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Laboratory Medicine and Pathobiology
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LECTURE NINE: ADRENAL DISEASES ADRENAL GLANDS AND HORMONES  Adrenal Gland: Small triangular shaped glands situated just above the kidney. They enlarge in chronic stress.  The hormones of the adrenal glands are essential for survival (the adrenal gland also helps make the reproductive hormone)  Adrenal consists of cortex (outside) and medulla (part of the sympathetic nervous system)  Adrenal cortex consists of: Zona Glomerulusa (this is the most outer layer; Aldosterone), Zona Fasciculate & Zona Reticularis (cortisol and adrenal androgens and estrogens)  Adrenal medulla – epinephrine, norepinephrine, dopamine ACTH (this is there driver of the cortisol synthesis BIOSYNTHESIS OF STEROID HORMONES Cholesterol side-chainHOLESTEROL (this is the precursor for the steroid hormone) cleavage enzyme 17 OH’ ase (this is the important enzymes for these 2 (cortisol and te17, 20 OH’ ase PREGNENOLONE -----------------------------------------> 17-OH PREGNENOLONE ----------------------------- 3β-hydroxysteroid Dehydrogenase / Isomerase PROGESTERONE 17-OH PROGESTERONE ANDROSTENEDIONE 21 OH’ ase DEOXYCORTICOSTERONE 11-DEOXYCORTISOL TESTOSTERONE 11 OH’ ase CORTICOSTERONE CORTISOL 18 OH’ ase – this is the important enzyme for this one ALDOSTERONE CORTISOL (it is also a counter regulatory hormone) – PHYSIOLOGY  Effects on metabolism: - Carbohydrate – promotion of gluconeogenesis (this is the making of new glucose in response to hypoglycemia) in liver, reduction in glucose use and uptake by peripheral tissues (helps us save the glucose that we have) - Protein – increase of muscle proteolysis to release the proteins - Fat – activation of lipolysis and release of free fatty acids * When present in excess, glucocorticoids cause central distribution of fat -- face, neck and trunk. (there is a redistribution of fat in cases of excess cortisol production)  Circulating forms: - 90% - 98% protein bound to cortisol-binding globulin (CBG) and albumin. CBG is increased in pregnancy and estrogen treatment. (the free form is the biologically active form – though most of its bound up)  Metabolic fate: after liver conjugation (this is under the normal physiology), excreted in urine (when there is excessive free cortisol it can also be gotten rid of in the urine (i.e. it is too much and can’t be bound by the binding proteins or albumin)  Hypothalamic – pituitary – adrenocortical axis CUSHING’S SYNDROME (it is a group of diseases that have the cortisol excess)  Results from prolonged excessive exposure of body tissues to cortisol or other glucocorticoid  Causes: - pituitary ACTH-producing tumor – Cushing’s disease (ACTH will be stimulating the adrenal to male more cortisol – this specifically Cushing’s disease (due to the tumor)) - ectopic ACTH (it is made by other cancer cells not in the pituitary): ACTH produced by the cells other than pituitary, e.g. small cell carcinoma in the lung may secrete ACTH - adrenal cortisol-producing tumor (adenoma or carcinoma): this is independent of ACTH - exogenous glucocorticoids (taken orally, inhaled or applied topically): cortisol-like compounds or medications CLINICAL FEATURES OF CUSHING’S SYNDROME - Not all of the patients have the same clinical picture but these are the common ones  Baldness and facial hirsuitism in females -Acne -Buffalo hump  Moon face -Plethoric cheeks - Hypertension  Osteoporosis (cortisol promotes bone lysis and inhibit the formation of the bone)  Skin thinning (the fat has gone somewhere else (abdominal)) - Increased abdominal fat (this is due to the redistribution of the fat)  Abdominal striae (purple stripes of the blood vessels (the skin is thinned and the blood vessels are exposed)  Easy bruising - Poor wound healing -Avascular necrosis of femoral head  Muscle weakness (due to the protein breakdown (lysis)) DIAGNOSIS OF CUSHING’S SYNDROME  Screening test: 24 hr urinary free cortisol (cortisol exceeds the plasma protein binding capacity, so unbound cortisol is filtered into urine) – elevated in Cushing’s; but stress and obesity can cause false positive results  Plasma cortisol: measured at 8:00am and 22:00pm. The normal ACTH DEPENDENT circadian rhythm (high peak in the morning) is not apparent in the patient with Cushing’s.  Low dose (1 mg) dexamethasone (cortisol analogue) test: suppresses cortisol production (>50%) in normal subject but not in patients with Cushing’s syndrome.  High dose dexamethasone test – for differential the cause of Cushing’s: suppresses cortisol production (>50%) in Cushing’s disease but not in other Cushing’s syndrome caused by adrenal adenoma or carcinoma, ectopic production of ACTH  Plasma ACTH: suppressed in adrenal tumors and very high in ectopic ACTH secreting tumors CASE 1, a 30-YEAR MAN WITH CUSHING’S  Clinical presentation: obese (fat redistribution), hypertensive (due to the cortisol production), glucose intolerance (this is due to the cortisol counter to the insulin effect), wasting of proximal limb muscles (due to the excessive cortisol), and abdominal striae  Laboratory findings: 1. Screening: Plasma cortisol concentrations measured at 8:00am was 400 nmol/L, and at 22:00pm 400 nmol/L. (the levels of the cortisol don’t change with the time of the day (possibility of Cushing’s) 2. Confirmation of Cushing’s: Low dose dexamethasone test: baseline 420 nmol/L, post 410 nmol/L (there is no suppression of the cortisol levels) 3. Differential diagnosis of cause of Cushing’s: - High dose dexamethasone test: baseline 420 nmol/L, post 400 nmol/L (hence it is not Cushing’s disease) - Plasma ACTH: at 8:00am, 150 ng/L (RI 7-51) (this is the high levels of ACTH from the pituitary (hence it cannot be caused by an adrenal tumor (levels of ACTH would be low)))  Diagnosis? Ectopic ACTH secreting tumor ALDOSTERONE – PHYSIOLOGY  Produced exclusively by the Zona Glomerulosa (this tissue possesses the specific enzyme to make cortisol) (lacks 17-hydroxylase but has 18-hydroxylase and 18-hydroxysteroid dehydrogenase for aldosterone biosynthesis)  Regulation of synthesis and secretion: primarily by the renin-angiotensin system (not using the HPA axis). Other factors, including ACTH, potassium are also involved.  Biological effect: - Sodium and water retention - Potassium and hydrogen ion secretion. * Raises BP (this is due to the NA and water retentio
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