14. Pathology of the endocrine glands

PATHOLOGY OF ENDOCRINE SYSTEM

ENDOCRINE SYSTEM • Function: maintenance of homeostasis through secretion of hormones • Hormones: signalling molecules secreted into the bloodstream, transported to and act on distant target organs by binding to specific receptors • Components of endocrine system: o Endocrine organs (glands) – entire parenchyma o Group of endocrine cells – e.g. islets of Langerhans, ovary, testis o Isolated endocrine cells – in GI tract

Endocrine diseases may manifest as: • Hormone overproduction o Primary overproduction by gland o Secodary to excessive trophic hormone • Hormone underproduction o Primary underproduction by gland (e.g. due to inflammation, post surgery) o Secondary to insufficient trophic hormones • Altered tissue responses to hormones o Target organ hormone resistance (insulin resistance in type 2 diabetes) • Tumors of endocrine glands

DISEASES OF THE

DISEASES OF THE

PITUITARY ADENOMAS

• Benign neoplasms derived from the epithelial cells of the adenohypophysis • Mainly sporadic, rarely associated with MEN1 syndrome (see below) • Types: o Functional – 80% ▪ With clinical manifestations of hormone excess (↑ blood hormone) → hyperpituitarism o Nonfunctional (silent) – 20% ▪ Without the clinical manifestations of hormonal excess ▪ Usually grow larger (few symptoms) → destruction of nontumorous parenchyma → + local mass effects • Size: o Microadenomas - <10 mm o Macroadenomas – >10 mm

LOCAL MASS EFFECT

• Larger, predominantly nonfuctional adenomas may compress or even infiltrate adjacent structures: cavernous sinus, hypothalamus, sphenoid bone (sella turcica), optic chiasm o Infiltrative spread is not a sign of malignancy • Enlargement of the sella turcica + optic chiasm compression → visual field abnormalities (bitemporal hemianopia) • Increased intracranial pressure (, nausea, vomiting) – especially in sudden • Hypopituitarism due to the destruction of the nontumorous parenchyma

HISTOLOGY OF PITUITARY ADENOMAS

LM: • Both nonfunctional and functional adenomas are usually composed of a single cell type (acidophilic, basophilic or chromophobic cells); cells are monomorphous

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• Functioning adenomas produce a single hormone • Hormone produced by the tumor cells can be detected by immunohistochemistry, this classifies the tumors into multiple subtypes: (lactotroph cell adenomas) - Somatotroph – (GH) Corticotroph - ACTH Gonadotroph – FSH/LH Thyrotroph - TSH EM: • Numerous membrane-bound secretory granules in the cytoplasm

FUNCTIONAL ADENOMAS AND HYPERPITUITARISM • Most common functional pituitary tumor • Most are macroadenomas • Dg: PRL (prolactin) immunostaining Clinical features • Amenorrhea • Galactorrhea • Loss of libido • Infertility Dg: • Easily made in women of reproductive age (because of absence of menstruation) • In older women and men the tumor may reach a considerable size before discovery (no recognizable endocrine symptoms)

Somatotroph cell adenoma • 2nd most common functional • Macroadenomas, which may become large since the clinical symptoms are mild • Clinical features and consequences: o Local mass effect o Excess GH with associated and • Gigantism o GH effect before the closure of the epiphyses o Generalized increase in body size with long arms and legs • Acromegaly o Increased GH levels only after the closures of the epiphyses o Enlargement of head, hands, feet, jaw, tongue and soft tissues

Corticotroph adenomas Morphology • Basophilic or chromophobe cells, ACTH positive • Microadenomas (mostly) • Chromophobic tumors are often larger and cause local mass effect

Clinical features • Usually in young females; excess production of ACTH → Hypercortisolism (Cushing syndrome) o If hypercortisolism is caused by excess ACTH production by a pituitary adenoma, we call it Cushing disease

Rare adenomas • Thyrotroph (TSH producing) adenomas → rare cause of hyperthyroidism • Gonadotroph (LH and FSH) adenomas → menstrual disturbances and decreased libido/impotence; local mass effects

Pituitary carcinomas • Very rare, mostly nonfunctional • Diagnostic feature: metastasis

HYPOPITUITARISM • Hypopituitarism is decreased pituitary hormone secretion resulting from the diseases of the hypothalamus or of the pituitary • At least 75% of the anterior pituitary parenchyma should be destroyed. • Symptoms vary, depending on which pituitary hormones are deficient and how severe the deficiency is • Panhypopituitarism – all trophic hormones are undersecreted

