Adrenal cortex I (biosynthesis of adrenal steroids; renin-angiotensin and glucocorticoid physiology)

Transcription

1 Adrenal cortex I (biosynthesis of adrenal steroids; renin-angiotensin and glucocorticoid physiology) Dr. Szathmári Miklós Semmelweis University First Department of Medicine 24. February 2014.

2 The adrenal cortex It secretes steroids which: Control either salt and water balance mineralocorticoids Regulate metabolic processes glucocorticoids Modulate secondary sexual characteristics in females - androgens and estrogens The adult adrenal cortex consists three relatively distinct bands of cells The outermost layer zone glomerulosa, expresses 18-hydroxylase and 18-dehydrogenase activity aldosterone production The middle zone zone fasciculata, expresses the enzyme 17- hydroxylase cortisol and corticosterone production The innermost zone zone reticularis androgen (preandrogens) production

3 Biosynthesis of adrenal steroids The basic structure of steroids is built upon a five ring nucleus C19 steroids with ketone group at C17 are termed 17- ketosteroids (dominantly androgens) C21 steroids have 2-carbon side chain and a hydroxyl group at position C17 (glucocorticoid or mineralocorticod properties) Cholesterol from the diet and from endogenous synthesis is substrate for steroid genesis The uptake of cholesterol is mediated by the LDL receptors ACTH increases the number of LDL receptors

4 Adrenal steroid biosynthesis Cholesterol Pregnenolon 17OH-Pregnenolon DHEA Progesterone 17OH-Progesterone Androstenedione DOC 11-desoxycortisol Corticosterone ALDOSTERONE P450scc- side chain cleaving 21-hydroxylase CORTISOL 3β-hydroxysteroid dehydrogenase 11β-hydroxylase, 18-hydroxylase and 18-hydroxydehydrogenase 17-hydroxylase and 17,20 lyase

5 Steroid transport Cortisol circulates in the plasma as free cortisol (<5%). Only the unbound cortisol is filterable at the glomerulus protein-bound cortisol High affinity, low capacity transcortin (CBG). This binding is decreased in areas of inflammation, thus increasing the local concentration of free cortisol. Most synthetic glucocorticoid analogues bind less efficiently to CBG, this may explain the propensity of some synthetic analogues to produce cushingoid effects at low dose Low affinity, high capacity albumin cortisol metabolits are biologically inactive Aldosterone Is bound to proteins to a smaller extent An ultrafiltrate of plasma contains as much as 50% of circulating aldosterone

6 Steroid metabolism and excretion Glucocorticoids Daily secretion μmol with a pronounced circadian cycle The major enzyme regulating cortisol metabolism is 11β-OHsteroid-dehydrogenase Isoform 1 in liver acts as a reductase, converting the inactive cortisone to the active glucocorticod cortisol Isofom 2 is expressed a number of tissues and converts cortisol to the inactive metabolite, cortison. Mutation in the HSD11β2 gene causes the syndrome of apparent mineralocorticoid excess Mineralocorticoids Daily secretion μmol >75% is inactivated by conjugation with glucoronic acid. In case of congestive heart failure this rate of inactivation is reduced. Adrenal androgens The major androgen is DHEA and DHEAS The daily secretion mg

7 ACTH physiology ACTH is synthesized and stored in basophilic cells of the anterior pituitary The release of ACTH is stimulated by corticotropin releasing hormone (CRH) Beside the CRH the major controlling factors of ACTH release are influenced by the free cortisol concentration in plasma stress (surgery, hypoglycemia, exercise, emotional stress, pyrogens) causes release of CRH and arginine vasopressin, these changes enhance the ACTH secretion the sleep-wake cycle (a peak just prior to waking and a nadir before sleeping)

8 The effects of immune system on the HPA axis + CRH Hypothalamus + ACTH Hypophysis Interleukins (IL-1, IL-6) Cortisol Adrenal cortex - corticotrophin Immune challenge macrophages TNF and other toxic substances The physiological regulatory influence of glucocorticoids is to prevent the immune system from causing damage to the body

