When hypertension is a result of an underlying identifiable abnormality, the latter's early discovery can lead to a timely cure of the hypertension and the prevention of its complications. We present a case of high blood pressure lowered by pregnancy, suggestive of an endocrine cause. This was confirmed following a detailed history which revealed severe hypertension intractable to therapy, yet which remitted during pregnancy. A diagnosis of 11-beta hydroxylase deficiency was made consequent upon the finding of raised serum 11-desoxycorticosterone levels. The blood pressure was finally controlled with glucocorticoid replacement therapy and spironolactone.peer-reviewe

Attard, Gerhardt

Cachia, Mario J.

English

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Malta Medical Journal    Volume 16   Issue 02   July 2004 39Remission during Pregnancy of Severe ChronicHypertension due to 11-ß Hydroxylase DeficiencyCase ReportGerhardt Attard, Mario J CachiaAbstractWhen hypertension is a result of an underlying identifiableabnormality, the latter’s early discovery can lead to a timely cureof the hypertension and the prevention of its complications. Wepresent a case of high blood pressure lowered by pregnancy,suggestive of an endocrine cause. This was confirmed followinga detailed history which revealed severe hypertensionintractable to therapy, yet which remitted during pregnancy. Adiagnosis of 11-beta hydroxylase deficiency was madeconsequent upon the finding of raised serum11-desoxycorticosterone levels. The blood pressure was finallycontrolled with glucocorticoid replacement therapy andspironolactone.Case ReportIn August 2000, a 32-year-old lady was referred to theendocrine clinic with a six year history of uncontrolledhypertension despite aggressive medical treatment.At the age of 26, her general practitioner found a bloodpressure of 160/110 mmHg on routine checking. The only bloodpressure readings taken prior to this occasion were during herfirst pregnancy, two and a half years previously. They were allwithin normal range. Her blood pressure was 140/98 mmHg ather first medical out-patients visit in July 1994 (Figure 1).Extensive investigations for a secondary cause were normal andincluded a renal ultrasound, an intravenous urogram and anisotope diethylenetriamine penta-acetic acid (DTPA) renal scanwith captopril.An echocardiogram showed mild mitral valve prolapse butnormal sized ventricular walls. Her serum sodium andpotassium were 144 mmol/l (normal range 135 - 145 mmol/l)and 3.8 mmol/l (normal range 3.5 - 5.1 mmol/l) respectively.Her blood pressure, over the next 18 months,  remainedpersistently above 150/90 mmHg despite a step-wise increasein labetalol to a maximum dose of 1200 mg daily and the earlyaddition of co-amilozide 2.5/25 mg once daily (Figure 1).Her general practitioner reviewed her in the first week ofJanuary 1996 after an episode of syncope. Her blood pressurehad dropped to 90/60 mmHg. She was six weeks pregnant withher second child. He stopped her treatment. One week later, ather first antenatal clinic visit, her blood pressure was 120/80mmHg. She remained normotensive throughout her pregnancy,even though she had stopped all antihypertensive treatment(Figure 1).She presented again one and a half years later, in April 1998,with a blood pressure of 180/120 mmHg despite treatment withenalapril 20 mg daily and bumetanide 1 mg daily (Figure 1).She was extensively reinvestigated for a renal cause; includinga renal angiogram that was normal. The only abnormality wasa serum potassium as low as 2.8 mmol/l. A suspicion of Conn’ssyndrome was excluded biochemically and her treatment wasstepped up further. Increased doses of ACE inhibitors and theaddition of a calcium-channel blocker failed to achievesatisfactory blood pressure control (Figure 1).At her first endocrine clinic visit, her blood pressure was170/100 mmHg in both arms whilst sitting. She was takingenalapril 20 mg, bumetanide 1 mg and atenolol 100 mg in oncedaily doses and nifedipine slow release 20 mg twice a day(Figure 1). Her menstrual cycles were regular since menarcheat the age of 11.5 years. There was no abnormal pigmentation.On direct questioning, she admitted to a slight excess of bodyhair, especially in the peri-areolar region. Her sister sufferedfrom central diabetes insipidus and a maternal aunt had hadsurgical removal of a pituitary macroadenoma. Her serumpotassium was 2.8 mmol/l and her serum sodium was 140mmol/l. 9 am cortisol was at the lower range of normal. It wasimportant to exclude an endocrine cause for her hypertensionin