ENDO 01: Thyroid

Normal Thyroid Physiology, Synthesis, and Regulation

A. What does the thyroid do?

The thyroid gland is a butterfly-shaped organ in the neck that produces thyroid hormones (T3 and T4). These hormones affect every tissue in the body and regulate:

• Metabolism (energy production, oxygen use)

• Growth and development (especially important in fetuses and infants)

• Thermoregulation (body temperature control)

• Cardiovascular function (heart rate and blood pressure)

• CNS function (brain activity, mood, cognition)

B. How are T3 and T4 made?

The thyroid makes hormones through a process called iodine organification. Here's how it works:

1. Iodine Uptake

   • Iodine (I⁻) from food enters thyroid follicular cells through the Na+/I⁻ symporter (NIS).

   • This step is TSH-dependent (stimulated by TSH from the pituitary).

2. Thyroglobulin Production

   • The follicular cells produce thyroglobulin (TG), a large protein that serves as a template for making thyroid hormones.

3. Iodination of Tyrosine (Catalyzed by Thyroid Peroxidase, TPO)

   • Inside the follicle, iodine is oxidized by thyroid peroxidase (TPO).

   • TPO helps attach iodine to tyrosine residues on thyroglobulin, forming:

     • Monoiodotyrosine (MIT) (1 iodine)

     • Diiodotyrosine (DIT) (2 iodines)

4. Coupling of MIT and DIT

   • TPO also catalyzes coupling reactions:

     • MIT + DIT → T3 (triiodothyronine)

     • DIT + DIT → T4 (thyroxine)

   • T4 is the main product (90%), but it’s mostly inactive. T3 is more active but only produced in small amounts.

5. Storage and Release

   • The iodinated thyroglobulin is stored in thyroid follicles.

   • When the body needs thyroid hormone, thyroglobulin is broken down, and T3 and T4 are released into the blood.

C. How is thyroid hormone regulated?

The thyroid operates on a negative feedback loop:

1. Hypothalamus releases TRH (Thyrotropin-Releasing Hormone)

   • TRH stimulates the anterior pituitary to release TSH (Thyroid-Stimulating Hormone).

2. TSH stimulates the thyroid

   • TSH increases:

     • NIS activity (more iodine uptake)

     • TPO activity (more iodination)

     • TG production (more storage)

     • Hormone release

3. T3 and T4 inhibit TRH and TSH (negative feedback)

   • High T3/T4 levels suppress TRH and TSH → less stimulation of the thyroid.

   • Low T3/T4 levels increase TRH and TSH → more hormone production.

Think of it like a thermostat:

• If the temperature (T3/T4) is too high, the system turns off (TSH goes down).

• If the temperature is too low, the system turns on (TSH goes up).

D. T3 vs. T4: Why is T3 more active?

• T4 is a prohormone – it must be converted to T3 to be active.

• This conversion happens in peripheral tissues (mainly liver and kidney) by deiodinases (D1, D2, D3).

• T3 binds to nuclear receptors → activates gene transcription → metabolic effects.

• T3 is 3-4× more potent than T4.

Summary So Far:

• Thyroid hormones are made from iodine and tyrosine.

• T4 is the main hormone released, but T3 is more active.

• The HPT axis (hypothalamus-pituitary-thyroid) controls hormone levels via negative feedback.

• TSH is the main regulator of thyroid function.

Pathophysiology of Thyroid Disorders

A. Hypothyroidism: When the Thyroid is Underactive

Hypothyroidism happens when there’s not enough T3 and T4, leading to slowed metabolism.

1. Causes of Hypothyroidism

There are different ways this can happen:

1. Primary Hypothyroidism (Most Common) – Thyroid Gland Dysfunction

   • Hashimoto’s Thyroiditis (autoimmune destruction)

   • Iodine deficiency or excess (both can suppress thyroid function)

   • Post-thyroidectomy or radioactive iodine (RAI) therapy

   • Drugs (e.g., amiodarone, lithium, thionamides, interferon)

