Endocrine Pathology

Pituitary Gland Pathology 1. ANTERIOR Pituitary : 

Secretes trophic hormones (trophic mean target another gland to secrete another hormone) Acidophil cells (pink in color); somatotroph, prolactin Basophil cells (blue in color); corticotroph, gonadotroph, thyrotroph. Under influence of feedback; +ve from hypothalamus and -ve from the body. Most are stimulatory factors except for prolactin. Most diseases arise from the pituitary itself (not hypothalamus)

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 FUNCTIONING Abnormality : A) Hyperpituitarism :   

Excessive secretion of one or more of hormones. Most common cause: functional adenoma (benign tumor). Then: hyperplasia, carcinoma, exogenous source (like from therapy) Few adenomas are bilineage (GH + prolactin)

B) Hypopituitarism :   

Deficiency of one or more of pituitary hormones. Damage to more than 75% of anterior pituitary gland. Most common cause: non-functional adenoma (it might be not-synthesizing or non-secretory)

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Others: congenital dysgensis, ischemia (specific to pituitary called; Sheehan syndrome occur post-partum), surgery, radiation, inflammatory diseases (ex. Sarcoidosis), bone diseases. Pituitary tumors causes damage to optic nerve (bitemporal heianopsia) and increase intracranial pressure (headache, nausea, vomit)

 Pituitary adenoma :   

Classified according to the cell origin, with corresponding hormonal synthesis. Mostly develop in middle aged adults (30-50 years). 75% functional, secreting (one or more hormone) 25% functional, silent (synthesizing but not-secreting) rarely hormone negative (non-synthesizing at all)  Most are sporadic, 3% are syndromic (multiple endocrine neoplasia). (sporadic mean come in individual, no family Hx and it won’t pass to the 2nd generation)  1 cm called macro-adenoma; (symptom related to the mass; optic nerve damage ‘bitemporal heianopsia’ & increased intracranial pressure ‘headache, nausea, vomit’ ) Up to 20% of healthy adults have silent micro-PA (3 mm).

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Pathogenesis : - Mutation in G-proteins that transmit a signal transduction to intracellular effectors (adenyl-cyclase), generating 2nd messengers cAMP, a potent mitogenic factor. - Normally, G-proteins are activated upon ligand binding. - Mutant G-proteins have autonomous, permanent activity (activation without ligand).

A) Prolactinoma  Most common PA. 

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galactorrhea, amenorrhea, loss of libido and infertility. Symptoms appear obviously in menstrual and premenopausal women than in men and postmenopausal women Stalk effect: any interruption in hypothalamus-pituitary axis would cause prolactinoma.

B) Growth Hormone-Producing Adenomas      

Second most common Secrete little amount of GH, at the time of symptoms it mean the adenoma is advanced = large. Very Big + Functional adenoma = most likely it is related to growth hormone adenoma. GH stimulates secretion of insulin-like growth factor-1 from liver. Gigantism in children, Acromegaly in adults (face, hands, feet, soft tissue). Also develops hypertension, heart failure, diabetes.

C) Corticotroph Cell Adenomas     

Most are small at the time of diagnosis very sensitive (secrete small amount of hormone causing symptoms in contrast to GH-adenoma) CUSHING DISEASE: bilateral adrenal enlargement. NELSON SYNDROME: develop after bilateral adrenalectomy (no negative feedback from the body), clinically aggressive. Hyperpigmentation characteristic for CCA because ACTH & MSH share precursor

D) Thyrotroph & Gonadotroph 

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Rare, Produce little amount of hormones, usually symptoms are related to mass effect.

2. POSTERIOR Pituitary   

Secretes anti diuretic hormone (ADH), Acts on kidneys to promote reabsorption of water. ADH deficiency is called DIABETES INSIPIDUS (polyuria, polydipsia, dilute urine, hypernatremia), caused by head trauma, tumors or surgery. Excessive ADH is called SIADH (hyponatremia causing brain edema which may lead to death), mostly secondary to paraneoplastic syndrome (small cell carcinoma of lung; because they secrete ADH).

