Endocrinology - Exam 2 (Thyroid Hormone & Conditions)

Where is the thyroid gland located?

In front of trachea (C5-T1 vertebral level)

What are the two cell types of the thyroid gland?

1) Follicular epithelial cells (thyroid epithelial cells/thyrocytes)

2) Parafollicular (C) cells

What do the follicular epithelial cells of the thyroid release? What do the Parafollicular (C) cells of the thyroid release?

Follicular = Thyroid hormones (Thyroxine - T4; Triiodothyronine - T3)

C cells = Calcitonin

In the 4 parathyroid glands, what cell type do they have? What hormone does this release?

Cell type: Chief cells

Release: Parathyroid hormone

What stimulates the thyrotropes in anterior pituitary from the hypothalamus? What nucleus is this secreted from?

Thyrotrophin Releasing Hormone - TRH

-- Paraventricular nuclei

What type of hormone is TRH? What mechanism does it use?

Peptide hormone

(Phospholipase C mechanism)

What hormone do the thyrotropes secrete? What mechanism does this hormone use?

thyroid stimulating hormone (TSH) / Thyrotropin

-- Adenylyl cyclase mechanism (cAMP)

What does TSH stimulate the secretion of?

T3 & T4 from thyroid

What is the function of T3/T4?

Body metabolism, growth, development of tissues

(controls most intracellular chemical reactions in body)

What type of hormone is T4 (Thyroxine) and Triiodothyronine (T3)? What mechanism does it use?

Amines

-- Steroid mechanism

Other than TRH acting on thyrotropes to stimulate both transcription & secretion of TSH, what action can TRH have on the anterior pituitary?

Little stimulation of secretion of prolactin by anterior pituitary lactotrophs/mammotrophs

The thyrotropes of the anterior pituitary develop and begin secreting TSH at approximately gestational week ______?

Week 13

NOTE same time fetal thyroid gland begins secreting thyroid hormones

The actions of TSH on the thyroid gland are initiated when ____ binds to a membrane receptor, which is coupled to adenylyl cyclase via Gs protein?

TSH

What are the two types of actions that TSH has on the thyroid gland?

1) Increase synthesis & secretion of thyroid hormones (T4/T3) by stimulating EACH step of biosynthetic pathway

2) TSH has trophic effect on thyroid gland (overall SUPPORT of thyroid for growth & blood supply)

-- shown when TSH levels are elevated for sustained period of time leading to hypertrophy and hyperplasia of thyroid follicular cells and increased thyroidal blood flow

Which hormone has SOME influence on TSH from the anterior pituitary? Which hormone has A LOT of feedback on hypothalamus and anterior pituitary?

SOME = T4

A LOT = T3

What feedback loop does TRH, TSH, T3, T4 regulated by?

Negative feedback system

What are antibodies to the TSH receptor that mimic the same effect as TSH and bind receptors, increasing production of TH (hyperthyroid)? What immunoglobulin (Ig) are they components of?

Thyroid-stimulating immunoglobulins (TSI)

(also known as;: TSHR-abs (thyroid stimulatingW hormone receptor antibodies); TR-Ab (TSH receptor antibody); TBI-ab (TSH binding inhibiting antibodies))

-- IgG

What does Thyroid-stimulating immunoglobulins (TSI) cause?

Synthesis/secretion and hypertrophy/hyperplasia of gland; causing oversecreting and hyperthyroidism (GOITER)

If TSI index is showing greater than 1.8, what can this indicate? what if its between 1.3-1.8?

1.8 = Graves

1.3-1.8 = Subclinical hyperthyroidism

What is the only difference between Triiodothyronine (T3) and Thyroxine (T4)? What location is where this difference is located?

Differ by one single atom of iodine (3 or 4)

5' location

T4/T3 can be free (unbound), but since they are LIPOPHILIC, they are most commonly bound to ______ in circulation.

Thyroxine-binding globulin (TBG)

(carrier protein)

T/F: When T3/T4 is bound to TBG, it is physiologically active.

