Hyperthyroidism: Pathology review

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Case study0:00–0:54

On the Endocrinology ward, two individuals came in. The first one is 55 year old Gregor, who came in complaining about weight loss, heat intolerance, chest pain, palpitations and insomnia.
On the clinical examination, he’s anxious and restless. He had warm and moist skin, his eyelids were retracted and there was exophthalmos of both eyes and tachycardia.
The other person is 37 year old Josie who migrated to the US from Panama. She came in with similar symptoms as Gregor but on clinical examination, she also had a goiter.
According to her, she recently had a contrast imaging procedure for a different problem. TSH and levels of T3 and T4 were taken for both individuals.
Levels of TSH were low, while levels of T3 and T4 were high. Okay, so both individuals had hyperthyroidism.

Physiology0:54–3:26

First, a bit of physiology. Normally, the hypothalamus detects low blood levels of thyroid hormones and releases thyrotropin-releasing hormone, or TRH, into the hypophyseal portal system.
The anterior pituitary then releases thyroid-stimulating hormone, also called thyrotropin, or simply TSH. TSH stimulates the thyroid gland which is a gland located in the neck.
The thyroid gland is made up of thousands of follicles, which are small spheres lined with follicular cells. Follicular cells convert thyroglobulin, a protein found in follicles, into two iodine-containing hormones, triiodothyronine or T3, and thyroxine or T4.
Once released from the thyroid gland, these hormones enter the blood and bind to circulating plasma proteins. Only a small amount of T3 and T4 will travel unbound in the blood, and these two hormones get picked up by nearly every cell in the body.
Once inside the cell T­4 is mostly converted into T3, and it can exert its effect. T3 speeds up the cell’s basal metabolic rate.
T3 increases cardiac output, stimulates bone resorption, thinning out the bones, and activates the sympathetic nervous system.
Thyroid hormones are also involved in a number of other things, like controlling sebaceous and sweat gland secretion, hair follicle growth, and regulating proteins and mucopolysaccharide synthesis by skin fibroblasts.
Now hyperthyroidism can happen a few different ways and all of them result in too much thyroid hormone and a hypermetabolic state, where cellular reactions are happening faster than normal.
First, hyperthyroidism can be primary, in which case the thyroid gland is the problem and it’s making too many hormones.
There are a few specific diseases associated only with hyperthyroidism but sometimes diseases like thyroiditis, which damages the thyroid and causes hypothyroidism, can cause stored thyroid hormones to leak out, resulting in an initial period of transient hyperthyroidism.
Then there’s secondary hyperthyroidism, where the problem is increased TSH secretion due to a problem with the pituitary gland, like a rare TSH secreting adenoma.
Now, let’s talk about some of the causes of primary hyperthyroidism. Graves disease is the most common cause of hyperthyroidism, which can sometimes manifests during periods of stress, like during pregnancy.

Graves3:26–5:19

This is an autoimmune disorder where B cells produce antibodies against several thyroid proteins. The most high yield autoantibodies you need to remember is thyroid-stimulating immunoglobulins, which are type G immunoglobulins that produce a type II hypersensitivity reaction.
They bind to the TSH receptor on follicular cells and imitate TSH. This results in growth of the thyroid gland and stimulates the follicular cells to produce excess thyroid hormone.
Now, these autoantibodies can also cause Graves ophthalmopathy. These antibodies activate the T-cells in the retro-orbital space causing them to secrete cytokines like TNF-alpha and IFN-gamma which increase fibroblast secretion of glycosaminoglycans which ultimately increase muscle swelling, muscle inflammation and increase the number of adipocyte count, leading to exophthalmos, which is anterior bulging of the eyes.
Now, thyroid stimulating immunoglobulins also increase the activity of dermal fibroblasts, resulting in pretibial myxedema, with the classical finding of waxy lesions with non-pitting edema that usually appear first on the lower legs.
Now, there is a gene complex involved in the regulation of the immune response and this is called the human leukocyte antigen system, or HLA system.
Interestingly, individuals with Graves disease often have specific HLA genes such as HLA-DR3 and HLA-B8, which are important clues on your exams.
Histology of the thyroid will show tall and crowded follicular epithelial cells with scalloped colloid. Another cause is toxic multinodular goiter where one or more follicles starts growing bigger and generating lots of thyroid hormones independently of TSH.

TMN goiter5:19–6:02

A high yield fact is that In about 60% of the cases, this happens due to mutations in the TSH receptors that inappropriately keeps these follicular cells active.
On histology, this appears as focal patches of hyperfunctioning cells with a lot of colloid inside. Now, nodules that produce a lot of thyroid hormones are called hot nodules because they show increased activity on radioactive iodine uptake tests.
They are rarely malignant. Another high yield concept is the Jod-Basedow phenomenon, or iodine-induced thyrotoxicosis.

