ENDOCRINE FORMS OF HYPERTENSION. Michael Stowasser

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1 ENDOCRINE FORMS OF HYPERTENSION Michael Stowasser Hypertension Unit, University Department of Medicine, Princess Alexandra Hospital, Brisbane 4102, Australia.

2 ENDOCRINE FORMS OF HYPERTENSION Mineralocorticoid Forms of Hypertension - Primary aldosteronism - DOC secreting tumors - Hypertensive forms of CAH - 11βHSD deficiency (SAME, licorice) - Mineralocorticoid receptor defects - Liddle syndrome Renovascular HT Pheochromocytoma Cushing Syndrome Acromegaly

3 TUBULE LUMEN K + α β MR Target gene transcription γ Na + Apical Sodium Channel Aldo Basolateral + + Na /K ATPase K + Aldo Na + BLOOD

4 TUBULE LUMEN K + α β MR Target gene transcription γ Na + Apical Sodium Channel DOC Aldo Basolateral + + Na /K ATPase K + DOC Aldo Na + BLOOD

5 TUBULE LUMEN K + α β γ Na + Cortisone MR Target gene transcription Apical Sodium Channel 11βHSD(2) Basolateral + + Na /K ATPase Cortisol DOC Aldo K + Cortisol DOC Aldo Na + BLOOD

6 TUBULE LUMEN K + α β γ Na + Cortisone MR Target gene transcription Apical Sodium Channel 11βHSD(2) Basolateral + + Na /K ATPase Cortisol DOC Aldo K + Cortisol DOC Aldo Na + BLOOD PRIMARY ALDO

7 Conn's first patient with primary aldosteronism, year old female with: Severe hypertension Severe hypokalemia, alkalosis Cured by removal of a 4cm aldosterone-producing adenoma situated in the right adrenal gland

8 Harrison's Principles of Internal Medicine, 1991 " primary aldosteronism accounts for less than 1% of all patients with hypertension " Clinical Hypertension, 1994 " the search for primary aldosteronism need only be undertaken in those with hypokalemia "

9 SCREENING FOR PRIMARY ALDOSTERONISM Aldosterone renin ratio Hiramatsu et al, 1981

10 Use of the Aldo/Renin Ratio at Greenslopes Hospital : Hypertension and hypokalemia : Plus resistant hypertension present: All hypertension

11 PRIMARY ALDOSTERONISM - Greenslopes Hospital (1970-) and Princess Alexandra Hospital (2000-) Patients Diagnosed Per Year Hypokalemic Normokalemic From all HTives screened (aldo/renin) 9.5% of 199 normokalemic hypertensive referrals 12% of 52 hypertensive drug trial volunteers Since 1992: new cases p.a. each confirmed by fludro suppression testing (FST) 21% Hypokalemic Total experience: >1400 patients >300 aldo-producing tumors removed (R Gordon & M Stowasser, et al)

12 PREVALENCE OF PAL - SINCE 1997 Some units reporting increased prevalence: Fardella, et al Gong, et al Widimsky, et al Douma, et al Benchetrit, et al Rossi, et al Mulatero, et al Nishikawa, et al (Chile) (China) (Czech Rep) (Greece) (Israel) (Italy) (Italy) (Japan) Eide, et al Loh, et al Rayner, et al MacDonald, et al Young Jr, et al Gallay, et al Calhoun, et al Schwartz, et al (Norway) (Singapore) (Sth Africa) (UK) (USA) (USA) (USA) (USA) Prevalence rates: mostly 5-15% Proportion normokalemic: %

13 John W. Funder, Robert M. Carey, Carlos Fardella, Celso E. Gomez-Sanchez, Franco Mantero, Michael Stowasser, William F. Young Jr, and Victor M. Montori J Clin Endocrinol Metab Sept 2008; 93:

14 DIAGNOSTIC WORKUP FOR PRIMARY ALDOSTERONSIM Screening - Aldosterone/renin ratio Confirming the Diagnosis - Fludrocortisone suppression test Distinguishing the Subtypes Genetic test for a rare familial form (FH-I) Adrenal CT scanning Adrenal venous sampling

15 Main regulators of ALDO synthesis 1) Renin/angiotensin II 2) Potassium 3) ACTH (Acute stim then suppression) ALDOSTERONE

16 Main regulators of RENIN synthesis 1) Sodium status 2) Renal blood flow 3) SNS (beta) 4) Ang II (-ve feedback) RENIN

17 SCREENING FOR PAL: ALDO/RENIN RATIO FALSE POSITIVES Beta blockers α-methyldopa, clonidine NSAIDs Renal impairment Ageing FALSE NEGATIVES Diuretics CCBs (esp DHPs) ACEIs, ARBs V. low salt intake Renovascular HT Malignant HT Hypokalemia

