Thyroid Gland Physiology andTesting¶
Chapter 394 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 394
Key Clinical Points¶
- T4 and T3 regulate metabolism, thermogenesis, and development via nuclear receptors (TRα and TRβ).
- TSH is the primary marker of thyroid function; a normal TSH generally excludes primary thyroid dysfunction.
- Iodine deficiency is a major cause of preventable intellectual disability (cretinism) and requires specific supplementation in pregnancy.
- Euthyroid hyperthyroxinemia (e.g., FDH, high TBG) presents with high total T4/T3 but normal free hormones and TSH.
- Resistance to thyroid hormone (RTH) is an autosomal dominant disorder caused by TRβ mutations.
- Pregnancy significantly alters thyroid dynamics: hCG stimulates TSH-R, TBG rises, and free T4 decreases in the third trimester.
- Deiodinases (Type I, II, III) regulate local T3 levels; Type III is upregulated in illness (sick euthyroid syndrome).
- Physical exam must assess for goiter, bruits/thrills (hyperthyroidism), and retrosternal extension (Pemberton's sign).
- Congenital hypothyroidism occurs in ~1 in 4000 newborns; early replacement is critical.
- Biotin supplements (>1000 µg) can cause false low TSH and high T4/T3.
DEFINITION & CLASSIFICATION¶
• Thyroid Hormones: T4 (thyroxine) and T3 (triiodothyronine). • Mechanism: Act via nuclear receptors TRα and TRβ to regulate cell differentiation, organogenesis, thermogenic homeostasis, and metabolism. • Pathology: • Thyrotoxicosis: Overproduction of thyroid hormones. • Hypothyroidism: Glandular destruction leading to hormone deficiency. • Anatomy: • Structure: Two lobes connected by an isthmus; located anterior to the trachea between cricoid cartilage and suprasternal notch. • Size: 12–20 g, highly vascular, soft consistency. • C Cells: Medullary cells producing calcitonin (calcium-lowering); origin of medullary thyroid cancer.
Developmental Anatomy¶
• Origin: Develops from the floor of the primitive pharynx during the 3rd week of gestation. • Migration: Moves along the thyroglossal duct to its final neck position. • Clinical Significance: → Ectopic tissue at base of tongue (lingual thyroid) or thyroglossal duct cysts occur along this path.
EPIDEMIOLOGY¶
• Congenital Hypothyroidism: Occurs in ~1 in 4000 newborns; requires early replacement to prevent developmental issues. • Iodine Deficiency: • Affects ~2 billion people globally. • Causes: Goiter, hypothyroidism, and cretinism (intellectual disability + growth retardation). • Risk Factors: High altitude regions, Central Africa, South America, Northern Asia. • Iodine Requirements: • Pregnancy: 220 µg/day (RDA) or 250 µg/day (WHO). • Breastfeeding: 290 µg/day (RDA) or 250 µg/day (WHO). • Prenatal Vitamins: Should contain 150 µg per tablet.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Thyroid Axis: • Feedback Loop: Hypothalamus (TRH) → Pituitary (TSH) → Thyroid (T4/T3). • Regulation: T4/T3 provide negative feedback primarily via TRβ2 to inhibit TRH and TSH. • TSH Characteristics: 31-kDa hormone; α subunit shared with LH, FSH, hCG; β subunit is unique. → Released in a pulsatile manner with a diurnal rhythm (highest at night). • Iodine Metabolism: • Transport: Iodide uptake mediated by NIS (basolateral membrane); Pendrin mediates apical efflux. • Regulation: Low iodine → increased NIS; High iodine → suppressed NIS. • Pendred Syndrome: Mutation of pendrin gene → defective organification, goiter, and sensorineural deafness. • Deiodinases: • Type I: Thyroid, liver, kidney; low affinity for T4. • Type II: Pituitary, brain, brown fat, thyroid; high affinity for T4 → regulates local T3. • Type III: Inactivates T4/T3 to rT3; upregulated in illness (sick euthyroid syndrome). • Binding Proteins: • T4 & T3 are ~99.98% and 99.7% protein-bound, respectively. • TBG: High affinity for T4; concentration 1–2 mg/dL; carries ~80% of bound hormones. • Albumin: Low affinity but high concentration (~3.5 g/dL); binds up to 10% T4 and 30% T3. • TTR: Carries ~10% of T4; little T3. • Pathology of Binding: • X-linked TBG deficiency: Low total T4/T3 but normal free hormones → euthyroid. • High TBG (Pregnancy/Estrogen): Increased total T4/T3, normal free levels. • Euthyroid Hyperthyroxinemia: Caused by mutations in TBG, TTR, or albumin; high total hormone but normal free hormone.
