Week 3: Hypo/Hyper Thyroidism

Draw the feedback control loop for the thyroid gland

hypothalamus → TRH → (+) anterior pituitary thyrotrophs → TSH → (+) thyroid gland → T4/T3 → effects / (-) ant pit thyrotrophs / (-) hypothalamus

Describe the 3 effects of stimulating TSH-R

1. increased T4/T3 synthesis

2. growth

3. stimulation of NIS (Na⁺/I^- symporter)

What is the importance of iodide?

important for synthesis of T4/T3 hormones

What is hypothyroidism?

low T4/T3

What are the 3 main causes of hypothyroidism (primary, secondary, tertiary)?

1. 1° - thyroid gland problem

2. 2° - ant pit problem

3. 3° - hypothalamus problem

How does hormone production change in response to 1° hypothyroidism (thyroid gland ablation)?

decreased T4/T3 → increased TRH → increased TSH

How does hormone production change in response to 2° hypothyroidism (ant pit ablation)?

decreased TSH → decreased T4/T3 → increased TRH

How does hormone production change in response to 3° hypothyroidism (hypothalamus ablation)?

decreased TRH → decreased TSH → decreased T3/T4

What is the most common cause of hypothyroidism?

1° - thyroid gland damage

What type of receptor is TSH-R?

nuclear intracellular receptor

Which hormone is made in larger amounts: T4 or T3?

T4 is the primary hormone made (prohormone) → converted to T3 which is the biologically active hormone (gives majority of the effects)

What are the 5 main causes of 1° hypothyroidism?

1. autoimmune

2. radioactive iodide therapy

3. thyroidectomy

4. drugs

5. excessive iodide intake

6. iodide deficiency

How does autoimmune cause 1° hypothyroidism?

autoimmune attack of the thyroid gland causes damage

What is the name of the autoimmune disorder that causes destruction of the thyroid gland?

Hashimoto’s Thyroiditis → chronic inflammation of the thyroid that causes deficiency of the TG and decreased T4/T3

How does radioactive iodide therapy cause 1° hypothyroidism? What is it typically used to treat?

typically used as treatment for hyperthyroidism → destroys the thyroid gland → decreased T4/T3

What is a thyroidectomy and how can it cause 1° hypothyroidism? What is this usually used to treat?

removal of thyroid gland → leads to decreased T4/T3

used as hyperthyroidism or thyroid cancer treatment

What are the 2 drugs that can cause 1° hypothyroidism and what are they typically used to treat?

1. lithium → bipolar disorder

2. antithyroid drugs → hyperthyroidism

What is the role of Lithium in hypothyroidism?

Li⁺ gets in to TG and interferes with TG function via NIS → decreased iodide uptake = decreased TG synthesis

How does excessive iodide intake cause 1° hypothyroidism?

iodide used to make T4/T3

if we have excess iodide it becomes too concentrated in TG → internal feedback mechanism within TG will decrease hormone synthesis and release

How does iodide deficiency lead to 1° hypothyroidism?

iodide is needed to make T4/T3

without it → can’t make the hormones and thyroid gland will try to compensate by increasing TSH

What are the 3 clinical findings of 1° hypothyroidism in newborns/infants/children?

1. intellectual disabilities

2. neurological deficits

3. decreased linear growth

Why is it important to do routine screening in newborns?

TH is important developmentally and the clinical findings we see could be permanent

In adults, the clinical findings are highly variable. What is a good way to think of the presentation of 1° hypothyroidism?

think of it as a general slowing of processes in the body

How is the body’s energy impacted by hypothyroidism?

1. fatigue

2. lethargy

What is the impact on the brain? (2)

1. decreased concentration

2. depression

What is the impact on metabolism? (3)

1. cold intolerance

2. weight gain

3. constipation

How is muscle strength impacted?

myopathy → weakness

How is the menstrual cycle impacted?

abnormal menstrual (sensitive to endocrine disturbances)

What are the other effects on the skin and voice? (3)

1. cool, dry, rough skin with yellow color

2. puffy face/hands

3. hoarse voice

What is the impact on muscle stretch?

delayed relaxation of muscle stretch reflexes

How is the heart impacted?

bradycardia → TH-R upregulates B₁ on the heart, so w/o it = decreased B₁ expression

Why do we see anemia with hypothyroidism?

TH regulates EPO production

• decreased EPO

• decreased absorption of Fe²⁺ and folate

What are 2 other findings we may or may not see with hypothyroidism? (±)

• ± hyperprolactinemia

• ± diffuse goiter

Why could we see hyperprolactinemia with hypothyroidism?

1° and 2° hypothyroidism leads to increased TRH → excess TRH stimulates PRL production = increase PRL

What are the effects of increased PRL in men vs women?

