Thyroid Physiology, Pathophysiology, and Pharmacology

What is the role of thyroglobulin?

Scaffold for thyroid hormone synthesis

Which hormone is produced in greater amounts: T3 or T4?

T4 (Tetraiodothyronine)

Which thyroid hormone is more potent: T3 or T4?

T3 (Triiodothyronine)

Which hormone is the active form of thyroid hormone?

T3 (Triiodothyronine)

How much more potent is T3 than T4?

About 4 times

What are the two requirements for thyroid hormone synthesis?

Iodine and tyrosine

What is the first step of thyroid hormone synthesis?

Iodide trapping via NIS

What transporter is responsible for iodide uptake into thyroid cells?

Na⁺/I⁻ symporter (NIS)

What enzyme oxidizes iodide to iodine and catalyzes the coupling of iodotyrosines to iodothyronines?

Thyroid peroxidase (TPO)

What forms T4?

DIT + DIT

What forms T3?

MIT + DIT

Where does NIS get its energy?

Na⁺/K⁺ ATPase

What happens with excess iodide?

Suppresses NIS activity

What is the recommended daily iodine intake?

150 mcg/day

What happens in iodine deficiency?

Increased TSH and increased T3 production

What happens in iodine excess?

Decreased hormone synthesis and release

What does T4 convert into?

T3 and reverse T3

Which enzyme converts T4 to T3?

Deiodinase

Which form of thyroid hormone is inactive?

Reverse T3 (rT3)

Where does most T3 come from?

Peripheral conversion of T4

Which form is biologically active?

Free hormone

What are the three binding proteins?

- TBG

- Transthyretin

- Albumin

What is the main binding protein?

TBG

Why is protein binding important?

Transport and stable hormone levels

Which enzyme types are involved?

Deiodinases D1, D2, D3

Where is D1, D2, and D3 most abundant?

- D1 = liver, kidney, muscle

- D2 = brain, pituitary

- D3 = brain, placenta, fetal tissue

Which enzyme produces reverse T3?

D3

What does TRH stimulate?

TSH release

What does TSH stimulate?

Thyroid hormone production

What kind of feedback do T3/T4 provide?

Negative feedback

What happens to TSH when T3/T4 are low?

Increases

What happens to TSH when T3/T4 are high?

Decreases

Where is TRH produced?

Hypothalamus

What receptor does TRH bind to?

GPCR

What regulates TRH gene expression?

T3 (negative feedback)

What is another name for TSH?

Thyrotropin

What signaling pathways are activated by TSH?

cAMP and phosphoinositol

What are the effects of TSH on thyroid cells?

Increased growth, synthesis, and hormone release

What structural change does TSH cause?

Pseudopod formation

What does TSH increase in the thyroid?

Iodide uptake, TPO, thyroglobulin

What does high TSH lead to?

Goiter

What inhibits TSH release?

- High T3/T4

- Somatostatin

- Dopamine

- Glucocorticoids

What stimulates TSH release?

Low T3/T4

Which hormone has the longest half-life?

T4

How do thyroid hormones act at the cellular level?

Bind nuclear receptors

What is the result of thyroid hormone binding?

Changes in gene expression

What is the overall metabolic effect of thyroid hormones?

Increased BMR

What effect do thyroid hormones have on heat production?

Increased heat

What cardiovascular effects do thyroid hormones have?

Increased HR and contractility

What receptor sensitivity is increased by thyroid hormones?

β-adrenergic

What effect do thyroid hormones have on oxygen consumption?

Increase

What effect do thyroid hormones have on the GI tract?

- Increased gut motility

- Constipation in HYPOthyroidism

- Diarrhea in HYPERthyroidism

What effect do thyroid hormones have on growth?

- Increase growth

- Absence = slows bone growth and delays epiphyseal closure

What neuromuscular effects do thyroid hormones have?

- Hyperthyroidism = increased protein turnover and muscle loss

- Increases speed of muscle contraction

What neurological effects do thyroid hormones have?

- Essential for normal development of CNS

- Failure of fetal thyroid = severe mental retardation

What is the net effect of thyroid hormones on carbohydrate metabolism?

Increased glucose turnover

What is the net lipid effect of hyperthyroidism?