9 The principal controlling influences on aldosterone production Aldosterone Adrenal cortex Distal nephron K Na liver ECF angiotensinogen Angiotensin II ACE Tubular lumen Renin Afferent arteriole Angiotensin I Juxtaglomerular cells, pressure transducer, sensing renal perfusion pressure

10 Glucocorticoid physiology The term glucocorticoid is used for adrenal steroids whose predominant action is on intermediate metabolism. Their overall actions are directed at enhancing the production of the high-energy fuel, glucose, and reducing all other metabolic activity. Glucocorticoids bind to intracellular glucocorticoid and mineralocorticoid receptors with nearly equal affinity, however only glucocorticoids bind to the glucocorticoid receptors. The mean glucocorticoid is cortisol.

11 Glucocorticoid physiology Carbohydrate metabolism Antagonizes the secretion and the peripheral action of insulin on glucose uptake Stimulates hepatic gluconeogenesis Increases deposition of glycogen in the liver Protein metabolism Inhibits amino acid uptake and protein synthesis in extrahepatic tissues Potent protein catabolic agent in peripheral tissues such as muscle, skin, and bone Stimulates amino acid uptake of the liver which are gluconeogenesis precursors Fat metabolism Increases mobilization of fatty acids Stimulates the lypolysis in adipose tissue Increases the deposition of fat in the facial and truncal areas

12 Glucocorticoid physiology (other effects of glucocorticoids) Effect on immune response Mineralocorticoid activity mostly in case of cortisol excess Water metabolism Increases glomerular filtration rate, and negative feedback effect on vasopressin Cardiovascular effect Potentiating the vasoconstrictor effect of other vasoactive molecules such as catecholamine and even vasopressin Growth inhibitory effect on somatotrophin release and direct inhibitory action on insulin-like growth factor I production Response to stress various stressors are associated with dramatic increase in the blood concentrations of corticotrophin and cortisol

13 Mineralocorticoid physiology Effects on epithelia Aldosterone binds to the MR in the epithelial cells (in the renal cortical collecting duct) Sodium passively enters these cells from the urine via epithelial sodium channels and is actively extruded from the cell via the Na/K activated ATPase (sodium pump) located on the basolateral membrane. The sodium pump also provides the driving force of potassium loss into the urine through potassium selective luminal channels Water passively follows the transported sodium Hydrogen ion is also actively secreted There is an escape phenomenon (from the sodium-retaining action of aldosterone). Hemodynamic factors may play a role in the escape, the level of atrial natriuretic peptide is also increases

14 Mineralocorticoid physiology Effect on nonepithelial cells (neurons in the brain, endothelial cells, myocytes, vascular smooth-muscle cells) They do not modify sodium-potassium homeostasis The aldosterone in non-epithelial cells modifies the expression of several collagen genes controlling tissue growth factors, e.g. TGFβ, PAI-1, adiponectin, leptin Some effects on non-epithelial cells may be via nongenomic mechanism.

15 Regulation of aldosterone secretion Renin angiotensin system controls ECFV via regulation of aldosterone secretion Potassium ion directly stimulates aldosterone secretion, independently of the circulating renin-angiotensin system Indirectly modifies aldosterone secretion by activating the local renin-angiotensin system in the zona glomerulosa. (this effect can be blocked by ACE inhibitors) ACTH Stimulates aldosterone secretion, but this action is not sustained Sodium ion Decreasing sodium intake sensitizes the response of the glomerulosa cells to acute stimulation by ACTH, angiotensin II, and/or potassium Others Serotonin (Stim), dopamine (Inh), ANP (Inh)

16 Adrenal androgens Minimal effects in males In females several androgen-like effects, e.g. sexual hair, are largely mediated by adrenal androgens DHEA and androstenedione are weak androgens and exert their effects via conversion to the potent androgen testosterone in extraglandular tissues. Adrenal androgen production is regulated by ACTH, not by gonadotropins