• men: erectile dysfunction, gynecomastia

• women: menstrual irregularities, galactorrhea, infertility

How can we see ± diffuse goiter with hypothyroidism?

hypothyroidism = increased TSH

high TSH → increases TSH-R stimulation on thyroid gland → GROWTH

Under which 2 conditions would we see NO diffuse goiter with hypothyroidism? What is required to see diffuse goiter?

1. no TG due to surgical removal

2. no TG due to autoimmune attack (hashimoto’s)

REQUIRES:

• thyroid gland cells

• increased TSH-R activity

What could happen if someone with hypothyroidism did not take their TH replacement?

SEVERE UNTREATED HYPOTHYROIDISM

What is the rare but extremely serious complication of severe untreated hypothyroidism?

MYXEDEMA COMA

What are the 5 clinical findings in myxedema coma?

1. HYPOthermia

2. HYPOventilation (and acidosis)

3. HYPOglycemia

4. HYPOnatremia

5. coma → death

What are the 4 labs we should see done to check for hypothyroidism?

1. TSH

2. FT4

3. Antibodies

4. LDL-C

Which 2 antibodies should we test for?

• anti-TPO

• anti-Tg

What is anti-TPO?

thyroid peroxidase = protein in thyroid gland that is required to make thyroid hormone

anti-TPO = decreased TH hormone

What is anti-Tg? What does presence of this indicate?

thyroglobulin = protein responsible for storing thyroid hormone

• anti-Tg = indicates autoimmune process

How could LDL-C be impacted by hypothyroidism and why?

ELEVATED LDL-C

• T4/T3 upregulate LDL-R on the liver

• with low T4/T3 → decreased LDL-R → decreased cholesterol uptake = hypercholesterolemia

What is the main method of treatment?

thyroid hormone replacement

What is the name of the drug use for hypothyroidism?

Levothyroxine (T4 replacement)

How is T4 converted to T3 (active hormone)?

5’ Deiodinase

What is the advantage of taking a thyroid hormone replacement?

once steady state is reached, TH has a long half life of 7 days → not as sensitive to missed doses

What is dose dependent on?

body weight

• if bigger = higher dose

• if smaller = lower dose

What is the overall goal of treatment?

to NORMALIZE TSH (decrease TSH) and reduce symptoms

Why do we wait 4-6 weeks to check if Levothyroxine is working?

half life is 1 week → need enough time to reach steady state and for drug to meet maximum levels

What are 2 advantages of taking T4 over T3?

• T4 is more physiologic (it mimics what the thyroid typically does)

• has a long half life so we get stable T4 levels

What is the AE of Levothyroxine?

Thyrotoxicosis (too much TH) → causes symptoms of hyperthyroidism

Explain how a hypothyroid patient should take their levothyroxine replacement therapy

on empty stomach for max absorption

Explain how the FT4, FT3, and TSH will change in a primary hypothyroid patient starting their levothyroxine

primary = issue at thryoid gland

initially FT4 increases → FT3 increases → TSH decreases

What is hyperthyroidism?

too much TH (T4/T3) released

What are the 3 major causes of hyperthyroidism?

1. Grave’s Disease

2. Exogenous thyroid hormone toxicity

3. TSH secreting adenoma

What is Grave’s Disease?

an autoimmune disease that creates an antibody that stimulates TSH-R to produce TH

What is the name of the antibody and what does it do?

TSI = thyroid stimulating immunoglobulin

it functions like TSH → stimulates TSH-R and causes TG growth and hyperthyroidism

Which other receptor can TSI stimulate that is located behind the eye and what does this cause?

can stimulate IGF-R on fibroblasts behind eye → causes a buildup and bulges the eye forward

What is the effect of exogenous thryoid hormone toxicity?

taking too much TH through meds → causes thyrotoxicosis

How can we think about the symptoms caused by hyperthyroidism?

opposite to hypothyroidism → “SPEEDING things up”

What are the 4 brain related and 3 metabolism related findings of hyperthyroidism?

brain:

• fatigue

• lethargy

• anxiety

• nervousness

metabolism:

• weight loss

• diarrhea

• heat intolerance

Why do we see hypokalemia with hyperthyroidism?

TH causes increased activity of the Na+/K+ ATPase → more K⁺ is taken up into cells causing decreased K⁺ in the plasma

Because TH upregulates B receptors, what are 2 symptoms we could see?

1. SKM tremor (increased B₂)

2. tachycardia

We can also see ± diffuse goiter with hyperthyroidism, what does this indicate?

if YES: this means GRAVE’S DISEASE or TSH ADENOMA

• graves = TSI = stimulates TSH-R on thyroid for growth

• TSH adenoma = tumor secreting TSH = TSH-R activity = growth

Why can we see diffuse goiter with both hypo and hyperthyroidism?

diffuse goiter just means we have increased TSH-R activity → which can occur with both (so we cant tell which one it is)

What is an extra AE caused by Grave’s Disease involving the eyes?

