thyroid

• Location: anterior to laryngeal cartilages, over the trachea → close relationship to trachea/esophagus (mass effect can cause dysphagia or airway symptoms).

• Shape: butterfly — two lobes connected by an isthmus; lobes ≈ 4 cm each.

• Vascularity: highly vascular → supplied by superior and inferior thyroid arteries; drained to internal jugular veins → surgical/resection implications (bleeding risk).

• Weight variation: normal ≈ 20 g (varies with body size and iodine supply).

• Functional unit: follicle → spherical, lumen filled with colloid (thyroglobulin reservoir).

• Cells: follicular epithelial cells (thyrocytes) line follicles → synthesize and secrete T3/T4.

• Parafollicular (C) cells: located between/adjacent to follicles → secrete calcitonin (calcium homeostasis).

• Correlation: follicular cells handle thyroid hormone production/storage → C cells are embryologically distinct and have separate function.

• Flow: TRH (hypothalamus) → stimulates pituitary → TSH release → stimulates thyroid → produces T4 and T3.

• Negative feedback: ↑ T3/T4 → ↓ TRH & ↓ TSH (homeostasis).

• Clinical correlation: pituitary or hypothalamic lesions → secondary/tertiary hypothyroidism (low TSH/low TRH despite low thyroid hormones).

• TSH effects: stimulates all steps of hormone secretion, ↑ follicular cell height, ↑ vascularity and gland activity. [

• Prolonged ↑ TSH → follicular cell hypertrophy and hyperplasia → gland enlargement = goiter.

• Clinical arrow: iodine deficiency → ↓ hormone synthesis → ↑ TSH → goiter formation.

• Iodine is essential for iodination of tyrosyl residues in thyroglobulin → formation of MIT/DIT → T3/T4.

• Public-health: iodized salt added for primary prevention of goiter and iodine-deficiency disorders. Excess iodine eliminated by kidney (not toxic); only not in hyperthyroidism

• Correlation: excessive iodine vs deficiency → different clinical effects (see Wolff–Chaikoff, goiter types).

• Catabolic effects: increase breakdown of proteins, carbohydrates, lipids → high hormones → weight loss; low hormones → weight gain. p.12 • Clinical correlation: unexplained weight changes warrant thyroid evaluation (check free T3/T4 + TSH).

• Definition: transient inhibition of thyroid hormone synthesis after marked iodine excess → reduced organification and hormone release.

• Mechanisms: ↓ iodide organification, ↓ TSH signaling (cAMP), ↓ proteolysis of thyroglobulin.

• Clinical use: high-dose iodine (e.g., Lugol’s) preoperatively to render gland less vascular and reduce thyroid storm risk.

• Basolateral uptake: NIS (sodium/iodide symporter) actively transports I- into thyrocytes → essential for hormone synthesis; expressed also in salivary glands, gastric mucosa, lactating breast, placenta.

• Apical transfer: Pendrin transports iodide into the colloid (follicular lumen) for organification.

• Correlation: NIS expression underlies radioiodine diagnostics/therapy; extra-thyroidal NIS explains tracer uptake in other tissues. p.6-8

• Tg: large glycoprotein scaffold stored in colloid → tyrosyl residues iodinated → source of T3/T4 on demand. Can leak into BS

• Anti-Tg antibodies: commonly detected but are nonspecific → can appear with thyroid turnover, inflammation or surgery; not strongly diagnostic alone. p.6

• Correlation: anti-TPO antibodies are more disease-specific (Hashimoto).

• Anti‑TPO antibodies: directed against thyroid peroxidase → indicate autoimmune thyroid destruction (Hashimoto’s).

• Clinical consequence: often associated with progressive hypothyroidism; check T3/T4 levels to assess function.

• Diagnosis: NIS expression → uptake of tracers (technetium-99m or radioiodine) → whole-body scintigraphy to localize residual thyroid tissue/metastases.

• Therapy: radioactive iodine (I‑131) taken up by NIS → beta radiation ablates thyroid cancer cells (effective for differentiated cancers that retain NIS).

• Limitation: anaplastic cancers often lose NIS → radioiodine ineffective.

NIS expression has also been found in other tissues and tumors, such as breast cancer; no TPO so no retention - radioiodine ineffective

• Breast cancer cells may express NIS → can uptake iodine, but they lack TPO to organify and retain iodine → tracer leaks out → therapy ineffective. p.9 • Research: combining iodine with TPO-like mechanisms is being explored to trap iodine in breast tumors.