17 Laboratory evaluation of adrenocortical function Blood levels ACTH is secreted in a pulsatile manner, leading to a rapid fluctuation superposed on the circadian rhythm (lower levels in the early evening). Peripheral plasma renin activity: the renin activity is measured by the generation of angiotensin I during a standardized incubation period (diurnal variation: peak values in the morning and a nadir in the afternoon. Cortisol: episodic secretion, and varies during the day with peak value at the morning and low levels in the evening. Aldosterone: like cortisol, and Increased by dietary potassium loading Increased by sodium restriction Increased by assumption of the upright position Adreanal androgens: measurement of the DHEAS is a useful index of adrenal androgen secretion

18 Urine levels Laboratory evaluation of adrenocortical function Urinary free cortisol correlate with states of hypercortisolism, reflecting changes in the levels of unbound, physiologically active circulating cortisol Urinary 17-ketosteroids In normal women 90% is derived from the adrenal In normal men 60-70% is of adrenal origin

19 Laboratory evaluation of adrenocortical function Stimulation tests diagnosis of hormone deficiency states Test of glucocorticoid reserve 25 U (0.25 mg) of ACTH iv., plasma cortisol measurements before, and 30 and 60 min after administration. Normal response: stimulated cortisol level >500 nmol/l (18 μg/dl), and the minimal stimulated increment of cortisol is >200 nmol/l (7 μg/dl) above baseline. Test of mineralocorticoid reserve Administration of a potent diuretic (40-80 mg furosemide), followed by 2-3h of upright position. Normal response: two- to fourfold increase in plasma aldosterone levels.

20 Laboratory evaluation of adrenocortical function Suppression tests to document hypersecretion of adrenal hormones involve measurement of the target hormone response after standardized suppression of its tropic hormone Tests of pituitary-adrenal suppressibility Overnight dexamethasone suppression test: The measurement of plasma cortisol at 8 A.M following oral administration of 1 mg dexamthesone previous midnight. Normal response: 8 A.M. value of plasma cortisol should be <140 nmol/l (5 μg/dl) Administration of 0.5 mg dexamethasone every 6 h for two successive days while collection of urine over a 24h period for determination of free cortisol and creatinine (in case of normal hypothalamuspituitary ACTH release mechanism, a fall in the urine free cortisol to <25 nmol/d (10 μg/d) is seen.

21 Laboratory evaluation of adrenocortical function Test of mineralocorticoid suppressibility: Expansion of extracellular fluid volume Iv. infusion of 500 ml/h of normal saline solution for 4 h, which normally suppresses plasma aldosterone levels to <140 pmol/l (5 ng/dl) from a normal sodium intake. High sodium diet for 3 days with 0,2 mg fludrocortisone twice daily. (normal response: urinary aldosterone excretion on the third day should be < 28 nmol/d (10 μg/dl)

22 Laboratory evaluation of adrenocortical function Tests of pituitary-adrenal responsiveness Insulin hypoglycemia test (iv regular insulin U/kg) to reduce the fasting glucose level to at least 50% below basal. Normal cortisol response is a rise >500 nmol/l Metyrapone test: administration of metyrapone (11βhydroxylase inhibitor) inhibition of conversation of 11-deoxycortisol (compound S) to cortisol CRH-test: 1 μg/kg ovine CRH iv, than measurement of plasma ACTH within min. Normal response: mean increment of the ACTH is 9 pmol/l (40 pg/ml) ACTH-test

23 Adrenal cortex hyperfunction. Cushing s syndrome and primary hypermineralocorticism Dr. Szathmári Miklós Semmelweis University First Department of Medicine 24. February 2014.

24 Cushing s syndrome, prevalence Cushing syndrome is a rare disease predominantly affecting women in the age group 30 to 50 years (The ectopic ACTH production occurs more frequently in male patients because of the higher prevalence of lung cancer) Incidence: 3.5/million/year Prevalence: 39/million

25 Causes of Cushing s syndrome Corticotrophin-dependent Cushing s syndrome Cushing s disease 64% Ectopic Cushing s syndrome 13% Ectopic CRH syndrome 1% Corticotrophin-independent Cushing s syndrome Adrenal adenoma 10% Adrenal carcinoma 8% Adrenal hyperplasia 2% Pseudo-Cushing s syndrome Depression 1% Alcoholism 1%

