July 2008.indd SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL JULY 2008, VOLUME 8, ISSUE 2, P. 165-169 SULTAN QABOOS UNIVERSITY© SUBMITTED - 19TH JANUARY 2008 ACCEPTED - 22ND APRIL 2008 1Department of Medicine, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman; 2Department of Medicine, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman; 3Department of Medicine, Mubarek Al-Kabeer Hospital, Kuwait *To whom correspondence should be addressed. Email: omayma0@hotmail.com Familial Mineralocorticoid Induced Hypertension in the Sultanate of Oman Nicholas JY Woodhouse,1 *Omayma T Elshafie,2 Fatma Ben Abid,2 Suhail A Doi3 Objectives: In Oman, many hypertensive patients with a family history of the disease respond to treatment with spironolactone, a mineralocorticoid receptor (MC-R) blocking agent thus suggesting a high prevalence of mineralocorticoid (MC) induced disease. The aim of this study was to document the prevalence of MC induced disease in patients with a positive family history of hypertension (HTN). Methods: Serum calcium, potassium, creatinine, aldosterone and renin levels were measured under standard conditions in all patients together with an abdominal ultrasound scan and an adrenal computed tomography (CT) scan in four patients. Results: In this small study, we show that 8 of the 27 patients (66%) had undetectable (suppressed) renin levels with usually normal aldosterone values (4 patients) and respond to treatment with spironoactone. Conclusion: We suggest that MC induced hypertension is likely to be common in the Middle East. In evolutionary terms, this makes sense as the ability to conserve salt in hot climates might be expected to confer a definite survival advantage. Key words: Hypertension, familial; Mineralocorticoids; High prevalence; Oman في نِيَّة دِ املَعْ رانِيَّات شْ القِ عن الناجت الوراثي الدم ضغط �ارتفاع عمان سلطنة دوا سهيل عابد، بن فاطمة الشفيع، اميمة وودهاوز، نيكوالس لعقار ــتجابوا اس والذين ــي الدم الوراث ضغط ــاع بارتف ــني املصابني العماني ــن املرضى م كبيرا ــددا ع ــابقة س ــة ــص: الهــدف: وجدنا في دراس امللخ عن الناجت ضغط الدم ــار انتش ارتفاع على يدل وهذا ، الكلى فوق املوجودة نِيَّة دِ َعْ امل ــرانِيَّاتُ شْ القِ ــتلمات مس وظيفة يبطل ، وهو عقار ــبايرونوالكتون س لذلك موجب عائلي تأريخ لديهم الذين العمانيني عند العالي الدم ضغط من النوع هذا نسبة ارتفاع إثبات البحث هذا نريد في املعدنية. القشرانيات إلى باإلضافة ، املرضى كل عند وااللدوستيرون الرينني هرموني وكذلك ، والكرياتنني والبوتاسيوم الكالسيوم أمالح قياس مستويات مت املرض. الطريقة: هذه في النتائج: وجدنا 4 مرضى. ــب في وسَ حَ مُ يٌّ عِ طَ قْ مَ ويرٌ تَصْ وعمل املرضى والكلى في كل للغدة الكظرية الصوت فائقة بطنية ــة تفريس عمل لهرمون طبيعي مستوى مع (منخفض) محسوس غير رنني (66 %) لديهم مستوى 27 مجموع 18 من املرضى من الصغيرة نسبة عالية الدراسة في الوراثي الدم نتوقع كثرة انتشار ارتفاع نسبة ضغط ــة الدراس اخلالصة: من هذه سبايرونوالكتون. لعقار ــتجابوا واس (14 مريضا) ــتيرون الدوس البقاء. أجل من نوعية ميزة رمبا يعطي احلار اجلو في امللح على احلفاظ على القدرة ، وأن األوسط الشرق عمان. انتشار عالي، نِيَّة، دِ َعْ امل رانِيَّاتُ شْ القِ العائلي، الدم، ضغط ارتفاع الكلمات: مفتاح C L I N I C A L A N D B A S I C R E S E A R C H Advances in Knowledge • This is the first study uniquely selecting patients with familial hypertension • Mineralocorticoid induced hypertension is reported in 10% or more of the general hypertensive population. We have only studied patients with a positive familial history of the disease and found a much higher prevalence (66%) with mineralocorticoid (MC) induced disease Application to Patient Care • Patients with a positive family history of hypertension should undergo a short one month trial of a mineraloco- rticoid blocking drug such as spironolactone. 