Thyroid Gland Physiology and Testing¶
Chapter 394 | Part 12: Endocrinology and Metabolism
KEY CLINICAL POINTS¶
- Thyroid hormones (T4 and T3) regulate metabolism, growth, and development via nuclear receptors TR α and TR β .
- Iodine deficiency is a global public health issue, causing goiter, hypothyroidism, and cretinism.
- TSH secretion is regulated by TRH and thyroid hormone feedback, with TSH levels reflecting thyroid function.
- Thyroid hormone synthesis involves iodide uptake, organification, coupling, and storage in thyroglobulin.
- Thyroid function testing includes TSH, free T4, and T3, with special considerations in pregnancy and drug interactions.
1. DEFINITION & OVERVIEW¶
The thyroid gland produces T4 and T3, which regulate metabolism, growth, and development. Thyroid dysfunction includes hypothyroidism (low hormone production) and hyperthyroidism (excess hormone).
Table 394-1: Characteristics of Circulating T4 and T3¶
| HORMONE PROPERTY | T4 | T3 |
|---|---|---|
| Serum concentrations | 8 mg/dL | 0.14 mg/dL |
| Fraction of total hormone in the unbound form | 0.02% | 0.3% |
| Unbound (free) hormone | 21 × 10–12M | 6 × 10–12M |
| Serum half-life | 7 d | 2 d |
| Fraction directly from the thyroid | 100% | 20% |
| Intracellular hormone fraction | ~20% | ~70% |
| Relative metabolic potency | 0.3 | 1 |
| Receptor binding | 10–10M | 10–11M |
1.1 Thyroid Hormone Synthesis¶
Thyroid hormones are synthesized from iodide via the sodium-iodide symporter (NIS), organification by thyroid peroxidase (TPO), and coupling of iodotyrosines. Thyroglobulin stores the hormones until release.
1.2 Thyroid Hormone Action¶
T4 and T3 bind to nuclear receptors TR α and TR β , modulating gene expression. T3 is more potent than T4 and is converted from T4 peripherally via deiodinases.
2. EPIDEMIOLOGY¶
Iodine deficiency affects ~2 billion people globally, causing goiter and hypothyroidism. Congenital hypothyroidism occurs in ~1 in 4000 newborns, with neonatal screening in industrialized countries.
Table 394-3: Global Iodine Nutrition Status (2021)¶
| Iodine Intake | Median Urinary Iodine Concentration (mg/L) |
|---|---|
| Insufficient | <100 |
| Adequate | 100–299 |
| Excess | ‡300 |
2.1 Iodine Deficiency¶
Prevalent in mountainous regions, central Africa, and parts of Asia. Iodine deficiency causes cretinism, intellectual disability, and growth retardation in children.
2.2 Thyroid Disorders in Pregnancy¶
Pregnancy increases thyroid hormone requirements by 45%. Subclinical hypothyroidism affects 2% of women, while overt hypothyroidism occurs in 1 in 500.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Thyroid hormone synthesis depends on iodine availability, NIS, TPO, and deiodinases. Genetic mutations in TPO, NIS, or TR β cause congenital hypothyroidism.
Table 394-2: Conditions Associated with Euthyroid Hyperthyroxinemia¶
| DISORDER | CAUSE | TRANSMISSION | CHARACTERISTICS |
|---|---|---|---|
| Familial dysalbuminemic hyperthyroxinemia (FDH) | Albumin mutations (R218H) | AD | Increased T4, normal unbound T4/T3 |
| Acquired excess TBG | Estrogen, pregnancy, cirrhosis | Acquired | Increased total T4/T3, normal free hormone |
| Resistance to thyroid hormone (RTH) | TRb mutations | AD | Elevated T4, normal TSH, variable T3 levels |
3.1 Iodine Metabolism¶
Iodide is actively transported via NIS, oxidized by TPO, and coupled to thyroglobulin. Pendrin mutations cause Pendred syndrome with deafness and goiter.
3.2 Deiodinases¶
Type 1 deiodinase converts T4 to T3 in peripheral tissues. Type 3 deiodinase inactivates thyroid hormones and is upregulated in hypothyroidism.