2. Secondary Hypothyroidism – Pituitary Dysfunction

   • Pituitary fails to produce TSH → thyroid isn’t stimulated

   • Causes: pituitary tumor, surgery, radiation

3. Tertiary Hypothyroidism – Hypothalamic Dysfunction

   • Hypothalamus fails to release TRH → pituitary doesn’t release TSH

   • Causes: brain trauma, tumor, radiation

2. Symptoms of Hypothyroidism

Since thyroid hormones regulate metabolism, a lack of them slows everything down:

3. Lab Findings in Hypothyroidism

• Primary Hypothyroidism → ↑ TSH, ↓ T4, ↓ T3

• Secondary/Tertiary Hypothyroidism → ↓ TSH, ↓ T4, ↓ T3

• Hashimoto’s Thyroiditis → Positive anti-TPO antibodies (TPOAb)

B. Hyperthyroidism: When the Thyroid is Overactive

Hyperthyroidism happens when there’s too much T3 and T4, causing an overactive metabolism.

1. Causes of Hyperthyroidism

1. Graves’ Disease (Most Common) – Autoimmune Overstimulation

   • TRAb (TSH receptor antibodies) stimulate the thyroid like TSH, leading to excess T3/T4 production.

2. Toxic Multinodular Goiter (TMNG) & Toxic Adenoma

   • Autonomous nodules produce T3/T4 without TSH stimulation.

3. Thyroiditis (Inflammation of the Thyroid)

   • Subacute thyroiditis (viral infection) → thyroid dumps stored T3/T4 → transient hyperthyroidism.

4. Excess Iodine (Jod-Basedow Phenomenon)

   • Sudden large iodine intake (e.g., contrast dye, amiodarone) triggers hyperthyroidism in susceptible individuals.

2. Symptoms of Hyperthyroidism

Since thyroid hormones speed up metabolism, everything goes into overdrive:

3. Lab Findings in Hyperthyroidism

• Primary Hyperthyroidism → ↓ TSH, ↑ T4, ↑ T3

• Graves’ Disease → Positive TRAb (TSH receptor antibodies)

C. Drug-Induced Thyroid Dysfunction

Some medications can interfere with thyroid function:

Key Takeaways

• Hypothyroidism = slow metabolism (cold intolerance, weight gain, fatigue).

• Hyperthyroidism = fast metabolism (heat intolerance, weight loss, anxiety).

• Graves’ Disease is the most common cause of hyperthyroidism.

• Hashimoto’s Thyroiditis is the most common cause of hypothyroidism.

• TSH is the best test for thyroid dysfunction.

3⃣ Diagnosing Hypothyroidism & Hyperthyroidism

Since symptoms of thyroid disorders can overlap with other conditions, lab testing is crucial.

A. Key Thyroid Function Tests

B. How to Diagnose a Patient with Suspected Thyroid Dysfunction

1. Step 1: Measure TSH

• If TSH is high → Likely hypothyroidism → Check fT4.

• If TSH is low → Likely hyperthyroidism → Check fT4 and fT3.

2. Step 2: Look at fT4 & fT3 Levels

• ↓ fT4 with ↑ TSH → Primary Hypothyroidism

• ↓ fT4 with ↓ TSH → Secondary Hypothyroidism (pituitary issue)

• ↑ fT4 with ↓ TSH → Primary Hyperthyroidism (Graves’ or toxic nodules)

• ↑ fT4 and fT3 with ↑ TSH → TSH-secreting tumor (rare)

3. Step 3: Check for Antibodies if Autoimmune Thyroid Disease is Suspected

• Anti-TPO Ab → Present in Hashimoto’s.

• TRAb → Present in Graves’ Disease.

4⃣ Pharmacology & Treatment of Thyroid Disorders

A. Hypothyroidism Treatment

The goal is to replace thyroid hormone and normalize TSH levels.

1. Levothyroxine (L-T4) – First-Line Therapy

• Synthetic T4 (body converts it to T3 as needed).

• Best taken on an empty stomach (food, calcium, iron can reduce absorption).

• Dosing:

  • Healthy adults: 1.6 mcg/kg/day

  • Elderly: Start low (25-50 mcg/day) to avoid cardiac strain.

  • CAD patients: Start very low (12.5-25 mcg/day) → Too much T4 can worsen angina.

• Monitoring:

  • Re-check TSH in 4-8 weeks after starting or adjusting dose.

