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ENDOCRINE PATHOPHYSIOLOGY

ENDOCRINE PATHOPHYSIOLOGY. Disturbances of Adrenal Gland. Distribution of Cortisol in Plasma. Normal values (µmol/l). TOTAL. 75%. CBG 13 - 53. CORTISOL. (15 -70 µmol/l). Albumin 2 - 10.5. 15%. 10%. Free 1.4 - 7.

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ENDOCRINE PATHOPHYSIOLOGY

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  1. ENDOCRINE PATHOPHYSIOLOGY Disturbances of Adrenal Gland

  2. Distribution of Cortisol in Plasma Normal values (µmol/l) TOTAL 75% CBG 13 - 53 CORTISOL (15 -70 µmol/l) Albumin 2 - 10.5 15% 10% Free 1.4 - 7

  3. Factors Influencing the Concentration of Corticosteroid-binding protein in Serum • Increased CBG concentration • Hyperthyroidism • Hyperestrogenic states (pregnancy, estrogen treatment) • Diabetes • Congenital • Certain hematologic diseases • Decreased CBG Concentration • Congenital • Hypothyroidism • Protein deficient states: • malnutrition • nephritic syndrome • severe liver disease

  4. Action of Cortisol I. Target Organs Effect Liver Increases: gluconeogenesis, amino acid release, glycerol and FFA release Decreases: protein synthesis Extrahepatic tissues Inhibits: peripheral glucose uptake in muscle and adipose tissue Adipose Tissue Increases: lipolysis, release of glycerol and FFA Connective Tissue Inhibits: fibroblast  stria formation Bone Inhibits: bone formation by decreasing cell proliferation Stimulates: bone resorption  osteolysis the action of PTH and D3 vitamin Calcium Metabolism Increases: PTH secretion urinary Ca excretion Decreases: intestinal Ca absorption tubular reabsorption of phosphate

  5. Action of Cortisol II. Affected Function Effect Immunologic Increases: number of circulating PMN Decreases: number of monocytes, lymphocytes and eosinophils Cardiovascular Increases: cardiac output, vascular tone Renal Increases: GFR, sodium and water retention potassium excretion Central Nervous System Excess: euphoria, irritability, emotional lability impairment in cognitive functions Failure: apathy, depression, negativism etc. Decreases: TBG, T4  T3 conversion Thyroid Gonadal In man Decreases: responsiveness (lower testosterone) In females Decreases: LH responsiveness to GnRH low level of estrogen, amenorrhea

  6. Measurement of the Products Secreted by the Adrenal Gland • Plasma cortisol RIA, Competitive protein-binding assay fluorometric assay, HPLC • Plasma ACTH • Plasma beta-Lipotropin and β-Endorphin • Urinary corticosteroids • free cortisol • 17-Hydroxycorticosteroids • 17-Ketogenic Steroids

  7. Laboratory Evaulation of Adrenal Gland • Determine concentration of hormones or biologically inactive products • Examine the function of adrenal gland • ACTH stimulation test • Evaluate the hypothalamic-pituitary-adrenal axis • Suppression test: • Dexamethasone (low and high dose) • Stimulation tests: • Metyrapone test • CRH test • Hypoglycemia (with insulin)

  8. Metyrapone Test

  9. Acute Adrenocortical Insufficiency

  10. Clinical Features of Acute Adrenal Crisis • Hypotension and shock • Fever • Dehydration • Nausea, vomiting, anorexia • Weakness, apathy, depressed mentation • Hypoglycemia

  11. Waterhouse-Friderichsen’s Syndrome

  12. Chronic adrenocortical insufficiency

  13. Clinical Features of Primary Adrenocortical Insufficiency % • Weakness, fatigue, anorexia, weight loss 100 • Hyper pigmentation 92 • Hypotension 88 • Gastrointestinal disturbances 56 • Salt craving 19 • Postural symptoms 12

  14. Primary Adrenocortical Insufficiency(Addison`s Disease) • Major Causes: • Autoimmune (about 80%) • Tuberculosis (about 20%) • Rare Causes: • Adrenal hemorrhage and infarction • Fungal infection • Metastasis and lymphomatous replacement • Amyloidosis • Sarcoidosis • Radiation therapy • Congenital • Cytotoxic agents

  15. Secondary Adrenocortical Insufficiency • Etiology: • exogenous glucocorticoid therapy • Clinical Features: • usually chronic • no hyper pigmentation occurs • no volume depletion, dehydration electrolyte abnormalities, hypotension • Laboratory Findings: • anemia, lymphocytosis, eosinophilia • basal ACTH low or normal • ACTH reserve impaired • stimulation test subnormal