Thyroid Gland Pathology  The Diseases associated with increased OR decreased function & Tumors. A) Thyrotoxicosis :  

It is elevation of circulating free T3 and T4 leading to Hypermetabolic state. Mostly secondary to hyperthyroidism (increased function of thyroid gland), less common: exogenous source (as intake of thyroid drug) or thyroiditis

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Causes : Associated with hyperthyroidism

˃ Primary : 1) Diffuse toxic hyperplasia (Graves Diseasea) 2) Hyper-functioning (toxic) multinodular goiter 3) Hyper-functioning (toxic) adenoma ˃ Secondary : 1) TSH-secreting pituitary adenoma “rare”

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1) 2) 3)

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Not associated with hyperthyroidism Subacute granulomatous thyroiditis (painful) Subacute lymphocytic thyroiditis (painless) Struma ovarii “ovarian teratoma with thyroid tissue also called ectopic thyroid” Factitious thyrotoxicosis (exogenous thyroxine intake)

Symptoms : - Heat intolerance, excessive sweating. - Skin: soft, flushed, warm - Muscles (characteristic): proximal upper and lower muscle weakness. - Cardiac (most dangerous): arrhythmia, palpitation. - GIT: soft diarrhea, malabsorption, weight loss. - Nervousness, irritability, increased sympathetic stimulation, tremor.

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Ocular: lid lag, wide staring eyes (most obvious in Grave’s disease)

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Apathetic hyperthyroidism: asymptomatic, in elderly because there metabolism is normally low, only diagnosed by blood test. Extreme situation called Thyroid storm = life-threatening.

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ost obvious in Grave’s disease, secondary to accumulation of soft tissue behind the eye globes

B) Hypothyroidism :  

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Low level of circulating T3 & T4 leading to hypometabolic state. Very important to check pregnant women (cause the baby depend on his mother thyroid) and the baby at birth for thyroid function because it may lead to mental retardation Cretinism: infants or early childhood (low iodine, inborn enzymatic errors), impaired skeletal, mental retardation, short stature, coarse faces, protruding tongue. Myxedema: adult, cold intolerance, bradycardia, heart failure, constipation, weight gain, slow mental process, apathy, anemia. Causes : ˃

Primary 1) Post-ablative: surgery, radioiodine therapy or external radiation. 2) Hashimoto thyroiditis* 3) Iodine deficiency* 4) Dyshormonogenetic goiter (Congenital biosynthetic defect)* 5) Drugs: lithium, iodides, p-aminosalicyclic acid* 6) Thyroid dysgenesis (Rare developmental abnormalities of the thyroid)

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Post-ablative & Hashimoto thyroidism are the vast majority of hypothyroidism cases in adequate dietary iodine region. * = Associated with enlargement of thyroid (goitrous hypothyroidism) Secondary Pituitary or hypothalamic failure (uncommon)

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 Chronic Lymphocytic (Hashimoto) Thyroiditis

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Most common cause of hypothyroidism Autoimmune disease Peak incidence 45-65 10 times more in women than in men because autoimmune diseases more prevalent in females

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Pathogenesis - Progressive depletion of epithelial cells, replaced by inflammatory cells (lymphocytes and plasma cells). - Abnormality begin with; Autoreactive CD4+ T-lymphocytes against normal thyroid antigens → produces INF-γ → Recruitment of macrophages, CD8+ T lymphocytes, causing damage to epithelium. - Also activate plasma cells of B-lymphocyte to synthesize auto antibodies (diagnosis by the AB) - Genetic predisposition (not hereditary): family history, HLA-DR3, HLA-DR5

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Clinical - Painless goiter - Initial transient phase of thyrotoxicosis. Followed by gradual, progressive hypothyroidism. - Risk of B-cell lymphomas but NOT thyroid carcinoma. - Other autoimmune diseases are common (like; lopus arthritis, immune gastritis, …)

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Morphology - Grossly: diffuse enlargement of thyroid gland, Intact capsule, Not adherent to adjacent structures. - Micro: dense infiltration of B-lymphocyte (forming germinal centers), plasma cells, T-lymphocytes and macrophages. - Follicular epithelium is atrophic, show metaplastic changes into larger, pink cuboidal cells (full of mitochondria) called HURTHLE CELLS or OXYFIL CELLS - With disease advance: fibrosis and atrophy.