Thyroid Hormone Resistance (RTH)¶
• Mechanism: Autosomal dominant mutation in TRβ gene. • Pathophysiology: Mutant receptors act as 'dominant negative' antagonists of normal receptors. • Clinical Presentation: Goiter, ADHD, reduced IQ, tachycardia; often appear euthyroid due to compensation. • Diagnosis: Elevated unbound T4/T3 with inappropriately normal or elevated TSH. • TRα Mutation: Distinct form → growth retardation, skeletal dysplasia, severe constipation. → Lab: Normal TSH, low/normal T4, normal/elevated T3.
CLINICAL FEATURES¶
• Physical Examination: • Technique: Palpate with both hands; use a combination of front and side views. • Assessment: Size (12–20 g), consistency, nodularity, tenderness, fixation. • Vascularity: Bruit or thrill → increased vascularity (hyperthyroidism). • Retrosternal Extension: If lower borders not felt; may cause Pemberton's sign (venous distension/breathing difficulty when arms raised). • Lymphadenopathy: Must assess supraclavicular and cervical regions. • Pregnancy Specifics: • hCG Effect: High hCG in 1st trimester → weak TSH-R stimulation → transient gestational hyperthyroxinemia (may cause hyperemesis gravidarum). • TSH Dynamics: Falls in 1st trimester; rises to nonpregnant levels by mid-gestation. • Hormone Levels: Total T4/T3 are ~1.5x higher; Free T4 decreases by 3rd trimester. • Management of Hyperemesis: Parenteral fluids sufficient unless Graves' suspected.
DIFFERENTIAL DIAGNOSIS¶
• Euthyroid Hyperthyroxinemia (Table 394-2): • FDH: Albumin mutations; AD; High T4, Normal free T4. • High TBG: Estrogen/Pregnancy; XL or Acquired; High total T4/T3, Normal free T4. • Transthyretin Excess: Islet tumors; Acquired; Normal T4/T3. • Mutations: Increased affinity for T4/T3; AD; High total T4/T3, Normal free T4. • Decreased T4 → T3 conversion: Drugs (amiodarone, propranolol); Acquired; High T3, Normal/High TSH. • RTH: TRβ mutations; AD; High unbound T4/T3, Normal/High TSH. • Secondary Hypothyroidism: Pituitary/Hypothalamic disease → Low T4 with variable (low-high normal) TSH.
Table 394-1: Characteristics of Circulating T4 and T3¶
• T4 Properties: • Total: 8 µg/dL • Unbound fraction: 0.02% • Unbound (free): 21 × 10⁻¹² M • From thyroid: 100% • Intracellular: ~20% • Receptor binding: 10⁻¹⁰ M • T3 Properties: • Total: 0.14 µg/dL • Unbound fraction: 0.3% • Unbound (free): 6 × 10⁻¹² M • From thyroid: 20% • Intracellular: ~70% • Receptor binding: 10⁻¹¹ M
DIAGNOSTIC APPROACH¶
- Primary Screening: Measure TSH.
- Normal TSH → excludes primary thyroid dysfunction (except in secondary hypothyroidism).
- Sensitivity Check: Use assays sensitive to ≤ 0.01 mIU/L to distinguish suppressed values.
- Biotin Interference Check:
- If TSH is unexpectedly low and T4/T3 are high, check for biotin intake (>1000 µg in last 18h).
- Differentiation of Euthyroid Hyperthyroxinemia:
- Measure Free T4/T3 → if free levels are normal but total is high, consider FDH or High TBG.
