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Here is a comprehensive overview of thyroid disorders, drawn from Robbins & Kumar Basic Pathology, Goldman-Cecil Medicine, and Harrison's Principles of Internal Medicine.
Thyroid Disorders
Physiology & Regulatory Axis
The thyroid gland weighs 10–20 g and consists of two lobes connected by an isthmus. It is composed of follicular cells (which produce T4 and T3) and parafollicular C-cells (which produce calcitonin). Follicular cells organize into units surrounding a colloid center containing thyroglobulin.
HPT Axis (negative feedback):
- Hypothalamic TRH → pituitary TSH → thyroid T4/T3 synthesis
- T3 and T4 feed back to suppress both TRH and TSH
- T3 is the biologically active form (10× greater receptor affinity); most circulating T4 is converted to T3 in peripheral tissues
- Iodine (~150 µg/day dietary intake) is essential; it is actively transported into follicular cells by the sodium-iodide symporter (NIS)
Classification of Thyroid Disorders
| Category | Condition | Direction of T4/T3 | TSH |
|---|---|---|---|
| Hyperthyroidism | Graves disease, toxic MNG, toxic adenoma | ↑ | ↓ |
| Hypothyroidism | Hashimoto thyroiditis, iodine deficiency, iatrogenic | ↓ | ↑ (primary) |
| Thyroiditis | De Quervain, postpartum, Hashimoto | Variable | Variable |
| Goiter | Iodine deficiency, MNG | Variable | Variable |
1. Hyperthyroidism (Thyrotoxicosis)
Causes (in order of frequency):
- Graves disease — ~85% of cases; autoimmune TSH receptor-stimulating antibodies (TRAb)
- Toxic multinodular goiter
- Toxic (hyperfunctioning) adenoma
- Transient: thyroiditis, iodine-induced (Jod-Basedow)
Clinical Features:
| System | Manifestations |
|---|---|
| Constitutional | Heat intolerance, weight loss despite ↑ appetite, sweating, warm/flushed skin |
| Cardiovascular | Palpitations, tachycardia, high-output heart failure (elderly) |
| GI | Hypermotility, diarrhea, malabsorption |
| Neuromuscular | Anxiety, tremor, irritability; proximal myopathy (~50%) |
| Ocular | Lid lag, wide staring gaze; exophthalmos (Graves-specific) |
Special situations:
- Thyroid storm — abrupt severe thyrotoxicosis (often precipitated by infection, surgery, or stopping anti-thyroid drugs); life-threatening cardiac arrhythmias
- Apathetic hyperthyroidism — blunted presentation in elderly; discovered on workup for unexplained weight loss or new cardiovascular disease
Diagnosis:
- ↓ TSH is the single most sensitive screening test (suppressed even in subclinical disease)
- ↑ Free T4; occasionally T3 toxicosis with normal/low T4
- Radioactive iodine uptake (RAIU): diffusely ↑ in Graves, focally ↑ in toxic adenoma, ↓ in thyroiditis
Treatment:
- Thioamides (methimazole, propylthiouracil) — first-line medical therapy
- Radioactive iodine-131 (¹³¹I) — definitive treatment; contraindicated in pregnancy
- Beta-blockers — symptomatic relief (palpitations, tremor)
- Surgery — thyroidectomy for large goiters or when other treatments fail
- Thyroid eye disease (Graves): teprotumumab (IGF-1R antagonist) is an approved biologic therapy
2. Hypothyroidism
Causes (Primary):
| Cause | Mechanism |
|---|---|
| Hashimoto thyroiditis | Autoimmune destruction |
| Iodine deficiency | Most common cause worldwide (affects ~2 billion) |
| Iatrogenic (surgery, radiation, ¹³¹I) | Loss of thyroid tissue |
| Drugs (lithium, amiodarone) | Interfere with synthesis |
| Congenital (thyroid dysgenesis) | 1 in 3500 births |
| Immune checkpoint inhibitors | Drug-induced autoimmunity |
Secondary (Central): TSH deficiency from pituitary/hypothalamic failure — rare, accounts for ~1% of cases.
Epidemiology: ~5% prevalence in the US/Europe; predominantly subclinical; higher in women; risk increases with age.