  • Once stable, check TSH yearly.

2. Other Treatment Options

B. Hyperthyroidism Treatment

The goal is to reduce thyroid hormone levels or block their effects.

1. Thionamides (Methimazole & PTU) – First-Line

🔹 Methimazole is usually preferred because:

• More potent and longer half-life (daily dosing vs. PTU 3×/day).

• Fewer side effects (less risk of liver failure than PTU).

• Exception: PTU is preferred in 1st trimester pregnancy (methimazole is teratogenic).

📌 Monitoring:

• Check TSH, fT4 every 4-6 weeks initially.

• Once euthyroid, check every 3-6 months.

📌 Side Effects:

• Agranulocytosis (↓ WBCs) – Monitor for fever, sore throat!

• Liver toxicity (PTU > MMI) – Watch for jaundice.

2. Beta-Blockers (Propranolol, Atenolol) – Symptom Control

Since hyperthyroidism increases heart rate, tremors, anxiety, beta-blockers help by:

• Blocking β-adrenergic effects → ↓ HR, tremors, sweating.

• Propranolol is preferred because it also blocks T4 → T3 conversion.

3. Radioactive Iodine (RAI) – Permanent Thyroid Destruction

• Mechanism:

  • I-131 is taken up by the thyroid and destroys thyroid cells over weeks/months.

  • Often leads to permanent hypothyroidism, requiring lifelong levothyroxine.

• When Used:

  • Graves’ Disease (preferred over long-term thionamides).

  • Toxic nodules (RAI shrinks them).

• Contraindications: Pregnancy & breastfeeding (radioactive exposure to fetus).

4. Surgery (Thyroidectomy) – Last Resort

• When Used:

  • Large goiter compressing airway.

  • Failed RAI or thionamide therapy.

  • Pregnancy where meds fail.

• Post-Surgery: Patients need lifelong levothyroxine.

5⃣ Special Cases: Myxedema Coma & Thyroid Storm

A. Myxedema Coma (Severe Untreated Hypothyroidism)

• Life-threatening emergency!

• Symptoms: Hypothermia, bradycardia, altered mental status.

• Treatment:

  • IV T4 (200-600 mcg) ± IV T3 (only used in Canada PO).

  • IV Hydrocortisone (in case of adrenal insufficiency).

  • Supportive care (warming, fluids, ventilation).

B. Thyroid Storm (Severe Untreated Hyperthyroidism)

• Life-threatening hyperthyroid crisis!

• Symptoms: Fever, delirium, tachycardia, arrhythmias, coma.

• Treatment (5 B’s):

  1. Beta-blockers (Propranolol) – ↓ HR, ↓ T4 → T3 conversion.

  2. Block synthesis (Thionamides: PTU or MMI).

  3. Block release (Iodine solution after thionamide).

  4. Block conversion (Steroids: hydrocortisone/dexamethasone).

  5. Bile acid sequestrants (cholestyramine to remove T4 in gut).

Final Summary

• TSH is the best test for thyroid disorders.

• Levothyroxine (T4) is the gold standard for hypothyroidism.

• Methimazole > PTU for hyperthyroidism, except in pregnancy.

• Beta-blockers help control symptoms of hyperthyroidism.

• RAI or surgery is needed for definitive Graves’ disease treatment.

• Myxedema coma & thyroid storm are life-threatening emergencies.

1. Thyroid Physiology

The thyroid gland is responsible for producing thyroid hormones (T3 and T4), which regulate metabolism, growth, and energy balance.

Thyroid Hormone Synthesis & Regulation

• Iodine (I⁻) intake: The thyroid absorbs iodine from the blood.

• Thyroglobulin (TG): A protein in the thyroid where T3 and T4 are made.

• Thyroid peroxidase (TPO): An enzyme that helps attach iodine to TG, forming T3 and T4.

• T4 (thyroxine): Inactive but can be converted into T3.

• T3 (triiodothyronine): The active form of thyroid hormone.

• TSH (thyroid-stimulating hormone): Released from the pituitary gland to signal the thyroid to produce T3 and T4.

• TRH (thyrotropin-releasing hormone): Released from the hypothalamus to stimulate TSH production.