Causes • Compression / infiltration o Large adenomas o Metastases o • Ischaemia or haemorrhage o Sheehan syndrome o Pituitary apoplexy • Iatrogenic (medically-induced)

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o Surgery o Irradiation

Empty sella syndrome • There is a defect in the diaphragma sellae → the cerebrospinal fluid (CSF) and the arachnoid mater herniate into the sella → compression atrophy of pituitary gland

Pituitary apoplexy • Sudden hemorrhage of an adenoma → Rapid increase of the size of the adenoma, • Clinical features: headache, neurological symptoms, hypopituitarism + death

Ischemic necrosis of the pituitary Causes • Sheehan syndrome: postpartum necrosis of the anterior lobe; the sudden infarction is precipitated by obstetric hemorrhage during delivery or after delivery leading to shock • DIC • Shock of any origin Outcome: over time the necrosis is replaced by fibrous tissue → panhypopituitarism Clinical features of panhypopituitarism in Sheehan syndrome • Lactation failure • Secondary hypothyroidism Cold sensitivity, • Adrenocortical insufficiency Weakness, hypotension, hypoglycaemia Loss of pubic hair • Gonadotropin insufficiency Amenorrhoea, infertility, loss of libido

THYROID GLAND Follicular epithelial cells Thyroid hormone synthesis • Actively uptake iodide (iodide concentration inside is 50x higher than in the plasma) and transport into the lumen of thyroid follicles; synthesize and secrete thyroglobulin (TG) into the lumen of thyroid follicles; tyroperoxidase present in the apical (colloid-facing) cell membranes fabricate triidothyronine and thyroxine (T3 and T4). • If thyroid hormones (THs) are needed, the follicular cells endocytose the colloid, digest T3 and T4 from TG and release T3 and T4 into the circulation. Regulation of thyroid hormone secretion • When TH levels decrease, the hypothalamus secretes TSH releasing hormone which alerts the pituitary to produce thyroid stimulating hormone (TSH); the thyroid responds by increasing the production of THs. The effects of thyroid hormones • Normal embryological development – nervous and skeletal system • Increase basal metabolic rate and heat production • Enhance the response to the sympatho-adrenergic system o Heart rate, contractility, etc. • Metabolic effects: glucose, cholesterol levels etc. Parafollicular cells • Secrete calcitonin, which helps control blood Ca level via blocking Ca resorption by osteoclasts

Thyroid disorders • Frequent, particularly in women; many of them has autoimmune pathogenesis • Euthyroidism - normal thyroid function that occurs with normal serum levels of TSH and T3/T4 • • Disturbed thyroid function can manifest as: o Hyperthyroidism (thyrotoxicosis) o Hypothyroidism • Classification of thyroid diseases: o Autoimmune thyroid disease ▪ Graves-Basedow disease ▪ Autoimmune (Hashimoto) thyroiditis ▪ Subacute lymphocytic thyroiditis o Other forms of thyroiditis o Goiters (impaired thyoroid hormone synthesis) o Neoplasms

Hyperthyroidism and thyrotoxicosis

Thyrotoxicosis is a hypermetabolic state caused by increased levels of circulating triiodothyronine (T3) and thyroxine (T4).

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Clinical features (for details see pathophysiology lecture): • Heart and circulation: increased cardiac output, increased cardiac contractility, increased peripheral oxygen requirements lead to tachycardia, cardiac hypertrophy, hypertension, and arrhythmias (particulary atrial fibrillation) • Sympathic nervous system overactivity: tremor, hyperactivity, inability to concentrate, anxiety, insomnia (inadequate or poor quality of sleep) • Skin: warm, moist and flushed to increase heat loss • Ocular changes: eyes are wide open and the frequency of winking is much slower than normally; ophtalmopathy (exophtalmus) only appears in Graves-Basedow disease! • GI tract: hypermotility, diarrhea; weight loss despite increased appetite

Diagnosis is based predominantly on: clinical features, laboratory data, imaging +/- fine needle aspiration cytology (if needed)

Diagnostic alterations in the blood • Primary hypethyroidism: o Decreased TSH (feedback inhibition) o Elevated T4 and T3 • Secondary hyperthyroidism: o Elevated TSH (TSH producing pituitary adenoma) o Elevated T4 and T3

