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Endocrine Hypertension

Hypertension is a feature of a number of endocrine disorders, including acromegaly, Cushing's syndrome and thyroid disease, in several of which, such as phaeochromocytoma, hyper­ tension is the presenting feature of the condition. Overall, endocrine causes of high blood pressure are relatively rare (estimates vary from 1-3%), although there is evidence (discussed below) that primary aldosteronism may be much more frequent than initially suspected. The importance of endocrine causes of hypertension is twofold:

1 The identification of an endocrine cause of hypertension often leads to cure of high blood pressure, and in some situations a life-threatening disorder (such as phaeochromo cytoma) may be corrected. 2 The study of endocrine forms of hypertension has elucidated im portant aspects of endocrine physi ology and pathophysiology. Perhaps the best example of this is the appreciation of the importance of local steroid metabolism (such as cortisol oxidation) in the regulation of access of steroid hormones to glucocorticoid and mineralocorti coid receptors in the kidney and elsewhere.
This brief review will consider the major forms of endocrine hypertension encountered in clinical practice.

Corticosteroids and hypertension1
Glucocorticoids Glucocorticoid excess causes hyper tension in humans and experimental animals (see Ref 2 for review). In man, the principal glucocorticoid is cortisol, which acts at specific receptors in a wide range of target tissues. Cortisol excess due to Cushing's syndrome is associated with hypertension in over 50% of cases (Fig I) 3. This is also a feature of iatrogenic glucocorticoid excess with the use of synthetic hormones such as prednisolone and dexamethasone.
The cause of glucocorticoid-induced hypertension remains uncertain. Cortisol excess causes acute renal sodium retention, but long-term gluco corticoid hypertension (eg in Cushing's syndrome) is not typically associated either with suppression of plasma renin or with hypokalaemia, both of which would be expected in sodium dependent forms of hypertension. An exception is ectopic adrenocorti cotrophic hormone (ACTH) syndrome in which hypokalaemia is often found. Studies in both experimental animals and humans have indicated that acute and chronic glucocorticoid excess also alters vasodilator prostanoid synthesis, increases pressor sensitivity to a-adrenoreceptor stimulation, and possibly, most importantly, alters vascular endothelial nitric oxide produc tion2. Thus, there is likely to be a range of mechanisms which result in glucocorticoid hypertension in humans.
Treatment of cortisol excess. Depending on the reason for the cortisol excess, surgery may be a treatment option (eg removal of an ACTH-secreting pituitary microadenoma or adrenalec tomy). For patients unsuitable for surgery, medical treatment with drugs such as metyrapone is an option, although side effects with such agents may be a problem. Additionally, metyrapone, by inhibiting 11 p-hydroxylation, causes increased adrenal secretion of 11-deoxycorticosterone, which itself raises blood pressure via a mineralocorticoid-dependent mechanism.

Mineralocorticoid hypertension
Mineralocorticoid hypertension is typically associated with renal sodium retention, potassium wasting, with con sequent hypokalaemia if this becomes excessive, and suppression of plasma renin activity. The classical form of mineralocorticoid hypertension is exem plified by primary aldosteronism, most commonly due to an adrenal adenoma secreting aldosterone (Conn's syn drome). These benign tumours, which are generally small, produce aldos terone independent of regulation by renin. As a consequence, patients exhibit suppression of plasma renin, with aldosterone values either at the upper end of the normal range or frankly elevated. Initially, Conn's syndrome was thought to be a relatively rare cause of hypertension, accounting for less than 1 % of cases. More recently, however, studies by Gordon's group4 and others, using a sensitive renin/ angiotensin ratio as a screening test, have suggested that primary aldostero nism due to Conn's syndrome is relatively common and may be found in up to 10% of patients with high blood pressure. This screening test may be useful in clinical practice, and can be used in patients taking antihypertensive medication, but should be interpreted in the context of other features, including more detailed dynamic tests and appropriate imaging investigations.

