Show Summary Details
Page of

Secondary hypertension 

Secondary hypertension
Chapter:
Secondary hypertension
Author(s):

Morris J. Brown

and Fraz Mir

DOI:
10.1093/med/9780199204854.003.161703_update_002

Update:

Conn’s syndrome – description of somatic mutations causing adrenal adenomas. Discussion of hypothesis that low renin hypertension could be driven in some cases by small adrenal adenomas that may be detected by newer radiotracer imaging, and how these adenomas might be treated.

Updated on 29 October 2015. The previous version of this content can be found here.
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2016. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 21 September 2018

Essentials

The term ‘secondary hypertension’ is used to describe patients whose blood pressure is elevated by a single, identifiable cause, with an important subdivision being into reversible and irreversible causes: clinically, it is important to exclude the former, but not necessarily to find the latter.

In the first two decades of life, the prevalence of secondary hypertension is greater than that of essential hypertension; thereafter, a patient is much more likely to have essential hypertension, but investigations for secondary hypertension should still be assiduous in the twenties and thirties because the alternative entails so many years of tablet-taking.

All patients with hypertension should have a minimum set of investigations (see Chapter 16.17.2). Common indications for further investigations are (1) any evidence of an underlying cause on history or examination; (2) proteinuria, haematuria, or elevated serum creatinine (eGFR<30; CKD 4/5); (3) hypokalaemia, even if caused by diuretics; (4) accelerated (malignant) hypertension; (5) documented recent onset or recent worsening of hypertension; (6) resistant hypertension (not controlled with three antihypertensive drugs); (7) young age—any hypertension at less than 20 years; any hypertension needing treatment at less than 35 years.

The minimum screen in younger patients should include serum electrolytes, plasma bicarbonate, renin, and metanephrines (or catecholamines) to exclude phaeochromocytoma; 24-h urinary sodium excretion should be measured either in all patients, or in those with abnormal renin levels.

Primary hyperaldosteronism (Conn’s syndrome)

Recent studies suggest that aldosterone-producing adrenal adenomas are the single commonest known cause of hypertension. Primary hyperaldosteronism causes increased sodium retention through the epithelial sodium channel (ENaC) in the distal tubule and cortical collecting duct, which leads to hypertension. It can be caused by (1) Conn’s adenoma—a small (0.5–3.5 cm) benign tumour of the adrenal gland; (2) bilateral adrenal hyperplasia—where there are macro- or micronodules in the adrenal cortex; (3) the very rare condition of glucocorticoid-remediable aldosteronism (see Chapter 16.17.4).

Diagnosis— this usually consists of three confirmatory features: suggestive clinical biochemistry; radiological imaging showing an adenoma; lateralization on selective adrenal sampling. A good blood pressure response to aldosterone antagonism with spironolactone can provide further reassurance but is not an essential, or always present, part of the diagnosis. The classic clinical picture is hypertension with plasma electrolytes showing low K+, elevated bicarbonate, and Na+ typically at the upper end of the normal range, together with suppressed plasma renin and elevated aldosterone—. . However, none of these findings is invariable, and a high index of suspicion is warranted in patients with hypertension resistant to conventional therapy. A suppressed plasma renin, despite treatment with ‘A+C+D’ drugs which normally elevate renin, is the most useful clue, whereas plasma aldosterone itself is often within the normal range but inappropriately high for the level of renin.

The imaging, like the biochemistry, is straightforward in classical patients, since the adrenals are easily imaged in most patients by either CT or MRI. However, patients with little intra-abdominal fat remain challenging, and it is important also to recognize that adrenals reported as ‘bulky’ often hide a small (<1 cm) adenoma. The key objective, once an adenoma is seen or suspected, is proving functional lateralization. This can be difficult, but is essential for predicting that removal of one adrenal will have a substantial benefit, as well as indicating which adrenal to remove. The most reliable technique in most specialist centres is adrenal vein sampling: all samples need to be assayed for aldosterone and cortisol, with the ratio compared between the two sides.

