High prevalence of primary aldosteronism in the Tayside hypertension clinic population

Transcription

1 (2000) 14, Mcmilln Publishers Ltd All rights reserved /00 $ ORIGINAL ARTICLE High prevlence of primry ldosteronism in the Tyside hypertension clinic popultion PO Lim 1, E Dow 2, G Brennn 3, RT Jung 3 nd TM McDonld 1 1 Hypertension Reserch Centre, Deprtment of Clinicl Phrmcology nd Therpeutics, nd 3 Deprtment of Endocrinology nd Dibetes, 2 Directorte of Biochemicl Medicine, Ninewells Hospitl nd Medicl School, University of Dundee, Dundee DD1 9SY, UK Primry ldosteronism (PA) ws thought to be rre but recent evidence from Austrli suggests tht it my be more common. As this hs importnt implictions in terms of hypertension mngement, we undertook to screen for this tretble condition in our hypertension clinic. We obtined blood smples in sequentil ptients referred for ssessment in our hypertension clinic in Tyside for plsm renin ctivity (PRA) nd ldosterone. The ldosterone to PRA rtio (ARR) ws used s n initil screening test to identify potentil ptients with PA. Those ptients with n elevted rtio ( 750) were dmitted for the slt loding nd fludrocortisone suppression test. These ptients lso underwent drenl CT scnning, nd in selected ptients, drenl scintigrphy. Between My 1995 nd Jnury 1997 (21 months), we screened totl of 495 ptients. ARR ws vilble in 465 (93.9%) ptients. Out of tht number, 77 (16.6%) hd n elevted rtio of 750, five of whom hd n drenl denom (one hd previous drenlectomy). Fortyfive of these ptients were dmitted for the slt loding nd fludrocortisone suppression test with 41 positive test results suggesting PA. One ptient with negtive slt loding test result however hd n denom proven on histology. A totl of 43 cses of PA were identified, giving minimum prevlence of 9.2% (43/465). Potentilly the prevlence my be up to 15% ssuming tht the ARR hs sensitivity of 93% (42/45) in predicting PA. In conclusion, bout one in 10 ptients ttending hypertension clinic my hve PA. This suggests tht the prevlence of PA in Tyside is s high s tht in the Austrlin hypertensive popultion, nd this is likely to be true elsewhere, with obvious importnt implictions for hypertension mngement. (2000) 14, Keywords: hypertension; primry ldosteronism; ldosterone to renin rtio Introduction Primry ldosteronism (PA) ws thought to be rre. Dt collected in the Glsgow Blood Pressure Clinic over 20-yer period only reveled 10/3783 (0.3%) cses of PA. 1 However, Jerome Conn, who first described PA in 1954 speculted tht its prevlence might be s high s 20%. 2 Indeed, evidence from Austrli 3 suggests tht it my ccount for up to 15% of the hypertensive popultion. Following this report, high prevlence of PA hs incresingly been reported in other centres. 4 7 We hve recently reported tht the prevlence of PA my potentilly be similrly high in hypertensives in the primrycre setting. 8 These new findings clerly hve importnt clinicl implictions. It would suggest tht mny hypertensive individuls with PA my remin undignosed t present, nd thus re deprived of pproprite clinicl mngement. Erly Correspondence: Dr Pitt O Lim, Hypertension Reserch Centre, Deprtment of Clinicl Phrmcology nd Therpeutics, University of Dundee, Ninewells Hospitl nd Medicl School, Dundee, DD1 9SY, UK Received 3 November 1999; revised nd ccepted 18 Februry 2000 dignosis of PA due to n drenl denom my offer cure or improved blood pressure control when surgiclly treted, 9 nd in cses due to bilterl drenl hyperplsi, spironolctone offers the best medicl tretment option if tolerted, 10 with miloride being n lterntive mediction. With the likely introduction of eplerenone, which is new genertion of specific ldosterone receptor ntgonist lcking the side effect profile of spironolctone, it is more urgent tht hypertensive ptients with nondenomtous PA should be identified. With the bove in mind, we undertook to screen for this tretble condition in sequentil ptients referred for ssessment in our hypertension clinic. Ptients nd methods All hypertensive ptients referred to our centre were mediclly ssessed in our Hypertension Assessment Unit to exclude secondry cuses of hypertension. Blood smples were tken for electrolytes s well s for plsm renin ctivity (PRA ng/ml/h) nd ldosterone (pmol/l) fter the ptients hd been sitting for bout 10 min. Antihypertensive mediction ws stopped for 7 10 dys in bout 60% of ptients, in those without contrindictions for discontinuing