FALSE

-- FREE thyroid hormones are physiologically active

-- Role of TBG is to provide a large reservoir of circulating thyroid hormones, which can be released and added to the pool of free hormones

Is T3 or T4 our active thyroid hormone?

T3!

(3x more effective)

Does the thyroid produce more T3 or T4?

More T4 (80%)

Does T3 or T4 have a longer half life?

T4 long half life of days; T3 shorter

What is the target tissues (3) that convert T4 to T3 (active form)?

Heart, Kidney, Liver

The follicular epithelial cells of the thyroid gland that synthesis thyroid hormones have epithelial cells in circular follicles, and has what in the lumen/center of the follicle? What is this and why is it important?

Colloid

--> protein rich reservoir of materials needed for thyroid hormone production

What is the 6 step mechanism for Thyroid Hormone Synthesis?

1) Active transport of iodide into follicular cell via Sodium-Iodide Symporter (NIS)

2) Thyroglobulin (Tg), a large glycoprotein rich in Tyrosine, is formed in follicular ribosomes and placed into secretory vesicles

3) Exocytosis of Thyroglobulin into the follicle lumen, where it is stored as colloid

4) Iodide Oxidation and Iodination of Thyroglobulin (Organification)

5) Coupling

6) Endocytosis of iodinated thyroglobulin back into the follicular cell

(ATE ICE)

In step 1 of Thyroid Hormone Synthesis, Iodide levels are ______ in the blood and _____ inside the follicular epithelial cell? Sodium is ________ in the blood and ______ inside follicular cells?

Iodide: LOW in blood; HIGH in follicular cell

Sodium: HIGH in blood; LOW in follicular cell

NOTE: Undergo secondary active transport

In step 3 of Thyroid Hormone Synthesis, what is the backbone upon which thyroid hormone is synthesized?

Thyroglobulin

In step 4 of Thyroid Hormone Synthesis, Iodine is made reactive by oxidation by what enzyme?

Thyroid Peroxidase (TPO)

Iodine binds to the benzene ring on tyrosine residues of thyroglobulin to form what two molecules (depending on how many iodine binds)?

Monoiodotyrosine (MIT)

Diiodotryosine (DIT)

In step 5 of Thyroid Hormone Synthesis, the combination of what two molecules give rise to Triiodothyronine (T3) hormone? The combination of what two molecules give rise to Thyroxine (T4)?

T3 = MIT + DIT

T4 = DIT + DIT

What two steps of Thyroid Hormone Synthesis does TPO (Thyroid peroxidase) support?

Step 4: Iodide oxidation and iodination of thyroglobulin

Step 5: Coupling (conjugation)

T3 & T4 in step 5 of Thyroid Hormone Synthesis are stored where until the thyroid gland is stimulated to secrete its hormones (TSH)?

In follicular lumen as colloid

In step 6 of Thyroid Hormone Synthesis, why does the thyroglobulin undergo proteolysis by lysosomoes?

To cleave iodinated tyrosine residues from larger protein

-- release free T3 or T4

-- Thyroglobulin backbone recycled

What enzyme is used to convert T4 to T3? What enzyme is used during states of chronic stress to convert T4 to reverse T3?

5' deiodinase

(prime for the primary method, usually goes T4 --> T3 unless times of CHRONIC STRESS)

5 deiodinase

What is the important of iodine for the thyroid?

Iodine is an important component of thyroid hormones

--BUT, too much or too little is detrimental

What is a substance that disrupts the production of thyroid hormones by interfering with the body's use of iodine?

Goitrogens

What three Halogens can block iodine receptors in order to lower iodine in body?

Fluoride

Chloride

Bromine

What is the mechanism of action of Thyroid hormones (T3/T4)? (7 steps)

Steroid Hormone Mechanism

1) Diffuse across cell membrane to enter cytosol or nucelus

2) Binds to E domain

3) Hormone-receptor dimerize to bind C domain

4) Hormone-receptor complex becomes transcription factor regulating gene transcription

5) New mRNA is transcribed

6) Leaves nucleus

7) Translated new proteins which are specific to hormone

What major effect does T3/T4 have on the liver?

