• Hyperthyroidism means excessive thyroid hormone activity.
• Most effects are explained by the increased actions of thyroid hormones on body tissues.
• In many patients, the thyroid becomes 2–3 times larger than normal.
• The thyroid follicles show marked cell growth and folding, greatly increasing the number of thyroid cells.
• Each thyroid cell also increases its secretion several times.
• Some hyperplastic glands can secrete thyroid hormone at 5–15 times the normal rate.
• Graves disease is the most common form of hyperthyroidism.
• It is an autoimmune disease in which thyroid-stimulating immunoglobulins (TSIs) form against the thyroid TSH receptor.
• TSIs bind to the same receptors as TSH and continuously activate the cAMP system.
• This causes continuous thyroid stimulation and excessive thyroid hormone production.
• TSI stimulation lasts up to 12 hours, whereas TSH stimulation lasts a little over 1 hour.
• Increased thyroid hormone then suppresses pituitary TSH secretion.
• Therefore, TSH is usually very low or almost zero in Graves disease.
• The antibodies are thought to result from autoimmunity against thyroid tissue, possibly after thyroid cell antigens are released.
• Thyroid adenoma is another cause of hyperthyroidism.
• It is a localized thyroid tumor that produces large amounts of thyroid hormone.
• Unlike Graves disease, it is usually not associated with autoimmune disease.
• Excess hormone from the adenoma suppresses pituitary TSH secretion.
• Low TSH almost completely suppresses hormone secretion by the remaining normal thyroid tissue.

KEY CONCEPT

• Hyperthyroidism → excessive thyroid hormone production/action.
• Graves disease: TSI → TSH receptor → cAMP continuously activated → ↑ T₃/T₄ → ↓ TSH.
• Thyroid adenoma: tumor → ↑ T₃/T₄ → ↓ TSH → normal thyroid tissue suppressed.
• Graves: usually diffuse thyroid enlargement.
• Adenoma: localized hormone-secreting tumor.

CONCEPTUAL EXAMPLES

• Graves disease: TSI acts like persistent TSH → thyroid remains continuously stimulated.
• High T₃/T₄ in Graves: negative feedback → TSH ≈ zero.
• Adenoma: tumor produces T₃/T₄ independently → TSH falls → rest of thyroid becomes inactive.

Symptoms of Hyperthyroidism

• Hyperthyroidism commonly causes:
  • High excitability
  • Heat intolerance
  • Increased sweating
  • Weight loss, sometimes severe
  • Diarrhea
  • Muscle weakness
  • Nervousness or psychic disorders
  • Extreme fatigue with inability to sleep
  • Hand tremor
• Exophthalmos means protrusion of the eyeballs and is common in hyperthyroidism (Fig. 77.8).
• Severe exophthalmos occurs in about one-third of patients.
• Severe protrusion can stretch the optic nerve and damage vision.
• More commonly, incomplete eyelid closure causes the eyes to become dry, irritated, infected, and sometimes ulcerated.
• The protrusion results from swelling of tissues behind the eyes and changes in the extraocular muscles.
• Immunoglobulins reacting with eye muscles are often present, especially when TSI levels are high.
• Therefore, exophthalmos is likely related to an autoimmune process and usually improves when hyperthyroidism is treated.
• The most accurate usual diagnostic test is measurement of free thyroxine (and sometimes T₃) in plasma.
• Basal metabolic rate is usually increased by about 30–60% in severe hyperthyroidism.
• TSH is usually almost absent because high circulating T₄ and T₃ strongly suppress pituitary TSH secretion.
• TSI is usually high in thyrotoxicosis but low in thyroid adenoma.
• A direct treatment is surgical removal of most of the thyroid gland.
• Before surgery, propylthiouracil is usually given for several weeks until the basal metabolic rate becomes normal.
• Then high concentrations of iodides are given for 1–2 weeks to reduce thyroid size and blood supply before surgery.
• These preparations greatly reduce operative mortality.
• Radioactive iodine can also treat a hyperplastic, toxic thyroid gland.
• About 80–90% of injected iodide is taken up by the hyperplastic thyroid within 1 day.
• If the iodide is radioactive, it destroys many thyroid secretory cells.
• Usually about 5 millicuries is given, followed by reassessment after several weeks.
• Additional doses may be given until normal thyroid function is reached.

KEY CONCEPT

Hyperthyroidism → ↑ metabolism + ↑ excitability + heat intolerance + sweating + weight loss + diarrhea + weakness + tremor.

Diagnosis:
Free T₄/T₃ ↑ + TSH ↓; TSI ↑ in Graves/thyrotoxicosis but low in thyroid adenoma.

Treatment:
PTU → high-dose iodide → surgery, or radioactive iodine.

CONCEPTUAL EXAMPLES

• High T₃/T₄ → TSH almost zero → confirms strong negative feedback.
• TSI high → Graves-type thyrotoxicosis.
• TSI low → thyroid adenoma more likely.
• Exophthalmos + hyperthyroidism → autoimmune thyroid process likely.
• Radioactive iodine uptake by toxic thyroid → destroys secretory cells.