 Grave’s disease   

Most common cause of hyperthyroidism Autoimmune disease 20-40 years, females 7 times more than

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males. Triad: thyrotoxicosis, ophthalmopathy, localized infiltrative dermatopathy

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(called pretibial myxedema, minority of patients) Genetic predisposition (family history, HLA-DR3 and B8, other autoimmune

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diseases Transient episodes of hypothyroidism within the course of the disease.

On the left; pink follicle (Hurthle cell) On the right; germinal center

 Pathogenesis -

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Break in CD4 tolerance against normal thyroid antigens → Activates mainly B-lymphocytes to secrete auto antibodies, Also responsible for the infiltrative ophthalmopathy. Types of AB:

a) Thyroid-stimulating immunoglobulin (TSI): most important, autoAB that binds TSH receptor and mimics action of TSH, stimulating adenylyl cyclase, results in secretion of thyroid hormones (specific) b) Thyroid growth-stimulating immunoglobulins (TGI): another AB against TSH receptor, stimulates proliferation of follicular epithelium = goiter c) TSH-binding inhibitor immunoglobulins (TBII): prevents TSH from normal binding to its receptor and: I. stimulates proliferation of follicular epitheliem, II. other forms inhibit thyroid function (coexist) That’s why grave’s disease may have episode of hypothyroidism. d) Anti-thyroglobulin, anti-thyroid peroxidase Abs (not specific) related to hashimito dis.

 Infiltrative ophthalmopathy : -

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Increased size of extra orbital muscles and retro orbital soft tissue causing exophthalmos by: a) Infiltration by inflammatory cells b) Inflammatory edema c) Accumulation of extracellular matrix (hyaluronic acid and chondroitin sulfate) d) Increased fat cells Exophthalmos is irreversible even post treatment

Morphology: - Diffuse goiter, soft, non-adherent, intact capsule - Micro: follicular epithelial cells are hyperplastic (tall columnar, crowded→ formation of small papillae, project into follicular lumen, lack fibrovascular cores) - Colloid is pale, scalloped margins - Lymphoid infiltrate in between the cells (T > B-cells & plasma cells), germinal centers - Skin: edema, lymphocytes, glycosaminoglycans (hyaluronic acid and chondroitin sulfate)

 Subacute Granulomatous (de Quervain) Thyroiditis    

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More common in women Most common 30-50 year old. Viral infection or post viral inflammation (history of upper respiratory tract infection) Self-limited, not progressive. Clinical & Morphology : - Diagnosis is clinically

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Acute painful goiter, could be asymmetrical, not adherent. Fever, malaise, transient hyperthyroidism, leukocytosis.

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Micro: disruption of thyroid follicles, infiltration begin by granulocytes → followed by lymphocytes, plasma cells and macrophages (different than hashimoto they do not form germinal center) Extravasated colloid initiates foreign body reaction → forming granulomas

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 Subacute Lymphocytic Thyroiditis  

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Silent, painless, No or minimal goiter Develop in post-partum women auto immune, initial thyrotoxicosis then euthyroid, return in future pregnancies. Diagnosis is clinically Micro: lymphocytic infiltrate, germinal centers and NO Hurthle cells.

 Riedel thyroiditis     

Rare, chronic, Unknown etiology, autoimmune?? Progressive fibrosis of thyroid and surrounding structures (adherent) Hard goiter mimicking cancer. Associated with fibrosis in other organs (retroperitoneum as pancreas, kidney, Aorta) Micro: thick fibrous bands, minimal follicles

 Palpation thyroiditis :   

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It is result from Vigorous clinical palpation of the thyroid gland. Results in multifocal follicular disruption associated with chronic inflammatory cells and occasional giant-cell formation Unlike de quervain thyroiditis, abnormalities of thyroid function are not present, and palpation thyroiditis is usually an incidental finding in specimens resected for other reasons Asymptomatic.

