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Seminar Outline: Biochemical Aspects and Disorders of the Pituitary, Adrenal, and Thyroid Glands

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PART I — THE PITUITARY GLAND

1. Introduction to the Hypothalamic-Pituitary Axis (p. 2234)

• Anatomical overview: anterior vs. posterior pituitary; embryology
• Hypothalamic releasing and inhibiting hormones (TRH, CRH, GHRH, GnRH, somatostatin, dopamine)
• Hypothalamic-pituitary portal system — functional significance
• Anterior pituitary hormones: GH, TSH, ACTH, FSH, LH, Prolactin
• Posterior pituitary hormones: ADH (vasopressin), Oxytocin
• Negative feedback regulation of the HP axes (HPA, HPT, HPG)

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2. Cushing Disease (Pituitary Origin of Hypercortisolism)

2a. Biochemical Definition (p. 2283)

• Cushing disease = ACTH-secreting pituitary adenoma (corticotroph adenoma) → accounts for ~80% of endogenous ACTH-dependent Cushing syndrome
• Results in bilateral adrenocortical hyperplasia and excess cortisol
• Biochemical hallmarks: elevated 24-h urinary free cortisol (UFC), loss of diurnal cortisol rhythm, elevated plasma ACTH, failure of low-dose dexamethasone suppression

2b. Diagnostic Algorithm (p. 2282–2284)

• Screening tests:
  • 24-h urine free cortisol (UFC): elevated >2× ULN confirms hypercortisolism
  • Late-night salivary cortisol: uses circadian nadir; loss of circadian rhythm in Cushing
  • Overnight 1 mg dexamethasone suppression test (DST): normal response = morning cortisol <1.8 μg/dL (<50 nmol/L); failure to suppress is >95% sensitive
• Confirmatory & localization:
  • Low-dose DST (2-day, 0.5 mg q6h) → confirms hypercortisolism
  • High-dose DST: UFC suppressed >50% of baseline in Cushing disease (pituitary source) but NOT in ectopic ACTH or adrenal tumor
  • Plasma ACTH: elevated/normal in pituitary Cushing; suppressed (<10 pg/mL) in adrenal tumor; markedly elevated (>300 pg/mL) in ectopic ACTH syndrome
  • Desmopressin stimulation test (p. 2289): corticotroph adenomas aberrantly express V2 receptors → ACTH peak >27 pg/mL is 75–87% sensitive, 90–91% specific for Cushing disease
  • Inferior petrosal sinus sampling (IPSS) — gold standard to distinguish pituitary vs. ectopic ACTH

2c. Pseudo-Cushing Syndrome (p. 2287)

• Mimics: alcoholism, depression, obesity, exogenous glucocorticoids — must be excluded
• CRH stimulation after low-dose DST: cortisol >1.4 μg/dL post-CRH = highly specific for true Cushing

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3. Diabetes Insipidus (DI)

3a. Biochemistry of ADH/Vasopressin (p. 2255–2260)

• ADH = nonapeptide; encoded by AVP gene at chromosome 20p13
• Prepro-ADH (164 aa) co-encodes neurophysin 2 and copeptin (C-terminal provasopressin, a stable surrogate marker)
• V2 receptor (Xq28): mediates renal water reabsorption via cAMP → aquaporin-2 insertion in collecting duct
• V1a receptor (12q14): vascular smooth muscle vasoconstriction
• V1b receptor: pituitary ACTH secretagogue activity
• Regulation: primary stimulus = plasma hyperosmolality (osmoreceptors in hypothalamus); secondary = volume depletion via baroreceptors (volume regulation overrides osmoregulation when volume change >10%)

3b. Types of DI (p. 2258–2260; Box 55.7, p. 2262)

• Causes of central DI: trauma, neurosurgery, pituitary tumors, histiocytosis X, Wolfram syndrome (DIDMOAD)
• Nephrogenic DI: X-linked (V2 receptor mutations), autosomal recessive (AQP2 mutations), drugs (lithium, demeclocycline), hypercalcemia, hypokalemia

3c. Biochemical Features & Diagnosis (p. 2262; Box 55.7)

• Polyuria (>3 L/day), polydipsia; urine specific gravity <1.005; urine osmolality <300 mOsmol/kg
• Water deprivation test with desmopressin challenge:
  • Dehydrate → measure urine and plasma osmolality
  • Administer desmopressin: urine osmolality rises >50% in central DI; minimal rise in nephrogenic DI; already maximally dilute urine in primary polydipsia (plasma osmolality stays low)
• Serum and urine osmolality ratio (U/P ratio) — critical diagnostic parameter
• Copeptin measurement (p. 2260): rising alternative to water deprivation test; a level >21.4 pmol/L after hypertonic saline distinguishes primary polydipsia from central DI with >95% accuracy