26 Cushing s syndrome (clinical features) 1. Gain of weight (due to steroid-induced lipogenesis, central obesity) 2. Decreased subcutaneous fatty tissue - thinness and easy bruising of the skin plethora, bleeding 3. Purple striae on lower abdomen, hip region, upper arms (due to catabolic effects on protein structures in the skin) 4. Acne and hirsutism (moderate). Dominant hirsutism suggest adrenal carcinoma) 5. Hyperpigmentation in the inguinal and axillar regions 6. Increased risk of bacterial and fungal infections 7. Proximal muscle weakness (due to steroid myopathy and hypokalaemia 8. Back pain (due to suppressed bone formation) 9. Amenorrhea (due to suppression of pituitary-ovarian axis by cortisol)

27 Cushing s syndrome (clinical features) 10. Psychiatric symptoms (depression, affective disorders) 11. Hypertension (due to sodium retention, cortisol excess causes increased mineralocorticoid activity) 12. Hyperglycemia (due to steroid-induced glukoneogenesis) 13. Hypokalaemia (due to mineralocorticoid effect of hypercortisolaemia) 14. Hyperlipidaemia 15. By children short stature (due to inhibition of growth hormone release and due to direct inhibitory effect of cortisol on the bone response to growth factors)

28 Cushing s syndrome purple striae The purple striae are found on lower abdomen, upper arms and thighs, which reflect the catabolic effects on protein structures in the skin. The thinness and easy bruising of the skin are additional manifestations of this process

29 Special clinical characteristics of Cushing s syndromes with different etiology 1. Adrenal adenoma: slow progression. Because of the suppressed ACTH (MSH) without hyperpigmentation. No hyperrandrogenism. 2. Adrenal carcinoma: rapid progression, dominant hirsutism. Severe hypertension and hypokalaemia because of presence of intermediate compounds with mineralocorticoid activity. Tumor-induced compression symptoms 3. Macronodular hyperplasia: familiarity 4. Ectopic ACTH-syndrome: sudden onset of symptoms, Extremely elevated ACTH hyperpigmentation. Extremely high cortisol level severe metabolic abnormalities. Weight loss instead of cushingoid habit. Symptoms of primary tumor.

30 Cushing s syndrome: Investigations 1. Characteristic but not specific laboratory abnormalities: Polyglobulia, leukocytosis, hypokalaemia, moderately elevated sodium, metabolic alkalosis, hyperglycemia, moderately elevated serum calcium level and alkaline phosphates activity. 2. Confirmation of cortisol excess: Overnight dexamethasone suppression test (1 mg oradexon at night, plasma cortisol at the morning; normally less than 5 μg/dl or 140 nmol/l, sensitivity 97-98%) Twenty-four hour urinary excretion of free cortisol > 140 nmol/d, or 50 μg/day, high sensitivity, lower specificity) CRH-test combined with dexamethasone (4x0,5 mg dexamethasone two days, thereafter 100 μg CRH and after 15 min. blood sample for plasma cortisol (plasma cortisol > 1,4 μg/dl suggests Cushing s syndrome)

31 Cushing s syndrome: Investigations 3. The differential diagnosis between ACTH-dependent and ACTHindependent Cushing s syndrome ACTH measurement ( <10 pg/ml suggests adrenal origin) High-dose dexamethasone suppression (4x2 mg two days): In case of Cushing s disease (the inhibitory effect of exogen glucocorticoids is partially maintained in corticotroph tumor cells) the urinary free cortisol excretion will decrease with 90%. Less decrease in free cortisol excretion suggests adrenal origin or ectopic ACTH secretion. Plasma DHEAS measurement: high value in Cushing s disease, low value in case of adrenal origin. In case of adrenal carcinoma the DHEAS value variable.

