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hyperaldost

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    1. HYPERALDOSTÉRONISME PRIMAIRE André Lacroix, MD Service d’endocrinologie Centre hospitalier de l’Université de Montréal Cours Résidents de Médecine Programme de Médecine Interne 27 février 2008 Dear colleagues I wish to thank the organizing committee for inviting me to participate in this exciting symposium and to share the work done by our group over the last 15 years on the role of aberrant hormone receptors in adrenal Cushing’s syndromeDear colleagues I wish to thank the organizing committee for inviting me to participate in this exciting symposium and to share the work done by our group over the last 15 years on the role of aberrant hormone receptors in adrenal Cushing’s syndrome

    2. Primary adrenal Cushing’s syndrome is most often secondary to unilateral benign or malignant cortisol secreting tumors However in approximately 10% of cases, bilateral lesions are present and can be secondary either to PPNAD with or without Carney ’s complex To bilateral adenomas or to bilateral AIMAH The pathophysiology of theses lesions is becoming progressively better known and include Gs a constitutive activation in isolated bilateral macronodular adrenal hyperplasia or McCune Albright Aberrant hormone receptors in AIMAH and unilateral adenomas which I will concentrate on as my expert symposium colleagues will cover the next two topicsPrimary adrenal Cushing’s syndrome is most often secondary to unilateral benign or malignant cortisol secreting tumors However in approximately 10% of cases, bilateral lesions are present and can be secondary either to PPNAD with or without Carney ’s complex To bilateral adenomas or to bilateral AIMAH The pathophysiology of theses lesions is becoming progressively better known and include Gs a constitutive activation in isolated bilateral macronodular adrenal hyperplasia or McCune Albright Aberrant hormone receptors in AIMAH and unilateral adenomas which I will concentrate on as my expert symposium colleagues will cover the next two topics

    4. Cortex Surrénalien

    5. Normal regulation of cortisol secretion

    6. Other regulators of adrenal cell

    7. Synthetic pathways for adrenal steroid synthesis

    8. Aldosterone effects on the kidney

    9. Definition: primary aldosteronism Syndrome resulting from excess production of aldosterone Renin-independent production Causes cardiovascular damage, hypertension, sodium retention, renin suppression, potassium excretion that if prolonged and severe may lead to hypokalemia Funder et al J Clin Endocrinol Metab 2008, in press

    10. Epidemiology of primary aldosteronism 29-31 % incidence of HBP in USA population > 18 yo (NHANES) Low-renin essential hypertension: 25% Primary aldo: 0.05-2.2 % of HBP (1970-1990) Primary aldo: 7-10% of HBP (1995-2008) Mulatero et al J Clin Endo Metab, 89:1045, 2004 Rossi et al J Am Coll Cardiol 48:2293, 2006 Mosso et al Hypertension 42: 161, 2003 Gordon et al Clin Exp Pharmacol Physiol 21:315:1994

    11. Etiologies of Primary Aldosteronism Aldosterone-producing adenomas (APA): 30-60 % ACTH-responsive (80-85%) Renin-responsive (15-20%) Idiopathic hyperaldosteronism (IHA): 40-70 % Primary adrenal hyperplasia (PAH): < 2% Bilateral macronodular adrenal hyperplasia: < 2% Aldo/DOC-producing adrenal carcinoma: < 2% Aldosterone-producing ovarian tumor: < 1% Familial hyperaldosteronism (FH): < 2% Glucocorticoid-remediable aldosteronism (GRA;FH type I) Familial hyperaldosteronism type II (APA or IHA)

    12. Glucocorticoid-remediable aldosteronism

    13. Clinical presentation PA Slight hypervolemia, no oedema HBP: 184/112 in adenoma and 161/105 in IHA (Ann Intern Med 121:877, 1994). Rare malignant HBP Hypokalemia: K<3.5 in 50% APA and 17% IHA Metabolic alcalosis Na+: 143-147 meq/L (vasopressin suppression) Hypomagnesemia Muscle weakness when hypokalemia is severe Increased cardiovascular risk: stroke, MI, AF