Think of this as a thermostat: If T3/T4 levels drop, TSH increases to boost production. If T3/T4 is high, TSH decreases.

2. Hypothyroidism (Underactive Thyroid)

Causes

1. Primary hypothyroidism (problem in the thyroid itself)

   • Hashimoto’s thyroiditis (autoimmune destruction of the thyroid)

   • Iodine deficiency

   • Iatrogenic (thyroidectomy, radioactive iodine therapy)

   • Drug-induced (amiodarone, lithium, interferon)

2. Secondary hypothyroidism (pituitary issue → low TSH)

3. Tertiary hypothyroidism (hypothalamus issue → low TRH)

Symptoms (Slowed metabolism)

• Fatigue, depression, weight gain

• Cold intolerance

• Dry skin, brittle hair, hair loss

• Bradycardia (slow heart rate)

• Constipation

• Menstrual irregularities

• Puffy face, hoarseness

• Severe cases: Myxedema coma (life-threatening!)

Diagnosis

• TSH ↑, fT4 ↓ (primary hypothyroidism)

• TSH ↓, fT4 ↓ (secondary hypothyroidism)

• TPO antibodies → Hashimoto’s thyroiditis

Treatment

• Levothyroxine (T4)

  • Start 1.6 mcg/kg/day in healthy adults.

  • Elderly = Start low (50mcg/day)

  • CAD patients: Start low (12.5-25 mcg/day) to avoid heart complications.

  • Take on an empty stomach for better absorption.

  • Monitor TSH every 4-8 weeks until stable, then yearly.

  • Avoid interactions: Iron, calcium, sucralfate, cholestyramine decrease absorption.

• Myxedema Coma Management

  • IV T4 (200-600 mcg loading, then 50-100 mcg daily)

  • Consider IV T3 (5-20 mcg loading, then 10 mcg q4h)

  • IV hydrocortisone (to prevent adrenal insufficiency)

3. Hyperthyroidism (Overactive Thyroid)

Causes

1. Graves' disease (autoimmune, TRAb antibodies stimulate TSH receptors)

2. Toxic multinodular goiter (autonomous hormone production)

3. Thyroiditis (temporary hormone release after inflammation)

4. Excess iodine intake (e.g., amiodarone, radiocontrast agents)

5. TSH-secreting pituitary tumor

Symptoms (Increased metabolism)

• Weight loss, heat intolerance, sweating

• Tremors, anxiety, insomnia

• Tachycardia (fast heart rate), palpitations, atrial fibrillation

• Exophthalmos (bulging eyes - Graves' disease)

• Increased bowel movements (diarrhea)

• Fine, thinning hair

• Osteoporosis risk (excess thyroid hormone increases bone breakdown)

Diagnosis

• TSH ↓, fT4 ↑, fT3 ↑

• TRAb positive → Graves' disease

• Radioactive iodine uptake test:

  • High uptake → Graves' or toxic multinodular goiter

  • Low uptake → Thyroiditis, iodine-induced

Treatment

1. Beta-blockers (Propranolol, Atenolol)

   • For symptoms only (tachycardia, tremors)

2. Thionamides (Methimazole, PTU)

   • Methimazole (MMI) is first-line (except in 1st trimester pregnancy).

   • PTU (preferred in pregnancy, but risk of liver toxicity).

   • Monitor CBC (risk of agranulocytosis), LFTs (hepatotoxicity).

3. Radioactive iodine (I-131)

   • Destroys thyroid cells, often leading to hypothyroidism.

   • Avoid in pregnancy.

4. Thyroidectomy (surgery)

   • For large goiters, cancer suspicion, severe Graves’ ophthalmopathy.

   • Pre-treat with methimazole + beta-blockers.

5. Thyroid Storm (Life-threatening hyperthyroidism)

   • Propranolol (beta-blocker)

   • High-dose PTU or methimazole

   • Steroids (hydrocortisone)

   • Lugol’s iodine (blocks T4/T3 release)

   • IV fluids, cooling measures

4. Drug-Induced Thyroid Disorders

5. Subclinical Thyroid Disorders

• Subclinical hypothyroidism (TSH 4.5-10, normal fT4) + NO SIGNS AND SYMPTOMS

  • Treat if TSH >10 or if symptoms present.