Decreased total cholesterol and decreased LDL

What is the net lipid effect of hypothyroidism?

Increased total cholesterol and increased LDL (± increased triglycerides)

What are primary thyroid disorders?

Problem in thyroid gland

What are secondary thyroid disorders?

Problem in pituitary

What are tertiary thyroid disorders?

Problem in hypothalamus

In primary hypothyroidism, what happens to TSH and T3/T4?

- TSH = Increases

- T3/T4 = Decrease

In primary hyperthyroidism, what happens to TSH and T3/T4??

- TSH = Decreases

- T3/T4 = Increases

In secondary hypothyroidism, what happens to TSH and T3/T4?

- TSH = Decreases

- T3/T4 = Decreases

In secondary hyperthyroidism, what happens to TSH and T3/T4?

- TSH = Increases

- T3/T4 = Increases

What is subclinical thyroid disease?

Abnormal TSH, normal T3/T4

What is overt thyroid disease?

Abnormal TSH and T3/T4

What are symptoms of HYPOthyroidism?

- Fatigue

- Cold intolerance

- Constipation

- Dry skin

- Depression

- Myxedema

- Weight gain

- Slow speech

- Bradycardia

- Menstrual disturbance

- Infertility

- Slow movements

- Hyporeflexia

What are symptoms of HYPERthyroidism?

- Tachycardia

- Nervousness

- Fatigue

- Tremor

- Weight loss

- Increased sweating

- Heat intolerance

- Muscle catabolism

- Menstrual disturbances

- Frequent bowel movement or diarrhea

What is hypothyroidism?

Low T3/T4

What is another name for severe hypothyroidism?

Myxedema

What skin finding occurs in myxedema?

Puffy and swollen skin

What is the most common cause of hypothyroidism?

Hashimoto's thyroiditis

What is the mechanism of Hashimoto's thyroiditis?

Autoimmune destruction of thyroid

What antibodies are present in Hashimoto's?

Anti-TPO and anti-thyroglobulin

What is postpartum thyroiditis?

Autoimmune thyroiditis after childbirth

What is myxedema coma?

Severe untreated hypothyroidism

What effect does Hashimoto's have on TSH and T3/T4??

- TSH = increased

- T3/T4 = decreased

What complication can Hashimoto's cause?

Goiter (due to increased TSH stimulation)

What is cretinism?

Congenital hypothyroidism in newborns (causes severe developmental delay)

What is a state where cells of the body are exposed to high levels of T4/T3?

Thyrotoxicosis

What is the most common cause of hyperthyroidism?

Graves disease

What is the mechanism of Graves disease?

Autoantibodies stimulate TSH receptor (TSIs, thyroid stimulating antibody, TSH-receptor)

What happens to TSH and T3/T4 in Graves disease?

- TSH = decreased

- T3/T4 = increased

What are the features of hyperthyroidism?

- Thyrotoxicosis

- Goiter

- Exophthalmos (bulging eyes)

- Dermopathy

What type of hyperthyroidism causes autonomous follicles surrounded by normal or nonfunctioning follicles?

Plummer's Disease

What are the symptoms of thyroid storm?

- Decompensated thyrotoxicosis

- High fever

- Tachycardia

- Tachypnea

What is the normal TSH range?

0.3-4 IU/L

What are the 2 thionamides to treat hyperthyroidism?

Methimazole and PTU

What is the black box warnings for thionamides?

Hepatotoxicity

What are the ADRs of thionamides?

- Agranulocytosis

- Birth defects in first trimester

What is the mechanism of thionamides?

Inhibit thyroid peroxidase (TPO)

What does TPO inhibition block?

Iodination and coupling

Which drug also blocks T4 → T3 conversion?

PTU

What is the Wolff-Chaikoff effect?

Inhibiting TPO

What is the MOA of potassium iodide?

Relies of the Wolff-Chaikoff effect which is a sudden excess of iodide temporarily inhibiting hormone synthesis by suppressing iodide organification

When is potassium iodide used?

- Thyroid Storm

- Preoperative preparation for surgery

- Adjunct after RAI

Which beta-blocker is commonly used to control sympathomimetic effects associated with thyrotoxicosis?

Propranolol (or any without ISA)