32 Cushing s syndrome: Investigations 4. Differential diagnosis between Cushing s disease and ectopic ACTH production In case of ectopic ACTH production the plasma ACTH is higher (in most patients the level is >40 pmol/l (200 pg/ml) High-dose dexamethasone suppression-test (low sensitivitiy and specificity) Metirapone-test ( 4x750 mg metirapone/day; 4 hours after the last metirapone intake blood sample for the measurement of 11-deoxycortisol; in case of Cushing s disease the elevation is more than 400%, in case of ectopic ACTHproduction the response is decreased. CRH-stimulation-test (After iv.100 μg CRH measurement of plasma ACTH and cortisol. In Cushing s disease the elevation of ACTH more than 35%, elevation of cortisol more than 20%. In case of ectopic ACTH production these values remain unchanged. Blood sample with catheterization of inf. v. sinus petrosus. Sinus petrosus inf. ACTH conc/peripheral blood ACTH conc > 2 in Cushing s disease.

33 Cushing s syndrome: Investigations Radiography: Radiography of the skull rarely reveals enlargement of sella turcica Sella CT or MRI (mostly microadenoma, the sensitivity is only about 50-60%) Abdominal radiography may reveal calcification in an adrenal tumor Abdominal CT or MRI Adrenal venography. This technique also allows sampling of the adrenal vein for cortisol determination in an attempt to demonstrate high concentration gradient between the adrenal vein and vena cava characteristic of the tumor.

34 Cushing s syndrome- treatment 1. Pituitary-dependent Cushing disease With transsphenoideal surgical approach the microadenomas can be selectively removed. External irradiation using cobalt source or radioactive implants of yttrium or gold have been used in selected centers. Bilateral adrenalectomy after irradiation of hypophysis (previously used method), however, in between 10-25% of cases the pituitary adenoma enlarged, resulted in rapid pituitary fossa expansion, as well as increased pigmentation due to escalating ACTH levels (Nelson s syndrome). On the basis that primary ACTH excess may be hypothalamus dependent attempts have been made to treat Cushing disease with: - Dopamine agonist, serotonin antagonist or ketakonazole.these treatments are supplemental managements when other therapies have produced incomplete results.

35 Cushing s syndrome- treatment 2. Primary adrenal lesions Surgical removal of the tumor (if the diameter of tumor is less than 6 cm laparoscopic surgery). During and after the surgery the glucocorticoid substitution is mandatory because of the atrophy of the contralateral adrenal gland. In case of adrenal carcinoma the control of the associated Cushing s syndrome is generally incomplete following surgery, and additional adrenal blocking drugs are needed: o,p -DDD, metirapone, aminoglutethimide, ketakonazole. In case of bilateral adrenal hyperplasia bilateral adrenalectomy following by glucocorticoid and mineralocorticoid substitution. 3. Pseudo-Cushing s syndrome Chronic alcoholism is associated with a number of clinical features suggesting cortisol excess: central obesity, striae, facial plethora, atrophy of skin, hypertension. Although the mechanism is not clear, evidence accumulated that CRH excess and impaired hepatic clearance of cortisol are responsible. Chronic depression: Although other clinical features may be lacking, patients show impaired suppressibility of plasma and urinary cortisol to exogenous steroid, indicative of increased neuroendocrine drive to hypothalamic CRH release. Normal suppressibility returns with successful treatment of the psychiatric disease.

36 5. Liddle-syndrome (increased potassium reabsorption in the kidney) Primary hyperaldosteronism and other mineralocorticoid excess states Definition: Mineralocorticoid excess, suppressed renin activity, hypertension, hypokalaemia, metabolic alkalosis. Etiology: 1. Primary hyperaldosteronism Autonomic adrenal adenoma arising from zona glomerulosa (30%) Bilateral hyperplasia of the zona glomerulosa (65-70%) 2. Hyperdesoxycorticosteronism Congenital adrenal hyperplasia (11ß-hydroxylase or 17α-hydroxylase deficiency Adrenal adenoma producing DOC 3. Apparent mineralocorticoid excess 11ß-hydroxysteroid-dehydrogenase deficiency Drug-induced 4. Cortisol resistance

37 Adrenal steroid biosynthesis Cholesterol Pregnenolon 17OH-Pregnenolon DHEA Progesterone 17OH-Progesterone Androstenedione DOC 11-desoxycortisol Corticosterone ALDOSTERONE P450scc- side chain cleaving 21-hydroxylase CORTISOL 3β-hydroxysteroid dehydrogenase 11β-hydroxylase, 18-hydroxylase and 18-hydroxydehydrogenase 17-hydroxylase and 17,20 lyase

