Endocrine Pathology

Pathology (dr. Yabut) Endocrine Patholgy 09 January 08

PITUITARY GLAND A pea-sized gland, weighs 0.5 gm & measures 1cm, attached to the hypothalamus by a stalk  Two lobes: anteroir & posterior  Anterior lobe (adenohypophysis) -

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derived from Rathke’s pouch

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contains cells that secrete secrete trophic hormones that activate peripheral endocrine glands

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hypothalamic releasing hormones are delivered via a portal venous system 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 paraventricular nuclei in the hypothalamus neurons in the supraoptic & paraventricular nuclei produce produce ADH & oxytocin ADH & oxytocin are stored in axon terminals in the post. Lobe

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

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Hypothalamic Releasing Hormone Gonadotropin Releasing Hormone (GnRH) * Growth Hormone Releasing Hormone (GRH) * Corticotropin Releasing Hormone (CRH) * Thyrotropin Releasing Hormone (TRH) * Dopamine **

Corresponding Anterior Pituitary Hormone(s) Luteinizing Hormone (LH) Follicular Stimulating Hormone (FSH) Growth Hormone (GH)

Adrenocorticotropic Hormone (ACTH) Thyroid Stimulating Hormone (TSH) Prolactin (PRL)

* stimulatory ** inhibitory DISEASES OF THE ADENOHYPOPHYSIS ⇑ function: Hyperpituitarism

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⇓ function: Hypopituitarism

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nonfunctional adenoma

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inflammatory lesions

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ischemic injury mass effects -

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enlargement of sella turcica

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visual field defects (classically (classically bitemporal hemianopsia) -

⇑ intracranial pressure

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headache, blurring blurring of vision

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nausea and vomiting

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Pwets

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Pathology – Endocrine Pathology by  Pathology by  Dr.  Dr. Yabut 

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CAUSES OF HYPERPITUITARISM 1 2 3 4

- Primary hypothalamic disorders (rare) - Primary Pituitary Hyperplasia (rare) - Functioning carcinomas (extremely rare) - 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 (amenorrheagalactorrhea syndrome)  The MC pituitary hyperfunction syndrome. Caused by: by: 1- Prolactinomas; Prl secreting adenoma (sparsely granulated, chromophobic) -

F/M >1, peak incidence 20-30 yrs. of age

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serum prolactin level > 300 ug/L is diagnostic

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Rx: surgery (transsphenoidal) (transsphenoidal) bromocriptine bromocriptine (dopamine receptor agonist) radiation 2- Hypothalamic diseases. Hypothalamus normally produces dopamine (Prl-inhibitory factor). -

head trauma, etc.

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stalk effect 3- Anti-dopaminergic drugs (phenothiazines, (phenothiazines, haloperidol) 4- Estrogen therapy 5- Primary Primary Hypothyroidism Hypothyroidism (⇑ TRH ⇒ ⇑ Prl) -

Signs & Symptoms: women: galactorrhea, amenorrhea, infertility, ⇓ libido -

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men: ⇓ libido, impotence & rarely galactorrhea & gynecomastia

SOMATOTROPH SOMATOTROPH ADENOMAS Acromegaly; Acromegaly; adult onset excess growth hormone (GH) ⇒ enlargement enlargement of the skull, skull, facial bones, jaw, jaw, hands, feet, soft tissues & organs. diabetes, hypertension, muscle weakness, arthritis, gonadal dysfunction, cardiovascular cardiovascular disease Gigantism; Gigantism; GH excess occurs in children (before closure of  epiphyses). generalized increase in body size disproportionately disproportionately long arms and legs -

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Pathology – Endocrine Pathology by  Pathology by  Dr.  Dr. Yabut 

* Morphology: Morphology: macroadenomas, macroadenomas, composed of  densely or sparsely granulated “acidophilic” cells, strongly positive for GH by immunostains. 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 transsphenoidal surgery, octreotide acetate, radiation -

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Pathologic Entity ACTH Secreting Pituitary Adenoma

Low High Dose Dose – +

Cortisol Secreting – Adrenocortical Neoplasm ACTH Secreting – Nonendocrine Neoplasm

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OTHER FUNCTIONING ADENOMAS Gonadotroph adenomas: majority produce FSH, some FSH & LH, rarely only LH -