Glycogenolysis & Gluconeogenesis

-- increase blood glucose levels

What major effect does T3/T4 have on the basal metabolic rate (BMR)? Why?

Increases BMR by increasing cellular synthesis of additional sodium-potassium pumps, more oxygen usage, and lipolysis

-- for ATP production, glycolysis, gluconeogenesis, and heat production

Does thyroid hormones have an anabolic or catabolic effect? Why?

Catabolic

-- because they increase both protein synthesis and degradation

What major effect does T3/T4 have on the muscle? Why?

Normal muscle function and development

-- catabolic function results in decreased muscle mass

The metabolic effect (catabolism) on muscles by thyroid hormones occurs because thyroid hormones induce the synthesis of what?

Key metabolic enzymes

(cytochrome oxidase, NADPH cytochrome C reductase, alpha-glycerophosphate dehydrogenase, malic enzyme,a nd several proteolytic enzymes)

What major effect does T3/T4 have on the adipose tissue?

Lipolysis

What major effect does T3/T4 have on the Heart?

Promotes normal cardiac output

What major effect does T3/T4 have on the CNS?

Increase synapse, myelination, and dendrites

--> normal nervous system development/maturation

NOTE: effects age dependent; perinatal period its ESSENTIAL (w/o cause intellectual disabilities); in adults can cause other symptoms

Do thyroid hormones interact with the sympathetic or parasympathetic nervous system?

Sympathetic nervous system

NOTE: this is why significance in B-adrenergic blocking agents as treatment of many symptoms of hyperthyroidism

What major effect does T3/T4 have on the GI?

Support normal motility and secretion

What major effect does T3/T4 have on the skin?

Promote normal hydration of skin

What major effect does T3/T4 have on the Growth/Bone?

Normal bone growth and maturation

Thyroid hormones act synergistically with growth hormone and somatomedins/IGFs to promote what?

Bone formation

-- thyroid hormone promotes ossification and fusion of bone plates and bone maturation

With metabolism, increased oxygen consumption depends on increased availability of substrates for what process?

Oxidative metabolism

Thyroid hormones increase oxygen consumption in all tissues except what 3 by inducing synthesis and increasing activity of Na-K ATPase, which is responsible for primary active transport of Na and K in all cells?

1) Brain

2) Gonads

3) Spleen

In hypothyroidism, we see that bone age is ____ than chronological age.

LESS

Who is more likely to have a thyroid condition?

Women (5-8x)

Decreased metabolic weight, fatigue, depression, weight gain w/o increased food intake, decreased heat production and cold intolerance, decreased heart rate, hoarseness, slowing movement, slurred speech, slowed mental activity, lethargy, periorbital puffiness, constipation, hair loss, menstrual dysfunction, pain/stiffness/swelling in joints, and a goiter (if cause is defect in thyroid) are all symptoms of what condition?

Hypothyroidism

Weight gain, increased food intake, excessive heat production/sweating, increased oxygen consumption, rapid heart rate, palpitations, breathlessness on exertion, tremors/nervousness/irritability/weakness, frequent bowel movements, fine hair/loss, enlarged thyroid, and decreased menstrual flow/infertility are all symptoms of what condition?

Hyperthyroidism

What is the clinical manifestation of excessive thyroid hormone action at the tissue level due to inappropriately high-circulation thyroid hormone?

Thyrotoxicosis

TSH (thyroid stimulating hormone) will be low with Thyrotoxicosis... Why?

Anterior pituitary senses levels for thyroid hormone are high (negative feedback loop)

What is a type of thyrotoxicosis that is the over activity of the thyroid gland, resulting in excessive secretion of thyroid hormone and accelerated metabolic effects?

Hyperthyroidism

What is the most common cause of hyperthyroidism (70-80%) with a diffuse goiter and is autoimmune?

Graves' Disease

In Graves' disease, the immune system releases what antibody that attack/binds to thyroid cells and increases secretion of thyroid hormones and hypertrophy of the gland? What hormone does this mimic?