Key Points
Underlying endocrine disorders may account for 1 -3% of hypertension Endogenous glucocorticoid excess can cause hypertension and may be amenable to surgical treatment Mineralocorticoid hypertension due to Conn's syndrome may be more prevalent than previously thought A number of genetic disorders of mineralocorticoid metabolism can present with hypertension Phaeochromocytoma may present in association with other potentially life-threatening endocrine disorders Acromegaly, hyperthyroidism, hypothyroidism and hyperparathyroidism can cause hypertension; high blood pressure may persist despite normalisation of hormone levels Primary aldosteronism may also be found in patients without a localising adenoma, when the condition is due to bilateral adrenal hyperplasia. Adrenal surgery is inappropriate in this situation, so distinguishing these patients from those with a solitary adenoma is clearly important. In the absence of a clearly identified unilateral lesion on adrenal computed tomography (CT) scanning, adrenal vein sampling for measurement of aldosterone can help localise hormone production, and consequently guide the decision on the need for surgical therapy. In the absence of surgical treatment, therapy with either amiloride or spironolactone is often effective in controlling hypertension.
Aldosterone excess causing hyper tension may occur rarely due to the autosomal dominant condition of glucocorticoid-suppressible hyperaldostero nism. In this disorder, a fusion gene resulting from unequal crossover at meiosis between the genes encoding aldosterone synthase (CYP11B2) and adrenal 11 p-hydroxylase (CYP11B1) produces aldosterone in an ACTHdependent manner5. This leads to marked aldosterone excess throughout life, with resultant hypertension.
Patients with this disorder can be treated with low-dose dexamethasone (which suppresses ACTH); alternatively, the use of amiioride or spironolactone can control hypertension6. The condi tion can be easily detected using a test for the presence of the chimeric gene (using a long polymerase chain reac tion). Patients who have a strong family history of aldosterone excess should be tested.

Mineralocorticoid hypertension with suppression of aldosterone levels
A number of rare disorders result in mineralocorticoid-type hypertension in which aldosterone levels are not high. Sodium retention accounts for the expected suppression of plasma renin. As with other forms of mineralocorticoid hypertension, potassium levels in the bloodstream are reduced to a varying extent, probably depending on the con comitant sodium intakesubjects with a high sodium intake will have a tendency to potassium wasting, and consequently hypokalaemia.
Liddle's syndrome. Liddle's syndrome, a rare form of mineralocorticoid-type hypertension inherited in an autosomal dominant manner, is due to constitutive activation of either the p or y subunit of the amiloride-sensitive epithelial sodium channel in the distal renal tubule. This results in excess sodium reabsorption, and consequently renal potassium wasting7. Aldosterone levels are not high, so spironolactone has no effect on blood pressure, but patients respond to amiioride. The diagnosis previously rested on clinical suspicion, a positive family history, the biochemical abnormality (low renin and aldosterone) and response to amiioride. Mutation screening of the 0 and y subunits of the sodium channel is now a useful alterna tive, particularly in family screening.

Apparent
mineralocorticoid excess: 11 p-hydroxysteroid dehydrogenase deficiency. Cortisol binds avidly to both mineralocorticoid and glucocorticoid receptors. To prevent overwhelming activation of mineralocorticoid recep tors by the glucocorticoid, cortisol is normally oxidised to cortisone by the enzyme 11 p-hydroxysteroid dehydro genase. This enzyme is present in the kidney (isoform II) and in a range of other tissues (isoform I). Mutations in the type II enzyme result in a rare, auto somal recessive form of hypertension in which cortisol inactivation is abnormally reduced so that cortisol can activate mineralocorticoid receptors, resulting in severe hypertension associated with suppression of plasma renin and hypokalaemia8. Treatment with dexa methasone will suppress adrenal production of cortisol, and thus lower blood pressure. This rare disorder can be mimicked by excessive ingestion of liquorice which inhibits the activity of the above enzyme.

Rare inborn errors of adrenal steroid metabolism can result in hypertension due to mineralocorticoid excess (reviewed in detail in Ref 9):
1 Deficiency of 17a-hydroxylase leads to inability to synthesise cortisol and, in the gonad, sex steroids. Affected subjects produce excessive deoxycorticosterone (DOC), which acts as a mineralocorticoid, leading to hypertension with suppression of plasma renin and hypokalaemia.
2 11p-hydroxylase deficiency results in an inability to synthesise cortisol and aldosterone, while excessive ACTH drive to the adrenal gland leads to increased DOC production.
Both these autosomal recessive dis orders can be successfully treated by suppressing ACTH with dexamethasone. These rare conditions should be consid ered in the differential diagnosis when juvenile-onset hypertension is associ ated with abnormal virilisation or altered secondary sexual development.