    15. Differential diagnosis HBP and hypokalemia Primary Aldosteronism Renovascular hypertension Thiazide diuretics Cushing’s syndrome (ectopic ACTH or very high UFC) Licorice :glycyrrhetinic acid inhibition of 11BHSD2 Apparent mineralocorticoid excess (AME: 11BHSD2 mut) Congenital adrenal hyperplasia: CYP17 or CYP 11B1 Renin-secreting tumors (mostly young patients) Liddle’s syndrome (mutations beta- gamma-ENaC) Glucocorticoid resistance

    20. Recommendations:case detection Aldosterone/renin ratios: Moderate, severe, resistant hypertension HBP and hypokalemia HBP and adrenal incidentaloma HBP and family history of early HBP or stroke before 40 y.o. First-degree relatives of cases of PA

    21. Drugs with little effects on aldosterone secretion

    22. Factors which affect ARR

    23. Factors which affect ARR

    24. Conduct of ARR Correct hypokalemia Liberal salt intake Discontinue spironolactone-eplerenone-amiloride-thiazides-licorice x 4 weeks If ARR not diagnostic, stop B-blockers, clonidine, methyl-dopa, AINSA, ACE, ARB, renin-inhibitors, dihydropyridine CCA x 2 weeks Stop estrogens if using renin concentration Mid-morning, ambulant > 2h, after sitting x 5-15 min Funder et al 2008, submitted

    25. Conduct of ARR Discontinue spironolactone-eplerenone x 6 weeks Continue other drugs unless high doses of amiloride triamterene If renin elevated with ACE or ARB: could be false negative If renin suppressed with B-blocker: could false positive Morning around 8 h00 Young, Kaplan, Rose, UpToDate 2007

    26. Interpretation of ARR Plasma aldosterone: 1 ng/dL: 27.7 pmol/L > 15 ng/dL (> 416 pmol/L); some authors, not consensus Renin activity of 1 ng/ml/h of Ang-1converts to 8.4 mU/L of direct renin concentration Importance of sensitivity of renin assay in low ranges: more data on PRA with long incubations Positive ratios > 20-40 (> 555 in SI units) Negative ratios: <10 (<277 in SI units) Young, Kaplan, Rose, UpToDate 2007 Funder et al submitted 2008

    29. Confirmatory tests for PA Oral sodium loading (6g x 3 days) and 24-h urinary aldosterone >12-14 mcg/d (>33-38 nmol/d (replace potassium adequately). Ur Na+ > 200 meq/d Saline 0.9% 2L/4 h infusion in supine posture: aldosterone at 4 h: > 277 nmol/L (10 ng/dL): PA; 138-276 nmol/L unclear Florinef 100 mcg q6h x 4 days oral: K+ supplements and monitoring q 8h. Aldo on day 4 > 6 ng/dL (>162 nmol/L) with PRA < 1 ng/ml/h Captopril 25-50 mg oral after sitting 1 h. Aldo 1-2 hr later decreases <30% and PRA remains suppressed

    30. Adrenal imaging Adrenal CT without contrast is recommended, mainly to exclude rare large adrenal carcinoma or bilateral macronodular adrenals Small irregular adrenal nodules < 1cm are not of sufficient diagnostic value MRI has no advantage over CT for evaluation of PA. It is more expensive and has less spatial resolution than CT Iodocholesterol is of little value and limited availability

    31. Adrenal vein sampling When surgical treatment is desired and possible, distinction between unilateral and bilateral disease should be made by adrenal vein sampling Experienced angioradiologist (right adrenal vein success >75-90%) Certain centers do surgery without sampling in patients < 40 y.o. with unilateral nodules > 2 cm Sequential vs simultaneous bilateral sampling ACTH bolus 250 mcg vs perfusion with 50 mcg/h Aldosterone/cortisol ratios post ACTH between each side: unilateral > 4:1 ratio on side of adenoma; < 3: bilateral disease