Management—medical treatment is preferred for bilateral adrenal hyperplasia, control of hypertension and hypokalaemia before surgery for adenoma, older patients with adenoma who are well controlled, or where there is any doubt about diagnosis or lateralization. Spironolactone is the treatment choice but causes gynecomastia in men. Eplerenone or amiloride are less effective alternatives, and amiloride can be used-cautiously in combination with either of the other two drugs. Elective surgery is indicated for younger patients with adenomas, and older patients intolerant of—or uncontrolled by—medical treatment.

Renovascular hypertension

This is most commonly due to intrinsic disease of the intima (acquired, atherosclerosis, etc.) or media (congenital, fibromuscular dysplasia (FMD), etc.). FMD accounts for only 10–20% of all cases, but is the commonest cause under the age of 40.

Most cases of renovascular hypertension are probably not diagnosed because of the absence of sensitive clinical or biochemical markers. The main clinical clue is the finding in 50% of cases of a bruit anteriorly or posteriorly over a renal area, but it is important to remember that such a bruit is never diagnostic. In centres where it is routinely measured in younger patients, an elevated plasma renin is the commonest trigger to investigation for FMD. The diagnosis is made radiologically, most commonly by CT or MR angiography.

In FMD, angioplasty is usually curative, with about three-quarters of patients able to discontinue antihypertensive treatment. In atheromatous disease, angioplasty is much less likely to be successful: complete cure of hypertension is rare, and often the purpose of intervention is to protect declining renal function.

Coarctation of the aorta

Coarctation causes less than 1% of all cases of hypertension. The classical clinical finding is radio–femoral pulse delay or weak lower limb pulses. Diagnosis is confirmed by two-dimensional echocardiography, or by CT or MR angiography. Treatment is by surgery, balloon dilatation, or stenting.

Phaeochromocytoma

Phaeochromocytomas are rare tumours of chromaffin tissue that account for 0.1 to 1% of cases of hypertension: 90% are benign and 90% are located in the adrenal gland (4% of adrenal incidentalomas are phaeochromocytomas). Most are sporadic, but some are associated with genetic syndromes, including von Hippel–Lindau and multiple endocrine neoplasia (MEN) type 2.

Hypertension, usually in association with one or more symptoms of headache, sweating, anxiety, and palpitations, is the most common presentation. Other rarer presentations include unexplained heart failure or paroxysmal arrhythmia.

Diagnosis—this is usually not difficult once the possibility of phaeochromocytoma has been entertained; more difficult is excluding the diagnosis in patients who have clinical and/or biochemical features of physiological catecholamine excess. Investigation must first determine whether the patient has a phaeochromocytoma, and then where the tumour is. The best screening test is to measure plasma normetanephrine (normetadrenaline) and metanephrine (metadrenaline): levels or, if unavailable, 24-h urine metanephrines: both assays in a reliable laboratory are more sensitive and specific than measurement of catecholamines or vanillylmandelic acid (VMA). Detection of elevated metadrenaline is a useful clue to the usual adrenal location of the phaeochromocytoma. A pharmacological suppression test can be performed where doubt about the diagnosis remains: physiological elevations of noradrenaline release are temporarily suppressed by administration of the ganglion-blocking drug pentolinium, or the centrally acting α‎2-agonist clonidine, but these drugs do not suppress autonomous secretion by tumour. CT or MRI scanning usually provides excellent imaging of the adrenal. Radioisotope scanning with the iodinated analogue of noradrenaline, m-iodobenzylguanidine (mIBG), beis usually helpful in localizing extra-adrenal tumours. Selective venous sampling is occasionally required.

Management surgery—is the definitive treatment that cures hypertension in most patients—; the task for the physician is to make it safe. This should be done by α‎-blockade with phenoxybenzamine, with a low dose of a β‎1-selective blocker used to prevent reflex tachycardia.

Introduction

The term ‘secondary hypertension’ is used to describe patients whose blood pressure is elevated by a single, identifiable cause. Until recently, there has been an optimistic view that description of new causes of hypertension would mean that those regarded as having ‘essential hypertension’ would be an ever-diminishing group. However, as discussed in Chapter 16.17.1, genome-wide investigation into the genetic bases of hypertension have shown that there are no common inherited susceptibility alleles that can explain more than 1 to 2 mmHg of a person’s blood pressure. Hence it is now almost certain that essential hypertension differs from secondary hypertension not only in being unexplained, but in being, within each patient, due to a multiplicity of inherited and acquired characteristics.

