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A 6-hour-old male delivered at 37 weeks’ gestation is found to have a lesion on the right side of his scalp, as shown in the image below. On further inspection, the lesion is non-inflammatory and involves both the epidermis and upper dermis. The infant was delivered by normal vaginal delivery and has microcephaly and polydactyly of the right hand. The mother had little prenatal care and has no past medical history, aside from hyperthyroidism which was treated with methimazole throughout the pregnancy. Which of the following is the most likely diagnosis?
Contributors:Pauline Rowsome, BSc (Hons), Robyn Hughes, MScBMC, Sam Gillespie, BSc, Marisa Pedron, Jake Ryan, Alaina Mueller, Anuj Paul
Medications used to treat hyperthyroidism either reduce the level of thyroid hormones or treat the symptoms by targeting the affected tissue.
There are 2 different thyroid hormones; triiodothyronine or T3, and thyroxine or T4.
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 further into these follicular cells, we’ll see their 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.
Synthesis of thyroid hormones begins when follicular cells take in inorganic iodide ions from the blood, along with two sodium ions, via a sodium- iodide symporter.
This step is known as ‘iodide trap’.
The iodide ion is pumped via the pendrin protein, into the viscous fluid inside the follicle called the colloid, which contains thyroglobulin; the precursor of thyroid hormone.
In the colloid, inorganic iodide undergoes oxidation via the enzyme thyroid peroxidase or TPO, to become organic iodide, which then binds to the tyrosine in thyroglobulin.
This step is known as iodination.
Some tyrosine residues bind to only one iodine and form monoiodotyrosine or MIT, whereas others bind to two iodine atoms to form diiodotyrosine or DIT.
These molecules are then coupled together by the same enzyme thyroid peroxidase.
This process is known as coupling.
Coupling one MIT with one DIT creates T3, while coupling 2 DIT molecules creates T4.
T4 is generally created in greater amounts than T3, with T3 being the more active form with a half life of 1 to 2 days, while T4 is less active but has a longer half life of 6 to 8 days.
Once released from the thyroid gland, most of the T3 and T4 travels via the blood by binding with the thyroxine - binding globulin, or TBG, to reach the target cell.
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.
Thyroid hormones also help activate the sympathetic nervous system which is responsible for the fight or flight response.
Thyroid hormones also increase the gastrointestinal or GI motility and they are necessary for normal neuronal development in growing fetuses and young children.
Now, hyperthyroidism can happen in a few different ways.
The most common cause is Graves’ disease, an autoimmune disorder where B cells produce autoantibodies against thyroid stimulating hormone receptors on follicular cells.
These autoantibodies bind to the receptors and activate them, which causes the thyroid follicles to grow and produce more thyroid hormones.
One complication is Graves’ ophthalmopathy which is inflammation and edema in the tissue around the eyes, causing the eyeball to be displaced forwards, eyelids to retract and giving the eyes a “bulging” appearance.
Other disorders like toxic multinodular goiter and thyroiditis can also cause increased release of thyroid hormones.
Now, the symptoms of hyperthyroidism include weight loss despite an increase in appetite because of the higher basal metabolic rate; heat intolerance because the body is producing more heat; and rapid heart rate or tachycardia, sweating, hyperactivity, anxiety and insomnia because of the effect of thyroid hormones on the sympathetic nervous system.
Untreated hyperthyroidism combined with a stressor like an infection or illness can trigger a life- threatening complication called thyroid storm.
Now, there are several classes of medications to control hyperthyroidism.
First, we can target the thyroid gland itself, and either decrease the synthesis of thyroid hormones or prevent them from being released.
The other option, at the target tissue peripherally; is to decrease the effectiveness of the thyroid hormones; this only manages the symptoms but doesn’t treat the cause.
Let’s start with the radioactive iodine therapy, also known as “radioiodine ablation therapy”.
The isotope of iodine that is used is I131 .
It’s taken peroral and eventually gets taken up by the thyroid.
Over the course of a few weeks, the radioactive isotope collects in the colloid and emits beta radiation that causes permanent damage to the thyroid.
This is the definitive treatment for hyperthyroidism caused by Graves’ disease and toxic multinodular goiter, but it could also worsen Graves’ ophthalmopathy.
Radioactive iodine crosses the placenta and is secreted in breast milk, so it should be avoided in people who are pregnant or breastfeeding.
Therefore, administration of radioactive iodine to childbearing individuals requires a negative pregnancy test!
Both of these medications are given perorally and are absorbed by the thyroid where they inhibit thyroid peroxidase.
This stops the oxidation of iodide ions into organic iodine, the iodination of tyrosine residues in thyroglobulin, and the coupling of MIT and DIT to form T3 and T4.
It’s important to note that these medications do not inhibit the release of thyroid hormones; therefore they require several weeks until the thyroid depletes its storage of hormones to manifest their therapeutic effect.
In addition, PTU also works in the peripheral tissue by inhibiting 5’- deiodinase to block the conversion of T4 into T3, which makes it the preferred medication during thyroid storms.
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