Thyroid-stimulating immunoglobulins (TSI)

-- mimics TSH

NOTE: remember is stimulates thyroid gland to grow/produce thyroid hormones

T/F: Graves' disease is familial

TRUE

Graves' disease puts individuals at risk for developing what other two conditions?

Type 1 disease

Addison's Disease --> autoimmune on adrenal cortex

What are 6 other causes for why hyperthyroidism can occur, other than Graves' disease (most common)?

1) Thyroiditis

2) Taking too much Thyroid medication

3) Toxic nodular goiter

4) Hyper-functioning thyroid adenoma

5) Jod-Basedow syndrome

6) Neonatal Hyperthyroidism

Which cause of hyperthyroidism involves newborns with a mother who has Graves' Disease, so they start to generate too much TH as a response of TSI crossing the placenta?

Neonatal Hyperthyroidism

Which cause of hyperthyroidism is due to mutated TSH receptors, keeping the follicular cells alive?

Toxic nodular goiter

Which cause of hyperthyroidism is an iodine-induced thyrotoxicosis?

Jod-Basedow syndrome

Which cause of hyperthyroidism is where the follicular cells grow uncontrollably, forming a benign tumor producing excessive exogenous TH?

Hyper-functioning thyroid adenoma

What are 5 complications of hyperthyroidism?

1) Heart (rapid heart rate, atrial fibrillation, Congestive heart failure)

2) Brittle bones (osteoporosis, decreased Ca in bones)

3) Eye problems (bulging eyes due to upper eyelids receding or protrusion; light sensitivity, vision loss)

4) Red swollen skin (grave's dermopathy)

5) Thyrotoxic crisis/Thyroid storm

What is severe hyperthyroidism called where there is too much thyroid hormone in the body and all normal symptoms become exaggerated? Is this a medical emergency?

Thyroid Storm/Thyrotoxic Crisis

-- YES medical emergency bevcause it can lead to mulitple organ dysfunction

Why can a thyroid storm (thyrotoxic crisis) arise? (6 reasons)

1) stop treatment

2) develops an infection

3) has surgery

4) change in THs bind to transport proteins

5) Change in TH receptors at the target tissue

6) Exaggerated sympathetic response

What are 5 treatments for a thyroid storm/crisis?

1) Anti-thyroid meds

2) Iodine to block release of TH (Wolf-Chaikoff effect)

3) Antagonist for peripheral effects (Beta-blocking)

4) Supportive care

5) Treat the cause

To diagnose hyperthyroidism, a history/exam, ophthalmic exam, ECG/EKG and Tests/Labs must be done. What four tests/labs can be done?

1) Blood tests : measuring T4 & TSH

2) Radioactive iodine uptake (RAIU): measuring how much radioactive iodine has been absorbed by thyroid

3) Thyroid scan: radioactive isotope ejected to show how iodine collects

4) Thyroid ultrasound: used to detect nodules, no exposure to radiation

If there is a high uptake of radioactive iodine in RAIU test, what does this indicate? What if there is a low uptake of radioactive iodine in RAIU test?

High uptake = thyroid producing too much thyroxine (Graves disease or hyperfunctioning thyroid nodes)

Low uptake = T4 stored in thyroid leaking into bloodstream (thyroiditis)

Which treatment for hyperthyroidism is taken orally and absorbed by the thyroid and causes it to shrink so it reduces symptoms (3-6 months), with excess disappearing within weeks to months? What is a possible consequence of this?

Radioactive iodine

-- may slow thyroid enough to to cause hypothyroidism (needing daily medications to replace T4)

What treatment for hyperthyroidism reduces the symptoms by preventing the thyroid form producing TH for 6-12 weeks, but continues for a year or often longer? What is a possible consequence of this?

Anti-thyroid medications

(Propylthiouracil (PTU), Carbimazole, Methimazole (Tapazole)

-- can lead to liver damage

What treatment for hyperthyroidism can help reduce tachycardia and palpitations?

Beta-blockers

(HP meds)

What treatment for hyperthyroidism can be used based on considerations such as the type and extend of the thyroid disease present, the anatomy of the thyroid gland affected? What is a consequence of this treatment?