Radioactive iodine, taken by the thyroid, has been used to o image the gland – thyroid scintigraphy ▪ ”hot nodules” – increased uptake ▪ ”cold nodules” – decreased uptake o applied in higher concentrations, the radiation destroys the follicular cells and this effect is used to treat hyperthyroidism or thyroid cancer

Graves-Basedow disease • Autoimmune disorder with diffuse thyroid enlargement (diffuse hyperplasia) and ↑ thyroid hormone production

Epidemiology • More common in women • Between 20-40 yrs of age • Most common cause of hyperthyroidism

Etiology and pathogenesis In genetically susceptible individuals, autoantibodies to TSH-receptor (TSH-R) are formed • Thyroid-stimulating immunoglobulins (TSI) mimic the action of TSH → hypertrophy and hyperplasia of thyreocytes → hypersecretion of thyroid hormones • Specific autoantibodies for Graves-Basedow disease • TSH-binding inhibitor immunoglobulins prevent TSH from interacting with the receptor → inhibit thyreocyte function → hyposecretion of hormones • Stimulating and inhibiting anti-TSH antibodies may coexist

Gross • Mild and symmetrical enlargement (60 to 70 g) • Cut surface: the parenchyma is soft and the normal colloid appearance is lacking LM • Epithelium that lines folliculi shows diffuse hypertrophy and hyperplasia • Follicules are lined by tall epithelium, crowding of columnar cells results in irregular papillary folds • The colloid is light staining and depleted (resorption vacuoles) Clinical features Clinical triad • Painless diffuse enlargement of the thyroid and hyperthyroidism • Ophtalmopathy - Exophthalmos (bulging eyes): orbital fibroblasts express TSH-R and become target of autoimmune attack → infiltration of the orbital tissues by mononuclear cells and edema • Dermopathy (pretibial myxedema):, accumulation of mucopolysaccharides in the dermis over the shins Treatment • Blockage of the increased adrenergic effect of thyroid hormones on the body with beta adrenergic blockers • Control of the over-production of thyroid hormones: • Antithyroid drugs, • Radioidodine ablation: via administration of radioactive iodine (radioactivity destroys overactive thyroid cells)

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• Surgery • Treatment may lead to hypothyroidism

Hypothyroidism Hypothyroidism is a hypometabolic state caused by decreased levels of circulating triiodothyronine (T3) and thyroxine (T4).

Causes: any structural or functional derangement in the hypothalamic-pituitary-thyroid axis that interferes with the production of thyroid hormones

Primary hypothyroidism (negative feedback results in ↑ TSH levels) 1. Hashimoto thyroiditis 2. Dietary iodine deficiency 3. Iatrogenic a. Surgical removal of the gland b. After radioiodine ablation c. Drugs 3. Genetic defects of thyroid hormone biosynthesis Secondary hypothyroidism • Decreased TSH secretion from the pituitary Tertiary hypothyroidism • Decreased TRH secretion from the hypothalamus (rare)

Clinical manifestations

Cretinism: if thyroid deficiency develops during the perinatal period or infancy Causes • Endemic: dietary iodine deficiency and endemic goiter • Sporadic: defect in hormone synthesis (dyshormogenesis) Clinical symptoms • Impaired development of skeletal and CNS with mental retardation

Myxedema: if thyroid deficiency develops in adults Clinical symptoms • Weigh gain (despite loss of appetite): ↓ basal metabolic rate • Cold intolerance: body is producing less heat – cold skin • Insidious slowing of physical and mental activity • Slowed heart rate (bradycardia), fatigue • Decreased sympathetic activity leads to cold intolerance • Constipation • Elevated blood cholesterol level • Periorbital edema; skin coarsening; hair loss; myxedema in the dermis (accumulation of mucopolysaccharide-rich ground substance) – nonpitting edema

Thyroiditis Types: • 1. Hashimoto thyroiditis • 2. Subacute lymphocytic (painless) thyroiditis • 3. Subacute granulomatous (de Quervain, painful) thyroiditis • 4. Riedel thyroiditis (IgG4-related disease)

Hashimoto thyroiditis Autoimmune chronic inflammation of the thyroid gland → gradual destruction of the thyroid parenchyma → hypothyroidism

Epidemiology Females > males; age 45-65 yrs Most common cause of non-iodine deficiency induced hypothyroidism