38 Prevalence of primary hyperaldosteronism in hypertensive population Endocrinology, 144:2208, 2003

39 The prevalence of primary hyperaldosteronism in different hypertensive populations In the general hypertensive population < 10% In patients with resistant hypertension 17-23% In patients, who have positive family history for cerebrovascular event >20% In patient with spontaneous or diuretic druginduced hypokalaemia 40% In patients with incidentally discovered adrenal adenoma 1-10 %

40 Primary hyperaldosteronism Conn-syndrome - 30 % aldosterone-producing adenoma, 65-70% bilateral adrenal hyperplasia. The carcinoma and the familiar hyperaldosteronism are curiosity. - Female/Male ratio=2-3:1, generally occurs in the 4-5. decade but the hyperplasia can occur more frequently in young or late adulthood. - App. 1-8% of patients with essential hypertension 1. Aldosterone-producing adenoma (APA, 30% of cases) - Smaller than 1 cm, more common on left side - Generally soliter, almost never malignant - The production of aldosterone is partly independent: the renin activity is suppressed, the angiotensin-ii does not stimulate aldosterone production. In contrary, the control of ACTH on aldosterone production is maintained, the aldosterone level changes according to the diurnal variation of ACTH. The hypokalaemia can also suppress the production of aldosterone. Removing of the adenoma alleviates the symptoms.

41 Primary hyperaldosteronism 2. Idiopathic hyperaldosteronism (IHA, 65% of cases) -Bilateral diffuse or nodular hyperplasia due to the extraadrenal stimulation. The consequence will be the hyperplasia of zona glomerulosa with or without of hyperplasia of zona fasciculata. In contrast with APA the angiotensin-ii stimulates the aldosterone release. 3. Familiar hyperaldosteronism (1% of cases) -Type I.: Due to the genetic abnormality an steroid-hydroxylase activitiy exists, which is controlled by ACTH and instead of cortisol it produces aldosterone in the zona fasciculata. ACTH stimulates, angiotensin-ii does not stimulate aldosterone production. The hyperaldosteronism can be suppressed by glucocorticoids. -Type II.: So far it was detect only in 20 families. The clinical and biochemical symptoms are similar to cases of aldosterone-producing adenoma or idiopathic hyperplasia.

42 Glucocorticoid remediable hyperaldosteronism Chimerical 11β-hidroxylase/aldosterone gene on chromosome 8. Overproduction in the zone fasciculata of both aldosterone and hybrid steroids due to oxidation of cortisol.

43 Primary hyperaldosteronism 4. Aldosterone-producing carcinoma (1% of cases) - Large tumor ( 6cm), calcification and necrosis in the tumor -Severe clinical and heterogeneous biochemical symptoms (elevated aldosterone, DOC, 18OH-corticosterone, cortisol, sexual steroid levels) -Ectopic aldosterone-producing adenoma or carcinoma (kidney or ovarian carcinoma)

44 Primary hyperaldosteronism Clinical symptoms of classical aldosterone-producing adenoma Hypertension (sodium and water retention and increased vascular resistance). The treatments generally used in hypertensive patients are ineffective. Serious hypertensive complications. Headache (due to the hypervolaemia) Hypokalaemia is usually but not obligatory dominant feature of the clinical presentation, giving rise to symptoms such as muscle weakness and polyuria, psychiatric changes and cardiac arrythmias. Metabolic alkalosis Impaired glucose tolerance (direct effect of hypokalaemia on insulin secretion or/and increased glucocorticoid effect) Mild hypernatraemia Edema is characteristically rare due to the renal escape phenomenon

45 Primary hyperaldosteronism I. Investigations in primary hyperaldosteronism 1. Screening is necessary in patients: with hypokalaemia and hypertension with normokalaemic hypertension but ineffective treatment with familiar accumulation of hypertension with hypertension younger than 50 years of age 2. Characteristic routine laboratory results Serum potassium is less than 3.4 mmol/l Hypokalaemia can be masked by low sodium containing diet! Increased urinary potassium excretion (more than 10 mmol/, which does not change with potassium depletion. Mild metabolic alkalosis Mild hypernatraemia