- RTH Diagnosis:
- Suspect when unbound T4/T3 are elevated without suppression of TSH.
- Confirm with DNA sequence analysis of TRβ gene.
Table 394-2: Conditions Associated with Euthyroid Hyperthyroxinemia¶
• FDH: Albumin mutations (R218H); AD; Increased T4, Normal unbound T4. • High TBG: Estrogen/Pregnancy/Cirrhosis; XL or Acquired; Increased total T4/T3, Normal unbound T4/T3. • Transthyretin Excess: Islet tumors; Acquired; Usually normal T4/T3. • Mutations: Increased affinity for T4/T3; AD; Increased total T4/T3, Normal unbound T4/T3. • Decreased T4 → T3 conversion: Drugs (amiodarone, propranolol); Acquired; Increased T3, Normal or increased TSH. • RTH: TRβ mutations; AD; Increased unbound T4/T3, Normal or increased TSH.
MANAGEMENT & TREATMENT¶
- Pregnancy Management:
- Identify hCG-induced hyperthyroxinemia (1st trimester).
- Treatment: Parenteral fluid replacement for tachycardia/hyperemesis; antithyroid drugs only if Graves' suspected.
- Iodine Deficiency:
- Supplementation required in high-risk regions to prevent cretinism.
- Congenital Hypothyroidism:
- Early thyroid hormone replacement is mandatory.
Special Populations: Pregnancy¶
• Screening: Target TSH testing for women planning pregnancy if they have risk factors (age >30, family history of autoimmune disease, etc.). • Levothyroxine Adjustment: Increase dose by up to 45% during pregnancy in hypothyroid women.
KEY PEARLS & HIGH-YIELD POINTS¶
• T3 vs T4: T4 is the precursor; T3 is more potent. T4 is secreted in 15-fold excess over T3. • Symptom of RTH: Patients may appear euthyroid because high hormone levels compensate for receptor resistance. • Biotin Trap: High dose biotin (>1000 µg) can cause false low TSH and high T4/T3; ensure patients are off supplements before testing. • Pemberton's Sign: Indicates a large retrosternal goiter causing venous compression. • Iodine Deficiency: Even mild deficiency can lead to reduced IQ in children.
Reference Tables¶
TABLE 394-1 Characteristics of Circulating T 4 and T 3¶
Harrison's 22e, p.3024
| HORMONE PROPERTY | T 4 |
T 3 |
|---|---|---|
| Serum concentrations | ||
| Total hormone | 8 μg/dL | 0.14 μg/dL |
| Fraction of total hormone in the unbound form | 0.02% | 0.3% |
| Unbound (free) hormone | 21 × 10–12M | 6 × 10–12M |
| 7 d | ||
| Fraction directly from the thyroid | 100% | 20% |
| 90 μg/d | ||
| Intracellular hormone fraction | ~20% | ~70% |
| 0.3 | ||
| Receptor binding | 10–10M | 10–11M |
TABLE 394-2 Conditions Associated with Euthyroid Hyperthyroxinemia DISORDER Familial dysalbuminemic hyperthyroxinemia¶
Harrison's 22e, p.3024
| DISORDER | CAUSE | TRANSMISSION | CHARACTERISTICS |
|---|---|---|---|
| Familial dysalbuminemic hyperthyroxinemia (FDH) |
Albumin mutations, usually R218H |
AD | Increased T 4 Normal unbound T 4 Rarely increased T 3 |
| Increased TBG production Medications (estrogen), pregnancy, cirrhosis, hepatitis |
XL Acquired |
||
| Transthyretina | |||
| Excess | Islet tumors | Acquired | Usually normal T, T 4 3 |
| Mutations | Increased affinity for T or T 4 3 |
AD | Increased total T, T 4 3 Normal unbound T, T 4 3 |
| Decreased T → T conversion 4 3 |
Acquired | ||
| Resistance to thyroid hormone (RTH) |
Thyroid hormone receptor β mutations |
AD | Increased unbound T, T 4 3 Normal or increased TSH Some patients clinically thyrotoxic |