18 SCREENING FOR PAL: ALDO/RENIN RATIO Correct hypokalemia Unrestricted dietary salt intake Cease diuretics (including spiro) for > 4 weeks Cease beta blockers, α-methyldopa, clonidine, NSAIDs, dihydropyridine CCBs, ACEIs and ARBs for > 2 weeks Substitute with other medications that have a lesser effect on the ratio to maintain HT control - e.g. verapamil slow-release, hydralazine, prazosin Samples collected morning after > 2 hours out of bed Patients seated

19 SCREENING FOR PAL: ALDO/RENIN RATIO NORMAL CUT-OFFS: ALDO units ng/dl RENIN units ng/ml/h (PRA) pmol/l mu/l (DRC)

20 DIAGNOSTIC WORKUP FOR PRIMARY ALDOSTERONSIM Screening - Aldosterone/renin ratio Confirming the Diagnosis - Fludrocortisone suppression test Distinguishing the Subtypes Genetic test for a rare familial form (FH-I) Adrenal CT scanning Adrenal venous sampling

21 DEFINITIVE TESTING FOR PAL - FLUDROCORTISONE SUPPRESSION TEST Plasma aldo response during 4 days of fludrocortisone (0.1 mg 6 hrly) and oral salt loading (Slow Na + 30 mmol tds and high salt diet) Failure of aldo (upright, 1000 h) to suppress to <165 pmol/l by day 4 diagnostic of PAL PROVIDED THAT 1) Renin suppressed 2) K + normal 3) No ACTH rise on morning of collection (indicated by plasma cortisol levels

22 OTHER CONFIRMATORY TESTS FOR PAL Saline infusion test - plasma aldo response during i.v. infusion of normal saline, 2L over 4h Urinary aldo after oral salt loading - 24h urinary aldo following 3 days of oral salt loading (>200 mmol sodium/day)

23 SUBTYPES OF PRIMARY ALDOSTERONISM BILATERAL ADRENAL HYPERPLASIA (BAH) - both adrenals overproducing aldo ALDOSTERONE-PRODUCING ADENOMA (APA) - a benign adrenal tumor overproducing aldo ALDOSTERONE-PRODUCING CARCINOMA - a malignant adrenal tumor overproducing aldo GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM - a rare, genetic form of PAL that runs in families (Familial Hyperaldosteronism Type 1, FH-I)

24 DIAGNOSTIC WORKUP FOR PRIMARY ALDOSTERONSIM Screening - Aldosterone/renin ratio Confirming the Diagnosis - Fludrocortisone suppression test Distinguishing the Subtypes Genetic test for a rare familial form (FH-I) Adrenal CT scanning Adrenal venous sampling

25 FAMILIAL HYPERALDOSTERONISM TYPE I (FH-I, Glucocorticoid-Remediable Aldosteronism) First described Sutherland et al Often early onset of HT, and may result in early death from stroke Hyperaldosteronism and hypertension controlled by glucocorticoids in small doses Hybrid gene - Lifton et al 1992

26 FAMILIAL HYPERALDOSTERONISM TYPE 1 (Glucocorticoid-Remediable Aldosteronism) 11ß-OHase regulatory sequences HYBRID GENE Aldo Synthase coding sequences Regulated by ACTH Encodes Aldo Synthase ALDO Small doses of glucocorticoids, by suppressing ACTH, suppress the hybrid gene and ameliorate PAL and HT

27 FH-I - RESPONSE TO DEX (0.5mg q6h)

28 LONG-PCR TESTING FOR FH-I

29 FH-I - Long PCR NORMAL FH-I Aldo Synthase Hybrid Gene Aldo Synthase Hybrid Gene

30 SUBTYPES OF PRIMARY ALDOSTERONISM BILATERAL ADRENAL HYPERPLASIA (BAH) - both adrenals overproducing aldo ALDOSTERONE-PRODUCING ADENOMA (APA) - a benign adrenal tumor overproducing aldo ALDOSTERONE-PRODUCING CARCINOMA - a malignant adrenal tumor overproducing aldo GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM - a rare, genetic form of PAL that runs in families (Familial Hyperaldosteronism Type 1, FH-I)

31 DIAGNOSTIC WORKUP FOR PRIMARY ALDOSTERONSIM Screening - Aldosterone/renin ratio Confirming the Diagnosis - Fludrocortisone suppression test Distinguishing the Subtypes Genetic test for a rare familial form (FH-I) Adrenal CT scanning Adrenal venous sampling