46 The diagnosis of primary aldosteronism 1. Screening Aldosterone/renin ratio: positive test result: PAC/PRA > 30 ng/dl/ng/ml/h és a PAC > 15 ng/dl 2. Confirmation Confirmation of the autonom aldosterone production 3. Differential diagnosis Unilateral (adenoma) or bilateral (hyperplasia) disease

47 Primary hyperaldosteronism II. Investigations in primary hyperaldosteronism 3. Hormonal examinations High basal plasma aldosterone concentrations (> 20 ng/dl), together with suppressed plasma renin activity (< 1ng/ml/h). Hypokalaemia should be corrected before assessing aldosterone secretion, since it has direct inhibitory effect on adrenal aldosterone release, even from adenomas. Dynamic tests for the differential diagnosis of different forms of primary hyperaldosteronism and for the differential diagnosis of primary and secondary hyperaldosteronism with hypertension. postural test: after 4 hours lying position administration of 80 mg furosemid and 4 hours upright position or walking. Examination the renin dependency of aldosterone production. salt and/or fludrocortison-suppression-test (500 ml NaCl infusion/hour trough 4 hours with or without 4x0,1 mg fludrocortison/day captopril-test (inhibition of production of angiotensin-ii). 50 mg captopril at the morning in lying position dexamethasone-test (4x0,5 mg dexamethasone trough 3-4 weeks)

48 Primary hyperaldosteronism (dinamic tests for differencial diagnosis) Tests Normal response APA (ACTHdependent IHA (renindependent) FH-I. GSH (ACTH-dep) PRA PAC PRA PAC PRA PAC PRA PAC Postural test Salt-load and/or fludrocortisone Captopril Dexamethasone

49 Primary hyperaldosteronism Radiology: 1. CT (in APA the tumor is hypodens, the contralateral adrenal gland is atrophic 2. 75Se-cholesterol scintigraphy with dexamethasone suppression (4x0,5 mg daily trough 6 days). The suppression of ACTH does not inhibit the cholesterol uptake in APA, but inhibits the isotope uptake in IHA. 3. Adrenal venography and taking adrenal vein samples may be used to determine whether the excess aldosterone is unilateral or bilateral in origin. The normal adrenal vein/vena cava aldosterone concentration ratio is 10. In case of adenoma this value is

50 Primary hyperaldosteronism Therapy: In case of single adenoma: surgical removal. The serum potassium level will normalize within a few hours, the hypertension will normalize within a few days (in 50% of patients). Before the operation spironolactone is used to normalize the serum potassium level and to treat the hypertension. The normalization of blood pressure with spironolactone before the surgery anticipates the good effect of the tumor removal. In case of bilateral hyperplasia and in patients with APA because of contraindications of surgery treatment with an aldosterone antagonist, spironolactone ( mg/day) provides good long-term control of hypertension and hypokalaemia. In case of glucocorticoid remediable hypertension daily dose of mg dexamethasone at night can suppress the ACTH secretion and the high aldosterone levels, and normalize the blood pressure.

51 Mineralocorticoid excess states Hyperdesoxycortisolism 11ß-hydroxylase and 17α-hydroxylase deficiency Adrenal adenoma producing DOC Half of cases is malignant. Severe hypertension and hypokalaemia. In majority of cases 11ß-hydroxylase deficiency can be proven Apparent mineralocorticoid excess 11ß-hydroxysteroid dehydrogenase deficiency. This enzyme transform active cortisol to inactive cortisone. The cortisol binds to mineralocorticoid receptors of distal tube in kidney and produces symptoms of mineralocorticoid excess. Severe hypertension, hypokalaemia, polydipsia, left ventricle hypertrophy, nephrocalcinosis already during childhood or young adulthood. Treatment: Spironolactone and because of hypercalciuria hydrochlorothiazid. Cortisol resistance Glucocorticoid-receptor gene defect - Peripheral tissue cortisol resistance high plasma ACTH and cortisol levels the elevated ACTH stimulates the DOC, corticosteron and androgen production renin-suppression aldosterone suppression