Pathogenesis • Breakdown in self tolerance to thyroid autoantigens • Gradual autoimmune-mediated destruction of the thyroid gland • Mediated by o autoantibodies to thyroglobulin (anti-TG) and thyroid peroxidase (anti-TPO); o CD8+ cytotoxic T cells, and/or o TH1 cytokine activation of macrophages • Strong genetic predisposition: frequent association with other autoimmune diseases like SLE, Sjögren sy, type I diabetes Gross • The gland displays mild diffuse, symmetric enlargement (40 to 60 g; normal 20 to 30 g) • The parenchyma is paler than normal, with greyish-white nodular appearance (caused by chronic inflammatory infiltrate) LM • Infiltration of the follicles by lymphocytes, plasma cells, and macrophages, often with the formation of lymphoid follicles with germinal centers • Residual atrophic follicles show Hürthle cell metaplasia (eosinophilic cytoplasm) • Delicate fibrosis Clinical features

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• Painless enlargement of the thyroid and hypothyroidism • Blood tests: increased TSH, decreased T4 and T3 • Early in the disease there may be transient thyrotoxicosis (“Hashi-toxicosis”) • Risk of subsequent marginal zone lymphoma

Subacute lymphocytic (painless) thyroiditis Pathogenesis • An autoimmune thyroiditis; Most patients have anti-thyroid antibodies • Self-limited Gross • The thyroid appears normal or mild symmetric enlargement LM • Lymphocyte infiltrates with germinal centers and follicular disruption, but no Hürthe cell metaplasia and fibrosis Clinical features • Occurs in postpartum women, and in middle-aged women • A triphasic course of thyreotoxicosis → hypothyroidism → return to normal thyroid function

Subacute granulomatous (painful) thyroiditis (de Quervain thyroiditis) Pathogenesis • Probably caused by viral infection or postviral inflammation resulting in cytotoxic T-cell-mediated follicular epithelial damage Macroscopy • Variable irregular or symmetric glandular enlargement Microscopy • Early lesions: patchy follicle disruption with neutrophilic infiltrates • Later: collapsed follicles are surrounded by mononuclears and multinucleated giant cells which enclose colloid fragments Clinical features • Peak between 30-50 yrs of age; women are more often affected • Causes thyroid pain • Inflammation and the resultant thyrotoxicosis are transient, lasting for 2-6 weeks; thyreotoxicosis is followed by euthyroidism, mild hypothyroidism, and ultimately restoration of normal thyroid function • Recovery is complete

IgG4-related disease and Riedel thyroiditis Riedel thyroiditis is IgG4-related disease (IgG4-RD) of the thyroid gland.

IgG4-RD • A large group of chronic autoimmune diseases, most prevalent in middle-aged and elderly men • Synchronously or metachronously occurrying inflammatory ”pseudotumors” • Histology: • characterized by lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells, • dense fibrosis, and • obliterative phlebitis • Commonly involved organs: the submandibular and lacrimal glands, the orbit, the pancreas (chronic autoimmune pancreatitis), the retroperitoneum, and the thyroid • Serology: elevated serum IgG4 levels • Response to steroids

Riedel fibrosing thyroiditis • Thyroid parenchyma is replaced by dense fibrous tissue, penetrating the capsule and extending into contiguous neck structures; IgG4-positive plasma cells Clinical features • Hard, fixed, painless, rapidly growing thyroid mass, mistaken for infiltrating thyroid cancer • Hypothyroidism in 30% of patients

Goiter Definition

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• Goiter refers to an abnormally enlarged thyroid gland • Diffuse goiter – generalised, symmetrical enlargement • Nodular goiter – irregular, lumpy enlargement • It’s a clinical sign - many thyroid diseases manifest as goiter (see above)

Goiters caused by impaired thyroid hormone synthesis

Thyroid enlargement without inflammatory, autoimmune and neoplastic alterations; most patients are euthyreoid = nontoxic goiter (rarely hypothyroidism or hyperthyreoidism = toxic goiter)

Causes • Dietary iodine deficiency • Goitrogenic diet or drugs altering iodine metabolism or hormone synthesis • Genetic defects of enzymes in the biosynthesis of hormones

Pathogenesis • Dietary iodine deficiency → decreased TH synthesis (low T3/T4 levels) → compensatory increase in TSH → thyrocyte hyperplasia → diffuse goitrous enlargement • Clinically, if the compensated thyroid hormone synthesis normalizes T3/T4 levels → EUTHYROIDISM • Undercompensation → HYPOTHYROIDISM • Overcompensation → HYPERTHYROIDISM