Jod-Basedow6:02–10:05

The Jod-Basedow phenomenon is hyperthyroidism that happens shortly after administering iodine, even in the form of iodine IV contrast.
The phenomenon does not affect people with normal thyroid function but will affect individuals that’s iodine deficient and have a goiter, or in people with Graves disease, toxic multinodular goiter, or thyroid adenomas.
The key point is that all these disorders have autonomous thyroid tissue that act independently of TSH regulation, so when there’s extra iodine, it provides more material for thyroid hormone production without negative feedback from decreased TSH.
You can think of the Jod-Basedow phenomenon as the opposite of the Wolff-Chaikoff effect where a large increase in iodine actually leads to temporary decrease in thyroid hormone synthesis.
Regardless of cause, symptoms of hyperthyroidism are similar and remember that with hyperthyroidism, everything goes faster.
Metabolic findings include include heat intolerance, weight loss, and increased sweating, due to increased basal metabolic rate.
The skin can be warm and moist, mostly due to vasodilation and increased sweating. The hair is fine and friable, while there’s onycholysis where the nails separate from the nail bed.
Ocular findings include lid lag or retraction and this happens due to increased sympathetic stimulation of the levator palpebrae superioris muscle.
In graves disease there’s also graves ophthalmopathy. Finally, long term hyperthyroidism can increase the risk of bone fractures since T3 increases bone resorption, leading to osteoporosis.
Gastrointestinal findings include diarrhea and hyperdefecation due to increased gastrointestinal motility and the appetite is increased.
Musculoskeletal findings include thyrotoxic myopathy which usually manifests as proximal weakness, but levels of CK are normal.
This probably happens because thyroid hormones interfere with cell metabolism, including muscle cell metabolism. Reproductive findings include oligomenorrhea or amenorrhea, low libido and infertility in females and gynecomastia in males.
One of the mechanisms involved is that with hyperthyroidism, there’s also an increase in sex hormone-binding globulin or SHBG and as a result levels of total testosterone, dihydrotestosterone and estradiol are increased and this can interfer with normal hormonal processes.
Regarding menstrual disturbances, the mechanism involved can be that thyroid hormones interfere with GnRH signaling, which in turn, affects LH and FSH pulses.
Neuropsychiatric findings include hyperactivity, restlessness, anxiety, insomnia and this is due to increased beta-adrenergic activity.
Additionally, reflexes are brisk. Cardiovascular findings include tachycardia, palpitations, dyspnea, arrhythmias, chest pain and systolic arterial hypertension, and these are caused by increased activation of beta-adrenergic receptors, and increased expression of cardiac sarcolemmal ATPase, which allows the heart to contract faster.
There’s also decreased expression of phospholamban, which is a protein that regulates the calcium pump in cardiac muscle cells.
Okay, finally let’s talk about thyroid storm which is a rare, but life-threatening complication of hyperthyroidism where the body goes into a state of severe hypermetabolism.

Thyroid storm10:05–10:41

This can happen when hyperthyroidism isn’t treated or isn’t completely under control and can worsen during acute stress such as infections, trauma and surgery.
All of the normal symptoms of hyperthyroidism become exaggerated and the individual presents with fever, tachyarrhythmias, agitation, delirium, even coma.

Diagnosis10:41–11:30

Diagnosing hyperthyroidism is done by measuring blood levels of TSH, T3, and T4. If it’s due to a primary cause, TSH will be low and unbound thyroid hormones will be high.
This should be one of the first things you consider when you encounter a hyperthyroid problem on your tests. Once hyperthyroidism is confirmed, a radioactive iodine uptake test and a thyroid scan can help determine the specific cause of the disorder.
There’s diffuse uptake in Graves disease, patchy uptake in toxic multinodular goiter centered around each nodule, and decreased uptake in thyroiditis.
For secondary causes, if TSH level is normal or high, this points to a pituitary tumor, which can be confirmed with an injection of thyrotropin-releasing hormone.

Treatment11:30–12:13

Treatment for hyperthyroidism involves beta-blockers like Propranolol in order to reduce the effects of thyroid hormones.
There’s also Propylthiouracil which decreases thyroid hormone synthesis, corticosteroids like Prednisolone to inhibit T4 to T3 conversion.
Finally, there’s potassium iodide, also called Lugol solution, which can cause decreased thyroid hormone synthesis via the Wolff-Chaikoff effect, and it also decreases vascularization in the thyroid.
Propranolol, propylthiouracil, and corticosteroids are all used as first line treatment of thyroid storm while Lugol solution is used as a 2nd line treatment.
Allright, as a quick recap, Hyperthyroidism can happen a few different ways and all of them result in too much thyroid hormone and a hypermetabolic state.

Review12:13–13:54

Symptoms of hyperthyroidism affect multiple systems. Metabolic findings include include heat intolerance, weight loss and increased sweating.
Skin and hair findings include warm and moist feel of the skin,fine and friable hair, and onycholysis. Ocular findings include lid lag or retraction.
Gastrointestinal findings include diarrhea and increased appetite. Musculoskeletal findings include thyrotoxic myopathy.
Reproductive findings oligomenorrhea or amenorrhea, low libido and infertility in females and gynecomastia in males. Neuropsychiatric findings include hyperactivity, restlessness, anxiety, insomnia and brisk reflexes.
Cardiovascular findings include tachycardia, palpitations, dyspnea, arrhythmias, chest pain and systolic arterial hypertension.
With primary hyperthyroidism, TSH will be low and unbound thyroid hormones will be high, but with secondary hyperthyroidism, TSH is normal or high.
Regarding causes of hyperthyroidism, Graves disease is the most common. Other causes include toxic multinodular goiter, thyroiditis, and Jod-Basedow phenomenon.
A thyroid storm is a rare, but life-threatening complication of hyperthyroidism where the body goes into a state of severe hypermetabolism.
Okay, back to our cases. Gregor came in with classic symptoms of hyperthyroidism, like weight loss, heat intolerance, chest pain, palpitations, insomnia, anxiety, restlessness, moist and warm skin, and retracted eyelids.

Summary13:54–14:36

Labs confirm that he’s suffering from hyperthyroidism, and the exophthalmos points towards Graves disease. Josie came in with similar symptoms of hyperthyroidism that were confirmed by lab tests.
Given the history of recently having a contrast imaging procedure done, probably with iodine contrast, we can assume that Josie might be iodine deficient, the likely cause of her goiter, and probably suffers from Jod-Basedow phenomenon.
Hyperthyroidism: Pathology Review: Video, Causes | Osmosis