I-18. Pathogenesis of hypothyroidism and its symptoms

甲状腺機能低下症の発症機序と症状

Thyroid Hormone Physiology

Axis: TRH (hypothalamus) → TSH (pituitary) → T4 + T3 (thyroid). TRH also stimulates prolactin (↑breast milk, ↓GnRH-FSH-LH axis).
Thyroid hormones act intracellularly to regulate gene expression → synthesis of structural/functional proteins; ↑O₂ consumption, ↑basal metabolic rate, ↑ATP turnover, ↑cell respiration → heat → sweating. Iodine required for synthesis (high-dose iodine paradoxically inhibits uptake/release).
No TSH → thyroid atrophy, impaired CNS/organ development. Excess TSH → hypertrophy/hyperplasia → goiter.

Congenital Hypothyroidism

~1:4000, usually sporadic.
Primary: organogenesis disorder (no gland), hormone-synthesis defect, iodine deficiency (born with goiter).
Secondary: panhypopituitarism. Also thyroid hormone resistance.
Symptoms (impaired CNS/bone/skin development):
- CNS damage may be irreversible before age 2 → serious mental retardation.
- Impaired hearing/speech.
- Bone-growth retardation, dwarfism (GHRH production/receptor are T3-dependent).
- Cold, dry rough skin, bulging tongue; delayed puberty.

Acquired Hypothyroidism

Primary (~95%): ↓T4/T3, ↑TSH → goiter. Causes: Hashimoto thyroiditis, thyroid damage (e.g. radiotherapy), iodine deficiency (or excess), postpartum thyroiditis.
Central (~5%): ↓T4/T3, ↓TSH → no goiter. Causes: pituitary adenoma (compresses gland), hypothalamic tumor (↓TRH).

Hashimoto Thyroiditis

Autoimmune (chronic lymphocytic) thyroiditis; mostly middle-aged women; genetic predisposition + trigger (virus, iodine).
Most common cause of hypothyroidism where iodine is sufficient.
Initial hyperthyroidism (follicle destruction spills T4/T3), then hypothyroidism; ↓T4/T3, ↑TSH; small diffuse goiter.
Biopsy: B/T-lymphocyte infiltration, follicle destruction; anti-TPO and anti-TG autoantibodies.
Treatment: hormone replacement.

Organ Effects of Hypothyroidism

Cardiovascular: bradycardia, ↓SV/CO, ↓myocardial contraction, peripheral edema, pericardial effusion.
Vascular: ↑TPR, arterial wall stiffness, endothelial dysfunction → diastolic hypertension.
Dyslipidemia: TSH ↑hepatic cholesterol synthesis, ↓LDL-receptor expression → atherogenic profile.
Nervous: encephalopathy (memory loss, fatigue, slow speech), peripheral neuropathy, cognitive impairment, myopathy (↓reflexes, weakness).
Skin: peripheral vasoconstriction → dry/cold skin; myxedema (puffy, esp. periorbital).
GI: obesity (↓BMR), ↓motility/constipation, liver dysfunction (↑enzymes, NAFLD).
Renal: ↓RBF/GFR. Blood: anemia (no T3-driven EPO). Metabolism: dyslipidemia, insulin resistance.

Myxedema Coma (acute hypothyroidism)

Subclinical hypothyroidism triggered by acute stress (trauma, surgery, infection).
Symptoms: hypothermia + hypoglycemia (↓BMR), bradycardia, acute respiratory/circulatory failure → severe brain dysfunction.
Treatment: thyroxine infusion, glucose, glucocorticoids.

一問一答

▶How do thyroid hormones act and what are their main metabolic effects?

They act intracellularly to regulate gene expression, increasing O2 consumption, basal metabolic rate, ATP turnover, and heat production.

▶What is the thyroid hormone axis?

Hypothalamus releases TRH → anterior pituitary releases TSH → thyroid releases T4 and T3, with negative feedback on the hypothalamus and pituitary.

▶What are the causes of congenital hypothyroidism?

Thyroid organogenesis disorder, hormone-synthesis defect, and iodine deficiency.

▶What else does TRH stimulate besides TSH?

Prolactin — so in primary hypothyroidism, high TRH raises prolactin (↑breast milk, ↓GnRH → ↓FSH/LH).

▶How does TSH level affect thyroid gland size?

No TSH → thyroid atrophy; excess TSH → hypertrophy/hyperplasia → goiter.

▶Why is early detection of congenital hypothyroidism critical?

CNS damage becomes irreversible before age 2, causing permanent mental retardation (cretinism).

▶What labs and gland changes characterize acquired primary hypothyroidism?

Low T4/T3 with high TSH → goiter; it accounts for ~95% of acquired cases.

▶What characterizes acquired central (secondary/tertiary) hypothyroidism?

Low T4/T3 with low TSH and no goiter (~5% of cases); caused by pituitary adenoma or hypothalamic tumor.

▶Why does congenital hypothyroidism cause dwarfism?

GHRH production and its receptor are T3-dependent, so low thyroid hormone reduces growth hormone signaling → bone growth retardation.

▶What is the most common cause of hypothyroidism in iodine-sufficient areas?

Hashimoto thyroiditis (chronic autoimmune thyroiditis).

▶What is the typical course of Hashimoto thyroiditis?

An initial transient hyperthyroid phase (follicle destruction spills stored hormone) followed by hypothyroidism.

▶Which autoantibodies are found in Hashimoto thyroiditis?

Anti-TPO (thyroid peroxidase) and anti-TG (thyroglobulin) antibodies.

▶Who is typically affected by Hashimoto thyroiditis and what triggers it?

Middle-aged women; it requires a genetic predisposition plus a trigger (e.g., virus, excess iodine).

▶Why does hypothyroidism cause diastolic hypertension?

Increased total peripheral resistance, arterial stiffness, and endothelial dysfunction raise diastolic blood pressure.

▶What are the cardiac effects of hypothyroidism?

Bradycardia, reduced stroke volume/cardiac output, reduced contractility, peripheral edema, and pericardial effusion.

▶What are the skin findings in hypothyroidism?

Dry, cold skin and myxedema — puffy, non-pitting swelling (especially periorbital) from glycosaminoglycan accumulation.

▶Why does hypothyroidism cause dyslipidemia?

High TSH increases hepatic cholesterol synthesis and decreases LDL-receptor expression → elevated cholesterol/LDL.

▶Why does hypothyroidism cause anemia?

Reduced T3-driven erythropoietin production lowers red blood cell formation.

▶What triggers and characterizes myxedema coma?

Triggered by acute stress (trauma, surgery, infection); features hypothermia and hypoglycemia, severe bradycardia, and respiratory/circulatory failure.

▶What is the treatment of myxedema coma?

Thyroxine infusion, glucose, and glucocorticoids (with supportive care).