MC occur in middle-aged men & women

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usually are macroadenomas

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symptoms MC related only to local mass effects

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may cause amenorrhea or galactorrhea, ⇓ libido in men -

Thyrotroph adenomas produce TSH ⇒ hyperthyroidism

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HYPOPITUITARISM • Caused by either hypothalamic or pituitary lesions:

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

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plasma ACTH level

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dexamethasone suppression test

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MRI scan

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Dexamethasone Suppression Test

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Hypothalamic Hypothalam ic lesions : craniopharyngiom craniop haryngioma, a, gliomas & teratomas; metastatic carcinoma, infections Pituitary Pitui tary lesions lesio ns: MCCs are: nonsecretory adenomas, Sheehan’s o

syndrome, radiation or surgical ablation (of  ≥ 75% of the gland) LCCs are: metastatic carcinoma, inflammatory o disorders, disorders, infections, genetic genetic defects (pit-1) • Effects: Isolated hormone deficiencies deficiencies (e.g. GH or LH) Panhypopituitarism: in children ⇒ dwarfism & infantilism (retarded physical & sexual development) & in adults ⇒ hypogonadism, hypothyroidism hypothyroidism & hypoadrenalism hypoadrenalism -

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often stain negative for hormones with immunostains -

SHEEHAN’S SYNDROME = Post-partum Post-partum ischemic necrosis 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 Posterior lobe: usually is not affected -

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 calcification rupture of cystic tumors ⇒ inflammatory reaction -

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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 hypothalamic or pituitary lesions; lesions; idiopathic corrected readily by ADH administration. -

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Inappropriate ADH Secretion (SIADH): (SIADH) : ⇑ ADH ⇒ excessive reabsorption of free water oliguria, urine of high specific gravity, with inability to dilute it, and hyponatremia hyponatremia due to a compensatory ⇑ in ANP ⇒ no -

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

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hypervolemia, no ⇑ BP and no peripheral edema neurologic dysfunction: most likely 2 0 to hyponatremia MCC is ectopic ADH secretion by a small cell carcinoma of the lung Rx: fluid restriction restriction -

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THYROID GLAND

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Embryology: the thyroid develops from the primitive pharynx

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Pathology – Endocrine Pathology by  Pathology by  Dr.  Dr. Yabut 

the developing thyroid is attached to the base of  the tongue by the thyroglossal thyroglossal duct -

the thyroid descends in the midline & assumes its final position in the anterior neck below the larynx

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excessive descent gives rise to a substernal thyroid & incomplete descent ⇒ ectopic thyroid higher in the neck or tongue

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persistence persistence of remnants of the thyroglossal duct can ⇒ thyroglossal thyroglossal duct cyst -

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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, thyroiditis, struma ovarii, toxic carcinoma  TSH-secreting  TSH-secreting pituitary adenoma overtreatment with thyroid hormone tablets (factitious hyperthyroidism) hyperthyroidism) -

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HYPOTHYROIDISM = a hypometabolic state caused caused by deficiency deficiency of T3 & T4. Cretinism (congenital hypothyroidism) hypothyroidism) Clinical: severe mental retardation; short stature; stature; coarse facial features, protruding tongue - Causes: Endemic - due to dietary iodine deficiency Sporadic -

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thyroid dysgenesis

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inherited defects in thyroid hormone synthesis -

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

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Physiologic Physiologic Effects of  Thyroid Hormones

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gluconeogenesis,

glycogenolysis, lipolysis & ATPase’s

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basal metabolic rate ra te &

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heat

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production • •

protein catabolism muscle wasting, osteoporosis

HASHIMOTO’S THYROIDITIS - MCC of hypothyroidism hypoth yroidism in areas where iodine intake is adequate Clinically: seen predominately in middle-aged women hypothyroidism hypothyroidism with painless enlargement enlargement of the gland may have transient thyrotoxicosis early on -

HYPERTHYROIDISM = a hypermetabolic hypermetabo lic state, caused by increased levels of circulating T3 & T4.