EXOPHTHALMOS → protrusion of the eyes

• TSI stimulates TSH-R, which interacts with IGF-1 behind the eyes → causes inflammation and bulging of the eye

What is an extreme form of hyperthyroidism called and what is it caused by?

THYROID STORM

• casued by acute severe thyroid hormone excess where TH effects are exaggerated (ex: super high body temp)

Which 3 labs should we do to test for hyperthyroidism?

• TSH

• FT4

• antibodies → TSI

Predict the changes in TSH, FT4, FT3, LDL-C, and antibodies (TSI) in hyperthyroidism. Predict if they will have diffuse goiter: Grave’s Disease

TSH = low (high TH neg feedbacks)

FT4 = high

FT3 = high

LDL-C = low

TSI = detected

YES diffuse goiter

Predict the changes in TSH, FT4, FT3, LDL-C, and antibodies (TSI) in hyperthyroidism. Predict if they will have diffuse goiter:Exogenous Thyroid Hormone Toxicity

• TSH = low

• FT4 = high

• FT3 = high

• LDL-C = low

• TSI = none

• NO goiter

Predict the changes in TSH, FT4, FT3, LDL-C, and antibodies (TSI) in hyperthyroidism. Predict if they will have diffuse goiter: TSH secreting adenoma

• TSH = high

• FT4 = high

• FT3 = high

• LDL-C = low

• TSI = none

• YES goiter

When discussing treatment, why do we focus on Grave’s Disease? What is the goal of treatment?

it is the most common cause of hyperthyroidism

• goal: do something to TG to prevent excess TH production

What are the 3 general treatments for hyperthyroidism caused by Grave’s Disease?

1. surgery

2. radioactive iodine (I¹³¹)

3. Thionamides (pharmacological treatment)

Which surgery would be done for treatment and what additional drug is required to prevent hypothyroidism?

thyroidectomy = removal of thyroid gland

• requires Levothyroxine to avoid hypothyroidism

What are the 2 main complications that can occur with a thyroidectomy?

1. damage to the recurrent laryngeal nerve

2. hypoparathyroidism & hypocalcemia

What is the secondary effect to damaging the recurrent laryngeal nerve?

damage to the vocal chords → hoarseness

How can hypoparathyroidism occur with a thyroidectomy?

through accidental removal of the parathyroid glands located behind the thyroid gland

• parathyroid glands regulate Ca⁺⁺

• so removing the glands can cause hypocalcemia as well

Explain how radioactive iodine therapy (I¹³¹) helps treat hyperthyroidism

• radiation to target the thyroid gland

• I¹³¹ concentrates in the TG → enters through the Na⁺/I^- symporter → I¹³¹ destroys the gland

What are the names of the 2 Thionamide drugs?

• Methimazole

• PTU

What is the MOA of Thionamides?

they are ANTITHYROID GLAND DRUGS that INHIBIT synthesis of thyroid hormones by blocking Thyroid Peroxidase (TPO)

What is an additional MOA of PTU?

blocks 5’ Deiodinase

Explain why PTU would be preferred over methimazole in a patient who has acute severe hyperthyroidism (aka “thyroid storm”) and needs urgent therapy

PTU mostly preferred in emergency circumstances because it has the additional MOA of blocking 5’ Deiodinase → prevents T4 to T3 conversion and reduces excess TH production (in addition to blocking TPO)

What are the 4 AEs of Thionamide drugs PTU and methimazole?

1. rash

2. agranulocytosis (decreased WBC = increased risk of infection)

3. hepatotoxicity

4. hypothyroidism

Explain how beta blockers can help alleviate symptoms of hyperthyroidism

nonselective beta blockers are used for relieving TACHYCARDIA/TREMORS associated with hyperthyroidism

• B receptors are upregulated by TH → when blocked, it helps relieve these symptoms and could be especially helpful in thyroid storm before surgery

What is TED (thyroid eye disease)/ Grave’s Orbitopathy?

autoimmune inflammatory disease that occurs on the eye, typically with someone who has Grave’s disease

What is the pathophysiology of TED?

TSI binds TSH-R on retro orbital fibroblasts and co-activates IGF-1 receptors → causes release of glycosaminoglycans and inflammation and expansion of retroorbital tissue

What are the 5 main symptoms associated with TED?

1. proptosis (eye pushed forward)

2. diplopia (double vission)

3. eye pain/redness/swelling

4. decreased vision

5. eyelid retraction

What is the name of the drug that treats TED?

Teprotumumab

What is the MOA of Teprotumumab?

monoclonal antibody that binds and inhibits IGF-1 receptor (prevents it from being co-activated)