32 ALDOSTERONE-PRODUCING CARCINOMA

33 Examples of APAs removed from normokalemic patients with PAL In all patients: CT reported as normal; aldo lateralized on AVS; HT cured post-op

34 APAs - MASS ON CT (Jan August 1999) APA Size No. APAs Mass on CT (%) > 1 cm < 1 cm ALL (81%) 14 (24%) 56 (50%)

35 ALDOSTERONE- PRODUCING ADENOMA (APA) ADRENAL "INCIDENTALOMA"

36 (a) (b)

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38 DIFFERENTIATING APA FROM BAH ADRENAL VENOUS SAMPLING - only reliable way to separate APA from BAH and lateralise APAs pre-operatively - perform in ALL patients with PAL (except those found to FH-I by genetic testing) - compare aldo:cortisol ratios in blood collected from each adrenal vein with those in peripheral venous blood

39 WHY MEASURE CORTISOL IN AVS SAMPLES? Cortisol concentrations in AVS samples are an indication of the adequacy of sampling: [Cortisol]ADRENAL VEIN of > 3 = adequate sampling [Cortisol]PERIPHERAL VEIN [Cortisol]ADRENAL VEIN of < 3 = interpretation uncertain [Cortisol]PERIPHERAL VEIN Cortisol concentration corrects for dilution

40 AVS - EXAMPLE 1 Left AV PV Right AV PV Aldo (ng%) Cortisol (ug%) A/C ratio

41 AVS - EXAMPLE 1 Left AV PV Right AV PV Right AV2 Aldo (ng%) Cortisol (ug%) A/C ratio DIAGNOSIS - BILATERAL ALDO PRODUCTION

42 AVS - EXAMPLE 2 Left AV PV Right AV PV Aldo (ng%) Cortisol (ug%) A/C ratio DIAGNOSIS - LEFT APA

43 TREATMENT OF PRIMARY ALDOSTERONISM BILATERAL ADRENAL HYPERPLASIA (BAH) - MR antagonists: spironolactone, eplerenone - epithelial Na + channel blocker: amiloride ALDOSTERONE-PRODUCING TUMOR - laparoscopic adrenalectomy GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM - (Familial Hyperaldosteronism Type 1, FH-I) - small doses of dexamethasone or prednisolone

44 FAMILIAL HYPERALDOSTERONISM TYPE II (FH-II) Gordon, Stowasser et al 1990 Unlike FH-I, not glucocorticoid-remediable Not associated with the hybrid gene mutation patients (3 families); patients (49 families) Clinically, biochemically and morphologically indistinguishable from apparently non-familial PAL Linkage studies have demonstrated linkage in five families with a locus in chromosome 7 (p22)

45 TUBULE LUMEN K + α β γ Na + Cortisone MR Target gene transcription Apical Sodium Channel 11βHSD(2) Basolateral + + Na /K ATPase Cortisol DOC Aldo K + Cortisol DOC Aldo Na + BLOOD DOC TUMOR; CAH

46 HYPERTENSIVE FORMS OF CAH Cholesterol Pregnenolone 17αOHase 17-OH Pregnenolone 17/20 Lyase DHEA Progesterone 17αOHase 17-OH Progesterone 17/20 Lyase Androstenedione DOC 11-deoxycortisol Testosterone 11βOHase 11βOHase Corticosterone Cortisol 18-OH Corticosterone Aldosterone

47 11β-Hydroxylase Deficiency Recessive inheritance Hypertension Adrenal hyperplasia Excessive DOC Hypokalemia Low renin & aldo Virilization Defects in 11β-OHase (C8q) 17α-Hydroxylase Deficiency Recessive inheritance Hypertension Adrenal hyperplasia Excessive DOC Hypokalemia Low renin & aldo Feminization Defects in 17α-OHase (C10q)

48 TUBULE LUMEN K + α β γ Na + Cortisone MR Target gene transcription Apical Sodium Channel 11βHSD(2) Basolateral + + Na /K ATPase Cortisol DOC Aldo K + SAME BLOOD Cortisol DOC Aldo Na +

49 SYNDROME OF APPARENT MINERALOCORTICOID EXCESS (SAME, AME) Clinical description Enzyme defect 11βHSD(2) Raised urinary cortisol metabolites cortisone metabolites Liquorice, carbenoxolone - Recessive - Hypertension - Hypokalemia - Low renin, low aldo Genetic mutations in 11βHSD (C16q22)

50 TUBULE LUMEN MR MUTATION K + α β γ Na + Cortisone MR Target gene transcription Apical Sodium Channel 11βHSD(2) Basolateral + + Na /K ATPase Cortisol DOC Aldo K + Cortisol DOC Aldo Na + BLOOD