• Total T3/T4 = bound + free; binding proteins made by the liver (TBG, albumin) influence total levels. p.9 • Free T3/T4: biologically active fraction → reflects true thyroid function independent of binding‑protein changes (e.g., liver disease). p.9 • Clinical arrow: abnormal binding protein states → rely on free hormone assays for accurate assessment.

• Secretion pattern: thyroid predominantly secretes T4, a prohormone; small amount of T3 secreted directly. p.10 • Peripheral conversion: deiodinases (D1, D2, D3) remove iodine from rings → convert T4 → active T3 or inactive rT3. p.9-10 • Advantage: local (peripheral) conversion allows tissues to regulate active hormone levels on demand → fine-tunes metabolism.

• D1, D2, D3 — isoenzymes that catalyze 5′- and 5-deiodination. • D1/D2: convert T4 → active T3 in peripheral tissues (D2 important in CNS and pituitary). p.9-10 • D3: inactivates T4/T3 → produces reverse T3 (rT3) (hormone inactivation). p.9-10 • Clinical correlation: altered deiodinase activity affects local T3 availability (e.g., illness, drugs).

• Calorigenic action: thyroid hormones increase metabolic rate and heat production. • Quantitative note: ~1 mg thyroxine increases heat production by ≈ 1000 calories. p.12 • Tissue exceptions: minimal effect in adult brain, retina, gonads, lymphoid tissue, and lung.

• Effects:

• ↑ sinoatrial node activity & sensitivity to catecholamines → tachycardia, palpitations; may precipitate atrial fibrillation in hyperthyroid. p.12
• Hypothyroidism → bradycardia, reduced contractility. p.12 • Clinical arrow: elderly hyperthyroid patients may present primarily with atrial arrhythmias or heart failure. p.12,19

• GI: thyroid hormones ↑ secretion of digestive juices and intestinal motility → hyperthyroid → diarrhea, increased appetite; hypothyroid → constipation. p.13 • Respiratory: ↑ rate and depth of respiration with excess hormones → may amplify dyspnea or exercise intolerance.

• Functional status: hypothyroidism (low hormones), euthyroidism (normal), hyperthyroidism (high). p.13 • By pathology:

• Non-neoplastic: Hashimoto’s, Graves’, multinodular/goiter, thyroiditis. p.13-15
• Neoplastic: differentiated (papillary, follicular), medullary, anaplastic.

• Causes: thyroidectomy (surgical removal), systemic diseases (e.g., hemochromatosis with iron deposition), medications (e.g., lithium interfering with NIS uptake). p.15 • Correlation: medication history & prior neck surgery are critical in hypothyroid workup.

• Pathogenesis: autoantibodies (TSI/TGI) stimulate the TSH receptor → sustained thyroid stimulation → ↑ T3/T4 (thyrotoxicosis).

• Clinical features: diffuse toxic goiter, ophthalmopathy (exophthalmos), pretibial myxedema in some patients; symptoms: tremor, heat intolerance, weight loss, palpitations.

• Management correlation: antithyroid drugs often effective but relapse common → consider radioiodine or thyroidectomy if recurrent.

• Epidemiology: ~50% of people >60 have nodules; overall malignancy rate ≈ 5%.

• Risk factors for malignancy: age extremes, male sex, prior radiation, suspicious ultrasound features.

• Approach: ultrasound characterization → size/appearance → fine-needle aspiration for suspicious nodules; follow-up imaging for benign nodules (6–12 months).

• Differentiated (papillary, follicular): arise from follicular cells, often retain iodine uptake → amenable to surgery + radioiodine; generally good prognosis.

• Medullary: from parafollicular C cells (calcitonin-producing); does not take up radioiodine; associated with RET mutations → requires genetic testing; targeted RET inhibitors available.

• Anaplastic: undifferentiated, aggressive, poor prognosis; often refractory to radioiodine/chemo; rapid local invasion.

• Papillary carcinoma: most frequent (~80% of thyroid cancers).

• Features: solitary or multifocal nodules, calcifications, fibrosis, lymphatic spread to regional nodes; common BRAF and RET/PTC alterations. Methastasis to lungs

• Clinical implication: good prognosis; treat with surgery ± radioiodine depending on extent.

• FTC: 2nd most common differentiated cancer (10–20%). More frequent in women and older adults.

• Important diagnostic point: must demonstrate capsular and/or vascular invasion to distinguish carcinoma from adenoma.

• Association: RAS mutations common; increased incidence in areas of iodine deficiency.