166 N I C H O L A S J Y WO O D H O U S E , O M AY M A T E L S H A F I E , FAT M A B E N A B I D A N D S U H A I L A D O I IT HAS GENERALLY BEEN RECOMMENDED1-2 THAT screening for hyperaldosteronism be considered at least for hypertensive patients with spontane- ous hypokalemia (K <3.5 mmol/L), or with marked diuretic-induced hypokalemia (K <3.0 mmol/L), with hypertension refractory to treatment with three or more drugs or those found to have an incidental adre- nal adenoma. Previously, primary hyperaldosteronism (PAL) was not believed to be familial and thought to account for less than 1% of hypertensive patients and hypokalemia was considered a prerequisite for pursu- ing diagnostic tests2. Recent studies with screening of both hypokalemic and normokalemic hypertensives have reported now a much higher prevalence of this disease, with primary hyperaldosteronism accounting for up to 12% of hypertensive patients most of them being normokalemic.3-4 Furthermore, in 1991, a sec- ond form of familial hyperaldosteronism (FH-II) that was not glucocorticoid remediable was first reported. There were six patients, four with aldosterone-pro- ducing adenoma (APA) and two with bilateral adrenal hyperplasia (BAH)) among three families.5 Till 2001, a total of 68 patients among 27 families have been de- scribed, making FH-II more common than FH-I (34 patients among five families).6 To date, two familial forms of hyperaldosteronism have been identified: glucocorticoid suppressible, familial hypertension Type 1 (FH1) and glucocorticoid non-suppressible disease, (FH2).6-7 We recently reported a potentially high prevalence of familial mineralocorticoid (MC) induced hyper- tension (HTN) in patients attending our general en- docrine clinics8 and found that in 39 of 45 patients (80 %) their blood pressure could be controlled using spironolactone alone. We therefore concluded that the prevalence of MC induced disease in Oman might prove to be quite high8. In the UK, a recent study of more than 800 hypertensive patients in a general prac- tice setting, who were without a positive family history, revealed that 14% responded to spironolactone with a fall in BP of 26/11 mmHg. All of them had suppressed renin levels, but as in our study, the aldosterone levels were only occasionally raised.9 Only 1 of these patients had Conn’s syndrome. We are now providing a more detailed account of 27 additional subjects with familial disease, but in addition their circulating renin and al- dosterone levels were measured before starting treat- ment with spironolactone. M E T H O D S These 27 hypertensive patients were from different families having one or more affected parents and sib- lings, twenty four were Omanis and three Sudanese. They had been randomly selected from our general endocrine clinics if they had a positive family his- tory of hypertension. Serum calcium, potassium, cre- atinine, aldosterone (n. 28-440 pmol/L) and renin (n. 2.4-21.9 ng/L) levels were measured after lying supine for 6 hours and after stopping β-blockers under super- vision for 4 days.10 Renal ultrasounds were obtained in all patients, as well as a contrast adrenal computed tomography (CT) scan, with 2-3mm slices, in those with documented hyperaldosteronism and suppressed renin levels. The patients with suppressed renin levels were given a 1 month course of spironolactone 50-100 mg daily alone to four newly diagnosed patients, or in addition to other antihypertensives in the remainder. These were on a minimum of two drugs (16 patients) or ≥ three drugs (7 patients). The usual combination of medications was angiotensin-converting enzyme (ACE) inhibitors, angiotensin II (AT2) receptor block- ers, diuretics or beta-blockers (4 patients). No patients were taking methyldopa or clonidine. If the blood pressure (BP) was controlled (<140/80), after 2-4 weeks the other medications were sequentially with- drawn at weekly intervals until the patient was taking spironolactone alone for at least one month. Renin was measured using a renin immunoradiometric as- say (IRMA) kit (DSL-25100) from Diagnostic Systems Laboratories Inc. and aldosterone was measured via radioimmunoassay (RIA) kit from Dia Sorin Inc. The normal ranges used are from the North American data provided by the relevant companies. Formal sup- pression tests of aldosterone secretion were not per- formed. Fully informed consent was obtained from all patients. There was no conflict of interest financial or otherwise. R E S U L T S Of the 27 patients studied, renin levels were sup- pressed in 18 (66%), but aldosterone values were nor- mal in 13, elevated in 4 and undetectable in one case. The remaining 9 patients had normal values of aldos- terone, but renin levels were low in 3 of them [Table 1]. Of the 18 patients with suppressed renin levels, 14 were available for follow up whilst taking spironolac- tone and in 1 other case taking moduretic. Their final median BP was 130/70 with a range of 140/70-100/70. 