Clinical Features:
| System | Manifestations |
|---|---|
| Constitutional | Cold intolerance, weight gain, fatigue, dry skin |
| Cardiovascular | Bradycardia, pericardial effusion |
| GI | Constipation |
| Neuromuscular | Lethargy, impaired concentration, delayed DTRs |
| Myxedema | Severe longstanding hypothyroidism → non-pitting edema, altered consciousness (myxedema coma) |
Subclinical hypothyroidism: Normal T4/T3, TSH 4.5–20 mIU/L; treatment decision depends on TSH level, symptoms, age, and antibody status.
Diagnosis: ↑ TSH (overt: usually >20 mIU/L), ↓ free T4; positive anti-TPO and anti-thyroglobulin antibodies in Hashimoto.
Treatment: Levothyroxine (T4) — oral replacement; titrate to normalize TSH.
3. Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis)
The most common cause of hypothyroidism in iodine-sufficient regions. Female:male ratio = 10–20:1; peak onset 45–65 years.
Pathogenesis — two key mechanisms:
- CD8+ cytotoxic T cells directly kill thyroid epithelial cells via MHC-I recognition
- CD4+ Th1 cells produce IFN-γ → macrophage activation → follicular destruction
Genetic associations: CTLA4 polymorphisms; ~40% concordance in monozygotic twins.
Morphology: Diffuse lymphocytic infiltration with germinal centers; atrophic follicles lined by eosinophilic Hürthle (oxyphil) cells; progressive fibrosis.
Clinical course:
- Painless goiter + gradual hypothyroidism (often middle-aged woman)
- Transient thyrotoxicosis ("hashitoxicosis") can precede hypothyroidism due to follicle rupture and hormone release
- Elevated risk of primary thyroid lymphoma (B-cell)
4. Thyroiditis — Summary
| Type | Cause | Pain | RAIU | Clinical Course |
|---|---|---|---|---|
| Hashimoto | Autoimmune | No | ↓ | Progressive hypothyroidism |
| De Quervain (Subacute granulomatous) | Post-viral | Yes | ↓ | Triphasic: hyper → hypo → euthyroid |
| Postpartum/Painless | Autoimmune | No | ↓ | Biphasic; 10% of pregnancies |
| Riedel | Fibroinflammatory | No | ↓ | Hard "woody" goiter; rare |
Postpartum thyroiditis: Occurs within 12 months post-delivery; T3:T4 ratio <20 (reflecting stored hormone release, not new synthesis) — distinguishes it from Graves disease. TPO antibodies positive; TRAb negative.
5. Goiter
Thyroid enlargement from any cause. Can be:
- Diffuse (Graves, Hashimoto, iodine deficiency)
- Multinodular (MNG) — commonest thyroid disorder globally; TSH levels variable; requires evaluation for hot vs cold nodules
Iodine deficiency → ↓ T4/T3 → ↑ TSH → thyroid hyperplasia → goiter. Addressed worldwide by iodized salt.
Investigations at a Glance
| Test | Use |
|---|---|
| Serum TSH | Best initial screening test for any thyroid disorder |
| Free T4 | Confirms overt hypo/hyperthyroidism |
| T3 | Useful in T3 toxicosis (where T4 may be normal/low) |
| Anti-TPO, anti-TG antibodies | Hashimoto; postpartum thyroiditis |
| TSH receptor antibody (TRAb) | Graves disease (stimulating); replaces RAIU scanning in most cases |
| Radioactive iodine uptake (RAIU) | Differentiates causes of thyrotoxicosis; evaluates nodules |
| Ultrasound | Best anatomic imaging; guides FNA for nodule risk stratification |
| FNA biopsy | Evaluates thyroid nodules with suspicious features |
⚠️ Biotin interference: Patients taking >100 mg/day biotin can have spuriously low TSH and high T4/T3 on some assays — results normalize after stopping biotin for 2–3 days.
Key Drug Effects on Thyroid
| Drug | Effect |
|---|---|
| Amiodarone (40% iodine) | Hypo- or hyperthyroidism |
| Lithium | Hypothyroidism (blocks T4/T3 release) |
| Immune checkpoint inhibitors | Autoimmune thyroiditis → hypothyroidism |
| Tyrosine kinase inhibitors | Hypothyroidism |
| Interferon-α | Autoimmune thyroid disease |
Sources: Robbins & Kumar Basic Pathology, p. 729–733; Goldman-Cecil Medicine, Ch. 207; Harrison's Principles of Internal Medicine 22E, Ch. 207
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