs hooked together in the shape of a “V”.
Now, if we zoom into the thyroid gland, we’ll find thousands of follicles, which are small hollow spheres whose walls are lined with follicular cells or thyrocytes.
Zooming in, these follicular cells have an apical side that surrounds a central lumen filled with a viscous fluid called the colloid.
The colloid contains the precursor hormone thyroglobulin.
The basolateral side of follicular cells is in contact with blood vessels that supply these cells.
Now, synthesis of thyroid hormones inside the follicles involves a few important steps.
First, the inorganic iodide ions, present in a low concentration in the blood, are actively taken up by the basolateral side of the follicular cells, along with two sodium ions, via a sodium-iodide symporter.
This step is known as ‘iodide trap’.
The iodide ion is then pumped into the colloid via the pendrin protein, where it undergoes oxidation with the enzyme “thyroid peroxidase” or TPO, which changes it into an organic iodine atom.
It’s then attached to tyrosine amino acid residues which are found throughout thyroglobulin.
This step is known as iodination.
Some tyrosine residues are bound by only one iodine, whereas others are bound by two iodine atoms, yielding monoiodotyrosine or MIT, and diiodotyrosine or DIT, respectively.
These molecules are then coupled together by the same enzyme “thyroid peroxidase” or TPO.
This process is known as coupling.
Coupling one MIT with one DIT creates T3, while linking two DIT molecules creates T4.
In general, T4 is created in greater amounts than T3.
T3 is the more active form with a half life of one to two days, while T4 is the less active form with a longer half life of six to eight days.
Now, production and secretion of thyroid hormones is under the control of the hypothalamus- pituitary axis.
The hypothalamus, located at the base of the brain, secretes thyrotropin-releasing hormone, or simply ΤRH, which stimulates the anterior pituitary cells called thyrotroph cells, to release the thyroid-stimulating hormone, or TSH, into the bloodstream.
TSH then travels to the thyroid gland, and binds to the TSH receptors located in the membrane of the follicular cells of the thyroid gland.
When TSH binds to the TSH receptor, it goes on to promote every aspect of T3 and T4 production, ranging from the iodide trapping to the release of thyroid hormones into the bloodstream.
Once released from the thyroid gland, most of the T3 and T4 travel via the blood by binding with the thyroxine-binding globulin, or TBG, to reach the target cells.
Alternatively, small amounts of T3 and T4 stay unbound, and therefore they are referred to as “free” thyroid hormones.
Only “free” thyroid hormones are physiologically active because they are able to enter the cell.
Now, once inside the cell, T4 is mostly converted into T3 by the enzyme 5’- deiodinase.
T3 binds to thyroid hormone receptors which are within the cell’s nucleus, and these receptors regulate gene expression, which ultimately lead to various metabolic and physiologic effects in the body.
This increase in metabolism uses up sugars and fats for energy and produces more body heat.
Thyroid hormones also help activate the sympathetic nervous system which is responsible for the fight or flight response.
This increases heart rate and cardiac output, respiratory rate, and mental alertness.
Thyroid hormones also increase the gastrointestinal motility and they are necessary for normal neuronal development in growing fetuses and young children.
Now there are three types of hypothyroidism - primary, secondary, .
In primary hypothyroidism, the thyroid gland is the problem, because it isn’t making enough thyroid hormones.
Iodine deficiency can be a cause of primary hypothyroidism because the follicular cells don’t have the iodide ions they need to produce T3 and T4.
In countries that do fortify food with iodide, the most common cause of primary hypothyroidism is Hashimoto thyroiditis, an autoimmune disorder where T cells and autoantibodies like anti- thyroid peroxidase and antithyroglobulin infiltrate the thyroid and cause follicular cell damage and inhibit normal thyroid function.
Primary hypothyroidism can also happen after treatment for hyperthyroidism, which usually involve surgically removing the thyroid gland, or destroying it with radioiodine therapy.
Now in secondary hypothyroidism, also called central hypothyroidism, the issue is that the body doesn’t produce enough TSH.
TSH is a really important hormone which stimulates the thyroid gland to uptake iodide from the circulation and produce T3 and T4 when needed.
It typically happens because there’s a tumor in the anterior pituitary which compresses the gland and prevents TSH production, which leads to decreased level of T3 and T4,.
Finally, in tertiary hypothyroidism, the hypothalamus doesn’t produce enough thyrotropin-releasing hormone (TRH).
As a result, these individuals have decreased levels of TSH, and subsequently decreased production of T3 and T4.
Another form of hypothyroidism is congenital hypothyroidism, which is defined as thyroid hormone deficiency present at birth.
It can occur due to an absent or underdeveloped thyroid gland, which is known as thyroid dysgenesis; or due to an ineffective production of thyroid hormones, also known as thyroid dyshormonogenesis.
A person with low thyroid hormone levels typically has cold, dry skin, cold intolerance, hair loss, weight gain, and constipation.
They might also suffer mental symptoms like lethargy and fatigue.
In infants and children, hypothyroidism could delay physical and mental development.
Now, in some elderly individuals with low levels of thyroid hormones, any stressful event like an infection or a heart attack can lead to an acute decrease in T3 and T4.
This leads to a medical emergency known as myxedema coma, a rare condition associated with clinical features such as sudden drop in body temperature, low heart rate, low blood pressure, hypoventilation, confusion, and coma.
Okay, now in a person with hypothyroidism we want to increase the T3 and T4 to normal levels, and if the hypothyroidism is due to iodine deficiency, the treatment is to give foods rich in iodine like fish, eggs, meat and iodized salt.
On the other hand, in individuals with primary, secondary, tertiary, or congenital hypothyroidism, the treatment of choice is to give synthetic thyroid hormone replacements, or thyroid replacement therapy.
Now, the synthetic hormone that’s similar to T3 is called liothyronine, and the one that’s similar to T4 is called levothyroxine.
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