  • Consider treatment in pregnancy (TSH >4).

  • Many cases resolve spontaneously.

• Subclinical hyperthyroidism (TSH <0.1, normal fT4) + NO SIGNS AND SYMPTOMS

  • Treat if age >65, osteoporosis, atrial fibrillation, or cardiac disease.

6. Thyroid & Pregnancy

• Hypothyroidism

  • TSH goal: <2.5 in 1st trimester, <3 in later pregnancy.

  • Increase levothyroxine dose by 30% immediately upon pregnancy.

  • Monitor TSH every 4 weeks.

• Hyperthyroidism

  • PTU preferred in 1st trimester, then switch to methimazole.

  • RAI contraindicated.

  • Untreated Graves' → fetal hyperthyroidism risk.

Summary

1. Thyroid hormones (T3/T4) regulate metabolism; controlled by TSH from the pituitary.

2. Hypothyroidism: Slow metabolism, treat with levothyroxine.

3. Hyperthyroidism: Fast metabolism, treat with beta-blockers, thionamides, RAI, or surgery.

4. Thyroid disorders can be drug-induced (e.g., amiodarone, lithium).

1. Hashimoto’s Thyroiditis & Anti-TPO Antibodies

Hashimoto’s thyroiditis is an autoimmune disease where the body’s immune system attacks the thyroid and gradually destroys it, leading to hypothyroidism (low thyroid hormone levels).

What is Anti-TPO (Thyroid Peroxidase) Antibody?

• TPO (thyroid peroxidase) is an enzyme in the thyroid that helps make thyroid hormones by adding iodine to thyroglobulin (a protein that stores thyroid hormones).

• Anti-TPO antibodies are autoantibodies that attack and destroy TPO, making it harder for the thyroid to produce T3 and T4.

• This gradual destruction causes low thyroid hormone levels → hypothyroidism.

How to Identify Hashimoto’s?

• Symptoms: Fatigue, weight gain, cold intolerance, dry skin, hair loss, constipation.

• Labs:

  • High TSH (because the body is trying to stimulate a failing thyroid).

  • Low free T4 (because the thyroid isn’t making enough).

  • Positive Anti-TPO antibodies (key marker for Hashimoto’s!).

Key takeaway

• Anti-TPO antibodies = Hashimoto’s thyroiditis.

• They destroy the thyroid slowly over time → hypothyroidism.

2. Graves’ Disease & TRAb (TSH Receptor Antibodies)

Graves’ disease is also an autoimmune disease, but instead of destroying the thyroid, the immune system overstimulates it, causing hyperthyroidism (too much thyroid hormone).

What is TRAb (TSH Receptor Antibody)?

• The TSH receptor is a structure on thyroid cells that responds to TSH from the pituitary to make T3/T4.

• TRAb (Thyroid-Stimulating Immunoglobulin/TSH Receptor Antibody) mimics TSH and binds to the TSH receptor, tricking the thyroid into overproducing T3 and T4.

• This leads to excess thyroid hormone (hyperthyroidism).

How to Identify Graves’ Disease?

• Symptoms: Weight loss, heat intolerance, tremors, palpitations, anxiety, bulging eyes (exophthalmos).

• Labs:

  • Low TSH (because too much T3/T4 tells the pituitary to stop making TSH).

  • High free T3 & T4 (because the thyroid is overproducing hormones).

  • Positive TRAb (key marker for Graves’!).

Key takeaway

• TRAb = Graves’ disease.

• These antibodies overstimulate the thyroid, leading to too much thyroid hormone → hyperthyroidism.

Comparison Table: Hashimoto’s vs. Graves’

Analogy: Autoimmune Attack on a Factory

Imagine your thyroid is a factory that makes thyroid hormones.

• In Hashimoto’s: The immune system acts like vandals that slowly destroy the machines (TPO enzyme) over time, so the factory stops making hormones → hypothyroidism.

• In Graves’ disease: The immune system acts like a scammer, sending fake "urgent orders" (TRAb) to the factory, forcing it to overproduce hormones → hyperthyroidism.