ENDOCRINE

GRAVE’S DISEASE

Causes of hyperthyroidism
- Most common causes
→ Graves disease (Diffuse toxic goitre)
→ Toxic multinodular goitre (if only 1 nodule, it’s cancer)
→ Toxic adenoma (autonomously functioning nodule)
- Rarer causes
→ Thyroiditis or other cause of destruction
→ Thyrotoxicosis factitia
→ Iodine excess
→ Struma ovarii
→ Secondary causes (TSH or B-HCG)

Pathogenesis of Grave’s Disease
1. AutoAb production
→ Immune system produces autoAb, primarily Thyroid-Stimulating Immunoglobulins (TSIs) or TSH receptors antibodies (TRAb) that bind to and activate TSH receptor on thyroid follicular cell.
2. Stimulation of thyroid cells
→ These Ab bind to and stimulate TSH receptor, mimicking TSH
3. Increased thyroid hormone production
→ increased synthesis and release of T₃ and T₄ (hyperthyroidism) - excess thyroid hormones increase the BMR and enhance tissue sensitivity to catecholamines.
→ diffuse thyroid follicular hyperplasia → diffuse goitre
4. Lymphocytic Infiltration
→ In Ab-mediated stimulation, there is often an infiltration of lymphocytes in the thyroid → inflammation → further dysfunction of thyroid regulation

Pathophysiology of:
1. Increased HR (Tachycardia)
- d/t excess T3 and T4.
- upregulation of β₁-adrenergic receptors in the heart.
- increased sensitivity to catecholamines (adrenaline and noradrenaline).
- increased HR (+ve chronotropic effect).
- increased FOC (+ve ionotropic effect).
- increased CO.
- Tachy, palpitations and sometimes atrial fibrillation.

2. Excessive sweating
- d/t excess T3 and T4.
- increase BMR
- Increase O2 consumption and ATP turnover.
- Produce excess body heat (thermogenesis).
- Hypothalamus activates eccrine sweat glands to dissipate heat.
- Increased sympathetic activity also stimulates sweating.
- Heat intolerance and excessive sweating

3. Irregular menstruation
- d/t excess thyroid hormones affect the hypothalamic-pituitary-ovarian (HPO) axis by:
→ increased T3/T4 disrupt normal GnRH secretion
→ altered LH and FSH release impairs ovulation
→ increased sex hormone-binding globulin (SHBG) changes estrogen metabolism
→ anovulation and luteal phase defects occur
→ oligomenorrhea, amenorrhea, irregular menstrual cycles, reduced fertility

4. Exophthalmos
- TRAb and autoreactive T cells also target orbital fibroblasts, which express TSH receptors.
- Activated fibroblasts (loose CT) produce GAGs especially hyaluronic acid.
- GAGs attract water → orbital edema.
- Fibroblast dy/dx into adipocytes → increased orbital fat
- Inflammation and enlargement of the extraocular muscles → increase volume of orbital contents
- Since the bony orbit can’t expand → eyeball is pushed forward

5. Diplopia
- Autoimmune inflammation causes swelling and enlargement of the extraocular muscles.
- Over time, the inflamed muscles become fibrotic and stiff.
- The affected muscles can’t move the eye normally.
- Two eyes become misaligned (strabismus)
- Images fall on different areas of retinas, so the brain perceives double vision.

Clinical Characteristics of Goitre in GD
- Diffuce increase in thyroid gland size (goitre)
- Non-nodular
- Bruit and/or thrill
- Mobile
- Non-tender

Clinical Features of GD
- Goitre
- Thyrotoxicosis
- Exophthalmos
→ d/t accumulation of loose CT behind the eyeballs → eye protrude
-Thyroid acropachy
- TSIs

Morphology of GD
- Microscopic
→ Enlargement of thyroid follicular cells filled with colloid
→ Area of hemorrhage
→ Scalloped appearance of the edges of the colloid
→ Tall columnar thyroid epithelium
→ Prominent infoldings of the hyperplastic epith.
- Gross
→ Diffuse, symmetrical enlargement of the entire thyroid gland

Treatment (if pt. present with fast AF secondary to thyrotoxicosis)
- Carbimazole
→ prodrug that is converted to Methimazole in the body
→ to treat underlying thyrotoxicosis
→ MoA:
- (-) enzyme thyroid peroxidase (TPO)
- (-) oxidation of iodide → iodine
- (-) iodination of tyrosine residues on thyroglobulin
- (-) coupling of MIT → DIT to form T3 and T4
- decrease synthesis of new thyroid hormones

- Propylthiouracil
→ Drug of choice especially in the first trimester of pregnancy or thyroid storm
→ MoA:
- inhibit TPO and all things under TPO
- inhibit peripheral conversion of T4 to T3

- Propanolol
→ non-selective β₁- and β₂-adrenergic blocker.
→ MoA:
- block β₁-receptors in the heart → ↓HR, ↓ FOC, ↓ CO and relieves palpitations and tachycardia
- Blocks β₂ receptors, helping reduce tremor.
- at high doses, (-) peripheral conversion of T4 to T3 by (-) 5’-deiodinase → ↓ active thyroid hormone level.

- Definitive treatment with Radioactive iodine therapy or surgery if appropriate.

- Dietary advice
→ maintain a balanced, high-calorie, high-protein diet - because hyperthyroidism increases BMR and can cause weight loss
→ avoid excessive iodine intake
→ limit caffeine-containing drinks

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