 Diffuse & multinodular goiter    

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Reflects impaired synthesis of thyroid hormones, Commonly caused by iodine deficiency. Leads to compensatory rise in TSH causing hypertrophy & hyperplasia of follicular epithelium → goiter → euthyroid. Endemic goiter: it is 10% or more of population has goiter, in areas where soil, water and food contain little iodine (Himalaya). Sporadic goiter: mostly idiopathic, others: excessive calcium, cabbage, cauliflower uptake, enzymatic deficiency.

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Clinical : - The main complaint is mass in the neck (cosmetic, stridor, dysphagia, compression of vessels) - Not adherent - Plummer syndrome: when toxic nodule produces hyperthyroidism (no ocular disease) - Some patients have hypothyroidism - So, it can be euthyroid, hyperthyroidism or hypothyroidism.

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Morphology : - Early: diffuse goiter, similar to Grave’s disease - When euthyroid status is reached, TSH decreases, follicular epithelium becomes small and flat, with predominance of colloid (colloid nodule). - Normally: follicular epithelial cells are heterogeneous in response to TSH (some respond more than others) - With repeated attacks, proliferation is variable, fibrosis, hemorrhage, cystic degeneration, calcification goiter is irregular (multinodular goiter) - Some nodules become dominant & secrete excess hormones (toxic nodule) - Both mono & polyclonal nodules are present.

 Benign tumors : Follicular adenoma

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Benign neoplasm of follicular epithelium Solitary (resemble the toxic nodule) Mostly non-functional (cold nodule) Clinically and radiology Might be difficult to distinguish from hyperplastic (toxic) nodule or carcinoma, the diagnosis is by pathology (under the Microscope).

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Pathogenesis : a) Activating mutation in TSH receptor or α-subunit causing overproduction of cAMP  cell growth and mitosis Rarely, can be functional and produce hyperthyroidism b) 20% of cases have RAS mutation (also present in 50% of carcinoma)

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Morphology : - Solitary, well demarcated mass with intact, thin capsule (not present in hyperplastic nodules) - Micro: uniform follicles contain colloid distinct from the rest of thyroid, cells are uniform - If follicular cells show Hurthle cell change, called Hurthle cell adenoma - Atypia might be present, but does not mean malignancy (Atypia is normally common in endocrine system) - If capsular invasion is present  follicular carcinoma

Thy roid

 Carcinoma :    

Rare, Early adulthood, women (estrogen receptors) Old and pediatric cases might occur, risk factors (radiation) Types; Papillary carcinoma, follicular carcinoma, Medullary carcinoma & Anaplastic carcinomas. All derived from the follicular epithelium, except for medullary carcinomas (Ccell)

A) PAPILLARY CARCINOMA o o o o o o

Most common thyroid carcinoma (75 - 85%) Arise at any age (mostly middle aged women) Painless mass in neck, Solitary or multiple History of previous ionizing irradiation Commonly associated with local LN metastasis (does not affect the prognosis) Indolent disease with 10 year survival >95% (one of the best human cancer in prognosis)

o Pathogenesis - 2 pathways, end by activating mitogen activating protein (MAP) kinase signaling pathway: I. ⅓ of patient have BRAF gene mutation → activating MAP.

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II.

20% of patient have mutation in RET gene rearrangement (tyrosine kinase receptor), creating novel gene (ret/PTC) which activates RET and MAP. III. 10% Neurotropic tyrosine kinase receptor1 (NTRK1) mutation. o Morphology (important) - Well circumscribed, sometimes encapsulated - Micro: special nuclear features:  Optically clear nuclei, called ground glass or Orphan Annie eye  Nuclear grooves (pseudo-inclusions) like coffee bean Orphan Annie eye - Papillary architecture; Tip of papillae because it far from blood vessel may have ischemia and Calcification (psammoma body), cysts are common

B) FOLLICULAR CARCINOMA

o Second most common carcinoma (10- 20%) Older age than PTC. Associated with; iodine deficiency & RAS mutation in 50% Micro: normal looking follicles, may see Hurthle cells, capsular or lymphovascular invasion. Evaluating the integrity of the capsule is critical in distinguishing follicular adenomas from follicular carcinomas. o Clinically similar to MNG o o o o