Thyroidectomy (surgery)

-- could be lobectomy, subtotal, total, parathyroid glands

Lifetime treatment with levothyroxine

Which type of hyperthyroidism is determined by High T4 and low TSH in a blood test? Which is High T4 and High TSH?

High T4; Low TSH = Primary (thyroid problem)

High T4; High TSH = Secondary (problem is pituitary)

What is Subclinical Hyperthyroidism?

Individual has hyperthyroidism symptoms, but labs arn't showing this... (yet)

- Pituitary gland signals the thyroid to make less hormone

- labs aren't high enough to diagnose

- Normal thyroid hormones but LOW TSH

What is an inadequate production by the thyroid gland (decreased amount of T3/T4)?

Hypothyrodisim

What is the most common cause of Hypothyrodisim?

Hashimoto's thyroiditis

-- autoimmune thyroid disease (antibodies attack thyroid gland (Thyroglobulin/TPO antibodies))

Who is most at risk for hypothyroidism? What are other risk factors?

Women older than 60

- Autoimmune

- Family history

- Treatment with radioactive iodine or anti-thyroid medication

- Received radiation to neck or upper chest

- Thyroid surgery

- Pregnant or delivered within last 6 months

What are some causes of hypothyroidism? (7)

1) Medications

2) Thyroid surgery

3) Treatment for hyperthyroidism

4) Radiation therapy

5) Damage to pituitary gland

6) Congenital

7) Iodine deficiency

T/F: Not all people who have Hashimoto's have Hypothyroidism

TRUE

Hypothyroidism and adrenal (stress) relationship involves weak adrenals which leads to ________________, and adrenal stress with interferes with __________ and ___________.

1) Weak adrenals --> hypothyroid symptoms

2) Adrenal stress --> interferes w/ HPA axis and converstion of T4 to T3

T/F: Many patients with adrenal-related thyroid issues who are put on thyroid medications without adrenal support will see a relief in their symptoms.

FALSE

-- thyroid medication w/o adrenal support can actually make them get WORSE

Elevated levels of what in circulation can slow thyroid hormone production? What effects can this cause?

Cortisol

-- can cause conversion from T4 to rT3

- prolonged stress can also increase release of cytokines (decrease thyroid responsiveness), estrogen accumulation (increase TBG transporter which decreases T4), and suppress the immune system

What is the condition that can occur if hypothyroidism occurs in the perinatal period and is untreated? What are symptoms of this?

Cretinism

-- irreversible form of growth and intellectual disabilities

T/F: Hypothyroidism in children/teens demonstrates the same signs/symptoms as adults.

TRUE

NOTE: poor growth = shorter; delayed development of teeth; delayed puberty; poor mental development

How is hypothyroid diagnosed?

History, exam

-- blood tests (TSH & TH)

Which type of hypothyroidism demonstrates Low T3/T4 but High TSH? Which type of hypothyroidism demonstrates Low T3/T4 and Low TSH?

Low T3/T4; High TSH: Primary (Ant pituitary producing more TSH to stimulate thyroid since problem is thyroid)

Low T3/T4; Low TSH: Secondary (problem is pituitary)

What is the treatment for Hypothyroidism? How does it work?

Thyroid hormone replacaement therapy (usually T4)

-- Levothyroxine (titrated) measured monthly until TSH stable (TSH levels checked every year)

-- if TSH increased, means dose too low (increase dose)

-- if TSH decreased, means dose too high (decrease dose)

What is severe advanced hypothyroidism that needs medical care, often caused by a stressor that triggers an increase in metabolism and depletes the TH?

MYXEDEMA

NOTE: can lead to coma if not careful; life threatening 20-50% of cases

What are 7 complications of Hypothyroidism if left untreated?

1) Goiter

2) Heart Problems

3) Mental health issues

4) Peripheral neuropathy

5) Myxedema

6) Infertility

7) Birth defects

What condition is mild thyroid failure where the thyroid is losing the ability to produce TH and is early/mild form of hypothyroidism, with same causes/symptoms, but labs do not show it yet?

Subclinical Hypothyroidism