2 312 tretment, such s ccelerted hypertension, previous cerebrovsculr event or ischemic hert disese. The ldosterone to PRA rtio (ARR) ws used s n initil screening test to identify potentil ptients with PA. 11,12 Those ptients with n elevted rtio ( 750) were dmitted for slt loding nd Fludrocortisone Suppression Test (FST) over 4 dys (see below). Non-suppression of plsm ldosterone (ie, 140 pmol/l t 12.00, upright nd/or t 08.00, supine) t the end of the test period ws deemed dignostic for primry ldosteronism. 13 Abdominl CT scn ws performed to screen for n drenl mss or nodule consistent with n denom using 3-mm slices in ptients with n elevted ARR. If n drenl mss or nodule ws present, n drenl scintigrphy using 75Se-Scintdren s n gent with dexmethsone suppression ws performed to ssess function. We lso screened for glucocorticoid suppressible hyperldosteronism (GSH) using genetic testing 14 in ptients who exhibited drop in post-slt loding plsm ldosterone level t middy compred with morning level. Slt loding nd fludrocortisone suppression test (FST) Ptients with elevted ARRs were dmitted for FST to ssess the suppressibility of plsm ldosterone. The usul ntihypertensive medictions were withdrwn for between 7 to 10 dys. None of these ptients were on orl spironolctone which would require more prolonged drug withdrwl. Where necessry, n -blocker, doxsozin ws prescribed to control the blood pressure if the distolic blood pressure ws greter thn or equl to 110 mm Hg. All ptients were routinely given two tblets of Slow-K (600 mg potssium chloride ech) dily to prevent hypoklemi. On dy one, ech ptient ws given five Slow-Sodium (600 mg sodium chloride ech) tblets t nd following bseline supine nd mbulnt blood smplings for electrolytes, plsm cortisol nd ldosterone. On dy two, ech ptient ws given four Slow-Sodium tblets with fludrocortisone 0.5 mg t 08.00, nd further Slow-Sodium tblets, five t 12.00, four t nd four t The dy two regime ws repeted on dy three. On dy four, the tretment regime ws given following supine blood smpling, nd the middy bloods were smpled following 4 h of mbultion t Ptients were dischrged on their usul mediction pending the results of the investigtions. In totl, 48 Slow-Sodium tblets or mg of sodium chloride with 1.5 mg of fludrocortisone were given over 4-dy period. Ptients hd their blood pressures crefully monitored throughout the study period to identify possible complictions. vrition over yer ws 11% (QC men vlues 2.3 nd 6.1 ng/ml/h). Plsm ldosterone ws mesured using solidphse (coted tube) rdioimmunossy technique, DPC Cot--Count ssy (DPC, Llnberis, Cernrfon, Gwynedd) with n intrssy coefficient of vrition of 10% between 200 nd 3300 pmol/l, nd lest detectble concentrtion of 70 pmol/l. The inter-ssy vrition s clculted from QC pools run in ech ssy over yer ws 10% (QC men vlues 400 nd 1050 pmol/l). Results Between My 1995 nd Jnury 1997 (21 months), totl of 495 ptients were screened. ARR ws vilble in 465 (93.9%) ptients (Figure 1). Seventyseven ptients (16.6%) hd n elevted rtio of 750; five of whom hd n drenl denom (ARR 900, 1133, 1567, 3500, 6000). One (ARR 900) of these ptients however ws known to hve right sided drenl denom removed 10 yers previously, but ws referred to our hypertension clinic for blood pressure control within the screening period specified bove. This ptient ws not subjected to repet FST. There ws no GSH dignosed in this cohort of ptients. Forty-five ptients were dmitted for FST nd of these, 41 were positive, suggesting the dignosis of primry ldosteronism (Tble 1). One ptient with negtive FST (ptient 42) however hd right drenl denom which ws detected on CT scnning nd ws proved to be functionlly hyperctive (3.4 times more uptke in right drenl glnd) on drenl scintigrphy. This ptient underwent drenlectomy nd subsequent histologicl exmintion of the resected drenl glnd confirmed the presence of Conn s denom. Thus, totl of 43 (four denoms nd one post-drenlectomy PA) cses of PA were therefore identified using ARR s screening test, giving prevlence of 9.2% (43/465) of PA in n unselected hypertension clinic popultion. Assuming tht rised ARR hs sensitivity of 93% (42/45) in identifying PA, potentilly the prevlence of PA could be s high s 15% (72/465). Of the 32 out of 77 ptients with rised ARR who did not undergo FST, one hd previous Conn s denom removed, one immigrted overses nd one died from rod trffic ccident. The rest of the ptients hd ischemic hert disese, poor left Lbortory testing PRA ws mesured using Biodt Renin MAIA ssy (Serono Dignostics Ltd, Working, Surrey, UK) with n intrssy coefficient of vrition of 10% between 0.3 nd 18 ng/ml/h, nd lest detectble concentrtion of 0.3 mg/ml/h. The inter-ssy btch Figure 1 Distribution of ldosterone to renin rtio.