3d. Key Biochemical Values

• Normal plasma osmolality: 275–295 mOsmol/kg
• ADH secretion threshold: ~280 mOsmol/kg; maximum secretion at ~295–300 mOsmol/kg

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4. Syndrome of Inappropriate ADH Secretion (SIADH)

4a. Pathophysiology (p. 2262–2264; Box 55.8)

• Autonomous ADH secretion independent of osmotic or volume stimuli
• Consequence: excess water reabsorption → dilutional hyponatremia + low plasma osmolality + inappropriately concentrated urine
• Volume expansion → suppresses RAA axis → urinary sodium excretion (urine Na 20–40 mEq/L despite plasma hyponatremia) → patient is euvolemic

4b. Causes (Table 55.9, p. 2263)

• CNS disease: brain tumors, meningitis, encephalitis, seizures, psychiatric disease
• Non-CNS tumors: small cell carcinoma of lung (ectopic ADH production — most classic cause), leukemia
• Pulmonary disease: pneumonia, emphysema, hypoxia
• Drugs: anticonvulsants, antidepressants, SSRIs, carbamazepine, ACE inhibitors, antineoplastics, first-generation sulfonylureas, oxytocin
• Post-pituitary surgery: transient SIADH 8–9 days post-op (ADH release from pituitary remnant/hypothalamus)
• Gain-of-function V2 receptor mutation (nephrogenic SIADH) — rare

4c. Diagnostic Criteria (Box 55.8, p. 2264)

• Plasma sodium <135 mmol/L (hyponatremia)
• Plasma osmolality <275 mOsmol/kg
• Urine osmolality >100 mOsmol/kg (inappropriately concentrated relative to plasma)
• Urine sodium >20 mEq/L (despite hyponatremia)
• Clinical euvolemia (no edema, no dehydration)
• Exclude: hypothyroidism, adrenal insufficiency, renal failure, cardiac failure, cirrhosis, nephrotic syndrome

4d. Differential Diagnosis of Hyponatremia (p. 2263)

• Congestive heart failure, renal insufficiency, nephrotic syndrome, cirrhosis, hypothyroidism — all cause hyponatremia but with hypervolemia or different urinary findings

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PART II — ADRENAL GLAND

5. Adrenal Gland: Anatomy, Biochemistry, and Steroid Biosynthesis

5a. Adrenal Anatomy & Zones (p. 2267)

• Cortex (outer): 3 zones — Zona Glomerulosa (ZG), Zona Fasciculata (ZF), Zona Reticularis (ZR)
• Medulla (inner): chromaffin cells — catecholamine secretion
• Cortex: mesodermal origin; Medulla: neural crest origin

5b. Steroid Hormone Biochemistry (p. 2267–2270; Fig. 56.2)

• Cholesterol backbone: 17-carbon tetracyclic nucleus; rings A, B, C, D; cholesterol is the universal precursor
• ~80% of adrenal cholesterol from LDL receptors; ~20% de novo via mevalonate pathway
• Rate-limiting step: Cholesterol transport to inner mitochondrial membrane by StAR protein (steroidogenic acute regulatory protein; 285 aa; encoded by STAR gene at 8p11.2) — regulated by ACTH
• CYP11A1 (cholesterol side-chain cleavage enzyme, P450scc): converts cholesterol → pregnenolone (first committed step)
• Major biosynthetic pathways:
  • Zona Glomerulosa: Aldosterone synthesis — CYP11B2 (aldosterone synthase); regulated primarily by angiotensin II and serum K+
  • Zona Fasciculata: Cortisol synthesis — CYP11B1; regulated by ACTH
  • Zona Reticularis: DHEA, DHEA-S, androstenedione; regulated primarily by ACTH
• Key enzymes: 3β-HSD, 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2), 11β-hydroxylase (CYP11B1/B2)
• Steroid activity: Cortisol (glucocorticoid), Aldosterone (mineralocorticoid), DHEA/DHEA-S/Androstenedione (androgens)

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PART II-A — ADRENAL CORTEX DISORDERS

6. Cushing Syndrome (Adrenal and ACTH-Dependent) (p. 2282–2290)

6a. Classification (p. 2283–2284; Fig. 56.10)

• Incidence of endogenous Cushing: 0.7–2.4 per million per year (p. 2283)

6b. Clinical Features (p. 2284)

• Central obesity, moon face, buffalo hump, supraclavicular fat pads
• Purple striae, easy bruising, skin thinning
• Proximal myopathy, osteoporosis, vertebral fractures
• Hypertension, hyperglycemia/diabetes, hyperlipidemia
• Hypokalemia (especially ectopic ACTH — due to overwhelming 11β-HSD2 in kidney)
• Hirsutism, menstrual irregularity, gonadal dysfunction
• Immune suppression, psychiatric disturbances (depression, psychosis)

6c. Biochemical Diagnosis (p. 2282–2290; Box 56.5)

1. 24-h UFC (x2): >3–4× ULN → Cushing syndrome confirmed
2. Late-night salivary cortisol (x2): loss of nocturnal nadir (normal cortisol <4 nmol/L at midnight)
3. 1 mg overnight DST: normal = morning cortisol <1.8 μg/dL; >1.8 μg/dL = positive (95% sensitive, 80% specific)

• Plasma ACTH: suppressed (<10 pg/mL) = adrenal tumor; elevated (>50–300 pg/mL) = pituitary or ectopic
• High-dose DST (8 mg): UFC suppressed >50% of baseline = Cushing disease (pituitary); no suppression = ectopic or adrenal
• CRH stimulation test: cortisol rises >20% in Cushing disease; minimal in ectopic ACTH
• IPSS (inferior petrosal sinus sampling): IPS:peripheral ACTH ratio >2 (basal) or >3 (after CRH) confirms pituitary source

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7. Addison Disease (Primary Adrenocortical Insufficiency) (p. 2273–2277)

7a. Definition & Epidemiology

• Destruction/dysgenesis of the adrenal cortex → combined glucocorticoid + mineralocorticoid + androgen deficiency
• Prevalence: ~1 in 10,000 in developed countries (p. 2274)
• Symptoms only manifest when ≥90% of adrenal tissue is lost

7b. Etiology (Table 56.3, p. 2274)

• Developed countries: Autoimmune adrenalitis (most common; APS-1, APS-2)
  • APS-2 (Schmidt syndrome): Addison + autoimmune thyroiditis + T1DM
  • Autoantibodies: 21-hydroxylase antibodies (most sensitive marker for autoimmune AD)
• Worldwide: Tuberculosis (most common globally)
• Other: HIV/AIDS, fungal infections (histoplasmosis), metastatic malignancy, adrenal hemorrhage (Waterhouse-Friderichsen syndrome in meningococcemia), drugs (ketoconazole, etomidate, rifampicin), bilateral adrenalectomy
• Genetic: >80% of pediatric cases; ALD (adrenoleukodystrophy — very long chain fatty acids), congenital adrenal hypoplasia, STAR mutations

7c. Clinical & Biochemical Features (p. 2274)

• Fatigue, weakness, weight loss, anorexia, nausea/vomiting, abdominal pain, diarrhea
• Hyperpigmentation (ACTH↑ → melanocortin receptor stimulation): skin creases, buccal mucosa, scars — hallmark of primary adrenal insufficiency
• Hypotension, postural hypotension; hypoglycemia
• Laboratory: Hyponatremia, hyperkalemia, hypercalcemia; eosinophilia; low cortisol; elevated ACTH
• Addisonian crisis: Acute adrenal insufficiency — life-threatening medical emergency triggered by stress/infection; severe hypotension, vomiting, acute confusion

7d. Diagnostic Tests

• Basal morning cortisol (<100 nmol/L = adrenal insufficiency; >550 nmol/L = rules out)
• Short ACTH (Synacthen) stimulation test (250 μg cosyntropin IV/IM): Gold standard — cortisol peak <500 nmol/L at 30–60 min = abnormal (low sensitivity for secondary AI)
• Plasma ACTH: Markedly elevated (>2× ULN) in primary; low/undetectable in secondary
• Adrenal autoantibodies (21-OH antibodies): Positive in autoimmune AD
• ACTH stimulation algorithm (at-a-glance box, p. 2274)

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8. Primary Hyperaldosteronism — Conn's Syndrome (p. 2285–2292)

8a. Biochemistry of Aldosterone Regulation (p. 2268)

• Aldosterone synthesized exclusively in zona glomerulosa
• Primary regulation: Renin-Angiotensin-Aldosterone System (RAAS) and serum K+
• ACTH plays minor short-term role only
• Actions: Na+ retention, K+ and H+ excretion in collecting duct (via ENaC, Na+/K+-ATPase)

8b. Definition & Epidemiology

• Autonomous aldosterone production independent of RAAS
• Most common cause of secondary hypertension (5–10% of hypertensive patients)
• Causes: Aldosterone-producing adenoma (Conn's adenoma, ~35%), bilateral adrenal hyperplasia (idiopathic hyperaldosteronism, ~60%), adrenal carcinoma (<1%), familial hyperaldosteronism

8c. Clinical & Biochemical Features

• Hypertension (often refractory, difficult to control)
• Hypokalemia (spontaneous or easily provoked by diuretics): muscle weakness, cramps, polyuria/polydipsia
• Metabolic alkalosis
• Sodium retention, expanded extracellular volume (edema usually absent — "escape phenomenon")
• No hyperpigmentation (ACTH is normal/suppressed)

8d. Diagnostic Tests (p. 2285–2292)

• Aldosterone-to-Renin Ratio (ARR): First-line screening test; ARR >20–40 ng/dL per ng/mL/h is suspicious; plasma aldosterone >15 ng/dL plus suppressed renin activity (<1 ng/mL/h) = highly suspicious

1. Fludrocortisone suppression test (p. 2289): Failure to suppress aldosterone to <4 ng/dL (111 pmol/L) on day 3 = primary aldosteronism (>95% sensitive and specific)
2. Saline infusion test (Box 56.8, p. 2290): 2 L isotonic saline IV over 4 h; post-infusion aldosterone >10 ng/dL (280 pmol/L) = positive
3. Captopril challenge test (Box 56.9, p. 2290): ARR >200 ng/dL per ng/mL/h or aldosterone >12 ng/dL after captopril = primary aldosteronism (70–90% sensitive, 70–100% specific)

• Adrenal CT/MRI (first step for lateralization)
• Adrenal vein sampling (AVS) (p. 2292): Gold standard for lateralization — differentiates unilateral adenoma (surgically curable) from bilateral hyperplasia (medical management)

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9. Congenital Adrenal Hyperplasia (CAH) (p. 2277–2282)

9a. Overview (p. 2277)

• Autosomal recessive; deficiency of one of the enzymes in the cortisol biosynthetic pathway
• Cortisol deficiency → loss of negative feedback → pituitary ACTH ↑ → adrenal hyperplasia + accumulation of precursors proximal to the enzyme block
• 21-Hydroxylase deficiency: 95% of all CAH
• 11β-Hydroxylase deficiency: ~5% of all CAH
• Rare: 3β-HSD deficiency, 17α-hydroxylase deficiency, StAR deficiency, CYP11A1 deficiency

9b. 21-Hydroxylase Deficiency (CYP21A2) (p. 2278–2280)

• CYP21A2 converts progesterone → 11-deoxycorticosterone (DOC) and 17-OHP → 11-deoxycortisol (11-DC)
• Deficiency → accumulation of progesterone and 17-OHP (key diagnostic marker) → shunted to androgen pathway → excess adrenal androgens (androstenedione, DHEA)

• Females: Ambiguous genitalia at birth (androgen-induced virilization in utero)
• Males: May not be apparent until precocious puberty

• Serum 17-OHP: >1000 ng/dL (30 nmol/L) in classic form; 5–10× normal androstenedione
• Neonatal screening: 17-OHP measurement (most developed countries)
• 11-DC and 11-DOC are depressed in 21-OH deficiency (vs. elevated in 11β-OH deficiency)
• CYP21A2 gene overlaps TNXB (tenascin-X gene) → up to 10% of salt-wasting CAH patients also have Ehlers-Danlos syndrome features (p. 2278)

9c. 11β-Hydroxylase Deficiency (CYP11B1) (p. 2280–2281)

• Converts 11-deoxycortisol → cortisol; deficiency → glucocorticoid deficiency but not salt-wasting
• 11-DOC accumulates → mineralocorticoid activity → hypertension + hypokalemia (paradoxical mineralocorticoid hypertension, unlike 21-OH deficiency)
• Aldosterone levels usually normal
• Elevated 11-DOC and 11-DC; 17-OHP may also be elevated but less than in 21-OH deficiency
• Diagnosis: elevated serum 11-deoxycortisol (compound S)

9d. Rare Forms

• 3β-HSD deficiency: Elevation of Δ5 steroids (pregnenolone, 17-OH-pregnenolone, DHEA); salt wasting + incomplete virilization in males + virilization in females
• 17α-Hydroxylase deficiency: Accumulation of mineralocorticoid precursors (DOC, corticosterone) → hypertension, hypokalemia; absent sex steroids → sexual infantilism; no cortisol, no sex steroids
• StAR protein deficiency (Lipoid CAH): Most severe; no steroid synthesis; adrenal lipid accumulation

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PART II-B — ADRENAL MEDULLA

10. Pheochromocytoma (p. 2091–2110; Chapter 53)

10a. Definition & Classification (p. 2091)

• Pheochromocytoma: Catecholamine-producing tumor of adrenal medulla chromaffin cells
• Paraganglioma: Extra-adrenal chromaffin tumors (sympathetic or parasympathetic)
• 85% adrenal, 15% extra-adrenal (organ of Zuckerkandl most common extra-adrenal site)
• WHO classification: distinguishes adrenal pheochromocytoma from extra-adrenal paraganglioma

10b. Epidemiology (p. 2092)

• Incidence: 2–5 cases per million per year; prevalence 0.015–0.04% during life (autopsy prevalence ~0.1%)
• 0.2–0.6% prevalence among unselected hypertensive patients
• "Rule of 10s" (historical): 10% malignant, 10% bilateral, 10% extra-adrenal, 10% familial, 10% in children (now outdated — up to 30–40% have germline mutations)

10c. Genetic Associations (p. 2093)

• Up to 30–40% of pheochromocytomas are hereditary:
  • MEN2A & MEN2B: RET proto-oncogene mutations
  • von Hippel-Lindau (VHL): mainly norepinephrine-producing
  • Neurofibromatosis type 1 (NF1): NF1 gene
  • Hereditary paraganglioma-pheochromocytoma syndromes: SDH subunit mutations (SDHA, SDHB, SDHC, SDHD)
  • MAX, TMEM127, H3F3A mutations

10d. Catecholamine Biochemistry (Chapter 53, p. 2082)

• Biosynthetic pathway: Tyrosine → DOPA (by tyrosine hydroxylase, rate-limiting) → Dopamine → Norepinephrine (by DBH in chromaffin granules) → Epinephrine (by PNMT in adrenal medulla — requires high local cortisol from adrenal cortex)
• Storage: Chromaffin granules (contain catecholamines + chromogranin A + ATP + neuropeptides)
• Chromaffin reaction: Brown oxidation product with potassium dichromate, osmium tetroxide
• Metabolism: catecholamines → metanephrines (by COMT) and normetanephrines → VMA (vanillylmandelic acid by MAO) and metanephrines
• Key insight: Metanephrines are produced continuously within the tumor (not just during secretory episodes) → better diagnostic sensitivity than catecholamines

10e. Clinical Features (Table 63.7, p. 2092)

• Classic triad: Episodic headaches, palpitations, diaphoresis (sweating)
• Hypertension: sustained (50%) or paroxysmal (25%) — the "great mimic"
• Associated: tachycardia, pallor, anxiety/nervousness, weight loss, hyperglycemia (fasting), tremor, postural hypotension, constipation
• Hypertensive crisis: can be precipitated by contrast dye, beta-blockers (unopposed α), surgery, palpation, certain drugs

10f. Biochemical Diagnosis (p. 2094–2105)

• First-line test (preferred): Plasma free metanephrines (metanephrine + normetanephrine) — highest sensitivity (~99%) for adrenal pheochromocytoma
• Alternatively: 24-h urine fractionated metanephrines and catecholamines — high sensitivity (~97%)
• VMA (24-h urine vanillylmandelic acid): older test, lower sensitivity (~64%); now less recommended
• Chromogranin A: elevated in ~80%; useful tumor marker for monitoring; also elevated in paraganglioma
• Reference ranges:
  • Plasma free normetanephrine >0.9 nmol/L = suggestive
  • Plasma free metanephrine >0.5 nmol/L = suggestive
  • Values >4× ULN are virtually diagnostic
• Clonidine suppression test: Oral clonidine (0.3 mg) should suppress plasma catecholamines in normal subjects but not in pheochromocytoma; useful in borderline cases

10g. Localization

• CT/MRI of adrenals (first-line imaging once biochemistry confirms diagnosis)
• MIBG (metaiodobenzylguanidine) scintigraphy: Functional imaging; uptake via NE transporter; confirms catecholamine-secreting nature; used for metastatic/extra-adrenal disease
• Ga-68 DOTATATE PET: For SDH-mutated paragangliomas/pheochromocytomas

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PART III — THYROID GLAND

11. Thyroid Hormone Biochemistry & Physiology

11a. Structure of Thyroid Hormones (Table 57.1, p. 2304)

• T4 (thyroxine): 3,5,3',5'-tetraiodothyronine — 4 iodine atoms; major secretory product
• T3 (triiodothyronine): 3,5,3'-triiodothyronine — 3 iodine atoms; biologically active form (10× potency of T4)
• Reverse T3 (rT3): metabolically inactive (3,3',5'-triiodothyronine) — made from T4 by type 3 deiodinase; elevated in sick euthyroid syndrome

11b. Biosynthesis (p. 2304–2308)

• Iodine uptake: Sodium-iodide symporter (NIS) — active transport into follicular cells
• Thyroglobulin (Tg): Large glycoprotein (660 kDa); synthesized in follicular cells; secreted into follicular lumen; serves as scaffold for thyroid hormone synthesis
• Thyroid peroxidase (TPO): Key enzyme — catalyzes (1) iodination of thyroglobulin tyrosine residues (organification) and (2) coupling of iodotyrosines to form T3 and T4
• Formation: MIT + DIT → T3; DIT + DIT → T4
• Proteolysis of Tg: Releases T3, T4 (and MIT, DIT which are deiodinated and recycled)
• Peripheral conversion: T4 → T3 (active) by 5'-deiodinase in liver, kidney, and peripheral tissues (~80% of circulating T3)

11c. Transport in Plasma (p. 2308)

• Thyroxine-binding globulin (TBG): Main carrier (~70% of T4 and T3)
• Transthyretin (TTR): ~15%
• Albumin: ~15%
• Only free (unbound) fractions are biologically active: fT4 (~0.02% of total T4), fT3 (~0.3% of total T3)

11d. Regulation: HPT Axis (p. 2304)

• Hypothalamus → TRH → anterior pituitary → TSH → thyroid → T4/T3
• T4 and T3 exert negative feedback on both hypothalamus (minor) and pituitary (major — via THRB-2 receptor)
• TSH is the most sensitive indicator of thyroid hormone status — small changes in fT4 produce 10-fold changes in TSH (log-linear relationship)

11e. Biological Functions of Thyroid Hormones (p. 2304)

1. Control of basal metabolic rate and calorigenesis
2. Enhancement of mitochondrial oxidative phosphorylation
3. Stimulation of neural development and myelination (critical in utero and first 2 years)
4. Promotion of linear growth and skeletal maturation
5. Stimulation of adrenergic activity (↑ HR, ↑ cardiac contractility)
6. Stimulation of protein synthesis and carbohydrate metabolism
7. Increasing synthesis and degradation of cholesterol and triglycerides
8. Enhancing sensitivity of adrenergic receptors to catecholamines
9. Increasing calcium and phosphorus metabolism

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12. Hyperthyroidism (Thyrotoxicosis)

12a. Definition & Distinction

• Thyrotoxicosis: Clinical syndrome of excess thyroid hormone from any source
• Hyperthyroidism: Specifically, excess hormone production by the thyroid gland
• Biochemical: elevated fT4 and/or fT3 + suppressed TSH

12b. Causes (p. 2314–2315)

• Graves disease (most common — autoimmune) — TSH receptor-stimulating antibodies (TRAb)
• Toxic multinodular goiter (Plummer disease)
• Toxic adenoma (autonomously functioning nodule)
• hCG-induced (gestational thyrotoxicosis, trophoblastic tumors) — hCG has TSH-like activity
• Secondary hyperthyroidism (TSH-secreting pituitary tumor — rare)
• Struma ovarii (ovarian teratoma with thyroid tissue)

• Iodine-induced (Jod-Basedow phenomenon; amiodarone)
• Thyrotoxicosis factitia (exogenous T4/T3 ingestion)
• Subacute (de Quervain) thyroiditis: transient release phase

12c. Graves Disease (p. 2318–2320)

• Most common cause of hyperthyroidism (60–80% in iodine-sufficient areas)
• Autoimmune: TSH receptor antibodies (TRAb/TSI) bind and activate TSHR → autonomous stimulation of thyroid
• Thyroid autoantigen targets: TSHR (primary), TPO, Tg
• Both B and T lymphocytes involved; associated with HLA-DR3 and HLA-B8
• Distinctive features: Exophthalmos (proptosis), pretibial myxedema (dermopathy), acropachy — due to TSH receptor expression on orbital fibroblasts
• Laboratory: suppressed TSH, elevated fT4 and fT3, positive TSI/TRAb, elevated anti-TPO/anti-Tg in many patients

12d. Clinical & Biochemical Features of Thyrotoxicosis (Box 57.5, p. 2316)

• Cardiovascular: Palpitations, tachycardia, atrial fibrillation (highest morbidity/mortality risk), systolic hypertension, ↑ cardiac output, peripheral vasodilation, cardiac failure in susceptible
• Metabolic: Weight loss despite increased appetite, heat intolerance, ↑ BMR, diaphoresis
• Neuromuscular: Fine tremor, anxiety, hyperactivity, proximal myopathy, hyperreflexia
• GI: Hyperdefecation, shortened bowel transit time, nausea/vomiting
• Endocrine: Menstrual irregularity (oligo/amenorrhea), reduced fertility, gynecomastia in males
• Bone: Osteoporosis (↑ osteoclastic activity via thyroid hormone)
• Thyroid storm: Life-threatening — fever, extreme tachycardia, agitation, delirium, cardiac failure; Burch-Wartofsky score for diagnosis

12e. Laboratory Diagnosis (p. 2316)

• TSH: Suppressed (<0.1 mIU/L) — most sensitive initial test
• Free T4 and Free T3: Elevated (total T4/T3 less reliable due to binding protein changes)
• TRAb (TSI): Sensitive and specific for Graves disease; important in pregnancy
• Anti-TPO and anti-Tg: Elevated in Graves (and Hashimoto); not specific for cause
• Radioiodine uptake (RAIU): Elevated in Graves/toxic nodules; low in thyroiditis/factitia
• T3 toxicosis: isolated T3 elevation with suppressed TSH and normal T4 (early or mild Graves)

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13. Hypothyroidism

13a. Causes (p. 2314; Box 57.3)

• Autoimmune (Hashimoto thyroiditis): Most common in iodine-sufficient areas
• Iodine deficiency: Most common cause worldwide
• Post-thyroidectomy (thyroid cancer treatment)
• Post-radioiodine therapy
• Drugs: Lithium, amiodarone, antithyroid drugs (propylthiouracil, methimazole), excess iodine
• Congenital hypothyroidism: thyroid aplasia/dysplasia, TPO mutations, NIS mutations, pendrin deficiency (Pendred syndrome), dyshormonogenesis
• Riedel thyroiditis (fibrous replacement)

• Pituitary tumors (macroadenomas, craniopharyngiomas, meningiomas) — p. 2316
• Post-pituitary surgery or irradiation
• Sheehan syndrome (postpartum pituitary necrosis)
• Anti-POU1F1 (anti-PIT-1) antibody — acquired combined pituitary hormone deficiency (p. 2316)

13b. Hashimoto Thyroiditis (p. 2315–2316)

• Most common thyroid disease in iodine-sufficient areas
• Chronic lymphocytic thyroiditis: T-cell mediated destruction of follicular cells
• Histology: lymphocyte/plasma cell infiltration; secondary lymphoid follicles; Hürthle cell change (oxyphilic cells)
• Biochemical markers: anti-TPO antibodies (90% positive); anti-Tg antibodies (20–50%)
• Ultrasound: hypoechoic, heterogeneous gland; may present as goiter (initially) or atrophy
• Associations: primary B-cell lymphoma of thyroid; increased risk of papillary carcinoma
• Treatment monitoring: TSH (target normalization)

13c. Clinical & Biochemical Features (p. 2316–2317)

• Metabolic: Weight gain (fluid retention, reduced BMR), cold intolerance, fatigue, bradycardia
• Cardiovascular: Bradycardia, diastolic hypertension, pericardial effusion (up to 50%), cardiomegaly, diastolic dysfunction; risk of congestive cardiac failure in severe hypothyroidism
• GI: Constipation, reduced GI motility, gallstones (gallbladder hypotonia), anorexia
• Neuropsychiatric: Depression, poor concentration, cognitive dysfunction, psychosis (myxedema madness); carpal tunnel syndrome; cerebellar ataxia
• Musculoskeletal: Myalgia, proximal myopathy, arthralgia; elevated CK (loss of striations + fiber edema)
• Skin: Non-pitting edema/myxedema (glycosaminoglycan deposition — hyaluronic acid in dermis); coarse, dry skin; hair loss; macroglossia; periorbital puffiness
• Reproductive: Menorrhagia, anovulation, hyperprolactinemia (TRH ↑ → prolactin ↑)
• Neonatal: Cretinism if untreated — irreversible mental retardation, growth failure, prolonged neonatal jaundice (immature UDP-glucuronyltransferase)
• Myxedema coma: Severe hypothyroidism — hypothermia, coma, hypoventilation, hyponatremia; life-threatening emergency

13d. Laboratory Diagnosis (p. 2316–2319)

• TSH: Elevated (primary hypothyroidism) — most sensitive test; first-line
• Free T4: Decreased in overt hypothyroidism
• T3/fT3: May be normal until late stages (maintained by ↑ T4 → T3 conversion)
• Subclinical hypothyroidism: TSH elevated, fT4 normal — treat if TSH >10 mIU/L or symptomatic
• Central hypothyroidism: TSH low/normal + low fT4 — use fT4 for monitoring (NOT TSH)
• Anti-TPO antibodies: elevated in Hashimoto; risk marker for progression to overt hypothyroidism
• Other findings: Hypercholesterolemia, elevated LDL, elevated CK, hyponatremia, macrocytic anemia

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14. Goitre (Goiter)

14a. Definition & Classification (p. 2315)

