Disorders of the Thyroid

Question 1

Overview of Thyroid hormones production

Answer 1

TSH is secreted from the anterior pituitary into circulation where it binds to its receptor on the thyroid follicular epithelium resulting in activation of adenylyl cyclase and cAMP via Gs activation leading to T4 and T3 production. In circulation, T4 and T3 are bound to carrier proteins such as TBG to their target organs where the effects of T3 predominate and bind to nuclear thyroid hormone receptors

Question 2

The thyroid gland follicles also contain a population of parafollilcular, or C, cells. What is their function?

Answer 2

These synthesize and secrete the hormone calcitonin which promotes absorption of calcium by the skeletal system and inhibits osteoclast activity

Question 3

Hypothyrodism is more common in what patient populations?

Answer 3

Much more common in the elderly and in women

Question 4

What are the symptoms of hypothyroidism?

Answer 4

Fatigue, weakness, feeling cold and cold intolerance, constipation, hair and memory loss, weight gain with poor appetite, and menorrhagia (abnormally heavy bleeding)

Question 5

What are the signs of hypothyroidism?

Answer 5

dry, coarse skin, puffy extremities or face (myxedema), alopecia, bradycardia, cavity effusions, carpal tunnel syndrome, and delayed tendon reflexes

Question 6

What are the symptoms of hyperthyroidism?

Answer 6

hyperactivity, irritability, heat intolerance and sweating, palpitations, weight loss with increased appetite (in severe cases), diarrhea, loss of libido, fatigue and weakness

Question 7

What are the signs of hyperthyroidism?

Answer 7

tremor, tachycardia/palpitations, goiter, warm skin, lid retraction, muscle weakness, pretibial myxedema (Grave’s disease)

Question 8

How is hypothyroidism treated?

Answer 8

hormone replacement and in severe hypothyroidism, replace corticosteroids first because the adrenals cannot handle the increase in metabolism that will degrade circulating catecholamines

Question 9

Half-lives of the thyroid hormones?

Answer 9

T4- 8 days

T3- 24 hrs

NOTE: It takes 4-5 half-lives to reach steady state (roughly 5 weeks in hypothyroidism patients in which you’d replace T4)

Question 10

What is thyrotoxicosis?

Answer 10

A hypermetabolic state caused by elevated levels of free T4 and T3 that is commonly referred to as hyperthyroidism but may also be due to excessive release of preformed thyroid hormone (as in thyroiditis) or to an extrathyroidal source, rather than gland hyperactivity

Question 11

What are the most common causes of hyperthyroidism?

Answer 11

• Diffuse hyperplasia of the thyroid associated with Graves disease (85%)
• Hyperfunctional multinodular goiter
• Hyperfunctional thyroid adenoma

Question 12

Why does the skin of patients with hyperthyroidism tend to be warm, soft, and flushed?

Answer 12

Because there is increase blood flow and peripheral vasodilation that facilitate heat loss once the BMR is elevated. Often times, sweating and heat intolerance are common and there is a weight loss despite increased appetite

Question 13

What is one of the earliest consistent manifestations of hyperthyroidism?

Answer 13

Elevated cardiac contractility and CO in response to increased peripheral oxygen demands can lead to tachycardia, palpitations, and cardiomegaly and can progress to a-fib or left-ventricular dysfunction

Question 14

Why would diarrhea be a symptom of hyperthyroidism?

Answer 14

sympathetic hyperstimulation results in hypermotility and diarrhea

Question 15

Other symptoms of hyperthyroidism?

Answer 15

Thryoid hormone stimulates bone resorption with a net effect of osteoporosis and an increased risk of fracture

Question 16

What is a thyroid storm? Tx?