Hypothyroidism

• Hypothyroidism generally produces effects opposite to hyperthyroidism.
• It is often caused by autoimmunity against the thyroid gland (Hashimoto disease).
• In Hashimoto disease, autoimmunity destroys the thyroid instead of stimulating it.
• Autoimmune thyroiditis causes inflammation → progressive deterioration → fibrosis → decreased or absent thyroid hormone secretion.
• Goiter means a greatly enlarged thyroid gland.
• Endemic colloid goiter occurs when the diet lacks enough iodine.
• About 50 mg of iodine/year is needed to make adequate thyroid hormones.
• Iodine deficiency → T₄/T₃ ↓ → less negative feedback → TSH ↑.
• High TSH continuously stimulates thyroid cells → large amounts of thyroglobulin colloid accumulate → thyroid enlarges.
• Because iodine is lacking, T₄/T₃ still cannot be adequately formed.
• The follicles may enlarge so much that the thyroid becomes 10–20 times normal size.
• Idiopathic nontoxic colloid goiter can occur even without iodine deficiency.
• The thyroid may produce normal or, more commonly, reduced amounts of thyroid hormone.
• Mild thyroiditis may cause slight hypothyroidism → TSH ↑ → growth of remaining thyroid tissue.
• This may produce a nodular thyroid, with some areas growing while others are damaged.
• Some colloid goiters result from abnormalities in thyroid hormone formation:
  • ↓ iodide trapping → inadequate iodide enters thyroid cells.
  • ↓ peroxidase activity → iodide is not properly oxidized.
  • ↓ coupling of iodinated tyrosines → T₄/T₃ cannot form.
  • ↓ deiodinase activity → iodine cannot be efficiently recycled.
• Some foods contain goitrogenic substances with antithyroid activity, especially certain varieties of turnips and cabbages.
• These substances can reduce thyroid hormone formation → TSH ↑ → thyroid enlargement.
• The physiological effects of hypothyroidism are generally:
  • Fatigue and extreme sleepiness, sometimes sleeping 12–14 hours/day
  • Muscular sluggishness
  • Slow heart rate
  • ↓ cardiac output
  • ↓ blood volume
  • Sometimes ↑ body weight
  • Constipation
  • Mental sluggishness
  • Reduced hair growth and scaly skin
  • Husky, frog-like voice
  • Severe cases → myxedema
• Myxedema occurs with almost total loss of thyroid hormone function (Fig. 77.9).
• Excess hyaluronic acid and chondroitin sulfate bound to protein accumulate in tissue spaces.
• This increases interstitial fluid, but the fluid becomes gel-like and mainly immobile.
• Therefore, the edema is nonpitting.
• Lack of thyroid hormone increases blood cholesterol because of altered fat metabolism and reduced liver cholesterol excretion into bile.
• Increased cholesterol can promote atherosclerosis.
• This can contribute to peripheral vascular disease, deafness, and coronary artery disease.
• In hypothyroidism, free T₄ is low.
• In myxedema, the basal metabolic rate falls about 30–50%.
• After a test dose of TRH, TSH usually increases greatly.
• This response is reduced in the rare cases where the pituitary responds poorly to TRH.
• Thyroxine treatment can maintain a steady thyroid hormone effect because its action lasts more than 1 month (Fig. 77.4).
• Therefore, daily oral thyroxine can maintain thyroid hormone activity at a steady level.
• Proper treatment can restore hypothyroid patients to near-normal function.
• Severe hypothyroidism during fetal life, infancy, or childhood causes failure of body growth and intellectual disability.
• Causes include congenital absence of the thyroid, genetic defects in thyroid hormone production, or iodine deficiency.
• A newborn without a thyroid may initially appear normal because some thyroid hormone was supplied by the mother before birth.
• After a few weeks, movements become sluggish and physical and mental growth become severely impaired.
• Early treatment with adequate iodine or thyroxine can restore normal physical growth.
• If treatment is delayed for more than a few weeks, mental development may remain permanently impaired because thyroid hormone is needed for neuronal growth, branching, and myelination.
• Skeletal growth is affected more than soft-tissue growth, producing an obese, stocky, short appearance.
• The tongue may become disproportionately large and can interfere with swallowing and breathing.

KEY CONCEPT

Hypothyroidism → T₃/T₄ ↓ → metabolism ↓ + TSH usually ↑ → thyroid enlargement may occur.

Iodine deficiency → T₃/T₄ ↓ → TSH ↑ → goiter.

Severe thyroid hormone deficiency → myxedema in adults; impaired growth and brain development in children.

CONCEPTUAL EXAMPLES

• Iodine ↓ → T₃/T₄ ↓ → TSH ↑ → thyroid grows → goiter.
• Hashimoto disease → thyroid destruction → T₃/T₄ ↓ → hypothyroidism.
• Hypothyroidism → metabolism ↓ → fatigue + cold/slow body functions + weight gain tendency.
• Severe deficiency → hyaluronic acid/chondroitin sulfate ↑ → gel-like tissue fluid → nonpitting myxedema.
• Childhood hypothyroidism untreated early → impaired brain development + poor growth.