167 FA M I L I A L M I N E R A L O C O R T I C O I D I N D U C E D H Y P E R T E N S I O N I N T H E S U LTA N AT E O F O M A N Serum calcium and potassium levels were normal in every patient. Serum creatinine levels were mildly el- evated in two cases at 129 and 147 µmol/L [Table 1]. There were 5 patients in consanguineous marriages in this group. D I S C U S S I O N The results of this study further support our original suggestion8 that there is a high prevalence of MC in- duced HTN in patients who have a strong family his- tory of the disease. Two thirds of our patients in this study had suppressed renin levels with autonomous Patient No Age Sex Renin ng/L Aldosterone pmol/L Final BP 1 45 F <0.5 380 125/70 2 49 M <0.5 140 125/70 3 56 F <0.5 57 130/70 4 44 F <0.5 112 130/70 5 55 M <0.5 168 LTFU 6 45 M <0.5 225 LTFU 7 44 F <0.5 70 125/70 8 58 M <0.5 108 100/70 9 42 F <0.5 227 LTFU 10 58 F <0.5 220 135/85 11 51 F <0.5 40 LTFU 12 46 F <0.5 136 135/70 13 42 M <0.5 351 130/80 14 44 F <0.5 <20 130/75 15 56 F <0.5 575 140/70 16 42 F <0.5 508 120/70 17 69 F <0.5 543 130/80 18 49 M <0.5 500 120/70 19 48 F 2.3 407 LTFU 20 42 F 0.5 321 130/70 21 38 F 1.3 323 110/75 22 36 M 2.7 79 150/85 23 39 F 2.5 140 145/85 24 54 M 4.7 383 155/90 25 45 M 3.1 381 150/80 26 42 M 2.6 300 140/80 27 50 F 20 448 145/80 Normal range Supine > 6 hrs 2.4-21.9 28-440 Table 1: Data from 27 patients with familial hypertension. The median basal blood pressure of the 4 patients not on medication was 155/105, with a range of 170/95 – 150/110 (patients 1, 3, 10, 17). Basal blood pressure values of patients already on treatment are not shown as they were only slightly elevated. 168 N I C H O L A S J Y WO O D H O U S E , O M AY M A T E L S H A F I E , FAT M A B E N A B I D A N D S U H A I L A D O I aldosterone production, and their BP was controlled using spironolactone a known MC receptor block- ing agent. It is now recognized that primary aldos- teronism occurs in more than 10 percent of the gen- eral hypertensive population and that hypokalaemia is an uncommon presenting feature.3-9 In fact, of the 72 patients with familial disease we have studied so far, only 6 were hypokalaemic at presentation including the one patient with Conn’s syndrome.8 We did not carry out dexamathasone suppression tests in these patients, but suspect that the majority have FH2 as we earlier found only one responsive family in 15 that were tested. The pathophysiology of FH2 is not known with certainty, but presumably results from one or more activating mutations in the renin/angiotensin/ aldosterone pathway. Of interest is the one patient who had suppressed renin and aldosterone levels. This combination occurs in Liddle’s syndrome and appar- ent mineralocorticoid excess (AME). Both result from excessive renal tubular reabsorption of sodium; the former caused by activating mutations of the epi- thelial sodium channels (ENaC) and the latter activa- tion of the type I MC-receptor. In AME there is an inherited or acquired deficiency of the renal isoform of 11-b-OH steroid dehydrogenase (11-b-OH SD). Normally this enzyme converts cortisol to inactive cortisone. In its absence, tissue cortisol levels increase activating the MC-receptor. Our patient does not have Liddle’s syndrome, however, as this disorder does not respond to a MC-receptor blocking drug. AME is also unlikely as there is no history of childhood ill health hypokalemia or ingestion of compounds known to in- activate 11-b-OH