• Origin: parafollicular C cells → secrete calcitonin (useful tumor marker).

• Genetics: familial cases often due to germline RET mutations (MEN2 syndromes) → screen relatives.

• Therapy: surgery is mainstay; RET inhibitors are effective in RET-mutant disease; radioiodine ineffective.

<2%

• Anaplastic carcinoma: undifferentiated, highly aggressive, usually in elderly; rapid local invasion (airway compression) and distant spread.

• Prognosis: very poor, limited effective therapies; often refractory to surgery and radioiodine.

• Clinical note: history of long-standing multinodular goiter may precede anaplastic transformation in some cases.

• Diagnostics: technetium-99m (shorter half-life ~6 h) often preferred for imaging; iodine-123 frequently used for diagnostics; I‑131 used more for therapy (β emission).

• Rationale: technetium and iodine uptake occur via NIS; I‑131 emits beta particles useful for ablation whereas Tc-99m is better for quick imaging and lower radiation burden.

• Liver: synthesizes carrier proteins (TBG, albumin) that bind T3/T4 → majority of hormones circulate protein-bound. p.9 • Clinical implication: liver disease or altered binding proteins change total hormone levels but not necessarily free hormone → measure free T3/T4 to assess thyroid function accurately.

• Diffuse goiter: uniform enlargement, often from iodine deficiency → gland may remain euthyroid or be hypothyroid; treat with iodine supplementation. Can be colloid.

• Nodular/multinodular goiter: long-term heterogeneous growth → nodules with variable function (hot/cold); some persist after iodine repletion → may need surgery if compressive or suspicious.

• Arrow: mild iodine deficiency → compensated ↑TSH → diffuse enlargement; severe/long-standing deficiency → nodularity.

• Pre-op iodine (Lugol’s): induces Wolff–Chaikoff → transiently suppresses hormone synthesis and reduces gland vascularity → decreases intraoperative bleeding and thyroid hormone surge risk.

Thyroid storm: very high hormone release can be precipitated by surgery/trauma in hyperthyroid patients → pre-op preparation reduces this risk.

• I- → transported into cell by NIS (active)→ moved into colloid via pendrin.

• In colloid: iodide → oxidized and bound to tyrosine residues on thyroglobulin (Tg) by TPO (thyroid peroxidase) → forms MIT/DIT → coupling → produce T3/T4 stored on Tg. p.6,10

• Release: Tg endocytosed → proteolysis → frees T3/T4 into circulation.

• Etiology: autoimmune attack; most common cause of hypothyroidism; more frequent in women (30–50 yrs).

• Mechanisms: autoreactive CD4+ T cells → CD8+ cytotoxicity, cytokine-mediated damage (IFN-γ), anti‑TPO antibodies → progressive thyrocyte destruction.

• Clinical: goiter, hypothyroid symptoms, ultrasound may show mixed echogenic areas from fibrosis/inflammation. low T4 and high TSH

• Cellular effects:

• ↑ mitochondria size & number → ↑ respiration and O2 consumption. p.11

• ↑ Na-K ATPase activity → influences membrane potential and thermogenesis. p.11

• ↑ amino acid transport → supports protein synthesis (but hormones are overall catabolic). p.11

• Activate proteolytic/lysosomal enzymes → protein turnover. p.11 • Physiological outcomes: increased basal metabolic rate, heat production (calorigenic), altered body weight.

• Common signs: nervousness, tremor, heat intolerance, weight loss, palpitations, tachycardia, increased sweating.

• Age differences: younger: nervousness/irritability; elderly: palpitations, atrial arrhythmias, weight loss may be prominent.

• Clinical arrow: atypical presentations in elderly (apathetic hyperthyroidism) require high suspicion.

• Primary hypothyroidism: intrinsic thyroid failure → low T4 with high TSH.

• Secondary (pituitary): ↓ TSH secretion (pituitary lesion) → low T4 with low/normal TSH.

• Tertiary (hypothalamic): ↓ TRH → secondary low TSH → low T4; rarer.

• Seven-gene panel: tests common driver mutations/rearrangements (BRAF, RAS, RET/PTC, PAX8/PPARγ) → support diagnosis and targeted therapy decisions.

• Gene expression classifier (167-GEC): mRNA profiling to better classify indeterminate cytology → reduce unnecessary surgery. Benign vs malignant if biopsy indeterminate

• Galectin-3 IHC: protein marker overexpressed in malignancy → supportive evidence for carcinoma.