3 Tble 1 Results of the slt loding test 313 Subject Age Sex Serum Plsm renin Plsm ARR Slt loding potssium ctivity ldosterone (ng/ml/h) (pmol/l) Aldosterone Aldosterone F F M M F M F M M d 48 F F F M F d 52 M M M F M F F F d 56 M F M M M F F M F M F F M M F M F M d 71 F b,d 62 F M b 52 M 5.1 c b 49 F Missing vlues; b Adrenl denom; c On potssium supplements; d Subjects with suppressed plsm ldosterone with slt loding. ventriculr function or were elderly, where FST ws inpproprite. The blood pressure of the ptient with post-drenlectomy ldosteronism ws normlised with combintion of miloride nd mlodipine. Of the remining four ptients with denomtous disese [ptients 15 (right 1.5 cm denom), 42 (right 2 cm denom), 44 (right 2 cm nd left 1.5 cm denoms) nd 45 (right 1 cm nd left 2 cm denoms)], three underwent drenlectomy. Ptient 15 s blood pressure ws not controlled despite drenlectomy, nd he ws intolernt of spironolctone. Ptient 42 s blood pressure ws improved following drenlectomy, nd needed only one gent, mlodipine to normlise her blood pressure. Ptient 44 presented with severe hypoklemi (1.9 mmol/l) nd rhbdomyolysis, subsequent drenl scintigrphy suggested incresed ctivity in the right drenl glnd by fctor of 2 in comprison with the left drenl glnd. He underwent right drenlectomy which normlised his blood pressure, nd histology of his drenl glnd confirmed Conn s denom with bckground hyperplsi. Ptient 45 s drenl scintigrphy suggested no functionl lterlistion, nd she ws treted with combintion of spironolctone nd mlodipine which normlised her blood pressure. Discussion In the present study, we estimted tht bout one in 10 clinic hypertensives in our centre did not suppress their plsm ldosterone with slt loding, suggesting the dignosis of PA. 15 The mjority of our cses were presumed to be due to drenl hyperplsi, on the bsis tht bdominl CT scnning

4 314 excluded obvious drenl denoms. This is in contrst with the findings of Gordon s group in Austrli where nerly one-third of their cses were due to drenl denoms. 16 This group however routinely used drenl venous smpling in their dignostic work up, nd hve reported tht this more invsive method hs superior detection rte for drenl denoms. In comprison, drenl CT scn hs sensitivity of only 53% in identifying drenl denoms. 16 It is likely tht we my hve missed denoms smller thn 1 cm in size. The trditionl view tht only ptients with n denom tended to drop their plsm ldosterone levels by middy is no longer supported by new dt. 15 There re ptients with renin-responsive denoms; ie, incresed plsm ldosterone secretion in response to mbultion nd erect posture or with ngiotensin II infusion. 17 Similrly, there re lso ptients with drenl hyperplsi who behve like non-renin responsive Conn s denom. 18 Thus, the chnge in plsm ldosterone levels in the morning supine nd middy erect postures is not relible in differentiting between drenl denom nd drenl hyperplsi. ARR s simple method of identifying ptients with possible PA ws first utilised by Hirmtsu nd collegues 11 in They used much higher rtio, equivlent to when converted to our units (Figure 1). They detected nine cses of drenl denoms mongst 348 hypertensive subjects, nd importntly, their results were reltively unffected by vrying slt intke or concurrent ntihypertensive mediction. Others hve confirmed tht ARR is effective in seprting out hypertensive ptients with PA from other etiologies, including essentil hypertension. 12,20 Gordon nd collegues, 21 using n ARR threshold of 693 (or 25, plsm ldosterone in ng/dl), reported PA prevlence of 23% (18/79) in group of selected hypertensive ptients who continued with their usul ntihypertensive mediction prior to blood smpling. This group subsequently reported tht the minimum prevlence of PA ws 8.5% in 199 consecutive normoklemic hypertensive ptients, bout 80% of whom continued their usul nti-hypertensive drug tretment, nd this time they used slightly higher ARR threshold of 831 (or 30, plsm ldosterone in ng/dl). 