SD such as liquorice or chewing to- bacco. We are currently exploring the possibility that she might be secreting another MC-receptor stimulat- ing compound. Figure 3: Shows aldosterone values in patients with supressed (•) normal renin (•) levels 169 FA M I L I A L M I N E R A L O C O R T I C O I D I N D U C E D H Y P E R T E N S I O N I N T H E S U LTA N AT E O F O M A N The Brisbane group has suggested that FH-II (fa- milial hypertension type 2) has an autosomal domi- nant mode of transmission with linkage to 7p22 and gender distribution that is roughly equal.6-11 How- ever, apart from being familial, FH-II has no specific clinical, biochemical or morphological hallmarks that permit distinction from apparently non-familial PAL, with the two groups demonstrating similar mean ages, gender distributions, hypokalaemic percentages, mean upright plasma aldosterone and PRA levels, with these and the use of other investigative techniques.10 This suggests that the genetic defects that underlie the development of FH-II may also be operative in many patients with apparently non-familial PAL and may be picked up earlier by family screening. Indeed, it has been suggested that PAL passes through four phases in its evolution: low renin nor- motension, normokalemic primary aldosteronism and finally hypokalemic primary aldosteronism.12 C O N C L U S I O N MC induced disease seems to be common in Oman. In evolutionary terms this makes sense as the ability to conserve salt in hot climates might be expected to confer a definite survival advantage. We recommend that all patients with a positive family history of HTN should be screened for MC induced disease or at least receive a short therapeutic trial of spironolactone to avoid unnecessary complications. To our knowledge there have been no previous reports documenting MC induced disease in patients screened using a positive family history only. R E F E R E N C E S 1. Hemmelgarn BR, McAllister FA, Myers MG, McKay DW, Bolli P, et al. The 2005 Canadian Hypertension Education Program recommendations for the manage- ment of hypertension: part 1- blood pressure measure- ment, diagnosis and assessment of risk. Can J Cardiol 2005; 21:645-656. 2. Ganguly A. Primary aldosteronism. N Engl J Med 1998; 339:1828-1834. 3. Gordon RD, Ziesak MD, Tunny TJ, Stowasser M, Klemm SA. Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihyperten- sive drug trial volunteers. Clin Exp Pharmacol Physiol 1993; 20:296-298. 4. Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, Chiandussi L, et al. Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hyper- tension 2002; 40:897-902. 5. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Finn WL, Krek AL. Clinical and pathological diversity of pri- mary aldosteronism, including a new familial variety. Clin Exp Pharmacol Physiol 1991; 18:283-286. 6. Stowasser M, Gunasekera TG, Gordon RD. Familial va- rieties of primary aldosteronism. Clin Exp Pharmacol Physiol 2001; 28:1087-1090. 7. Stewart PM. Dexamethasone-suppressible hyperten- sion. Lancet 2000; 356:697-699. 8. Woodhouse NJ, Elshafie OT, Mehar A, Johnston WJ, Al-Kaabi JM. Spironolactone responsive familial hyper- tension. A potentially high prevalence of mineralocorti- coid disease in Oman. Saudi Med J 2003; 24:229-231. 9. Hood S, Cannon J, Foo R, Brown M. Prevalence of primary hyperaldosteronism assessed by aldosterone/ renin ratio and spironolactone testing. Clin Med 2005; 5:55-60. 10. Seifarth C, Trenkel S, Schobel H, Hahn EG, Hensen J. Influence of antihypertensive medication on aldoster- one and renin concentration in the differential diagnosis of essential hypertension and primary aldosteronism. Clin Endocrinol (Oxf ) 2002; 57:457-465. 11. So A, Duffy DL, Gordon RD, Jeske YW, Lin-Su K, New MI, et al. Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predict- ed heterogeneity. J Hypertens 2005; 23:1477-1484. 12. Grim CE. Evolution of diagnostic criteria for primary aldosteronism: why is it more common in “drug-resist- ant” hypertension today? Curr Hypertens Rep 2004; 6:485-492.