HYPERALDOSTRONISME PRIMAIRE

1
HYPERALDOSTÉRONISME PRIMAIRE

• André Lacroix, MD
• Service dendocrinologie
• Centre hospitalier de lUniversité de Montréal
• Cours Résidents de Médecine
• Programme de Médecine Interne
• 27 février 2008

2
Objectifs pédagogiques

• Physiologie axe rénine-angiotensine-aldostérone
• Prévalence hyperladostéronisme primaire
• Etiologies hyperaldostéronisme primaire
• Tests de dépistage
• Tests de confirmation
• Traitement hyperldostéronisme primaire

3
(No Transcript)
4
Cortex Surrénalien
Aldostérone
Cortisol
Androgènes
Catécholamines (épinéphrine / norépinéphrine)
5
Normal regulation of cortisol secretion
6
Other regulators of adrenal cell
VP
Ehrhart-Bornstein M, Hinson JP, Bornstein S et
al. Endocrine Reviews
19101-143 1998
7
Synthetic pathways for adrenal steroid synthesis
8
Aldosterone effects on the kidney
ENaC
The primary effect of aldosterone is to increase
the number of open sodium channels in the luminal
membrane of the principal cells in the cortical
collecting tubule, leading to increased sodium
reabsorption. The ensuing loss of cationic sodium
makes the lumen electronegative, thereby creating
an electrical gradient that favors the secretion
of cellular potassium into the lumen through
potassium channels in the luminal membrane Young,
Kaplan, Rose UpToDate 2007
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 gt 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, 891045, 2004
• Rossi et al J Am Coll Cardiol 482293, 2006
• Mosso et al Hypertension 42 161, 2003
• Gordon et al Clin Exp Pharmacol Physiol
  213151994

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) lt 2
• Bilateral macronodular adrenal hyperplasia lt 2
• Aldo/DOC-producing adrenal carcinoma lt 2
• Aldosterone-producing ovarian tumor lt 1
• Familial hyperaldosteronism (FH) lt 2
• Glucocorticoid-remediable aldosteronism (GRAFH
  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 121877, 1994). Rare malignant HBP
• Hypokalemia Klt3.5 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

14
Paul M et al Physiol Rev 86, 747, 2006
15
Differential diagnosis HBP and hypokalemia

• Primary Aldosteronism
• Renovascular hypertension
• Thiazide diuretics
• Cushings 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)
• Liddles syndrome (mutations beta- gamma-ENaC)
• Glucocorticoid resistance

16
PAC/PRA ratio in hypertension and hypokalemia
Young et al UpToDate 2007
17
Submitted 2008
18
Funder et al submitted 2008,
19
Funder et al 2008, submitted
20
Recommendationscase 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

Funder et al 2008, submitted
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-th
  iazides-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 gt 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
• gt 15 ng/dL (gt 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 gt 20-40 (gt 555 in SI units)
• Negative ratios lt10 (lt277 in SI units)
• Young, Kaplan, Rose, UpToDate 2007
• Funder et al submitted 2008

27
PAC/PRA ratio in hypertension and hypokalemia
Young et al UpToDate 2007
28
Funder et al submitted 2008
29
Confirmatory tests for PA

• Oral sodium loading (6g x 3 days) and 24-h
  urinary aldosterone gt12-14 mcg/d (gt33-38 nmol/d
  (replace potassium adequately). Ur Na gt 200
  meq/d
• Saline 0.9 2L/4 h infusion in supine posture
  aldosterone at 4 h gt 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 gt
  6 ng/dL (gt162 nmol/L) with PRA lt 1 ng/ml/h
• Captopril 25-50 mg oral after sitting 1 h. Aldo
  1-2 hr later decreases lt30 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 lt 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 gt75-90)
• Certain centers do surgery without sampling in
  patients lt 40 y.o. with unilateral nodules gt 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 gt 41 ratio on side of
  adenoma lt 3 bilateral disease

32
Adrenal vein sampling in PA
Young et al Surgery 120913 1996
33
Adrenal vein sampling in PA
-15
0
ACTH 250 mcg iv
5
10
15
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 6596-110 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 lt44 vs gt44 yo
  OR 6.2
• duration HBP lt5 vs gt 5 years OR 5.1
• Celen, OBrien, Melby, Beazley, Boston U Med Cen,
  Arch Surg 131646-50, 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 69685-95,
  1968
• Brown JJ et al. BMJ 2729-34, 1972
• Saruta T et al., Acta Endocrinol 116229-34, 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 48369-72, 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