Primary and secondary hyperaldosteronism. Zsolt Turóczi, M.D. 2nd Department of Internal Medicine

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1 Primary and secondary hyperaldosteronism Zsolt Turóczi, M.D. 2nd Department of Internal Medicine

2 Adrenal gland

3 Adrenal cortex

5 Carey RM. Primary aldosteronism. Journal of Surgical Oncology 2012: 106;

6 Carey RM. Primary aldosteronism. Journal of Surgical Oncology 2012: 106;

7 Non-genomic effects oxidative stress, systemic inflammation (chronic) Insulin resistance Endothel dysfunction, relaxation disorder hypertension Heart cardiac fibrosis, remodelling, hypertrophia impaired diastolic function CVD (14-35%) Kidneys glomerular damage (membrane integrity disorder) proteinuria renovascularis effects interstitialis effects Chronic renal failure (8-24%)

8 Sowers et al Ann Intern Med. 2009; 150(11):

9 Mineralocorticoid overproduction Primary hyperaldosteronism Dezoxicorticosterone-producing adrenal tumors Congenital adrenal hyperplasia 11 -hydroxylase defect 17 -hidroxylase/17,20-liase defect Cortisol resistance Apparent mineralocorticoid excess Mineralocorticoid receptor mutations (activating) Liddle-syndrome Secundary hyperaldosteronism

10 Professor Jerome W. Conn, M.D., Sc.D. University of Michigen

Primary hyperaldosteronism (first documented case) 1954. apr.: 34 years old female.

11 Primary hyperaldosteronism (first documented case) apr.: 34 years old female. mild hypertension, hypokalaemia, hypernatraemic alkalosis, sustained renal function 1954 dec.: exploratory laparotomy: rigth adrenalectomy 1955: case report (J Lab Clin Med 45:661, 1955)

13 Prevalence suggested by Conn JAMA 190:220 (1964) I suggest....that as many as 20% of patients with so-called essential hypertension might be suffering from primary aldosteronism while still maintaining normal levels of serum electrolytes.

14 Prevalence suggested by Kaplan Clinical Hypertension textbook 5. ed. (1990) Primary aldosteronism [] has generated as many publications as the number of patients found to have it.

15 Prevalence of hyperaldosteronism Reality: 5-10% Fardella CE, et al. J. Clin Endocrinol Metab Lim PO, et al. J Hum Hypertens : Mosso L, et al. Hypertension : Rossi GP, & PAPY Study Investigators. J Am Coll Card Lars C. et al. Dtsch Arztebl Int 2009; 106(18): Therapy resistent hypertension 17-22% Calhoun DA, et al. Hypertension 2002; 40: Strauch B, J Hum Hypertens 2003;17:

16 Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. Funder J, Carey R, Fardella C, Gomez-Sanchez C, Mantero F, Stowasser M, Young W, Montori VM. J Clin Endocrinol Metab 2008, 93(9):

17 Primary hyperaldosteronism

18 Symptoms In 100% of the patients Hypertension Suppressed plasma renin activity Elevated plasma aldosteron levels in less than 50% Paraesthesia Seeing disorder Intermitting muscle paralysis Tetany In 50 90% Headaches Hypokalaemia/hypernatraemia Muscle weakness/tiredness Arrthymias, Polyuria/polydipsia Impaired glucose tolerancy Alkalosis

19 Suspect for primary hyperaldosteronism Hypertension and hypokalaemia Therapy resistant hypertension (3 or more antihypertensive drug combination with maximal dose) Adrenal incidentaloma and hypertension Anamnesis Young age (under 20 y), stroke under 40 years Severe hypertension (>160/100 mm Hg)

20 Screening Aldosteron-renin ratio (ARR) Standardized sample collection (morning, 15 min rest, normokalaemia) Drug interactions ACE-I, duretics, hypokalaemia: decrease beta-blockers, central alpha2 agonists: increase Funder J, et. al. J Clin Endocrinol Metab 2008, 93(9):

21 Evaluation of ARR Can not be assessed spironolacton eplerenon amilorid False positive results Beta blockers Alpha-methyldopa Clonidin NSAIDs False negative results ACE-inhibitors ARBs Other diuretics Dihidropiridin calciumchannel blockers Estrogenes

22 Correct evaluation For 6 weeks spironolactone eplerenone amilorid Estrogenes Do not need to Doxazosin Prazosin Verapamil Hidralazin For 2 weeks ACE-inhibitors ARBs Diuretics Dihidropiridin calcium-channel inhibitors Beta blockers Alpha-methyldopa Clonidin NSAIDs