Phaeochromocytoma
Tumours of the adrenal medulla are a rare, but eminently curable, form of endocrine hypertension10. The incidence of phaeochromocytoma is low but may account for approximately 0.1% of patients with high blood pressure. These tumours are usually found in the adrenal medulla, but also occur in other neurone ectoderm-derived tissue. Most phaeochromocytomas (90%) are benign, but a small percentage (10%) is malignant and these may metastasise to liver and bone. About 10% of phaeochromocytomas occur outside the adrenal, generally within the abdomen.
Patients may present with a classical history of paroxysmal symptoms, such as palpitation, sweating and acute anxiety, but the diagnosis should be considered in other circumstances: for example, hypertension resistant to con ventional agents, when there is marked variability in blood pressure readings, or hypertension where control deteriorates after 0-blockade.
The majority of phaeochromo cytomas secrete noradrenaline, although a small percentage predomi nantly produce adrenaline. In addition, a number of other peptide hormones with pressor activity can be produced by these tumours, including neuropeptide Y and endothelin.
Diagnosis and localisation. Diagnosis of phaeochromocytoma is most easily made by measurement of cate cholamines or catecholamine metabo lites in 24-hour urine collections or by plasma catecholamines. In a small number of patients, however, produc tion of hormones by tumours may be paroxysmal and several collections may be necessary where diagnostic suspi cion is high. In some circumstances, a cionidine suppression test may help differentiate between borderline nora drenaline excess of neural origin and that due to a phaeochromocytoma11.
Localisation of phaeochromocy tomas may be carried out using CT scanning (Fig 2). In situations in which there is no obvious adrenal tumour, imaging with metaiodobenzylguanidine may be helpful. Occasionally, venous sampling may be required to provide more accurate localisation, particularly for tumours lying outside the abdomen.
Some phaeochromocytomas are familial, and the majority of these tumours are bilateral. It is important, therefore, to take an accurate family history in patients with this disorder. In addition, patients with a familial history may have multiple endocrine neoplasia type II syndrome (MENIIA) which com prises medullary carcinoma of the thyroid and parathyroid hyperplasia. This autosomal dominant condition, now recognised to be due to an abnor mality on chromosome 10, is generally associated with bilateral phaeochromocytomas. For this reason, it is mandatory that the diagnosis of MENIIA is consid ered in all patients presenting with. phaeochromocytoma and that their plasma calcitonin is measured. Conversely, all patients presenting with medullary carcinoma of the thyroid need screening for phaeochromo cytoma. Long-term follow-up of these patients is essential, as is detailed family screeningwhich has now been simpli fied by the availability of appropriate genetic markers.
Treatment. The treatment of choice for phaeochromocytomas is surgical removal of the tumour. Pre-operative treatment with an a-blocker (phenoxybenzamine) is essential, and p!-blocker therapy may also be used to deal with tachycardia. It is important to ensure adequate a-blockade prior to p-blocker therapy because unopposed p-blockade in patients with phaeochromocytoma can lead to serious exacerbation of hypertension.

Acromegaly
Growth hormone (GH) excess has adverse effects on the cardiovascular system, most notably in the form of hypertension and left ventricular hyper trophy. The latter can be a feature of acromegaly in the absence of hyperten sion and is therefore likely to be sec ondary to trophic effects of GH, possibly mediated by insulin-like growth factor (IGF)-I. The precise mechanism of hypertension in acromegaly remains unknown. Total exchangeable sodium is increased in this condition, which suggests that the hypertension may be sodium-dependent. In support of this view, plasma renin activity tends to be reduced in acromegaly. Mineralo corticoid excess is not a feature of acromegaly, suggesting that sodium retention is due either to a direct action of GH/IGF-1 on renal tubules or to a blunting of the physiological secretion of atrial natriuretic peptide. It has also been suggested that changes in sympa thetic nerve activity may be responsible for hypertension in acromegaly, but the evidence for this is conflicting. Removal of excess GH can result in normalisation of blood pressure, but in some cases hypertension persists and should be treated with conventional therapy (see Ref 12 for review).

Thyroid disease
Hypertension is reportedly associated with both hyper-and hypothyroidism1. Thyrotoxicosis is usually associated with a high cardiac output, peripheral vaso dilatation and systolic hypertension, which resolves after normalisation of thyroid status. Hypothyroidism may be associated with diastolic hypertension, which tends to resolve following thyroid replacement13, although few well con trolled studies have adequately taken into account placebo effects and the tendency for blood pressure to fall with repeated measurements. The mecha nism of hypothyroid hypertension' is unknown, but may involve sodium and water retention or possible changes in sensitivity to circulating catecholamines. If hypertension persists several months after normalisation of thyroid status, conventional antihypertensive therapy should be instituted.

Hyperparathyroidism
Hypertension is reported to be associ ated with hyperparathyroidism in 10-60% of cases14. Surgical removal of the parathyroid adenoma usually normalises blood pressure. Parathyroid hormone itself may directly raise blood pressure, but there is also evidence for the existence of a co-secreted plasma factor which may be responsible for the hypertension in this condition15. An increased calcium concentration, for whatever reason, may be involved in abnormal vascular smooth muscle control resulting in hypertension. However, the data on calcium levels and blood pressure are unclear and often contradictory. As with thyroid disease, there are relatively few well controlled studies on blood pressure regulation in relation to parathyroid disease. Again, hypertension that persists after normalisation of para thyroid status should be tackled by conventional means.