An important subdivision of secondary hypertension is into reversible and irreversible causes: clinically it is important to exclude the former, but not necessarily to find the latter. Their elucidation may lead to improved medical therapy, e.g. by predicting the best diuretic in the monogenic causes of low-renin hypertension, or help assess prognosis, as in the patient with proteinuria. However, the resource implications of finding causes, which can be considerable, need to be balanced against achievable gains. These in turn are influenced by the patient’s age, usually meaning that a search for secondary causes is easier to justify in young patients in whom small benefits are multiplied over many years.

Age-related prevalence of secondary hypertension

Whereas essential hypertension is clearly an age-related phenomenon, the same is less true of secondary hypertension, although different causes predominate at different ages. The net likelihood of a given patient with hypertension having a secondary cause is higher at a young age (Fig. 16.17.3.1). In the first two decades, essential hypertension is so uncommon that even the absolute prevalence of secondary hypertension is greater than that of essential hypertension. Thereafter, a patient is much more likely to have essential hypertension, but investigations for secondary hypertension should still be aggressive in patients in their twenties and thirties because the alternative entails so many years of tablet-taking.

Fig. 16.17.3.1 The age-related prevalence of secondary hypertension. The red line shows the prevalence of essential hypertension by age (years), the dotted line the prevalence of secondary hypertension by age, and the bars show the percentage of all hypertensives with a secondary cause.

Fig. 16.17.3.1
The age-related prevalence of secondary hypertension. The red line shows the prevalence of essential hypertension by age (years), the dotted line the prevalence of secondary hypertension by age, and the bars show the percentage of all hypertensives with a secondary cause.

In the first decade of life the main causes of secondary hypertension are (1) the monogenic syndromes causing low-renin (Na+-dependent) hypertension and (2) congenital causes (e.g. coarctation). However, the rarity of blood pressure measurement or of complications in the first decade means diagnosis is often later, hence these are also the main causes of hypertension diagnosed in the second decade. Additional causes by this time are some acquired renal diseases, and the familial phaeochromocytoma syndromes. Conn’s syndrome becomes the commonest cause for the next two to three decades. From the fifth decade onwards, atheromatous renal artery stenosis is the main secondary cause of hypertension.

The clinical approach to secondary hypertension

All patients with hypertension should have a minimum set of investigations, as described in Chapter 16.17.2. Common indications for further investigations are shown in Box 16.17.3.1.

If possible, patients with blood pressure requiring treatment in their twenties or thirties should be investigated before initiation of treatment because this is rarely pressing at a young age, and some of the tests are easier to interpret off treatment.

The minimum screen in younger patients should include serum electrolytes, plasma bicarbonate, plasma renin, and metanephrines to exclude a phaeochromocytoma; 24-h electrolyte excretion should be measured either in all patients, or in those with abnormal renin levels, with the trend to using metanephrine excretion for phaeochromocytoma screening allowing a single collection (without preservative) to be used for both purposes. Sodium intake is most readily estimated at steady state (i.e. no recent change in diet or drugs) by measuring sodium excretion: intakes between 100 and 200 mmol (c.6–12 g)/day have little effect upon plasma renin, whereas outside this range there is a steep inverse relationship.

Further investigations pursuing specific diagnoses that might be considered in particular cases (Table 16.17.3.1) are described in the following sections.

Secondary hypertensionTable 16.17.3.1 Evidence in history, examination, or routine investigations suggesting a secondary cause for hypertension

Clinical

Evidence

Condition to consider

History

Paroxysmal features—palpitations, sweating, pallor, panic, headache or chest pain, cool peripheries Flushing, labile blood pressure

Phaeochromocytoma Carcinoid syndrome

Personal or family history of renal disease

Renal hypertension

Pregnancy

Pre-eclampsia, HELLP syndrome

Drug history—oestrogen-containing oral contraceptives; corticosteroids; non-steroidal anti-inflammatory drugs; sympathomimetics (amphetmaines, cocaine cold cures, nasal decongestants); corticosteroids; ciclosporin; leflunomide; liquorice; caffeine; carbenoxalone; sodium bicarbonate (often found in excessive amounts in effervescent medictions, antacids); ergotamine; triptans; monoamine oxidase inhibitors (with tyramine-containing foods); erythropoietin; ; chronic arsenic exposure; long-term alcohol use; smoking cessation therapies; tramadol (enhances serotonergic and adrenergic transmission)

Drug-induced hypertension

Tetany, muscle weakness, fatigue

Conn’s syndrome

Examination

General appearance

Cushing’s syndrome, acromegaly, thyroid disorders, obstructive sleep apnoea

Palpable kidney(s)

Adult polycystic kidney disease, tuberous sclerosis

Abdominal or loin bruits

Renovascular disease

Delayed or weak femoral pulses

Coarctation of the aorta

Investigations

Proteinuria, haematuria, or elevated serum creatinine (eGFR<30; CKD 4/5)

Renal or renovascular disease

Hypokalaemia , metabolic alkalosis Hypercalcaemia Hyperglycaemia

Conn’s syndrome Hyperparathyroidsim Phaeochromocytoma

Fig. 16.17.3.9 MR angiogram showing coarctation of the aorta (arrow).

Fig. 16.17.3.9
MR angiogram showing coarctation of the aorta (arrow).

Fig. 16.17.3.10 3D CT reconstruction of co-arctation of the aorta (arrow).

Fig. 16.17.3.10
3D CT reconstruction of co-arctation of the aorta (arrow).

Primary hyperaldosteronism (Conn’s syndrome)

History

In 1955, with the words ‘to our surprise and delight, a cortical adenoma was observed to be arising from the right adrenal gland’, Jerome Conn reported the first observation of the benign aldosterone-secreting tumour that now bears his name. The patient had presented with severe hypertension and hypokalaemia, shortly after the discovery of aldosterone (‘electrocortin’) in London by the Taits in 1953. On detecting a high level of aldosterone in the patient’s urine, Conn decided to remove both adrenals. There is an historical irony in this entirely right decision: not so much because the patient retained her left adrenal, but because the finding of unilateral disease in this patient has largely pre-empted the same decision being made in patients with truly bilateral disease.

Secondary hypertensionConn’s report led to a flurry of similar diagnoses and optimism that as much as 20% of hypertension might be due to his tumour. However, it soon became apparent that no adenoma could be found in perhaps 50% of patients with the clinical and biochemical features of primary hyperaldosteronism, some being diagnosed instead as having bilateral nodular hyperplasia. With waning enthusiasm for finding a curable cause of hypertension, estimated prevalence fell to less than 1% of hypertension, but the picture again reversed with the recognition that not all patients with primary hyperaldosteronism have an elevated plasma aldosterone concentration; indeed, it is now estimated that 5–10% of hypertensive patients have a potentially curable cause. Whereas previously low-renin hypertension was often considered a separate diagnosis, increasingly it is felt that even in such patients aldosterone drives the suppression of renin and that smaller adenomas are found when newer radiotracer imaging modalities are employed.

Aetiology and pathology

Secondary hypertensionConn’s adenoma is a small (0.5–3.5 cm) benign tumour. Although aldosterone is normally secreted selectively by the (outer) zona glomerulosa of the adrenal, classical Conn’s adenomas arise from the cortisol-secreting zona fasciculata, and secrete more cortisol than aldosterone; occasionally, the extra cortisol may be sufficient to cause suppression of the contralateral adrenal. In recent years, it has become apparent that aldosterone-producing adenomas of the zona glomerulosa are also common, but are commonly missed because of their smaller size. Adenomas arising in the two zones are characterized by somatic mutations in different genes (KCNJ5, a K+ channel, in zona fasciculata tumours; Cav1.3 (ATP2B3), an L-type Ca2+ channel, and Na+,K+-ATPase (ATP1A1) in zona glomerulosa tumours).