23 Normal values aldosterone (1 ng/dl 27,7 pmol/l) plasma renin activity (1 ng/ml/h 12,8 pmol/l/h) direct renin assessment (1 ng/ml/h 5,2 vs. 7,6ng/l) Primary hyperaldosteronism: Aldosterone-renin ratio > (ng/dl) / (ng/ml/h) (30%) Secondary hyperaldosteronism: <10 (ng/dl) / (ng/ml/h) Funder J, et. al. J Clin Endocrinol Metab 2008, 93(9):

24 Confirmation Oral saline load 300 mmol (6g) Na/ die for 3 days Daily K+ control, 24 h urine collection on the last day urinary aldosterone > 12 μg/die (33.3 nmol/die) urinary Na > 200 meq/24 h Mulatero P et al. Confirmatory tests in the diagnosis of primary aldosteronism. Horm Metab Res. 2010; 42 (6):

25 Confirmation Intravenous saline load 2l 0,9% NaCl solution over 4 hours ; patient at rest (sitting position) serum aldosterone > 5 ng/dl urinary Na > 200 meq/24 h Considerations: CRF, CHF, AF Sensitivity: 90%, Specificity: 84% Mulatero P et al. Confirmatory tests in the diagnosis of primary aldosteronism. Horm Metab Res. 2010; 42 (6):

26 Confirmation Fludrocortisone suppression test 3x30 mmol Na (slow-release) + 4x0,1 mg fludrocortizone for 4 days. serum aldosterone (10 am) > 6 ng/dl (166 pmol/l) plasma renin activity < 8.4 mu/l (1 ng/ml/h) Considerations: CRF, CHF - normokalaemia - serum cortizol (8 am > 10 am) Mulatero P et al. Confirmatory tests in the diagnosis of primary aldosteronism. Horm Metab Res. 2010; 42 (6):

27 Captopril challenge Confirmation 1 hour rest mg captopril 2 hour rest serum aldosterone > ng/dl aldosterone renin ratio > ng/dl/ng/ml/h) Considerations: CRF, CHF Increased false positive, false negative results Mulatero P et al. Confirmatory tests in the diagnosis of primary aldosteronism. Horm Metab Res. 2010; 42 (6):

28 Other (less used) tests Confirmation Furosemide upright test (40 mg iv., 2h) Losartan test (50 mg po., 2h) Mulatero P et al. Confirmatory tests in the diagnosis of primary aldosteronism. Horm Metab Res. 2010; 42 (6):

29 Which test should be performed? 1. Fludrocortizon test hospitalization 2. Intravenous saline load 3. Oral saline load 4. Captopril test Mulatero P et al. Confirmatory tests in the diagnosis of primary aldosteronism. Horm Metab Res. 2010; 42 (6):

30 Subtype confirmation 1. Aldosterone producing adenoma (APA) 30-35% 2. Bilateral adrenal hyperplasia (BAH) 65% 3. Familial forms Familial hyperaldosteronism type I (FH-I) 0,66-1% Familial hyperaldosteronism type II (FH-II) 2,8-6% Familial hyperaldosteronism type III (FH-III) N/A 4. Aldosterone producing carcinoma <1% 5. Ectopic adostern producing tumor unique

31 APA vs. BAH Aldosterone-producing adenoma severe symptoms fluid excess/ortostasis does not increase the aldosterone levels aldosterone precursors (18-hydroxicorticosterone) ACTH sensitive Bilateral adrenal hyperplasia mild symptoms fluid excess/ortostasis do increase the aldosterone levels

32 APA vs. BAH

33 Subtype confirmation 1. CT (MRI) scan nodules <1 cm (most nodules are mm) functioning vs non-functioning (2-10%) nodules 2. Adrenal venous sampling gold standard procedure hard to perform (96%) not required if: patient <40 years old, nodule is >1 cm. Rossi GP. Diagnosis and treatment of primary aldosteronism. Endocrinol Metab Clin North Am. 2011; 40:

38 Adrenal venous sampling Succesful: cortisol gradient >2 or >3 Aldosteron/cortisol ratio >2 and > contralateral

41 Subtype confirmation through history

42 NP-54 SPECT

43 Glucocorticoid remediable familial hyperaldosteronism Type I autosom dominant inheritance increased production of hibrid steroids (18-hydroxi-cortisol, 18-oxo-cortisol) suppression of ACTH production abolishes the clinical symptoms CYP11B1 / CYP11B2 gene chimera (8q24) Gill JR, J Clin Endocrinol Metab 53:331, 1982.