3 They postulted tht bout one in 10 clinic hypertensive ptients might hve PA, in greement with our findings. ARR hs proved to be n effective nd relible method for detecting PA. We chose n rbitrry threshold of 750, which incidentlly fell between the erlier nd lter thresholds used by the Austrlin group. 3,21 In our hnds, ptients with ARR greter or equl to 750 hd n bove 90% probbility of hving non-suppressible plsm ldosterone with FST. Interestingly however, one ptient with n drenl denom hd n elevted ARR but suppressed plsm ldosterone with FST (130 pmol/l t nd 70 pmol/l t 12.00). Thus, ARR my be more sensitive thn FST in identifying PA. It is importnt tht ptients with rised ARR should undergo routine drenl CT scnning despite its limittion in picking up denoms smller thn 1 cm in size. With the introduction of ARR s screening test, normoklemic PAs were incresingly dignosed. The men potssium level in our ptient cohort who underwent FST ws 4.1 (s.d. 0.5) mmo/l; only two ptients were hypoklemic. Thus, using only hypoklemi s dignostic criterion would hve led to gross underdignosis of PA in our centre. We hve lso explored the potentil of the frusemide stimultion test s nother dignostic test for PA. 22 This is nother simple test to perform, which ssesses the responsiveness of renin to frusemide chllenge nd mbultion, nd could be effectively crried out in the out-ptient deprtment. A stimulted PRA 1.5 ng/ml/h indicted positive test result. However, this test whilst being highly specific, unfortuntely hs poor negtive predictive vlue of 41.7% in ptients pre-screened with the ARR. The lrge number of flse negtives ws likely to be ccounted for by significnt number of ptients with PA who retined their renin responsiveness. Thus, the frusemide stimultion test hs little dignostic vlue to offer over nd bove tht of ARR. As our results hve indicted, most of our ptients with PA presumbly hd drenl hyperplsi s n etiology in the bsence of histologicl confirmtion. It is still n on-going debte whether or not nondenomtous normoklemic PA represents distinct dignostic entity, or simply forms prt of the spectrum of low renin essentil hypertension. 23,24 Hypertensive ptients with low renin nd non-suppressible ldosterone production hve been described more thn 3 decdes previously, who would hve been dignosed s hving PA with our present criteri We believe tht the key issue here is the response to tretment with specific ldosterone ntgonist, ie, spironolctone. We hve follow-up dt of up to 3 yers to suggest tht bout 50% of these ptients responded to low dose spironolctone (25 50 mg) monotherpy to chieve blood pressure control, nd the need for other djunctive ntihypertensive gents ws significntly reduced following the introduction of spironolctone. 10 Conclusions Primry ldosteronism is more common thn previously thought, nd most cses re probbly nondenomtous. At lest one in 10 ptients ttending hypertension clinic my hve primry ldosteronism. Acknowledgement All uthors were jointly involved in the design nd implementtion of the study. All uthors contributed to writing the pper. We thnk Mrgret Coull for her secretril ssistnce. Funding: Deprtmentl Reserch Fund. Conflict of Interest: None. References 1 Sinclir AM et l. Secondry hypertension in blood pressure clinic. Arch Intern Med 1987; 147:

5 2 Conn JW. Plsm renin ctivity in primry ldosteronism. JAMA 1964; 90: Gordon RD et l. High incidence of primry ldosteronism in 199 ptients referred with hypertension. Clin Exp Phrmcol Physiol 1994; 21: Brown MA, Crmp HA, Zmmit VC, Whitworth JA. Primry hyperldosteronism: missed dignosis in essentil hypertensives? Aust N Z J Med 1996; 26: Anis Anwr Y, White WB, Mnsoor GA, Tendler BE. Hyperldosteronism is common cuse of secondry hypertension missed by primry cre physicins nd ssocited with normoklemi. Am J Hypertens 1998; 11 (4 prt 2): 199A (M001). 6 Ryner BL, Opie LH, Dvidson JS. Primry hyperldosteronism: How common is it in ptients with severe hypertension? J Hypertens 1999; 17 (Suppl 3): S177 [P3.77]. 7 Young WF, Jr. Pheochromocytom nd primry ldosteronism: dignostic pproches. Endocrinol Metb Clin North Am 1997; 26: Lim PO et l. Potentilly high prevlence of primry ldosteronism in primry-cre popultion. Lncet 1999; 353: Ferriss JB et l. Results of drenl surgery in ptients with hypertension, ldosterone excess, nd low plsm renin concentrtion. Br Med J 1975; 1: Lim PO, Jung RT, McDonld TM. Rised ldosterone to renin rtio predicts nti-hypertensive efficcy of spironolctone. A prospective cohort follow-up study. B J Clin Phrmcol 1999; 48: Hirmtsu K et l. A screening test to identify ldosterone-producing denom by mesuring plsm renin ctivity. Results in hypertensive ptients. Arch Intern Med 1981; 141: McKenn TJ et l. Dignosis under rndom conditions of ll disorders of the renin-ngiotensin-ldosterone xis, including primry hyperldosteronism. J Clin Endocrinol Metb 1991; 73: Gordon RD. Minerlocorticoid hypertension. Lncet 1994; 344: Jmieson A et l. Clinicl, biochemicl nd genetic fetures of five extended kindred s with glucocorticoidsuppressible hyperldosteronism. Endocr Res 1995; 21: Gordon RD, Stowsser M, Klemm SA, Tunny TJ. Primry ldosteronism nd other forms of minerlocorticoid hypertension. In: Swles J (ed). Textbook of Hypertension. Blckwell Scientific: Oxford, 1994, pp Stowsser M, Tylor WL, Rutherford JC, Gordon RD. Dignosis of ldosterone-producing denom: ldosterone/renin rtio nd drenl venous smpling. J Hypertens 1998; 16 (Suppl 2): S Gordon RD, Hmlet SM, Tunny TJ, Klemm SA. Aldosterone-producing denoms responsive to ngiotensin pose problems in dignosis. Clin Exp Phrmcol Physiol 1987; 14: Bnks WA, Kstin AJ, Biglieri EG, Ruiz AE. Primry drenl hyperplsi: new subset of primry hyperldosteronism. J Clin Endocrinol Metb 1984; 58: Vllotton MB. Primry ldosteronism. Prt I. Dignosis of primry hyperldosteronism. Clin Endocrinol 1996; 45: Weinberger MH, Fineberg NS. The dignosis of primry ldosteronism nd seprtion of two mjor subtypes. Arch Intern Med 1993; 153: Hmlet SM, Tunny TJ, Woodlnd E, Gordon RD. Is ldosterone/renin rtio useful to screen hypertensive popultion for primry ldosteronism? Clin Exp Phrmcol Physiol 1985; 12: Lim PO, Brennn GM, Jung RT, McDonld TM. Dignosing primry ldosteronism with the frusemide stimultion test. Med Biochem 1999; (in press). 23 Pdfield PL, Brown JJ, Dvies D, Frser R, Lever AF, Morton JJ, Robertson JI. The myth of idiopthic hyperldosteronism. Lncet 1981; 2: Idiopthic ldosteronism: dignostic rtifct? Lncet 1979; 2: Helber A et l. Evidence for subgroup of essentil hypertensives with non-suppressible excretion of ldosterone during sodium loding. Klinische Wochenschrift 1980; 58: Luetscher JA et l. Effects of sodium loding, sodium depletion nd posture on plsm ldosterone concentrtion nd renin ctivity in hypertensive ptients. J Clin Endocrinol Metb 1969; 29: Weinberger MH, Dowdy AJ, Nokes GW, Luetscher JA. Plsm renin ctivity nd ldosterone secretion in hypertensive ptients during high nd low sodium intke nd dministrtion of diuretic. J Clin Endocrinol Metb 1968; 28: Collins RD et l. Abnormlly sustined ldosterone secretion during slt loding in ptients with vrious forms of benign hypertension; reltion to plsm renin ctivity. J Clin Invest 1970; 49: