Endocrine Pathology

ENDOCRINE PATHOLOGY Presented by Voltaire C. Yabut, M.D. DPSP

PITUITARY GLAND -

A pea-sized gland, weighs 0.5 gm & measures 1cm, attached to the hypothalamus by a stalk

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Two lobes: anteroir & posterior

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Anterior lobe (adenohypophysis) - derived from Rathke’s pouch - contains cells that secrete trophic hormones that activate peripheral endocrine glands - hypothalamic releasing hormones are delivered via a portal venous system

PITUITARY GLAND (CONT.) - Posterior lobe (neurohypophysis) - derived from outpouching from floor of 3rd ventricle - has a separate blood supply - consists of modified glial cells & axons extending from the supraoptic & paraventricular nuclei in the hypothalamus - neurons in the supraoptic & paraventricular nuclei produce ADH & oxytocin - ADH & oxytocin are stored in axon terminals in the post. lobe

THE ADENOHYPOPHYSIS - Five cell types in the adenohypophysis by immunostaining: 1- Lactotrophs (Mammotrophs): Prolactin (Prl) - acidophils. 2- Somatotrophs: growth hormone (GH) - acidophils. 3- Corticotrophs: proopiomelanocortin (POMC) precursor for adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH), β-endorphin, and β-lipotropin - basophils. 4- Thyrotrophs: thyroid stimulating hormone (TSH) - basophils. 5- Gonadotrophs: follicle stimulating hormone (FSH) & luteinizing hormone (LH) - basophils.

Hypothalamic Releasing Hormone

Corresponding Anterior Pituitary Hormone(s)

Gonadotropin Releasing Hormone (GnRH)

Luteinizing Hormone (LH) Follicular Stimulating Hormone (FSH)

Growth Hormone Releasing Hormone (GRH)

Growth Hormone (GH)

Corticotropin Releasing Hormone (CRH)

Adrenocorticotropic Hormone (ACTH)

Thyrotropin Releasing Hormone (TRH)

Thyroid Stimulating Hormone (TSH)

Dopamine

Prolactin (PRL)

Green = stimulatory Red = inhibitory

DISEASES OF THE ADENOHYPOPHYSIS − −

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⇑ function: Hyperpituitarism ⇓ function: Hypopituitarism - nonfunctional adenoma - inflammatory lesions - ischemic injury mass effects - enlargement of sella turcica - visual field defects (classically bitemporal hemianopsia) − ⇑ intracranial pressure - headache, blurring of vision - nausea and vomiting

CAUSES OF HYPERPITUITARISM 1 - Primary hypothalamic disorders (rare) 2 - Primary Pituitary Hyperplasia (rare) 3 - Functioning carcinomas (extremely rare) 4 - Functioning Adenomas (MCC). Classified as: 1. Prolactinomas (Prl) 2. Somatotroph (GH) adenomas 3. Corticotroph (ACTH) adenomas 4. Gonadotroph (FSH/LH) adenomas 5. Thyrotroph (TSH) adenomas 6. Pleurihormonal adenomas (GH+Prl). Monoclonal but polyhormonal, or mixed-cell adenomas.

HYPERPROLACTINEMIA (amenorrhea-galactorrhea syndrome) The MC pituitary hyperfunction syndrome. Caused by: 1- Prolactinomas; - Prl secreting adenoma (sparsely granulated, chromophobic) - F/M >1, peak incidence 20-30 yrs. of age - serum prolactin level > 300 ug/L is diagnostic - Rx: surgery (transsphenoidal) bromocriptine (dopamine receptor agonist) radiation 2- Hypothalamic diseases. Hypothalamus normally produces dopamine (Prl-inhibitory factor). - head trauma, etc. - stalk effect

HYPERPROLACTINEMIA (cont.) 3- Anti-dopaminergic drugs (phenothiazines, haloperidol) 4- Estrogen therapy 5- Primary Hypothyroidism (⇑ TRH ⇒ ⇑ Prl) Signs & Symptoms: - women: galactorrhea, amenorrhea, infertility, ⇓ libido - men: ⇓ libido, impotence & rarely galactorrhea & gynecomastia

SOMATOTROPH ADENOMAS Acromegaly; - adult onset excess growth hormone (GH) ⇒ enlargement of the skull, facial bones, jaw, hands, feet, soft tissues & organs. - diabetes, hypertension, muscle weakness, arthritis, gonadal dysfunction, cardiovascular disease Gigantism; - GH excess occurs in children (before closure of epiphyses). - generalized increase in body size - disproportionately long arms and legs - Morphology: macroadenomas, composed of densely or sparsely granulated “acidophilic” cells, strongly positive for GH by immunostains.

SOMATOTROPH ADENOMAS (cont.) - 30% elaborate both GH and Prl (a mixed cell adenoma or a single cell-type pleurihormonal adenoma). - 40% express the gsp oncogene - GH acts indirectly by ⇑ hepatic secretion of insulin-like growth factor-1 (IGF-1) - Diagnosis: - ⇑ serum GH & IGF-1 - serum prolactin may be elevated - glucose suppression test - imaging scans (MRI better than CAT scan) - Treatment: - transsphenoidal surgery, octreotide acetate, radiation

CORTICOTROPH ADENOMAS - MC small basophilic microadenomas that secrete ACTH Cushing’s disease. − ⇑ ACTH ⇒ ⇑ secretion of cortisol from the adrenal glands moon face, buffalo hump, truncal obesity, abdominal striae - diabetes mellitus, hirsutism and amenorrhea (ACTH stimulates androgen secretion) - increased skin pigmentation (MSH is secreted with pituitary ACTH) - hypertension, muscle weakness Diagnosis: - 24 hr urine for free cortisol & 17-hydroxycorticosteroids - plasma ACTH level - dexamethasone suppression test - MRI scan

Dexamethasone Suppression Test Pathologic Entity

Low Dose

High Dose

ACTH Secreting Pituitary Adenoma Cortisol Secreting Adrenocortical Neoplasm

– – –

+ – –

ACTH Secreting Nonendocrine Neoplasm –– = does not suppress + = does suppress

OTHER FUNCTIONING ADENOMAS -

Gonadotroph adenomas: - majority produce FSH, some FSH & LH, rarely only LH - MC occur in middle-aged men & women - usually are macroadenomas - symptoms MC related only to local mass effects - may cause amenorrhea or galactorrhea, ⇓ libido in men

- Thyrotroph adenomas: produce TSH ⇒ hyperthyroidism

HYPOPITUITARISM Caused by either hypothalamic or pituitary lesions: Hypothalamic lesions: craniopharyngioma, gliomas & teratomas;. metastatic carcinoma, infections Pituitary lesions: MCCs are: nonsecretory adenomas, Sheehan’s syndrome, radiation or surgical ablation (of ≥ 75% of the gland) LCCs are: metastatic carcinoma, inflammatory disorders, infections, genetic defects (pit-1) Effects: - Isolated hormone deficiencies (e.g. GH or LH) - Panhypopituitarism: in children ⇒ dwarfism & infantilism (retarded physical & sexual development) & in adults ⇒ hypogonadism, hypothyroidism & hypoadrenalism

HYPOTHALAMIC (SUPRASELLAR) NEOPLASMS 1- Craniopharyngioma (MC) 2- Gliomas 3- Germ cell tumors ⇒ mass effect ⇒ hypopituitarism &/or diabetes insipidus. Craniopharyngioma: - Accounts for 3- 5% of intracranial tumors - MC in the 2nd & 3rd decades - derived from vestigial remnants of Rathke’s pouch - arise in hypothalamus, may encroach on optic chiasm - benign, contain epithelial elements, often cystic with calcification - rupture of cystic tumors ⇒ inflammatory reaction

NON-SECRETORY ADENOMAS - 20% of pituitary adenomas - MC in 4th decade of life - May grow to a large size (macroadenomas = >1 cm). - ⇒ local mass effect (headache & visual disturbances), and panhypopituitarism (hypogonadism, hypothyroidism & hypoadrenalism). Histologically: - most consist of chromophobic cells or intensely eosinophilic cells (oncocytomas) - usually are sparsely granular - often stain negative for hormones with immunostains

SHEEHAN’S SYNDROME = Post-partum ischemic necrosis of the anterior pituitary. Precipitated by obstetric hemorrhage or shock ⇒ destruction of ≥ 75% of the gland. Pedisposing factors: - Anterior pituitary doubles in size during pregnancy - low pressure portal system unable to ⇑ blood supply - abrupt onset of hypotension ⇒ hypoperfusion ⇒ infarction. Morphology: Early: gland is swollen, soft & hemorrhagic. Later: replaced by a shrunken fibrous scar. Effects: Failure of lactation, amenorrhea, hypothyroidism, hypoadrenalism & decreased skin pigmentation. Posterior lobe: usually is not affected

POSTERIOR PITUITARY SYNDROMES ADH Deficiency (Diabetes Insipidus): − ⇓ ADH ⇒ decreased reabsorption of free water - urine of low specific gravity, with inability to concentrate it - polyuria, polydypsia and hypernatremia - caused by hypothalamic or pituitary lesions; idiopathic - corrected readily by ADH administration. Inappropriate ADH Secretion (SIADH): − ⇑ ADH ⇒ excessive reabsorption of free water - oliguria, urine of high specific gravity, with inability to dilute it, and hyponatremia - due to a compensatory ⇑ in ANP ⇒ no hypervolemia, no ⇑ BP and no peripheral edema - neurologic dysfunction: most likely 20 to hyponatremia - MCC is ectopic ADH secretion by a small cell carcinoma of the lung

THYROID GLAND - Embryology: - the thyroid develops from the primitive pharynx - the developing thyroid is attached to the base of the tongue by the thyroglossal duct - the thyroid descends in the midline & assumes its final position in the anterior neck below the larynx - excessive descent gives rise to a substernal thyroid & incomplete descent ⇒ ectopic thyroid higher in the neck or tongue - persistence of remnants of the thyroglossal duct can ⇒ thyroglossal duct cyst

Physiologic Effects of Thyroid Hormones • ⇑ gluconeogenesis, glycogenolysis, lipolysis & ATPase’s • ⇒ ⇑ basal metabolic rate & heat production • ⇑ protein catabolism • ⇒ muscle wasting, osteoporosis • ⇑ sympathetic activity • ⇒ tachycardia & arrythmias

HYPERTHYROIDISM = a hypermetabolic state, caused by increased levels of circulating T3 & T4. Effects: nervousness, warm moist skin, fine tremors, palpitations, rapid pulse, exophthalmos, weight loss, heat intolerance, muscle atrophy & weakness, osteoporosis Most Common Causes: Graves’ disease, toxic multinodular goiter, toxic adenoma Less Common Causes: - thyroiditis, struma ovarii, toxic carcinoma - TSH-secreting pituitary adenoma - overtreatment with thyroid hormone tablets (factitious hyperthyroidism)

HYPOTHYROIDISM = a hypometabolic state caused by deficiency of T3 & T4. Cretinism (congenital hypothyroidism) - Clinical: - severe mental retardation - short stature - coarse facial features, protruding tongue - Causes: - Endemic - due to dietary iodine deficiency - Sporadic - thyroid dysgenesis - inherited defects in thyroid hormone synthesis - inherited peripheral tissue resistance to thyroid hormone

HYPOTHYROIDISM (cont.) Myxedema (hypothyroidism in adults) - fatigue, lethargy, slowed speech, mental sluggishness - cold intolerance, weight gain, constipation - ⇓ sweating, bradycardia - accumulation of ECM substances (glycosaminoglycans) - coarsening of facial features, nonpitting edema Causes: - MCC is Hashimoto’s thyroiditis. - surgical ablation or radiation - iodine deficiency - drugs (e.g. propylthiouracil, lithium) - idiopathic primary hypothyroidism - hypothalamic & pituitary disorders

HASHIMOTO’S THYROIDITIS - MCC of hypothyroidism in areas where iodine intake is adequate Clinically: seen predominately in middle-aged women - hypothyroidism with painless enlargement of the gland - may have transient thyrotoxicosis early on - familial predisposition, associated with HLA-DR3 or HLA-DR5 Pathogenesis: defective function of thyroid-specific suppressor T cells ⇒ emergence of helper T cells reactive with thyroid antigens - helper T cells stimulate B cells to secrete antithyroid antibodies, directed against: thyroid peroxidase, TSH-receptors, iodine transporter, & thyroglobulin, etc. - thyroid injury is mediated by complement fixing cytotoxic antibodies, ADCC & CD8+ cytotoxic cells

GRAVES’ DISEASE Clinical: - MCC of hyperthyroidism, peak incidence 20-40 yrs. of age - a disease of females (F/M 10:1), affects 1-2% of women in US - hyperthyroidism, symmetrical thyroid enlargement - opthalmopathy and dermopathy (pretibial myxedema) - familial predisposition, associated with HLA-B8 & HLA-DR3 - Laboratory values: ⇑ T3 & T4, ⇓ TSH and ⇑ radioactive iodine uptake

GRAVES’ DISEASE (cont.) Pathogenesis: - An abnormality in T-suppressor cells ⇒ T-helper cells that react to thyroid Ag’s ⇒ elaboration of B-cell clones capable of producing autoantibodies reactive with TSH receptors. - IgG antibodies directed against TSH receptors, act as agonists ⇒ ⇑ thyroid hormone secretion. - The autoantibodies were originally called long acting thyroid stimulator (LATS), because the peak secretion of thyroid hormone occurs 16 hours after the exposure of thyroid tissue to antibody, compared with 2 hours for TSH. Therapy: − β-blockers, propylthiouracil, potassium iodide, radioiodine ablation, surgery

GOITER = enlargement of the thyroid, MC manifestation of thyroid disease ⇓ hormone synthesis ⇒ ⇑ TSH ⇒ hyperplasia & hypertrophy of follicular cells ⇒ gross enlargement - Diffuse nontoxic goiter: - endemic - iodine deficiency - goitrogens (e.g. cabbage, cauliflower, turnips, cassava root) -

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sporadic - goitrogens - hereditary defect in thyroid hormone synthesis Clinical: most patients are euthyroid

MULTINODULAR GOITER = nodular enlargement, derived from diffuse goiter - both monoclonal & polyclonal nodules (adenomatous goiter) Clinical: - most patients are euthyroid - mass effects: compression of trachea, vessels & nerves, & dysphagia - hyperthyroidism (toxic multinodular goiter) - due to a hyperfunctioning nodule - not accompanied by opthalmopathy or dermopathy Morphology: massive enlargement (up to >2000 gm), nodules, with a mixture of hyperplastic & dilated follicles, involutional changes: hemorrhage, fibrosis, calcification & cystic degeneration

THYROID NEOPLASMS - Solitary nodules are more likely to be neoplastic. - Nodules in younger patients (< 40 years) & in males are more likely to be neoplastic. - Most neoplasms (>90%) are benign (adenomas). - Functioning (hot) nodules on scintiscans are usually benign - Up to 10% of cold nodules are malignant - Diagnosis can be made by fine needle aspiration biopsy, or else by surgical excision biopsy.

THYROID ADENOMA - adenomas account for > 90% of thyroid tumors - thyroid adenomas are not premalignant Gross: a sharply demarcated solitary nodule Histology: a fibrous capsule separates the neoplastic tissue from the surrounding compressed gland. Patterns may be: trabecular (embryonal), microfollicular (fetal) macrofollicular and Hurthle cell (oncocytic) adenomas - most commonly cold (nonfunctioning) on RI-scan - rarely hot (functioning) & may cause hyperthyroidism

THYROID CARCINOMA - uncommon in the US (~ 1.5% of all cancers). - major risk facrtor is exposure to radiation - Variants include: 1- papillary carcinoma 80% 2- follicular carcinoma 15% 3- medullary carcinoma 5% 4- anaplastic carcinoma rare

PAPILLARY CARCINOMA MC form of thyroid Ca - Peak incidence: 3rd-5th decades, F > M. - Gene rearrangement on chromosome 10 ⇒ constitutive expression of tyrosine kinase domain of RET protooncogene ⇒ papillary thyroid carcinoma oncogene (RET/PTC) - Often multifocal, spreads to lymph nodes in 50% of cases, but distant spread in only 5%. Gross: unencapsulated,infiltrative, often cystic with foci of fibrosis & calcification. Histology: papillary fronds, empty looking nuclei “Orphan Annie eye”, nuclear grooves & psammoma bodies. Variants: encapsulated, follicular, tall cell Prognosis: 90% survival at 20 years. -

FOLLICULAR CARCINOMA - peak incidence: 5th-6th decades, F > M. - incidence is ⇑ in areas of dietary iodine deficiency Gross: varies from well circumscribed to extensively invasive Histology: MC small uniform follicles containing colloid with capsular and vascular invasion (sure sign of malignancy). Variants: trabecular, Hurthle cell - spreads widely to distant organs: bones, lungs, liver, etc. - tumor tissue may take up radioactive iodine - patients often Rx’ed postop with thyroid hormones to ⇓ TSH Prognosis: depends on tumor stage, 25 to 45% 10-yr survival rate for widely invasive tumors

MEDULLARY CARCINOMA - Neuroendocrine tumor of C cells, secrete calcitonin - May also secrete: CEA, serotoin, somatostatin, VIP, ACTH, etc. - Sporadic or familial (associated with MEN IIa & IIb, etc., in 20% of cases) - Familial cases are associated with germ line mutations in RET Gross: sporadic cases: discrete tumor in one lobe, peak incidence 5th-6th decades. MEN-associated: multicentric & bilateral , peak 3rd-4th decades Histology: cell nests or trabeculae, amyloid deposits in the stroma, C cell hyperplasia, + for calcitonin, chromogranin, - for thyroglobulin Prognosis: overall 5-yr survival rate is 60 to 80%, survival rates are better in familial cases due to screening programs, serum calcitonin & CEA levels are monitored post-op

PARATHYROID GLANDS - There are usually four glands (they can be as many as 12), weighting 30 to 40 mg each, situated in close proximity to the upper and lower poles of each thyroid lobe - Histology: composed of chief cells (the majority) and fat cells. The chief cells may undergo transition to oxyphil cells (mitochondria), and water clear cells (glycogen). - chief cells secrete PTH - secretion of PTH is regulated by the level of free Ca++

PARATHYROID GLANDS (cont.) ⇑ PTH secretion ⇒ ⇑ serum Ca++ by: 1. increasing synthesis of 1,25-(OH)2D, thus enhancing absorption of calcium from GIT. 2. activating osteoclasts ⇒ mobilizing calcium from bone 3. increasing renal tubular reabsorption of calcium while increasing urinary phosphate excretion . Causes of hypercalcemia: • autonomous PTH hypersecretion • osteolytic metastases • PTH-related protein (PTHrP)

PRIMARY HYPERPARATHYROIDISM = -

autonomous hypersecretion of PTH. Accounts for up to 90% of cases of hypercalcemia. Peak incidence 6th decade & older, F > M. Most cases are sporadic, but few cases are familial (associated with MEN I & MEN IIA) Causes: 1- Parathyroid adenoma (80%), 2- Primary hyperplasia (15%), 3- Carcinoma (<5%).

PRIMARY HYPERPARATHYROIDISM (cont.)

Morphology: - Adenoma - solitary & encapsulated, may consist of any of the 3 cell types - remaining glands are normal to ⇓ in size - may be in an ectopic location - Hyperplasia - classically all 4 glands are involved - may be nodular or diffuse - Carcinoma - solitary, dense capsule, may exceed 10 gm - cytologic features are not reliable, presence of invasion or metastases required to make Dx

PRIMARY HYPERPARATHYROIDISM (cont.) Clinical Features: - asymptomatic - 90% are asymptomatic & discovered on routine blood tests - Ca++ & PTH levels are ⇑ - symptomatic - 10% are symptomatic - osteitis fibrosa cystica - bone pain, pathologic Fx’s - ⇑ bone resorption with expansile areas (brown tumors) - nephrolithiasis - metastatic calcification - GI Sx’s: constipaton, nausea, peptic ulcers, pancreatitis - CNS Sx’s: depression, lethargy, seizures - NM Sx’s: weakness, fatigue

SECONDARY HYPERPARATHYROIDISM = Compensatory hypersecretion of PTH due to hypocalcemia - renal failure - vit. D deficiency Morphology: - hyperplasia of all (4) parathyroid glands - skeletal changes of “renal osteodystrophy” - metastatic calcification Clinical: few cases develop “tertiary” hyperparathyroidism, looks identical to primary hyperplasia

HYPOPARATHYROIDISM = PTH deficiency & hypocalcemia - neuromuscular irritability (tetany): carpopedal spasm, laryngospasm, mental status changes, convulsions - cardiac conduction abnormalities - calcification of the eye lens (cataract) - calcification of the basal ganglia (Parkinsonism), ⇑ ICP (headache & papilledema). - MCC: surgical excision of all glands (during total thyroidectomy). LCC: congenital parathyroid agenesis (DiGeorge’s syndrome), primary (idiopathic) atrophy - autoimmune damage - Lab. data: ⇓ serum Ca++ & ⇓ serum PTH level.

PSEUDOHYPOPARATHYROIDISM (PHP) = Hypocalcemia and hyperphosphatemia, with: − ⇑ serum levels of PTH with hyperplasia of the parathyroid glands - no osteitis fibrosa cystica - no vitamin D deficiency or renal failure. Pathogenesis: end-organ resistance to PTH, i.e. kidneys & bone do not respond to PTH stimulation. Clinical Features: similar to hypoparathyroidism (tetany, etc.) PHP type 1 - ⇓ cyclic AMP response to PTH (deficiency of Gsα ) short stature, round face, short neck, short metacarpals & metatarsals (Albright hereditary osteodystrophy). PHP type 2 - normal cyclic AMP response to PTH, but with ⇓ response to cyclic AMP, phenotypically normal

PSEUDOPSEUDOHYPOPARATHYROIDISM - In PHP type 1, other family members may exhibit the physical features of Albright hereditary osteodystrophy (short stature, round face, short neck, short metacarpals & metatarsals) but are metabolically normal, with normal serum calcium & normal PTH, i.e. false (pseudo) pseudohypoparathyroidism.

ADRENAL GLAND - Composed of two distinct units: steroid secreting cortex & catecholamine producing medulla - In the adult, the normal adrenal weighs 4 gm. - The cortex consists of three functional zones: 1 - zona glomerulosa 2 - zona fasciculata (75% of the cortex) 3 - zona reticularis - The cortex secretes three types of steroid hormones: 1 - mineralocorticoids (aldosterone) - zona glomerulosa. 2 - glucocorticoids (cortisol) - zona fasciculata mainly. 3 - sex steroids (testosterone) - zona reticularis mainly.

ADRENAL GLAND Cortisol: - regulated by ACTH (& hypothalamic CRH) - inhibits release of CRH & ACTH - circulates in the blood bound to plasma proteins - free unbound cortisol is physiologically active & enters target cells by diffusion - binds to cytoplasmic receptors, then translocated into the nucleus where it binds to hormone-responsive elements altering expression of specific genes. Biologic effects: − ⇑ gluconeogenesis & ⇓ uptake of glucose by fat & muscle − ⇓ protein synthesis & ⇑ protein degradation − ⇑ vascular tone & some mineralocorticoid activity - anti-inflammatory & immunosuppressive effects

ADRENAL GLAND -

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Aldosterone: Accounts for 95% of mineralocorticoid activity. regulated by renin-angiotensin & potassium levels. aldosterone promotes reabsorption of sodium and excretion of potassium. excess aldosterone ⇒hypernatremia & hypokalemia ⇒ hypervolemia ⇒hypertension. Testosterone: Excess testosterone in females causes defemenization & virilization; (hirsutism, acne, amenorrhea, clitoral enlargement, atrophy of the breasts & uterus, deepening of the voice & frontal balding). In boys, excess testosterone leads to precocious puberty.

DISEASES OF ADRENAL CORTEX Hyperfunction (hyperadrenalism): - Cushing’s syndrome - Hyperaldosteronism - Adrenogenital syndromes Hypofunction (hypoadrenalism): - Acute (e.g. Waterhouse-Friderichsen Syndrome) - Chronic: - primary (due to adrenal cortical insufficiency, e.g. Addison’s disease) - secondary (due to ACTH deficiency) - tertiary (rarely - due to hypothalamic CRH deficiency).

CUSHING’S SYNDROME Etiology: 1- Exogenous: high dose cortisone therapy (MCC). 2- Pituitary hypersecretion of ACTH (Cushing’s disease), accounts for 70% of endogenous hypercortisolism. Associated with hyperpigmentation of the skin (↑ MSH). 3- Autonomous hypersecretion of cortisol by an adrenal adenoma, carcinoma or primary hyperplasia (i.e. ACTH independent). 4- Ectopic production of ACTH or CRH by nonendocrine neoplasms (bronchogenic small cell carcinoma).

CUSHING’S SYNDROME (cont.) Clinical features: truncal obesity, moon face, hirsutism, cutaneous striae, muscle weakness, osteoporosis, hypertension & hyperglycemia Changes are reversible if the cause is corrected. Morphology: • Cushing’s disease: ACTH is elevated ⇒ adrenals are bilaterally hyperplastic. Changes are the same with ectopic ACTH or CRH. • Adrenocortical neoplasms: uninvolved adrenal cortex is usually atrophic due to ACTH suppression. • Adenomas are small & cytologically bland appearing • Carcinomas are large & often anaplastic Diagnosis: 24 hr urine free cortisol, plasma ACTH, Dexamethasone Suppression Test

PRIMARY HYPERALDOSTERONISM = excessive secretion of aldosterone independent of reninangiotensin system. Features: hypervolemia, hypokalemia, hypertension, low renin Causes: - MCC is aldosterone-secreting adenoma (Conn’s syndrome) in 80% of cases - Bilateral idiopathic hyperplasia (? due to an abnormal secretagogue) - Glucorticoid-suppressible hyperaldosteronism: hybrid cells produce both cortisol & aldosterone, ⇑ aldosterone under influence of ACTH, suppressible by administration of dexamethasone Prognosis: adenomas are curable by surgery.

ADRENOGENITAL SYNDROMES Adrenogenital syndromes (ambiguous genitalia & virilism in females, and precocious puberty in males) can be caused by: 1- Androgen-secreting adrenal cortical neoplasms. 2- Congenital Adrenal Hyperplasia (CAH): - corticosteroid biosynthetic defect - MC 21-hydroxylase deficiency (90% of cases; autosomal recessive) ⇒ ⇓ cortisol ⇒ ⇓ feedback inhibition of ACTH ⇒ ⇑ ACTH levels ⇒ bilateral adrenocortical hyperplasia - aldosterone synthesis is MCly affected as well ⇒ salt wasting adrenogenitalism (⇓ Na+, ⇑ K+, hypovolemia) − ⇑ production of androgens

ACUTE ADRENOCORTICAL INSUFFICIENCY MCC is sudden withdrawal of corticosteroids in cases of longterm steroid therapy, or destruction of adrenals by massive hemorrhage Waterhouse-Friderichsen syndrome: - overwhelming meningococcal septicemia - DIC with widespread purpura (esp. skin) - rapidly progressive hypotension ⇒ shock - massive bilat. adrenal hemorrhage ⇒ acute adrenocortical insufficiency - ? causes of adrenal hemorrhage: DIC, endotoxin-induced vasculitis, bacterial seeding of small vessels - high mortality rate

CHRONIC ADRENOCORTICAL INSUFFICIENCY Primary (adrenal) or secondary (hypothalamic/pituitary): Primary (Addison’s disease): MCC: autoimmune adrenalitis; tuberculosis, metastatic cancers (⇒ destruction of ≥ 90% of the cortex) ⇒ decreased cortisol & aldosterone, with feedback elevation of ACTH (+ MSH) ⇒ hyperpigmentation of skin, ⇑ K+, ⇓ Na+, ⇓ BP, weakness, anorexia, N&V, hypoglycemia Secondary: to hypothalamic or pituitary lesions associated with decreased ACTH ⇒ bilateral adrenal cortical atrophy, sparing the zona glomerulosa (skin color is pale and aldosterone is normal, i.e. no sodium or potassium abnormalities).

ADRENAL MEDULLA -

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Composed of specialized neuroendocrine (chromaffin) cells, and is the major source of catecholamines: epinephrine & norepinephrine. Chromaffin cells secrete catecholamines in response to signals from preganglionic sympathetic nerve fibers. These cells can also secrete a wide variety of bioactive amines and peptides, such as: histamine, serotonin, & neuropeptide hormones. Clusters of similar neuroendocrine cells form the extra-adrenal paraganglia - closely associated with the autonomic nervous system. The branchiomeric (carotid bodies) & intravagal paraganglia are parasympathetic, and the aorticosympathetic (organs of Zuckerkandl) are sympathetic.

PHEOCHROMOCYTOMA = neoplasm composed of chromaffin cells that secretes catecholamines (0.1 - 0.3 % of all cases of hypertension) The “10 %” tumor: • 10 % extra-adrenal • 10 % familial • 10 % in children • 10 % bilateral in sporadic cases, but 70% bilat.in familial cases • 10 % malignant in adrenal cases, but up to 40% malignant in extra-adrenal cases Clinical effects: hypertension (paroxysmal), tachycardia, arrhythmias, tremors, sweating, sense of apprehension, attacks can be fatal Diagnosis: 24 hour urine for catecholamines; or metanephrines & vanillylmandelic acid (VMA)

MULTIPLE ENDOCRINE NEOPLASIA: MEN I (Wermer’s Syndrome) - heritable disorder caused by loss of a tumor suppressor gene on chromosome 11. 1. Parathyroid hyperplasia or adenoma (95%) ⇒ ⇑ Ca++ 2. Pancreatic Islet Cell tumors (75%) ⇒ excessive secretion of: - gastrin ⇒ peptic ulcers (Zollinger-Ellison syndrome) - insulin ⇒ hypoglycemia - serotonin ⇒ carcinoid syndrome - VIP ⇒ watery diarrhea 3. Pituitary adenoma (66%); MC prolactinoma, also GH & ACTH producing adenomas

MEN IIA (Sipple’s Syndrome) - inherited mutation in the RET protooncogene on chromosome 10. 1. C cell hyperplasia or Medullary thyroid carcinoma (100%) 2. Pheochromocytoma (50%), often bilateral and may arise in the extra-adrenal paraganglia 3. Parathyroid hyperplasia or adenoma (25%)

MEN IIB (Gorlin’s Syndrome) inherited mutation in the RET protooncogene on chromosome 10, different from that seen in MEN IIA - neoplasms are as in MEN IIA: 1- C cell hyperplasia or Medullary thyroid carcinoma (100 %) 2- Pheochromocytoma (34%) 3- Parathyroid hyperplasia or adenoma (4%) plus 4- Ganglioneuromas of the skin, eyes and mucous membranes of the mouth, GI tract, respiratory tract & bladder (100%) 5- Marfanoid body habitus (65%) --------------------------------------------------------------------------