44 Aldosterone synthase/11-hydroxylase gene chimera

45 Aldosterone synthase/11-hydroxylase gene chimera

46 Familial hyperaldosteronism type II 2 or more family members are involved Autosomal dominant inheritance Gene localized at 7p22 (FOXK1, FSCN1, RNF216, EIF2AK1 and RAC1) No mutations

47 Familial hyperaldosteronism type III Autosomal dominant inheritance Germ cell mutations in the KCNJ5 gene (Kir3.4 K+ channel) Constitutive aldosteron secretion, cell proliferation Massive bilateral adrenal hyperplasia Therapy resistent hyperaldosteronism Bilateral adrenalectomy required

48 Monticone et al. Understanding primary aldosteronism: impact of next generation sequencing and expression profiling. Mol Cell Endocrinol. 2015; 399:

51 1. Surgery APA or BAH (highly selected cases SR: 19%) Hypertension is cured in 50% Improves self-assessed quality of life 2. Medical therapy Mineralocorticoid receptor antagonist spironolactone 12,5-50 mg/die (side effects), eplerenone mg/die (not approved) +/- angiotensin II receptor blockers Collecting duct acting diuretics Amilorid 2,5-20 mg/die Therapy

52 Mattsson C, Young WF, Primary aldosteronism: diagnostic and treatment strategies. Nat Clin Pract Nephrol. 2006; 2:

53 Steroid biosynthesis defects 11 -hydroxylase 17 -hydroxylase/17,20-liase Prevalence 1:100, published cases Symptoms hypertension, se.k hypertension, se.k hyperandrogenism hypogonadism Hormonal DOC, PRA DOC, PRA alterations androgenes sexual steroids cortisol cortisol Genetics CYP11B1 SNP CYP17 SNP (rarely del, ins) del, dupl, ins, exon del (exon 2, 7),

54 Chracteristics Symptoms of mineralocorticoid overproduction Antagonists do not decrease/abolish symptoms Intrauterin growth retardation Increased cerebrovascular complications Asypmtomatic parents (recessive inheritance?)

55 Hormonal characteristics Plasma levels of coricosteroids are normal Half-life of plasma cortisol increases from 80 to minutes low cortisone levels

56 Cortisol cortisone shuttle

57 Pathomechanism

58 Secondary hyperaldosteronism With hypertension Renovascular disease Renin-secreting tumors Malignant hypertension Pheochromocytoma Without hypertension Hyponatraemia, hypovolaemia (salt-wasting sy) Edema generating conditions congestive heart failure, nephrosis/nephritis syndrome, cirrhosis

59 Secondary hyperaldosteronism Secondary hyperaldosteronism with hypertension Arteria renalis stenosis Coarctatio aortae Malignant hypertension Chronic nephritis Renin-producing tumors Drug-induced (estrogenes)

60 Secondary hyperaldosteronism Secondary hyperaldosteronism with normotension Congestive heart failure Cirrhosis Idiopathic edema Gastrointestinal diseases (vomiting, diarrhea) Renal disease Renal tubular acidosis Nephrosis Bartter syndrome Gitelman syndrome Pseudo-Bartter syndrome

61 Secondary hyperaldosteronism Reason Hypovolaemia in the juxtaglomerular apparat Increased renin secretion Increased aldosterone secretion

62 Bartter syndrome first described in 1962, 1.7 of 100,000 defect in the thick ascending loop of Henle impaired salt reabsorption polyuria/polydypsia normotensive hypokalemic metabolic alkalosis hyperreninemic hyperaldosteronemia juxtaglomerular complex hyperplasia The prevalence of BS is 1.7 of 100,000 [7]. short stature, growth and mental retardation. BS type 3: harbor mutation in CLCNKB gene Manifests in infants or early childhood.

63 Gitelman syndrome first described in 1966 mutation in SLC12A3 gene (NaCl co-transporter (NCCT) mild manifestation, delayed presentation (in late childhood or adulthood) hypocalciuria, and hypomagnesemia [11].

64 Treatment Indometacin Spironolactone KCL Magnesium

65 Aldosterone in CHD Randomized ALdactone Evaluation Study (RALES) Duoble-blind, placebo-controlled Patients qith CHF (EF 35%) Additional spironolactone therapy (25 mg) N Engl J Med 341:709, 1999

66 Aldosterone in CHD Randomized ALdactone Evaluation Study (RALES) N Engl J Med 341:709, 1999

67 Aldosterone in CHD EPlerenone post-acute myocardial infarction HEart failure efficacy and SUrvival Study (EPHESUS) Duoble-blind, placebo-controlled Patients with CHF or previosus AMI Additional eplerenone therapy (25-50 mg) N Engl J Med 341:709, 1999

68 Aldosterone in CHD EPlerenone post-acute myocardial infarction HEart failure efficacy and SUrvival Study (EPHESUS) N Engl J Med 341:709, 1999

Primary aldosteronism clinical practice guidelines: a re-appraisal The Management of Primary Aldosteronism

Primary aldosteronism clinical practice guidelines: a re-appraisal The Management of Primary Aldosteronism Prof. FRANCO MANTERO Division of Endocrinology University of Padua Italy Case Detection, Diagnosis