Answer 16

Refers to the abrupt onset of severe hyperthyroidism most commonly seen in patients with underlying Graves disese and most likely is the result of acute elevation in catecholamine levels subsequent to infection, surgery, or other forms of stress. Pts. are typically febrile with intense tachycardia

Tx: Thionamide, Iodine (to shutdown production of thyroid hormone via Wolf-Cahikoff effect), Bile-acid binders (to remove thyroid hormone from enterohepatic circulation), Nutrition (to heal), and Glucocorticoids (delays conversion of T4 to T3). Do not go to surgery

Question 17

What is apathetic hyperthyroidism?

Answer 17

Thyrotoxicosis occurring in older adults in whom co-mordibities and aging may mask the features

Question 18

How is hyperthyroidism diagnosed?

Answer 18

After H&E make sure to get a serum TSH (this is the most important because its level typically decreases the earliest in disease progression). Serum TSH should be low and the diagnosis can be confirmed with a high T4.

In a small subset of patients, hyperthyroidism can present as high levels of T3 (and thus low T4 levels and TSH levels)

After confirming the diagnosis, radioactive iodine uptake can be measured to find the source of the defect

Question 19

How can secondary hyperthyroidism be diagnosed?

Answer 19

TSH levels are measured after an injection of TSH, and, if normal, TSH should rise to exclude secondary hyperthyroidism

Question 20

Using an iodine uptake test after diagnosis of hyperthyroidism, increased uptake to the whole gland suggests what? In a solitary nodule? Decreased uptake?

Answer 20

Whole gland- Graves disease

Solitary nodule- toxic adenoma

Decreased- thyroiditis

Question 21

How is hyperthyroidism typically treated?

Answer 21

Tx usually includes:

A BB to control symptoms from increased adrenergic tone

A thionamide to block new hormone synthesis

and agents that inhibit peripheral conversion of T4 to T3

Question 22

What is the major cause of congenital hypothyroidism?

Answer 22

endemic iodine deficiency in diet

Question 23

What is cretinism?

Answer 23

hypothyroidism that develops in infancy or early childhood that is characterized by impaired development of the skeletal system and CNS, manifested by severe mental retardation, short stature, protruding tongue, and *umbilical hernias*

Question 24

What is myxedema?

Answer 24

Hypothyroidism developing in older children or adults that is marked by a slowing of physical and mental activity that may mimic depression (as well as typical hypothyroid symptoms such as constipation, weight gain, etc.). Can present very insidiously!

Question 25

How does myxedema present?

Answer 25

Patients are cold intolerant, lethargic, fat, have cool and pale skin due to decreased blood flow, and commonly SOB and reduced exercise tolerance related to reduced cardiac output

Question 26

Why would hypothyroidism be associated with reduced CO?

Answer 26

Thyroid hormones promote transcription of of B adrenergic receptors and Ca ATPase needed for contractility

Question 27

A common source of mortality in hypothyroidic patients is CV related/atherosclerosis. Why?

Answer 27

Atherogenic molecules such as total cholesterol and LDL are upregulated in these states

Question 28

Why can nonpitting edema, broadening of facial features, and enlargement of the tongue also be seen in hypothyroidism?

Answer 28

There is often accumulations of GAGs and hyaluronic acid in skin, subQ tissue, and other visceral sites

Question 29

Would TSH levels be low or high in hypothyroidism?

Answer 29

TSH will be increased due to lack of negative feedback

Question 30

What are the most common causes of thyroiditis?

Answer 30

• Hashimoto Thyroiditis
• Granulomatous (de Quervain)
• Subacute lymphocytic

Question 31

What is Hashimoto thyroiditis caused by? HLA association?

Answer 31

An autoimmune disease common in women 45-65 characterized by circulating levels of anti-thyroglobulin or anti-thyroid peroxidase Abs and an association with HLA-DR3 and *HLA-DR5* that causes progressive thyroid failure and hypothyroidism

Question 32

Hashimoto’s, like most autoimmune diseases, has a strong genetic component (twin studies!!). What are the genetic risk factors?

