Graves Disease

GRAVES DISEASE

Definition and Key Features

• Autoimmune thyroid syndrome characterized by:
  1. Hyperthyroidism (elevated T3 and T4)
  2. Diffuse goiter
  3. Ophthalmopathy (eye involvement, including proptosis)
  4. Occasionally Dermopathy (pretibial myxedema, also called localized myxedema)
• Important Distinction: Graves disease is not synonymous with hyperthyroidism:
  • Some patients may have ophthalmopathy without hyperthyroidism.
  • Other causes of hyperthyroidism also exist (e.g., toxic multinodular goiter, toxic adenoma).
• Pathophysiology:
  • Caused by TSH receptor autoantibodies (also called thyroid-stimulating immunoglobulins, TSI) that stimulate thyroid growth and hormone production (T4, T3).

Epidemiology

• Female : Male ratio ≈ 8 : 1
• Most common during childbearing years, but can occur at any age (infancy → elderly).

Thyroid Gland Changes

1. Goiter:
   • Diffusely enlarged, up to several times normal size.
   • Right lobe often slightly larger than left.
   • Pyramidal lobe commonly enlarged.
   • Rarely, no palpable enlargement (occult or “clinically inapparent” goiter).
2. Vascularity:
   • Increased blood flow → a bruit heard with stethoscope; sometimes a thrill by palpation over the upper poles.
3. Histology:
   • Follicular hyperplasia with papillary infoldings.
   • Loss of colloid in follicle lumens.
   • Lymphocytic infiltration (T cells, occasionally B-cell follicles) in chronic or advanced disease.

Hypermetabolic State and Clinical Manifestations

1. Thyroid Hormones
   • Elevated T4 and T3.
   • Increased radioactive iodine uptake and turnover.
   • Increased oxygen consumption (basal metabolic rate).
   • Decreased total and HDL cholesterol levels.
2. Neuro-Psychological Changes
   • Nervousness, agitation, insomnia, emotional lability.
   • Difficulty concentrating, confusion, poor immediate recall.
3. Tremor
   • Often subtle; best seen by placing a piece of paper on outstretched fingers.
4. Cardiovascular Effects
   • Palpitations, sinus tachycardia, atrial fibrillation (in ~15%, especially in older patients), possible high-output heart failure.
5. Skin Changes
   • Warm, velvety, sometimes flushed.
   • Excess sweating from increased calorigenesis.
   • Vitiligo (autoimmune) in some patients.
   • Onycholysis (“Plummer nails,” nail loosening).
   • Infiltrative Dermopathy (Pretibial Myxedema):
     • Nonpitting, rubbery swelling over the lower legs (often lateral side) with violaceous discoloration, sometimes nodular lesions.
     • Usually associated with severe ophthalmopathy.
6. Other Autoimmune Associations
   • Hair changes: Finer hair or local hair loss over myxedematous areas.
   • Coexistence of other autoimmune findings.
7. Ophthalmic Findings
   • Eyelid Retraction (stare), eyelid lag (see also “Graves Ophthalmopathy” section).
   • Unique to Graves: true inflammatory ophthalmopathy with proptosis.
8. Muscle and Weight Changes
   • Weight loss despite increased appetite.
   • Muscle wasting and weakness (especially in proximal muscle groups such as quadriceps).
   • Possibly increased respiratory effort due to muscle weakness.
   • Mixed effects on glucose metabolism; often fasting hyperglycemia.
   • Possible hyperdefecation or malabsorption.
9. Reproductive Hormone Effects
   • In women:
     • Increased total estradiol (due to elevated sex hormone–binding globulin).
     • Decreased free estradiol, ↑ LH → oligomenorrhea or amenorrhea.
   • In men:
     • Increased total testosterone, low free testosterone, mild ↑ LH.
     • ↑ Aromatization to estradiol → gynecomastia, low libido, erectile dysfunction.
10. Bone Metabolism
    • Excess T4 and T3 stimulate bone resorption (↑ osteocalcin, ↑ bone-specific alkaline phosphatase).
    • Leads to reduced bone density, potential hypercalcemia, and osteoporosis over time.
11. Cardiac Effects
    • High-output state, short circulation time, potential for heart failure.
    • Systolic hypertension common.
    • Atrial fibrillation may revert to sinus rhythm after return to euthyroidism.
    • β-blockers can relieve many sympathetic-driven symptoms (palpitations, tremor, eyelid retraction) independently of T4/T3 changes.

GRAVES OPHTHALMOPATHY

Clinical Features

1. Eye Signs (in addition to eyelid retraction/lag common in hyperthyroidism):
   • Proptosis (Exophthalmos): Confirmed via exophthalmometer (normal: <20 mm in whites, <22 mm in blacks).
   • Periorbital Edema (swelling around the orbit).
   • Conjunctival Injection and Chemosis (edema).
   • Extraocular Muscle Weakness or palsies → diplopia, blurred vision.
   • Excess tearing, photophobia, gritty eye sensation.
2. Measurement
   • Exophthalmometer used to measure anterior projection of the cornea.
   • Firmness of orbital tissues assessed by gently pushing back on the globe over the closed lid.
3. Severe Cases
   • Inability to fully close eyelids → corneal ulceration, infection.
   • Rarely optic nerve compression → blindness.

Pathogenesis of Graves Ophthalmopathy

• Autoimmune Inflammation of retro-orbital tissues, extraocular muscles.
• Glycosaminoglycan (GAG) accumulation → osmotic swelling, infiltration by T lymphocytes, especially around TSH receptor–related antigens.
• Strong correlation of severe ophthalmopathy with high TSH receptor antibody titers.

Risk Factors and Clinical Course

1. TSH Receptor Antibody Titer: Higher → more severe ophthalmopathy.
2. Gender: More common in women (as with hyperthyroidism), but men tend to have more severe disease if present.
3. Cigarette Smoking: Strongly linked to increased risk and severity; believed to enhance GAG production and adipogenesis.
4. Radioiodine Therapy: May worsen or precipitate ophthalmopathy more than surgery or antithyroid drugs.
5. Hyperthyroidism Onset: Eye disease may precede (20%), coincide (40%), occur during treatment (~20%), or arise within 6 months after diagnosis (20%).
6. Euthyroid Restoration: Improves eyelid retraction but usually does not reverse established ophthalmopathy.

Management of Graves Ophthalmopathy

• Mild Cases:
  • Raise head of bed (reduce periorbital edema), frequent saline eye drops, sunglasses for photophobia.
• Moderate to Severe Symptoms:
  • Glucocorticoid therapy (e.g., IV methylprednisolone) if chemosis, diplopia, or threatened vision.
  • Orbital decompression surgery if vision endangered, corneal exposure worsens, or severe cosmetic exophthalmos.
  • Teprotumumab. An antibody that blocks the Insulin-like growth factor 1 receptor present on fibroblast cells.