• Simple/Non-toxic diffuse goiter: Thyroid enlargement without functional abnormality; most commonly due to iodine deficiency (endemic goiter; iodine intake <50 μg/day)
• Toxic goiter: Goiter with hyperthyroidism (Graves disease, Plummer disease/toxic multinodular goiter)
• Multinodular goiter: Multiple nodules; may be toxic or non-toxic
• Compensatory enlargement: inadequate T4 synthesis → ↑ TSH → gland hypertrophy

14b. Biochemistry of Iodine Deficiency

• Iodine <50 μg/day → impaired thyroid hormone synthesis → TSH ↑ → glandular hyperplasia
• Severe deficiency: hypothyroidism, cretinism in neonates
• Iodine excess: can also suppress thyroid function (Wolff-Chaikoff effect — transient) or precipitate hyperthyroidism in pre-existing nodules (Jod-Basedow)

14c. Nodular Thyroid Disease & Risk Assessment (p. 2328)

• Prevalence: palpable nodules ~5%; ultrasound nodules 13–30%; autopsy 49–57%
• Risk of cancer in a solitary nodule: ~5%; lower in multinodular goiter
• Risk factors for malignancy: young age/elderly, male sex, radiation exposure, family history, rapid growth, hard/irregular texture, cervical lymphadenopathy
• Key biochemical test: Serum TSH — suppressed TSH → autonomous nodule (low malignancy risk; may need treatment for thyrotoxicosis); normal/high TSH → FNA biopsy

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15. Thyroid Cancer (p. 2328–2330; Chapter 57)

15a. Epidemiology (p. 2328)

• Rare cause of cancer death (<0.4% in USA); female:male = 3:1
• Increasing incidence (partly overdiagnosis from high-resolution imaging)
• Mortality has remained stable despite rising incidence

15b. Classification (p. 2328)

• Papillary + follicular = differentiated thyroid carcinoma (DTC) — accounts for >90% (p. 2328)
• MTC: 80% sporadic; 20% hereditary (MEN2A, MEN2B, familial MTC)

15c. Key Biochemical Markers (p. 2328–2330)

• Serum Tg (Thyroglobulin): Primary tumor marker for post-thyroidectomy monitoring; Tg should be undetectable after total thyroidectomy + radioiodine ablation — any detectable Tg = residual/recurrent disease
  • Not recommended for preoperative diagnosis (not sensitive/specific enough)
  • Anti-Tg antibodies: Interfere with Tg measurement (falsely low); must be measured simultaneously
• TSH suppression therapy: Post-thyroidectomy — exogenous T4 to suppress TSH (TSH is trophic for DTC); monitor fT4, fT3, TSH; fT3 useful to ensure patient is not overtly hyperthyroid
• Stimulated Tg: After withholding T4 (or after rhTSH stimulation) — increases sensitivity for detecting recurrence

• Serum Calcitonin: Specific marker — produced by C-cells; correlates with tumor burden; used for screening in RET mutation carriers; pentagastrin/calcium stimulation test for early detection
• CEA (carcinoembryonic antigen): Less specific; elevated in advanced MTC; CEA doubling time (with calcitonin doubling time) predicts prognosis

• No specific useful serum marker; FNA/histopathology is diagnostic

• Genetic testing: RET proto-oncogene mutations (codons 609, 611, 618, 620 in exon 10; codon 634 exon 11 for MEN2A; codon 918 exon 16 for MEN2B)
• Prophylactic thyroidectomy in RET mutation carriers

15d. Role of Clinical Biochemistry in Thyroid Cancer Management (p. 2329)

1. TSH measurement at initial evaluation of thyroid nodule
2. Post-thyroidectomy TSH suppression monitoring (fT4, fT3, TSH)
3. Serum Tg + anti-Tg antibody for follow-up of DTC
4. Stimulated Tg testing for recurrence detection
5. Calcitonin and CEA for MTC monitoring
6. RET genetic testing in hereditary MTC families

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PART IV — INTEGRATION AND OVERVIEW

16. Summary: Key Biochemical Markers at a Glance

17. Suggested Seminar Flow

1. Introduction — hypothalamic-pituitary regulation (overview of all axes) → 5 min
2. Pituitary disorders — DI, SIADH, Cushing disease → 15–20 min
3. Adrenal cortex — biochemistry of steroidogenesis → Cushing, Addison, Conn's, CAH → 30–35 min
4. Adrenal medulla — catecholamine biochemistry → pheochromocytoma → 15 min
5. Thyroid — hormone biosynthesis/transport → Graves, Hashimoto, goiter, thyroid cancer → 25–30 min
6. Biochemical marker summary table + diagnostic algorithm review → 5–10 min

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Reference Index (Tietz Textbook of Laboratory Medicine, 7th Edition)

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