    32. Adrenal vein sampling in PA

    33. Adrenal vein sampling in PA

    34. Testing for glucocorticoid-remediable aldosteronism (GRA) FH-1 is autosomal dominant Clinically highly variable Family history of early severe hypertension or hemorragic stroke Genetic testing by Southern blot or long PCR reaction: more reliable than dexamethasone test International Registry GRA www.brighamand womans.org/gra/introduction.aspx

    35. Treatment of Primary Hyperaldosteronism Surgery: Aldosterone-producing adenomas (APA): Primary adrenal hyperplasia (PAH): Aldosterone-producing adrenal carcinoma: Aldosterone-producing ovarian tumor: Medical therapy: Idiopathic hyperaldosteronism (IHA): Glucocorticoid-remediable aldosteronism (GRA)

    36. Surgery: First Choice for APA « The treatment of choice for APA and PAH is unilateral total adrenalectomy » Dluhy RG, Williams GH: Williams textbook 1998 Edwards CW: De Groot textbook 1995 GangulyA, N Engl J Med 339 1828-34, 1998 Young WF, The Endocrinologist 7: 213-21 1997 Gordon RD, J Endoc Invest 18: 495-511 1995

    37. Surgical Treatment of Primary Aldosteronism Of 694 APA in19 series : 69% cured following adrenalectomy others improved Of 99 cases of IHA in 10 series: 19% cured following uni- or bilateral adrenalectomy Young WF et al Mayo Clin Proc 65:96-110 1990

    38. Factors Influencing Outcome of Surgery for PA 42 patients with PA 1970-1993 62% BP cures in APA Predictors of response: response to aldactone in APA(89%): OR= 8.2 age <44 vs >44 yo: OR= 6.2 duration HBP <5 vs > 5 years: OR= 5.1 Celen, O’Brien, Melby, Beazley, Boston U Med Cen, Arch Surg 131:646-50, 1996

    39. Medical Therapy Prior to Surgery in APA « Blood pressure response to spironolactone before surgery can be a predictor of surgical outcome in APA but not in IHA » Spark RF, Melby JC: Ann Intern Med 69:685-95, 1968 Brown JJ et al. BMJ 2:729-34, 1972 Saruta T et al., Acta Endocrinol 116:229-34, 1987

    40. Persistent HBP in APA after adrenalectomy: vascular damage of long-term HBP ? 32 patients with APA 19 cured and 13 persistent HBP Open renal biopsies at time of surgery Equal duration of HBP in both outcomes No differences in renal vascular pathology Conclusion: coexisting essential HBP Grady, et al Urology 48:369-72, 1996

    41. Long-term Medical Management of APA Retrospective study of 24 patients (15 M, 9 W) with APA treated medically after refusal of surgery Minimum of 5-yr follow-up (5-17 y); mean 8.7 years APA diagnosis by CT scan; no venous samples Treatment at final assesment: 4: potassium sparing diuretic 13: same + 1 anti HBP 6: same + 3 anti HBP 1: same + 4 anti HBP Ghose, Hall, Bravo Ann Intern Med. 131: 105-108 1999

    42. Long-term Medical Management of IHA In woman: spironolactone In men: minimal amounts of spironolactone combined with amiloride Eplerenone ARB Potassium supplements Poor results of surgery but old studies

    43. Long-term Medical Management of IHA Spironolactone (MR/AR antagonist) 12.5 mg/day up to 100 mg BID monitor K+ regularly gynecomastia/impotence: dose-dependent Eplerenone (MR antagonist) 25 mg BID up to 100 mg daily more expensive, less potent, USA-not Canada lacks anti-androgenis properties

    44. Long-term Medical Management of IHA Amiloride (ENaC antagonist) 5 mg/day up to 10 mg BID monitor K+ regularly does not block aldo effects on heart Other drugs hydrochlorothiazide ARB in IHA: close K monitoring Potassium supplements

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