Answer 32

polymorphisms in CTLA4 and protein tyrosine phosphatase-22 (PTPN22), both of which code for T-cell regulators (note that these are also risk factors for type I diabetes)

Question 33

How does Hashimoto’s progress histologically?

Answer 33

There is progressive depletion of thyroid epithelial cells by apoptosis and replacement of the thyroid parenchyma by mononuclear infiltrates, large germinal centers, and fibrosis and you commonly see Hurthle cell change which is manifested by more pink follicular cells with more abundant cytoplasm (below)

Question 34

What things are thought to facilitate follicular cell destruction in Hashimotos?

Answer 34

• CD8+ cytotoxic T cell mediated cell death
• Cytokine (such as IFN-y) mediated cell death from activated CD4+ cells
• ADCC via NK cells once Abs bind (less likely)

Question 35

How does Hashimoto’s progress clinically?

Answer 35

It typically presents as a painless enlargement of the thyroid with some degree of hypothyroidism in middle aged women. The enlargement is usually symmetric but can be lateralized and eventually progresses to gland atrophy. Classically, the hypothyroidism progresses gradually characterized by falling T4/T3 levels and increased TSH, but often times is preceded in the initial stages of disease by transient hyperthyroidism

Question 36

Hasimoto patients are placed at an increased risk for developing what other diseases?

Answer 36

Other autoimmune diseases such as type I diabetes, SLE, myastenia gravis, and Sjogren syndrome as well as

Non-Hodgkin’s B-cell lymphomas within the gland

Question 37

What is subacute lymphocytic thyroiditis?

Answer 37

aka painless thyroiditis. This disease presents as thyroid enlargement associated with mild hyperthyroidism, or both, most commonly in middle-aged adults that is associated with circulating levels of anti-thyroid peroxidase ABs and may progress to overt hypothyroidism (1/3 of time)

Question 38

Note about subacute lymphocytic thyroiditis

Answer 38

A disease process resembling painless thyroiditis can occur during the post-partum period in up to 5% of women (postpartum thyroiditis)

Question 39

Describe subacute granulomatous thyroiditis

Answer 39

A self-limiting autoimmune disease common in 40-50 year old women prodominantly believed to be triggered by URT viral infections mostly during the SUMMER that causes cross reactivity of cytotoxic T cells against follicular thyroid cells and is associated with **thyroid pain** and transient diffuse thyroid enlargement that is very firm

Question 40

How do the labs of granulomatous thyroiditis present?

Answer 40

There are almost always increased T4/T3 levels and low TSH during the transient hyperthyroidism, but, unlike other hyperthyroid states such as Graves disease, radiactive iodine uptake is diminished. Normal thyroid function typically returns to normal in 6-8 weeks

ESR and leukocyte count will also be elevated

Question 41

What is Euthyroid sick syndrome (ESS)?

Answer 41

When you get acutely sick your liver stops making TBG which means the levels of T4/T3 go acutely up and then go down over time so the thyroid gland senses this and starts to produce more TSH. This is a self-limiting syndrome

Question 42

How would you approach a newly pregnant women taking T4 supplements?

Answer 42

In pregnancy you make more TBG and more thyroid hormone is made so in this patient you need to increase her dose to prevent cretinism

Question 43

Ultrasound showing thyroid nodule suggesting cancer

Question 44

Describe what is being shown

Answer 44

Top Left: Normal
Bottom Left: Hot nodule (tx: with iodine)

Top Right: Large Goiter

Middle: Cold Nodule

Bottom Right: Cyst/Cancer

Question 45

What are the main risk factors for thyroid cancer?

Answer 45

• Hx of head/neck radiation
• male gender
• nodule 4+ cm
• Hoarse voice/vocal cord paralysis
• lymph node involvement
• Fam Hx

Question 46

The development of thyroid lymphoma is common in what patients?

Answer 46

Those with a longstanding Hx of Hashimoto’s