• Cyclic changes of hyperplasia and involution and variations of follicular cell responses to TSH stimulation → diffuse goiter transforms into multinodular goiter

Occurrence Endemic goiter • In geographic areas where soil, water and food contain too little iodine: mostly in mountainous areas (Alps, Andes, and Himalayas) • With iodine supplementation endemic goiter have significantly declined Sporadic goiter • Less frequent; usually in young adult females • Causes • Diet with high goitrogen content (e.g., cabbage, cauliflower, Brussels sprouts,) diminishes T3/T4 synthesis • Drugs • Autosomal recessive enzymatic defects (dyshormogenic goiter)

Morphological types Diffuse goiter Macro • Diffuse and symmetrical enlargement Micro: two stages 1. Hyperplastic stage: • Hypertrophy and hyperplasia of follicles with thin colloid 2. Colloid involution: • If the demand for thyroid hormones decreases, the stimulated epithelium involutes and forms enlarged colloid rich glands Clinical features • Euthyroidism • Diffuse enlargement of the thyroid gland

Multinodular goiter • Long lasting diffuse goiters convert into multinodular goiter • Cyclic changes of hyperplasia and involution (in endemic areas the goiter is hyperplastic in childhood, diffusely enlarged with colloid accumulation in adolescence, and nodular in adulthood) • Multinodularity is due to variations in follicular cell responses to hormonal stimulation Macro • Enlarged, asymmetric gland with nodules of various size in the parenchyma; thyroid may exceed 2000 g • The nodularity is associated with focal hemorrhage, fibrosis, calcification and cyst formation • The goiter may grow behind the sternum: intrathoracic goiter LM • Foci of follicular hyperplasia and follicular involution alternate

Clinical features • Most patients are euthyroid; complain cosmetical deformity • Mass effects: dysphagia due to esophageal compression, difficulty breathing and coughing because of tracheal compression; thyroid surgery is necessary • In 10% of patients, a hyperfunctioning nodule can develop and cause hyperthyroidism (toxic multinodular goiter)

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THYROID NEOPLAMS Manifest as solitary thyroid nodules, but only 1% of all nodules are neoplastic

Histologic classification: • I. Primary neoplasms o Epithelial ▪ Follicular epithelium • Benign: o Follicular adenoma • Malignant: o Papillary carcinoma o Follicular carcinoma o Anaplastic carcinoma ▪ Parafollicular (C-cells) • Medullary carcinoma o Non-epithelial ▪ Extranodal marginal zone B-cell lymphoma (MALT-lymphoma) in patients with Hashimoto thyroiditis • II. Metastases (rare)

Benign Follicular adenoma Morphology • Solitary, encapsulated tumor, variable size (1-10 cm) • Careful histopathological examination is necessary to distinguish from a minimally invasive follicular carcinoma • Dg.: lacks evidence of capsular and vascular invasion Clinical feature • Manifest as painless nodule • Can result in hyperthyreoidism, but mostly silent (non-hormone producing) Treatment • Lobectomy

Malignant Papillary carcinoma • 85% of all thyroid cancers • Most often in women between 20-50 yrs of age • Radiation-related thyroid cancers are almost always papillary Molecular pathology • Gain-of-function mutations in the MAP (mitogen-activated protein) kinase pathway (RTK [receptor tyrosine kinase] → RAS → BRAF → MEK → ERK) • BRAF mutations occur in almost half of papillary carcinomas Macroscopy • Solitary or multifocal infiltrative lesions LM • More than a dozen histologic variants exist; the classic papillary variant and the follicular variant of papillary carcinoma are the commonest • The dg is based on nuclear features (even in the absence of papillary architecture): • Hypochromatic empty nuclei, • Nuclear grooves (“coffee bean shaped” nuclei), • Intranuclear pseudoinclusions Clinical features • Nonfuctional tumors; painless thyroid mass • Papillary carcinomas are indolent lesions, with 10-year survival rates in excess of 95% • In 50% of the cases there are cervical lymph node metastases at the time of the diagnosis, and this may be the only symptom of the disease • Lung metastases are rare at presentation • The preoperative diagnosis is established by fine needle aspiration cytology (FNAC), based on the typical nuclear features Treatment • Thyroidectomy + lymphadenectomy, followed optionally by radioiodine ablation therapy to destroy any metastasis and residual thyroid tissue • Hypothyroidism → Lifelong thyroid hormone replacement therapy • After radioiodine therapy, the increase in serum thyroglobulin level indicates the presence of metastasis