51 ACTIVATING MUTATION OF THE MINERALOCORTICOID RECEPTOR Geller, Lifton et al 2000 Hypertension, low aldo and renin Serum potassium usually normal Hypertension exacerbated and hypokalemia induced during pregnancy Point mutation in MR leads to a conformation change in the receptor, which causes constitutive activation, and allows progesterone to act as an agonist Spironolactone also acts as an MR agonist in vitro

52 TUBULE LUMEN K + LIDDLES S α β γ Na + Cortisone MR Target gene transcription Apical Sodium Channel 11βHSD(2) Basolateral + + Na /K ATPase Cortisol DOC Aldo K + Cortisol DOC Aldo Na + BLOOD

53 LIDDLE S SYNDROME Clinical Features Hypertension Hypokalemia Autosomal dominant Renin - low Aldo - low Spironolactone ineffective Responds to low salt and amiloride

54 LIDDLE S SYNDROME Genetic Mutations Beta subunit epithelial sodium channel (C16p) Gamma subunit epithelial sodium channel (C16p) 1999 β and γ subunits truncated loss of intracytoplasmic binding sites for Nedd4, a regulatory protein which normally functions to inactivate sodium channels by promoting endocytosis and degradation

55 TUBULE LUMEN MR MUTATION K + LIDDLES S α β γ Na + Cortisone MR Target gene transcription Apical Sodium Channel 11βHSD(2) Basolateral + + Na /K ATPase Cortisol DOC Aldo K + SAME BLOOD Cortisol DOC Aldo DOC TUMOR; CAH Na + PRIMARY ALDO

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58 DIAGNOSTIC WORKUP FOR RENOVASCULAR HYPERTENSION Who to Screen? - Recent onset HT, worsening HT, resistant HT - Worsening renal function - Deterioration in renal function with ACEI, ARB - Risk factors for PVD; vasc disease elsewhere - Young women -?All hypertension?

59 DIAGNOSTIC WORKUP FOR RENOVASCULAR HYPERTENSION How to Screen - Renal artery duplex U/S - Renal isotope scan (DTPA or MAG3) - CT renal angiography Confirming the Diagnosis - Renal venous renin ratios - Renal angiography

60 RENAL ARTERY DUPLEX ULTRASOUND RIGHT LEFT (N) Renal Length (cm) PSV (m/s) - Prox -Mid -Distal (<2.0) (<2.0) (<2.0) Renal Aortic Ratio (RAR) (<3.5) Acceleration Time (msec) (<70) Resistive Index (%) (<70) Consistent with a haemodynamically significant L RAS of >60%...

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62 Renal Venous Renin Ratios Assess functional significance of RAS lesions When performed appropriately, results are highly predictive of BP response to revascularization or nephrectomy When performed without regard to factors that can complicate the interpretation of the results, high frequency of false negative results Less invasive, fewer complications than renal angiography argues for doing RVRRs first

63 Renal Venous Renin Ratio Results in a Patient with Bilateral Renal Artery Stenosis Renin levels (mu/l) Peripheral vein Right Renal V Left Renal V L/R Ratio Early Basal Post oral captopril Left/right RV renin ratio is significant (>1.5) Right RV renin level is no higher than peripheral (i.e. suppressed) Results consistent with a left renovascular cause of hypertension

64 Treatment of Renovascular HT 1) How to Treat? PTRA/stent Operative Medical Rx: - embolism, dissection, rupture - recurrence treat risk factors - endarterectomy, bypass, nephrectomy - solitary kidney or bilat RAS: avoid ACEI or ARB - treat CV risk factors 2) How to Decide? - BPs, side FX, renal function, age, comorbidities, local expertise, patient s wishes - Renovascular group - physician(s) interested in HT, nephrologist(s), vascular physician(s), vascular surgeon(s), interventional radiologist(s) Patients decides -

65 PHEOCHROMOCYTOMA

66 PHEOCHROMOCYTOMA Rare, but important not to miss (50% MR if detected at time of operation; Preoperative α and β blockade protects) Typical paroxysms in only 50% Screen by 24h urinary catechols - correct for creatinine excretion - others (plasma catechols or metanephrines; urinary metanephrines) Further investigations: - Clonidine suppression testing (plasma or urinary) - Contrast CT (α and β block first) or MRI (bright on T2) - MIBG (other scans: octreotide, PET with 6[F 18 ]fluorodopamine) - Consider familial conditions: MEN2 - RET Familial pheo - SDHD (succ dehydrog) VHL - VHL SDHB NF1 - NF1

67 PHEOCHROMOCYTOMA - CT

68 PHEOCHROMOCYTOMA - MRI T1 T2

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