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C) MEDULLARY CARCINOMA (5% ) Neuroendocrine neoplasm, arises from parafollicular cells (C-cells) Increased blood level of calcitonin (but no hypocalcemia) Sporadic in 80% of cases, old age 20% are familial (familial medullary thyroid carcinoma, or multiple endocrine neoplasia), young age, aggressive disease, bad prognosis o RET gene mutation o o o o

o Morphology - Solitary tumor (sporadic) or multiple (familial) - Micro: polygonal or spindle cells. - Secrete amyloid (derived from calcitonin), positive for congo-red stain - C-cell hyperplasia is in non-tumorous areas - Electron microscopy: membrane bound granules containing calcitonin.

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D) ANAPLASTIC CARCINOMA Rare disease (5 g

 SECONDARY HYPERPARATHYROIDISM :  

Develops in patients with long standing hypocalcemia. Most commonly seen in chronic renal failure (hyperphosphatemia suppresses

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calcium level & also no activation of vitamin D → no absorption of calcium from guts) Morphology: hyperplasia of the four glands, serum calcium then normalizes If patient develop progressive and autonomous hypercalcemia (usually even after a correction of the kidney by transplantation) it is called tertiary hyperparathyroidism

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 HYPOPARATHYROIDISM  

Rare Results from surgical removal, congenital absence, autoimmune, fungal

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infection Patients develop hypocalcemia (muscle weakness, neuromuscular abnormality)

Endocrine Pancreas Pathology  Diabetes mellitus: group of diseases that share a common feature of persistent hyperglycemia.  Defect in insulin secretion, function or both resulting in damage to multiple organs in the body.  Commonly cause; end-stage renal failure, adult onset blindness & non-traumatic L-limb amputation.  INSULIN FUNCTIONS - Increase uptake of glucose in skeletal, cardiac muscles (stored as glycogen) and adipocytes (stored as fat), both forming 2/3 of body weight. - Inhibit fat & glycogen degradation - Reduce production of glucose from liver

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Promote amino acid uptake into muscles & protein synthesis, inhibit degradation Promote DNA synthesis, cell growth & differentiation In fasting state, insulin is low

 Type 1 DM 

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Characterized by an absolute deficiency of insulin secretion caused by pancreatic β-cell destruction, usually resulting from an autoimmune attack (insulitis) → Break in tolerance to β-cells or insulin 10% of all cases. Begins in childhood, manifests in adolescence (abrupt onset) Genetic predisposition HLA-DR3 and HLA-DR4 CD4-T lymphocytes, secrete INF-γ → activate CD8-T lymphocytes & macrophages (secrete IL-1, TNF) → damage β-cells, also activate Blymphocytes to produce auto AB against insulin or β-cells Micro: β-cell necrosis & lymphocytes infiltration (insuliti)) T-cell inhibitory receptor (CTLA-4) Viral infection

 Type 2 DM 

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Caused by a combination of peripheral resistance to insulin action and an inadequate compensatory response of insulin secretion by the β cells ("relative insulin deficiency").

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Obesity is strongly associated with DM ↑ secretion of resistin and free fatty acid from adipocytes in obese (causing insulin resistance) & Decreased adiponectin secretion (insulin sensitizer) in obese

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Thliazolinediones drug family activates PPARγ gene in fat cells & reverse the abnormalities FFA & hyperglycemia adversely affects β-cells both qualitatively (loss of normal response to glucose ingestion) and quantitatively (loss of β-cells & deposition of islet cell amyloid (amilin)

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80% to 90% of cases. Genetic + environmental (dietary habit) Genes not related to immune tolerance or insulin signaling pathway (still unknown) Insulin resistance precedes DM by decades

 Monogenic DM :   

A single genetic mutation causing DM (in contrast to most cases of types 1,2 are genetically complex (multiple susceptible foci) Rare Either affect β-cell function (MODY genes) or cellular insulin signaling