Follicular carcinoma • 10% of all thyroid cancers • Mostly in women between 40-60 years • Increased prevalence in areas with iodine deficiency Molecular pathology • Translocation-induced PAX8/PPARG fusion gene, observed in half of the cases Macro • Single nodules that may be well circumscribed with pseudocapsule or infiltrative LM • Nuclear features of papillary carcinomas are never present

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• Most cases are reminiscent of thyroid tissue; demonstration of vascular or capsular invasion is the diagnostic feature Clinical features • Nonfunctional tumors (mostly); painless thyroid mass • Metastases are mostly hematogeneous: lung, bones and liver Prognosis is good, influenced by: • Tumor size, degree of vascular invasion, metastases and histologic atypia Treatment • Similar to papillary carcinoma

Anaplastic carcinoma • Undifferentiated, high grade anaplastic cancer • In patients above 65 years Clinical features: • Rapidly enlarging bulky mass; distant metastases are common; fatal

Medullary carcinoma • Neuroendocrine neoplasm, originates from parafollicular C-cells Epidemiology • Sporadic in 80% of the cases; 40-60 years of age • Rest occur in MEN-2 syndromes (Multiple Endocrine Neoplasia); 20-40 years of age Molecular pathology • Mutations of RET protooncogene (encodes a receptor tyrosin kinase) Morphology • Polygonal neuroendocrine cells form nests, not follicles • Tumor cells secrete calcitonin + serotonin, ACTH, and vasoactive intestinal peptide • Stromal amyloid deposits from altered calcitonin (congo red positive) Clinical course • Sporadic cases: thyroid mass sometimes associated with dysphagia • Sometimes manifestations related to the secretion of a peptide product (e.g.diarrhea) • Prognosis is variable, MEN-2b lesions are often aggressive.

THYROID NEOPLASMS (SUMMARY) • Most common tumors: o Benign: follicular adenoma o Malignant: papillary carcinoma • Follicular adenomas and carcinomas both are composed of well differentiated follicular epithelial cells; the latter are distinguished by presence of capsular and/or vascular invasion • Papillary carcinomas are recognized by nuclear features (empty nuclei, pseudoinclusions), even in the absence of papillae • Anaplastic carcinomas are highly aggressive and lethal • Medullary carcinomas are neuroendocrine neoplasms derived from the C-cells secreting calcitonin o Sporadic (80%) and MEN-2 syndrome associated o Calcitonin positivity and amyloid deposits are characteristic histologic findings

PATHOLOGY OF PARATHYROID GLAND Physiology • The parathyroid glands control calcium homeostasis by secreting parathyroid hormone (PTH) • Hypocalcemia stimulates parathyroid hormone (PTH) secretion • PTH acts in the bones, kidneys and gut, and increases Ca levels by - release of Ca from the bones via indirect stimulation of osteoclast-induced bone resorption - increasing renal tubular reabsorption of Ca and increasing urinary phosphate excretion - increasing renal vitamin D conversion to the active form which augments intestinal Ca reabsorption

Primary hyperparathyroidism • Definition: Excess PTH hormone secretion of one or more parathyroid glands independent of feedback control (autonomous PTH secretion) → hypercalcaemia (↑ Ca2+)

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• Causes • Parathyroid adenoma (most common) • Parathyroid hyperplasia (much less common) • Parathyroid carcinoma (rare) • Epidemiology • Most cases occur beyond 50 with a female preponderance • Most cases are sporadic, few are in inherited MEN syndromes

Parathyroid adenomas • Solitary tumors (0.5-5 g), surrounded by a delicate capsule; are usually composed of chief cells • Remaining glands are normal sized

Primary hyperplasia • Usually involves all glands although not necessarily uniformly • Combined weights rarely exceed 1 g

Parathyroid carcinomas • Enlarge one gland and may exceed 10 gm • Diagnosis of malignancy is based on the presence of local invasion, metastases or both

Consequences of PTH overproduction • Blood: elevated PTH, elevated calcium, elevated alkaline phosphatase (indicates bone disease, biliary obstruction) • Skeletal changes: osteoclast activation with bone resorption; the bones show thinned cortices with increased marrow fibrosus tissue + foci of hemorrhages and cyst formation (osteitis fibrosa cystica) • Metastatic calcification in cardiac valves, aorta, and arteries, and in organs performing H+ secretion (kidneys [nephrocalcinosis and renal stones], lungs, and stomach)

Clinical features Mostly asymptomatic Symptomatic cases: multiple manifestations • Bone pain secondary to pathological fractures • Decrease in renal function, renal stones • Cardiac manifestations: aortic and mitral valve calcifications • CNS alterations: depression and eventually seizures, weakness

Secondary hyperparathyroidism • Definition: Parathyroid hyperplasia and PTH hypersecretion in a response to chronic hypocalcaemia in the blood Causes • Chronic renal failure (most common) • Severe vitamin D-deficiency • Severe malabsorption

Pathogenesis • The commonest cause is chronic renal failure; o the diseased tubules retain phosphates instead of Ca → hypocalcemia and hyperphosphatemia → compensatory PTH hypersecretion o Impaired intestinal Ca resorption because of the lack of active form of vitamin D (caused by renal atrophy) o Skeletal resistance to the effects of PTH and vitamin D

Chronic hypocalcaemia → • Compensatory PTH hypersecretion and parathyroid hyperplasia → compensated (near) normal calcium levels • Occasionally an autonomous adenoma may develop: tertiary hyperparathyroidism → hypercalcaemia

Clinical consequence: renal osteodystrophy. See bone pathology.

ADRENAL GLANDS Physiology: Regulation of adrenocortical hormone synthesis • Mineralocorticoids are regulated primarily by the renin-angiotensin-aldosterone system (RAAS) • Glucocorticoids are regulated by hypothalamic-pituitary-adrenal axis, and it is under a feedback control of ACTH • ACTH not only stimulates glucocorticoids but also stimulates adrenal androgens and mineralocorticoids; but ACTH deficiency will not lead to aldosteron deficiency

Adrenal medulla • Composed of chromaffin cells and functionally related to the sympathetic nervous system; it secretes catecholamine hormones epinephrine and norepinephrine in response to sympathetic stimulation • Catecholamine effect (via α and β adrenergic receptors) → Stimulate stress response o ↑ Heart (rate, contractility) o ↑ Blood pressure o ↑ Sweating, ↑ blood glucose

Pathology of adrenal medulla Pheochromocytoma

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General features • A rare, catecholamine-secreting tumor (norepinephrin, epinephrin) derived from chromaffine cells • 10% are extra-adrenal and develop in the paraganglion chromaffin tissue of the nervous system, designated as paragangliomas ”Rule of 10’s” • 10% are extraadrenal (paragangliomas) – 90% adrenal • 10% of sporadic cases are multiple or bilateral (in familial types, at least 50%) • 10% are malignant • 10% (→ 25%) are familial • Familial syndromes associated with pheochromocytomas include • von Hippel-Lindau disease, • MEN 2, • neurofibromatosis type 1 • Just 10% are NOT associated with hypertension • Constant or paroxysmal release of catecholamines – headache, hypertension, tachycardia (palpitations), sweating Gross • Sporadic cases: usually unilateral; familial cases: frequently bilateral • Size may vary (1g to 2000 g); pale gray or brown with hemorrhage, necrosis and cystic change LM • Polyglonal chromaffin cells form small nests termed “Zellballen” • The cytoplasmic granules contain catecholamines Behaviour • Malignancy rate: 10% - nuclear pleiomorphism and even invasion does not reliably predict malignancy • Metastases in paraaortic lymph nodes, lung and bones Clinical features • Triad of pheochromocytoma: , palpitations (tachycardia), and sweating • Increased urinary excretion of catecholamines and their metabolites such as vanillylmandelic acid (VMA). • „Pheo crisis: paroxysmal life-threatening release of chatecholamines that can lead to cerebral hemorrhage, acute left-sided heart failure, arrhythmias

Pathology of adrenal cortex

Adrenocortical hyperfunction • Cushing syndrome (excess cortisol) • Hyperaldosteronism and adrenogenital syndromes (excess androgens) → see pathophysiology

Cushing syndrome Pathogenesis Caused by an elevation in glucocorticoid levels • 1. IATROGENIC: Most common: long administration of exogenous glucocorticoids → the cortex of adrenals become atrophic because of suppressed ACTH release • 2. PITUITARY CUSHING SY: Hypersecretion of ACTH by a pituitary adenoma (Cushing disease) → the cortex of adrenals become hyperplastic • 3. PARANEOPLASTIC CUSHING SY: ACTH-releasing neuroendocrine neoplasm, e.g. small cell carcinoma of lung → the cortex of adrenals become hyperplastic • 4. PRIMARY ADRENAL CUSHING SY: Hypersecretion of cortisol by an adrenal adenoma or carcinoma → the nontumorous and the contralateral adrenal cortex are atrophic because of suppressed endogeneous ACTH release

