Education Resource from the Society for Endocrinology
J M C Connell
Division of Cardiovascular and Medical Sciences.
University of Glasgow,
Western Infirmary, Glasgow, G11 6NT
Summer School 5-8 July 2005
St Aidan’s College, Durham University, Durham, UK
Recognition of secondary hypertension due to endocrine causes is important. Although many of the conditions are relatively rare, their detection offers the prospect of cure. Failure to identify the underlying cause may have long-term adverse clinical consequences for individual patients. However, screening all patients with hypertension for endocrine causes is impractical. Accordingly, a high degree of clinical suspicion is necessary in order that symptom complexes can be identified. In addition, it is reasonable to consider investigation in patients who are resistant to conventional anti-hypertensive management. In some circumstances particular clues may be present (for example, hypokalaemia as a feature of mineralocorticoid excess) that will guide this. In addition, unusual presentations (for example, high blood pressure with glucose intolerance in young patients with no other predisposing cause) deserve further investigation.
High blood pressure is a common finding in patients with acromegaly. Although the diagnosis is generally evident from physical features, a proportion of patients with acromegaly have relatively mild clinical signs and, in the circumstance, have atypical presentations including sleep apnoea and glucose intolerance.
Hypertension is a key feature of cortisol excess in patients with Cushing’s Syndrome. Gross examples are easily identified. However, patients with relatively mild Cushing’s Syndrome can be found at hypertension and diabetes clinics.
For this reason it is important to retain a high index of suspicion when hypertension presents along with central obesity and glucose intolerance. In this circumstance outpatient overnight dexamethasone suppression testing can provide a useful screening strategy.
More recently, the entity of sub-clinical Cushing’s Syndrome has been described in association with unilateral adrenal adenoma [1]. In patients with this presentation, hypertension is described that responds to unilateral adrenalectomy. Many of these tumours are identified as incidental findings, although abnormal dexamethasone suppressibility is well described.
Mineralocorticoid excess remains the commonest underlying secondary cause of hypertension. All types are characterised by suppression of renin activity and a tendency to hypokalaemia. However, it is now clear that less than 50% of patients with mineralocorticoid hypertension have spontaneous hypokalaemia. Accordingly, this cannot be relied on as a screening strategy to identify cases.
A small number of patients have mineralocorticoid hypertension due to rare conditions that include the syndrome of apparent mineralocorticoid excess (where cortisol acts as an agonist at the mineralocorticoid receptor); Liddle’s Syndrome (where this is constitutive activation of the aldosterone-regulated endothelial sodium channel); other rare causes include inborne errors of adrenal metabolism that result in excess deoxycorticosterone production (such as 11 and 17-hydroxylation deficiency)[for review, [2]. However, the great majority of patients with mineralocorticoid excess have Primary Aldosteronism.
It is now recognised that this presentation can occur in up to 10% of patients with unselected hypertension presenting to Primary Care or Secondary Care clinics. 40% of such patients may harbour a unilateral adrenal adenoma that secretes aldosterone (APA) while the rest have bilateral adrenal hyperplasia (idiopathic hyperaldosteronism) [3]. The pathogenesis of the latter condition remains uncertain – controversy persists as to the relation between this presentation and patients with low renin essential hypertension where aldosterone levels are not grossly elevated but are inappropriate for the prevailing level of renin [4]. In all cases, however, aldosterone suppressibility with sodium loading is abnormal.
Screening for Primary Aldosteronism can be carried out by measurement of the aldosterone to renin ratio. This is a useful outpatient test, although its performance is largely determined by the activity of renin. This can be influenced by drug therapy (particularly beta-blockers) and local laboratories need to standardise sampling conditions in order that appropriate normal ranges can be identified [5].
Following detection by screening, confirmation of Primary Aldosteronism can be carried out a variety of procedures including measurement of aldosterone following oral or intravenous sodium loading. Classification of Primary Aldosteronism is performed by imaging, supplemented where necessary by selective adrenal vein sampling to lateralise aldosterone production [6].
Phaeochromocytoma remains an important but rare cause of endocrine hypertension. Classic presentation with paroxysmal hypertension associated with palpitations, headache and sweating is uncommon, although symptoms are often evident on retrospective evaluation. It is now evident that a substantial proportion (up to 25%) of apparent sporadic Phaeochromocytomas occur as part of familial syndromes, including MEN2A and VHL. However, it has recently become apparent that mutations in the succinate dehydrogenase gene complex (SDH) are important causes of familial Phaechromocytomas [7]. As a result, a detailed family history is essential in all patients with this presentation; it is suggested that mutation screening is performed in all apparent sporadic tumours until the exact frequency and phenotypic presentation of these sub-types is better described.
A large number of different tests (and their combination) have been described in screening for Phaeochromocytoma [8]. Our own experience suggest that urinary free metadrenaline and nor-metadrenaline provide the best combination of sensitivity in specificity in screening for this condition.
The majority of endocrine hypertension relates to adrenal disorders. Opportunistic screening in selected patients with resistant hypertension or particular symptom combinations or signs is important as a means of detecting key clinical conditions.
The genetic associations of Phaeochromocytoma, in particular, emphasise the important of detecting these syndromes for larger scale finding.
[1] Terzolo M, et al . Subclinical Cushing's syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am. 2005: 423-39
[2] Stewart PM. Mineralocorticoid hypertension Lancet. 1999 ;353(9161):1341-7.
[3] Young WF Jr. Minireview: primary aldosteronism--changing concepts in diagnosis and treatment. Endocrinology. 2003 144(6):2208-13.
[4] Connell JM, et al Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension? Hypertension. 2003;41(5):993-9.
[5] Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone. J Am Soc Nephrol. 2004 15(8): 1993-2001.
[6] Rossi GP, et al Identification of the etiology of primary aldosteronism with adrenal vein sampling in patients with equivocal computed tomography and magnetic resonance findings: results in 104 consecutive cases.J Clin Endocrinol Metab. 2001 86(3):1083-90.
[7] Maher ER, Eng C. The pressure rises: update on the genetics of phaeochromocytoma. Hum Mol Genet. 2002;11(20):2347-54.
[8] Sawka AM, et al A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab. 2003;88(2):553-8.
The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society
Revised:
28-Jul-2005