 Other causes of DM  Loss of pancreatic tissue (carcinoma, fibrosis)  Increased hormones antagonizing insulin: (GH, cortisol, glucagon, thyroxin, adrenalins)  CMV, Coxsackie B pancreatitis  Syndromes: Down, Kleinfelter, Turner  Gestational diabetes (increased insulin requirement on a background of resistance)  Drugs; β-agonists (causing hyperglycemia)

 Effect of hyperglycemia: 1. Non-enzymatic glycosylation of proteins (sticking or adhering of glucose to protein) a) Glycated hemoglobin (HgA1C): reflects history and degree of hyperglycemia, because normally there is a low element of glycation, which will rise in DM patient to >6% of total Hb, more rising the worse is the hyperglycemia. b) Glycated extracellular matrix in vessels: collagen will have permanent changes (cross linking), called advanced glycosylation end products (AGEs), causing entrapment of plasma proteins (lipoproteins), causing accelerated atherosclerosis. c) In renal glomeruli, glycated basement membrane → becomes thickened & entraps albumin.

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d) glycated serum proteins are entrapped in endothelium, causing release of cytokines & growth factors. In the kidney, causes increased endothelial permeability, mesangial proliferation & synthesis of extracellular matrix. 2. Activation of protein C o Secondary to cytoplasmic hyperglycemia o Activated protein C produces transforming growth factor (TGF-β), causing angiogenesis o Increased deposition of extracellular matrix and basement membrane o critical in retina = blindness 3. Intracellular hyperglycemia with disturbance in polyol pathways o Important in organs that are insulin independent (brain, nerves, vessels, lens, kidneys) o Intracellular glucose is metabolized into sorbitol & fructose → increasing intracellular osmolality & water influx → swelling o Sorbitol metabolism depletes cellular anti-oxidants → cell damage.

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 PANCREATIC ENDOCRINE NEOPLASMS      

PEN, or islet cell tumor 2% of pancreatic tumors Present in adulthood Single or multiple Functional or non-functional Benign (commonly 3 mm) usually acquired later in life - Micro-nodular, pigmented, familial (early in life), other endocrine hyperplasia

 Ectopic ACTH : o Paraneoplastic syndrome 1. Small cell carcinoma of lung (most common) 2. Carcinoid 3. Medullary thyroid carcinoma. 4. Islet cell tumor of pancreas. 5. Ectopic corticotrophin releasing hormone (CRH)

 Morphology o Pituitary gland: Crooke hyaline change or Crooke bodies: homogenous light basophilic intracytoplasmic material, composed of intermediate keratin filaments. The normal granular basophilic cytoplasm of corticotroph cells is lost due continuous negative feedback. o Exogenous or ectopic cortisol: bilateral cortical atrophy in adrenals (atrophy of fasciculata & reticularis) o Adrenal hyperplasia: diffuse thickening of the cortex, may show multiple & bilateral 0.5-2cm nodules (nodular hyperplasia). Combined adrenal weight 30-50 g

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 Adrenocortical adenoma :    

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Single, encapsulated, yellow mass, Weight ≤ 30g Micro: similar to normal zona fasciculate which contain vacuoles full of lipid. Can be non-functioning (called incidentalinoma) found incidentally. If functioning, the other adrenal is atrophic

 Adrenocortical carcinoma       

Large, not capsulated, weight ≥ 200 g Micro: anaplastic cells, hemorrhage, necrosis. Can be functioning or not. If functioning, the other adrenal is atrophic Mostly are Sporadic or syndromic as; Li-Fraumeni ‘mutation in p53 which tumor suppressor’ & Beckwith-Weidman. Metastasis to lymph nodes, lung, but NOT bone. Clinical features: - Insidious, chronic onset (except for small cell carcinoma) - Early: weight gain (central, moon face), hypertension. - Muscle atrophy - Hyperglycemia (inhibit uptake of glucose) - Hyperpigmentation (more obivious in cushing dis.) - Hirsutism. - Mood disturbance (depression). - Menstrual abnormality.

B) The Zone Granulosa; Hyperaldosteronism : Hypernatremia, hypokalemia, hypertension

 Primary hyperaldosteronism :    

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Adenoma (80% of cases), Conn syndrome. characterized by low serum renin Adenoma is solitary, encapsulated,