4. CLINICAL FEATURES¶
Hyperthyroidism presents with weight loss, tachycardia, and heat intolerance. Hypothyroidism causes fatigue, weight gain, and cold intolerance. Thyroid nodules may be benign or malignant.
4.1 Thyroid Nodules¶
Benign nodules are common; malignant tumors (e.g., medullary thyroid cancer) require ultrasound and fine-needle aspiration biopsy.
4.2 Thyroid Eye Disease¶
Graves' ophthalmopathy involves orbital fat and muscle inflammation, causing exophthalmos and diplopia.
5. DIFFERENTIAL DIAGNOSIS¶
Differentiate thyroid dysfunction from nonthyroidal illness, pituitary disorders, or drug-induced effects. Consider pseudohypothyroidism due to TBG elevation.
5.1 Nonthyroidal Illness¶
Acute illness may mimic hypothyroidism with low T3/T4 and elevated TSH, but free hormone levels remain normal.
5.2 Pituitary Disorders¶
TSH-secreting adenomas cause secondary hypothyroidism with normal or elevated TSH and low free T4.
6. INVESTIGATIONS & DIAGNOSIS¶
TSH is the primary test for thyroid function. Free T4 and T3 measure biologically active hormone. Thyroid ultrasound and scintigraphy assess structure and function.
Table 394-4: Thyroid Hormone Binding Proteins¶
| Protein | Function | Affinity for T4/T3 |
|---|---|---|
| Thyroxine-binding globulin (TBG) | Major T4 carrier | High affinity for T4 |
| Transthyretin (TTR) | T4 carrier in cerebrospinal fluid | Moderate affinity for T4 |
| Albumin | General plasma carrier | Low affinity for T4/T3 |
6.1 Thyroid Function Tests¶
TSH is most sensitive for detecting hypothyroidism or hyperthyroidism. Free T4/T3 reflect unbound hormone levels. Total T4/T3 may be misleading due to protein binding.
6.2 Thyroid Imaging¶
Radioiodine uptake and thyroid scans identify functioning nodules (hot nodules) or areas of decreased uptake (cold nodules). Ultrasound detects nodules and structural abnormalities.
7. MANAGEMENT & TREATMENT¶
Thyroid hormone replacement (levothyroxine) for hypothyroidism. Antithyroid drugs (methimazole, propylthiouracil) for hyperthyroidism. Surgery for large nodules or cancer.
7.1 Hypothyroidism¶
Levothyroxine replacement restores TSH to normal. Dosage is adjusted based on TSH levels and patient age/weight.
7.2 Hyperthyroidism¶
Antithyroid drugs suppress hormone synthesis. Radioiodine ablation or surgery is used for toxic nodules or Graves' disease.
8. PROGNOSIS & COMPLICATIONS¶
Untreated hypothyroidism causes cardiovascular disease and infertility. Hyperthyroidism may lead to osteoporosis or thyrotoxic crisis. Thyroid cancer has a high survival rate with early detection.
8.1 Complications of Hypothyroidism¶
Myxedema coma, heart failure, and peripheral neuropathy in severe cases. Subclinical hypothyroidism may increase cardiovascular risk.
8.2 Thyroid Cancer¶
Papillary thyroid cancer is the most common type, with 95% 10-year survival. Medullary thyroid cancer is associated with RET gene mutations.
9. SPECIAL CONSIDERATIONS¶
Pregnancy requires higher iodine intake and careful TSH monitoring. Thyroid function tests may be altered by medications (e.g., amiodarone, lithium).
9.1 Thyroid in Pregnancy¶
Pregnant women need 250 µ g/day iodine. TSH reference ranges shift during pregnancy, with lower thresholds for hypothyroidism.
9.2 Drug Interactions¶
Biotin supplements ( ≥ 1000 µ g) interfere with TSH assays. Glucocorticoids and dopamine suppress TSH, while iodine may transiently inhibit hormone synthesis.
10. KEY POINTS & CLINICAL PEARLS¶
TSH is the most sensitive test for thyroid dysfunction. Free T4/T3 reflect biologically active hormone. Iodine deficiency remains a global health issue. Thyroid nodules require ultrasound and FNA biopsy if suspicious.