Clinical features • Central obesity, moon facies, cutaneous striae, hirsutism • Hypertension • Glucose intolerance/diabetes • Osteoporosis • Neuropsychiatric abnormalities • Etc.,

Adrenocortical neoplasms Adenomas • Poorly encapsulated, yellow-orange lesions in the cortex • The vast majority are non-secreting cortical adenomas

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• Adjacent adrenal cortex is of normal thickness in contrast to atrophic changes seen adjacent to functional adenomas Adrenal cortical carcinoma • Highly malignant neoplasms, usually of large size at the time of diagnosis • Lesions are yellow on cut surface, usually contain areas of necrosis • The tumors commonly invade vascular channels; metastases to paraaortic lymph nodes and lungs • They are more likely to be functional than adenomas and are therefore often associated with virilism or other clinical manifestations of hyperadrenalism

Adrenal insufficiency Acute adrenocortical insufficiency Causes • A sudden increase in glucocorticoid requirements in patients with chronic adrenocortical insufficiency • Rapid withdrawal of steroids from patients with long-term glucocorticoid therapy • Massive destruction of the adrenals (e.g., DIC, Waterhouse-Friderichsen syndrome).

Waterhouse-Friderichsen Syndrome Uncommon syndrome, characterized by • Overwhelming septicemic infection usually in children, caused by meningococci, less often by other virulent bacteria (pneumococci, gonococci, staphylococci). • Rapidly progressive hypotension and shock → DIC • High mortality rate Morphology: • Disseminated intravascular coagulation (DIC) and purpuras • Massive bilateral adrenal hemorrhage and

Chronic adrenocortical insufficiency Primary: Addison Disease • Most often in adults who suffer destruction of at least 90% of the adrenal cortex Causes • Autoimmune adrenalitis (60% to 70%) • Infectious processes, particularly tuberculosis and those caused by fungi • Metastatic neoplasms

Autoimmune adrenalitis Morphology • Atrophic adrenal glands • Lipid depletion of adrenal cortex, variable lymphocytic infiltrate in cortex • The medulla is spared Clinical features of Addison disease • Weakness, fatigue • Anorexia, nausea, vomiting • Hypotension, hypoglyceamia • Cutaneous hyperpigmentation Laboratory values • Elevated levels of ACTH (and MSH → hyperpigmentation); hyperkalemia, and hyponatremia (due to aldosterone deficiency)

Secondary adrenocortical insufficiency • Caused by any disorder of the hypothalamus or pituitary causing decreased ACTH production • Morphology: atrophy of the adrenal cortex, with sparing of the zona glomerulosa and medulla Diff dg from primary form: • Absence of hyperpigmentation • Normal aldosterone levels

MULTIPLE ENDOCRINE NEOPLASIA (MEN) Autosomal dominant syndromes charaterized by hyperplasia or tumors of several endocrine glands simultaneously.

MEN-1 (Wermer’s syndrome) characterized by 3 "Ps": involvement of Parathyroid, Pancreas, and Pituitary • Parathyroid hyperplasia or multiple adenomas 90-95% of cases (hypercalcaemia and renal stones) Pancreatic islet cell lesions: adenoma, carcinoma, hyperplasia. May produce various substances: gastrin (Zollinger-Ellison syndrome), insulin (hypoglycemia), serotonin, vasoactive intestinal peptide (diarrhea). • Pituitary adenomas, usually nonfunctional.

MEN-2a (Sipple’s syndrome) • Referred to as medullary thyroid carcinoma-pheochromocytoma syndrome. • Medullary thyroid carcinomas are usually multifocal and dominate the syndrome. Most pursue a malignant coarse. • Pheochromytomas are present in 50%, often bilateral and extra-adrenal. Most lesions are benign. • Parathyroid hyperplasia in 10-20% of the patients

MEN-2b • Similar to MEN-2a with additional fetature of neuromas or ganglioneuromas in GI tract and mucosal sites • Marfanoid habitus – overly long bones like in Marfan sy • No parathyorid hyperplasia

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