  16. Cushing`s Syndrome Clinical manifestation of chronic glucocorticoid excess. • ACTH dependent • Cushing`s disease • Ectopic ACTH syndrome • ACTH independent • Adrenal adenoma • Adrenal carcinoma

  17. Clinical Features of Cushing`s Syndrome • Obesity 94 % • Skin changes 84 % • Atrophy of the epidermis • Facial plethora • Striae • Hyper pigmentation • Hirsutism 82 % • Hypotension 75 % • Gonadal dysfunction 75 % • Amenorrhea • Decreased libido • Increased body hair • Psychologic disturbances 40 % • Depression • Poor memory etc. • Muscle weakness 60 % • Osteoporosis 58 % • Renal calculi 15 %

  18. Pathology of Cushing Syndrome • Anterior Pituitary Gland • Pituitary adenomas (90%) (micro <1 cm, macro >1cm) • Hyperplasia (Corticotroph cells) • Adrenocortical Hyperplasia (bilateral) • Simple adrenocortical hyperplasia • Ectopic ACTH syndrome • Bilateral nodular hyperplasia • Adrenal Tumors • Glucocorticoid-secretory adrenal tumors • Adrenal carcinomas

  19. Pathophysiology of Cushing`s Disease • Random ACTH secretion • Absence of normal • Failure in physiological feedback inhibition • Increased glucocorticoid secretion • There is no hyperpigmentation • Decreased secretion of TSH, GH, LH and FSH • Androgen excess • Woman: hirsutism, acne, amenorrhea • Men: decreased libido, impotence

  20. Ectopic ACTH syndrome • Random episodic secretion of ACTH • Elevated serum ACTH • Hyper pigmentation • Total feedback failure • Rapid onset Typical features of Cushing` syndrome are usually absent • Mineralocorticoid excess • Hypertension, hypokalemia

  21. Adrenal Tumors • Autonomous secretion random secretion, unresponsive to the manipulation of hypothalamic-pituitary axis • Adrenal adenomas secretion of one type of steroids, only • Adrenal carcinomas secretion of multiple adrenocortical steroids

  22. Primary Mineralocorticoid Excess(Conn`s Syndrome) • Etiology • Aldosterone-producing adenomas • Aldosterone-producing carcinomas • Hyperplasia • Deoxycorticosterone excess: a., 17-hydroxylase deficiency b., 11-hydroxylase deficiency

  23. Secondary Mineralocorticoid Excess • With Hypertension • Renovascular Disease (atherosclerosis, renal infarction etc.) • Renin-Secreting Tumors • Accelerated Hypertension • Estrogen Therapy • Without Hypertension • Sodium-Wasting Syndrome • Edematous States cirrhosis nephritic congestive heart failure • Bartter`s Syndrome (hypokalemia, hyperreninemia, hyperaldosteronism)

  24. Adrenogenital Syndrome

  25. Biosynthesis of Catecholamines TYROSINE  DOPA  DOPAMINE  NOREPINEPHRINE  EPINEPHRINE Tyrosine hydroxilase Dopa decarboxylase Dopamine -hydroxylase PNMT

  26. Metabolism and Inactivation of Catecholamine • Reuptake bye the Sympathetic nerve endings • Metabolism by Catechol-O-methyltransferase (COMT) • Metabolism by Monoamine oxydase (MAO) • Conjugation with Sulfate • Direct Excretions by the Kidney

  27. Physiologic Effects of Catecholamines • Cardiovascular: • Increase: rate and frequency of pulse, blood pressure • Extra vascular Smooth Muscle: • relaxation and contraction of myometrium • relaxation of intestinal and bladder smooth muscle • relaxation of tracheal smooth muscle • pupillary dilatation • contraction of bladder and intestinal sphincters • Metabolic Effects: • increased oxygen consumption • glucose and fat mobilization

  28. Disorders of Adrenal Medulla • Hypofunction • patients receiving glucocorticoid replacement therapy following adrenalectomy • orthostatic hypotension • Hyperfunction  Pheochromocytoma tumor arising from chromaffin cells in the sympathetic neuron system

  29. Common Symptoms in Patients with Hypertension Due to Pheochromocytoma • Symptoms during or following paroxysms • Headache • Sweating • Forceful heartbeat with or without tachycardia • Anxiety or fear of impending death • Tremor • Fatigue or exhaustion • Nausea and vomiting • Abdominal and chest pain • Symptoms between paroxysms • Increased sweating • Cold hands and feet • Weight loss • Constipation

  30. Diagnostic Tests and Procedures • Hormone assay: plasma or urine epinephrine, norepinephrine, dopamine vanillylmandelic acid (VMA) homovanillic acid • Glucagone test (Stimulation) to induce paroxysm(1 mg of glucagone iv.) • Clonidine test (Suppression) (0.3 mg clonidine) • Trial of Phenoxybenzamine

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