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Pathology – Endocrine Pathology by  Pathology by  Dr.  Dr. Yabut 

familial predisposition, predisposition, associated with HLA-DR3 or HLA-DR5 -

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 Therapy: β-blockers, propylthiouracil, potassium iodide, radioiodine ablation, surgery

Pathogenesis: defective function of thyroid-specific thyroid-specific suppressor  T cells ⇒ emergence of helper T cells reactive with thyroid antigens helper T cells stimulate B cells to secrete antithyroid antithyroid antibodies, directed against: thyroid peroxidase, TSH-receptors, iodine transporter, & thyroglobulin, thyroglobulin, etc. -

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thyroid injury is mediated by complement fixing cytotoxic antibodies, ADCC & CD8+ cytotoxic cells -

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

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goitrogens (e.g. cabbage, cauliflower, turnips, cassava root) sporadic -

GRAVES’ GRAVES’ DISEASE DI SEASE Clinical: MCC of hyperthyroidism, peak incidence 20-40 y/o a disease of females (F/M 10:1), affects 1-2% of  women in US hyperthyroidism, hyperthyroidism, symmetrical thyroid enlargement opthalmopathy and dermopathy (pretibial (pretibial myxedema) familial predisposition, associated with HLA-B8 & HLA-DR3 Laboratory values: ⇑ T3 & T4, ⇓ TSH and ⇑ radioactive iodine uptake Pathogenesis: An abnormality in T-suppressor cells ⇒ T-helper

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goitrogens

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

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cells that react to thyroid Ag’s ⇒ elaboration of Bcell clones capable of producing autoantibodies reactive with TSH receptors. IgG antibodies directed against TSH receptors, receptors, act as agonists ⇒ ⇑ thyroid hormone secretion. - The autoantibodies 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 compared with 2 hours ho urs for TSH. -

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MULTINODULAR GOITER = nodular enlargement, enlargement, derived derived from diffuse goiter goiter both monoclonal & polyclonal nodules (adenomatous goiter) Clinical: most patients are euthyroid mass effects: compression of trachea, vessels & nerves, & dysphagia hyperthyroidism hyperthyroidism (toxic multinodular goiter) -

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due to a hyperfunctioning nodule

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not accompanied by opthalmopathy or dermopathy * Morphology: massive enlargement enlargement (up to >2000 gm), nodules, with a mixture of hyperplastic & dilated follicles, involutional changes: hemorrhage, fibrosis, calcification calcification & cystic degeneration degeneration -

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Peak incidence: 3rd-5th decades, F > M. Gene rearrangement on chromosome 10 ⇒ constitutive expression 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, 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. -

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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 Functioning (hot) nodules on scintiscans scintiscans are usually benign Up to 10% of o f cold nodules are malignant - Diagnosis can be made by fine needle needle aspiration aspiration biopsy, or else by surgical excision biopsy. THYROID ADENOMA - adenomas account 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 macrofollicular and Hurthle cell (oncocytic) adenomas - most commonly cold (nonfunctioning) on RI-scan rarely rarely hot (functioning) & may cause hyperthyroidism -

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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% 10yr survival rate for widely invasive tumors

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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

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situated in close proximity to the upper and lower poles of each thyroid lobe - Histology Histology:: composed composed of chief cells cells (the (the majority) majority) and fat cells. The chief cells may undergo transition to oxyphil cells (mitochondria), and water clear cells (glycogen). - chief chief cell cells s secr secrete ete PTH secretion secretion of PTH is regulated by the level of free Ca++ ⇑ 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 phosphat e excretion Causes of hypercalcemia: hypercalcemia : autonomous PTH hypersecretion hypersecretion osteolytic metastases PTH-related protein (PTHrP) -

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MEDULLARY CARCINOMA - Neuroend Neuroendocrin ocrine e tumor of C cells, cells, secrete secrete calcitonin May also secrete: secrete: CEA, serotoin, serotoin, somatostatin, VIP, ACTH, etc. - Sporadic Sporadic or famili familial al (associ (associated ated with with MEN MEN IIa & IIb, IIb, etc., in 20% of cases) - Familial cases are associated with germ line mutations in RET * Gross: sporadic cases: 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, hyperplasia, + for calcitonin, chromogranin, 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 There are are usually usually four four glands glands (they (they can can be as as many as 12), weighting 30 to 40 mg each,

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