view of her age and low serum potassium. Although not aclearly described phenomenon, the normal blood pressure inboth pregnancies strengthened the argument for an endocrinecause.Gerhardt Attard, MD, MRCP (UK)Department of Medicine,St Luke’s Hospital, Gwardamangia, MaltaEmail: gertattard@doctors.net.ukMario J Cachia, MD, MRCP (UK)Department of Medicine,St Luke’s Hospital, Gwardamangia, MaltaEmail: mario.j.cachia@gov.mtKeywords11-beta hydroxylase deficiency, pregnancy, hypertension40 Malta Medical Journal    Volume 16   Issue 02   July 200417-hydroxy progesterone was mildly elevated: 2.1 ng/ml(day 10; normal range 0.3-1.0 ng/ml). Urinary 17-ketosteroidsand serum dihydroepiandrosterone (DHEA) sulphate werewithin the normal range. Erect and supine aldosterone andplasma renin activity were normal. Thyroid function tests(TFTs), day 10 follicular stimulating hormone (FSH), day 10luteinising hormone (LH) and sex steroid levels were allnormal for a menstruating female. Serum11-desoxycorticosterone was 4081  pmol/l (normal range 30-420 pmol/l). Stimulation with adrenocorticotropin (ACTH)produced a rise at 60 minutes to 16570 pmol/l (forty timesnormal). Her cortisol and 17-alpha hydroxy progesteronelevels showed a normal rise on dynamic testing with ACTH.This confirmed the diagnosis of partial 11-beta hydroxylasedeficiency. An echocardiogram showed mild left ventricularhypertrophy and a hypocontractile left ventricle. A computedtomography scan with fine cuts of the adrenal glandsconfirmed mildly enlarged adrenals.Glucocorticoid replacement therapy was started andstepped up until 24-hour ambulatory readings confirmedsuccessful control of the blood pressure. 9 am cortisol and11-desoxycorticosterone were successfully suppressed. Serumsodium and potassium remained in the normal range. Theantihypertensive treatment was successfully tailed down tospironolactone 25 mg daily (Figure 1).DiscussionDeficient 11-beta hydroxylase activity (mutation at CYP11B1on chromosome 8) accounts for 5-8% of cases of congenitaladrenal hyperplasia.1   This equates to a global incidence of 1 in100,000 live births.2 A considerably higher incidence isdescribed in Turks and in Jews of Moroccan or Iranian descent.3The patient discussed above has a mild type of the classicalform of 11-beta hydroxylase deficiency. Patients in this groupmay have normal basal levels of ACTH, cortisol and itsmetabolites. However, dynamic testing with ACTH shows anexaggerated rise in cortisol metabolites. This indicates that thereis partial impairment of 11-beta hydroxylation that, under basalconditions, does not result in maximum endogenous secretionof ACTH and plasma cortisol levels remain within normalrange.4 This group of patients is more likely to be diagnosed inearly adulthood and to be hypertensive at diagnosis thanpatients with a complete defect.5Patients with congenital adrenal hyperplasia andhypertension were first observed in the 1950s. Increasedsecretion of 11-deoxycortisol was assumed to be the cause ofFigure 1: Blood pressure readings from 1994 - October 2002. Blood pressure in mmHg on y axis; date scaled by category(not time) on x axisMalta Medical Journal    Volume 16   Issue 02   July 2004 41hypertension in 11-beta hydroxylase deficiency but thecorrelation appears unclear. Blood pressure appears to beindependent of 11-deoxycortisol levels. Importantly,hypertension may persist after suppression of 11-deoxycortisol5and in fact, continued treatment with anti-aldosterone agentsis often required. Possibly, one of the metabolites ofdeoxycortisol that is a more potent mineralocorticoid, such asthe 19-nor metabolite, is responsible for the raised bloodpressure.6Despite a striking expansion in blood volume and theactivation of the renin-angiotension-aldosterone mechanism,blood pressure tends to fall during pregnancy in bothnormotensive and chronically hypertensive females up to a lowat twenty eight weeks gestation, after which levels tend to returnto non-pregnant ones.7  It is likely that a number of mechanismsmediate this adaptation. Complete remission of hypertensionduring pregnancy has been described in cases of primaryaldosteronism and it is suspected that this is secondary to raisedprogesterone antagonising the excessive aldosteronesecretion.8, 9  Remission of hypertension in pregnant patientssuffering from 11-beta hydroxylase deficiency has not beenpreviously described. The authors speculate that thisphenomenon is secondary to the direct suppression of ACTHlevels by oestrogens or progesterones10 with a consequentsuppression of the feedback loop stimulating cortsiol productionin the adrenals. This hypothesis will be hard to prove due to theapparent rarity of this condition.References1. Merke DP, Tajima T, Chhabra A, Barnes K, Mancilla E, Baron J etal. Novel CYP11B1 mutations in congenital adrenal hyperplasiadue to steroid 11 beta-hydroxylase deficiency. J Clin EndocrinolMetab 1998; 83:270-273.2. Pang S, Wallace MA, Hofman L, Thuline HC, Dorche C, Lyon ICTet al. Worldwide experience in newborn screening for classicalcongenital adrenal hyperplasia due to 21-hydroxylase deficiency.Pediatrics 1988; 81:866-874.3. Kandemir N, Yordam N. Congenital adrenal hyperplasia inTurkey: a review of 273 patients. Acta Paediatr 1997; 86:22-25.4. Cathelineau G, Brerault JL, Fiet J, Julien R, Dreux C, Canivet J.Adrenocortical 11 beta-hydroxylation defect in adult women withpostmenarchial onset of symptoms. J Clin Endocrinol Metab1980; 51:287-291.5. Zachmann M, Tassinari D, Prader A. Clinical and biochemicalvariability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency; a study of 25 patients. J Clin EndocrinolMetab 1983; 56:222-229.6. Griffing GT, Dale SL, Holbrook MM, Melby JC. Relationship of19-nor-deoxycorticosterone to other mineralocorticoids in low-renin hypertension. Hypertension 1983; 5:385-389.7. Wilson M, Morganti AA, Zervoudakis J, Letcher RL, Romney BM,Von Oeyon P. Blood pressure, the renin-aldosterone system andsex steroids throughout normal pregnancy. Am J Med 1980;68:97-104.8. Murakami T, Watanabe Ogura E, Tanaka Y, Yamamoto M. Highblood pressure lowered by pregnancy. Lancet 2000; 356:1980.9. Biglieri EG, Slaton PE Jr. Pregnancy and primary aldosteronism.J Clin Endocr 1967; 27:1628-1632.10. Carr BR, Parker CR Jr, Madden JD, MacDonald PC, Porter JC.Maternal plasma adrenocorticotropin and cortisol relationshipsthroughout human pregnancy. Am J Obstet Gynecol 1981;139:416-422.PALS undergoes a metamorphosisinto the European foldThe Paediatric Advanced Life Support (PALS) Coursecontinues to be an ever-popular, successful, annual event.This year’s course was notable for three reasons - firstly,it was the first course run along European and not UKguidelines, hence the metamorphosis to European PaediatricLife Support - EPLS (Malta). Secondly, this was one of thevery few PALS or EPLS courses ever held locally and abroad,where no candidate was required to re-sit the basic life supporttesting!  Full credit to this year’s cohort who were extremelyenthusiastic and, incidentally, included several paediatricianstaking the course for a second time as a refresher!  Thirdly,Dr Tanya Esposito established a ‘first’ by taking responsibilityas the first home-grown Course Director.As always, this initiative requires considerableorganisation and support and remains indebted to thefinancial backing of the Health Division, as well as our fellowEPLS instructors from the United Kingdom who offer theirtime and services for no reward.  We are also extremelygrateful to the Maltese Paediatric Association for theirsponsorship, the Institute of Health Care for use of theirexcellent premises, the SAS Radisson for hosting the Coursedinner, the ever-present Mr Charles Messina and the localEPLS Organising Committee and Faculty including Drs.TanyaEsposito, Mario Zerafa, Maryrose Cassar, Jonathan Joslin,Debbie St John and Mrs Annabelle Abela.  To all thoseinvolved in EPLS - a heartfelt thank you!  Ultimately, however,it is the enthusiasm and eagerness of the candidatesthemselves that makes this course such a pleasurable andworthwhile event.  We are delighted to announce that we haverecently applied to register Malta as a free-standing ‘EPLS’training centre (rather than an offshoot of Great OrmondStreet Hospital’s training facility) and look forward to ourofficial registration with enthusiasm.Simon Attard MontaltoSecretary, EPLS (Malta) Organising Committee

beta-hydroxylation defect in adult women with postmenarchial onset of symptoms.

Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy.

Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 betahydroxylase deficiency; a study of 25 patients.

High blood pressure lowered by pregnancy. Lancet

Pregnancy and primary aldosteronism.

Relationship of 19-nor-deoxycorticosterone to other mineralocorticoids in lowrenin hypertension. Hypertension

Remission during pregnancy of severe Chronic Hypertension due to 11-ß Hydroxylase Deficiency

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Remission during pregnancy of severe Chronic Hypertension due to 11-ß Hydroxylase Deficiency

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