Bilateral adrenal hyperplasia is a distinct condition in which either radiologically or histologically there are macro- or micronodules in the adrenal cortex where the monolayered arcades of the normal zona glomerulosa are replaced by bi- or multicellular layered arcades. In the one type of primary hyperaldosteronism of known cause—glucocorticoid remediable aldosteronism (see Chapter 16.17.4)—there is no anatomical lesion in the adrenals other than expansion of the zona glomerulosa.

It remains unknown whether some patients develop single adenomas on the background of nodular hyperplasia, with suppression of all but the dominant nodule, or whether unilateral adenomas are usually a different condition from hyperplasia. In favour of the latter are a number of biochemical and pharmacological differences, and the fact that patients with glucocorticoid remediable hyperaldosteronism never develop a superadded adenoma. Patients with classical Conn’s adenomas show an exaggerated diurnal rhythm in aldosterone, consistent with an enhanced ACTH-dependent cAMP pathway. By contrast, patients with hyperplasia, and those with the small zona glomerula tumours, show exaggerated aldosterone response to stimulation by angiotensin II and therefore have higher erect than supine aldosterone levels.

Primary hyperaldosteronism causes increased sodium retention through the epithelial sodium channel (ENaC) in the distal tubule and cortical collecting duct. The chronic sodium retention leads to hypertension, which is an essential feature of Conn’s syndrome. Electroneutrality in the tubular cell is retained by secreting K+ and/or H+ ions in exchange for the Na+, + with consequent hypokalaemic alkalosis.

Secondary hypertensionEpidemiology

Adenomas are slightly commoner in women, bilateral hyperplasia commoner in men. Conn’s syndrome is not a cause of childhood hypertension, except for the rare monogenic syndrome of glucocorticoid remediable hyperaldosteronism. Hyperplasia is said to be commoner among older patients with hypertension However, it is difficult clinically to distinguish hyperplasia from -small zona glomerulosa adenomas. Since it is likely that the latter have been present for many years or decades before presenting with often resistant hypertension, the best and easiest time to look for them is in younger patients, where hyperplasia is less likely and surgical treatment is most rewarding. Another condition which needs distinguishing from aldosterone-producing adenomas in older patients is nonfunctioning adrenal adenomas (‘incidentalomas’), which are present in at least 4% of people over 50.

Overall prevalence remains contentious because of the detailed investigations required to establish presence or absence of functioning adenomas. In younger patients, where nonfunctioning adenomas and low-renin hypertension are both uncommon, and response to surgery is more clear cut, a conservative estimate would be 2% of those with hypertension, but the discovery of the smaller zona glomerulosa tumours may double this number. The prevalence among older patients with hypertension is probably similar. At present, a higher, proportion of the older age group are likely to be investigated, having presented with either resistant hypertension, or an adrenal incidentaloma, but in reality a smaller proportion are likely to benefit from surgery. Whether investigations reduce or increase in coming years may depend on the success of less invasive modalities than in current use for both investigation and treatment of adenomas, and extension of the latter into bilateral disease.

Clinical features

Patients with primary hyperaldosteronism ‘escape’ from the effects of aldosterone before sufficient Na+ is retained to cause overt oedema, hence the clues and confirmation of the diagnosis are largely biochemical. The classic picture in Conn’s syndrome is hypertension in which the plasma electrolytes show a low K+, elevated bicarbonate, and a Na+ typically at the upper end of the normal range, but sometimes above this. The hypertension is often resistant to treatment with conventional treatment for the patient’s age group—e.g. angiotensin converting enzyme (ACE) inhibition in a younger patient, or to multiple drugs including a thiazide diuretic in the older age groups. It is important to mention, however, that the classical hallmark—hypokalaemia—is not always present, and yet the consequences of K+ depletion—weakness, tiredness, U wave on ECG—might still be manifest. The severity of hypokalaemia varies steeply with the Na+ load presented to the ENaC, this depending partly on dietary Na+ intake and partly on drugs—principally thiazide diuretics—which affect the proportion of the filtered Na+ load reaching the distal tubule. The commonest reason for the biochemical features of Conn’s to be masked is concurrent treatment with a calcium channel blocker, hence when considering the possibility of Conn’s in a patient with hypertension apparently resistant to conventional treatment, it is important to look not just at the current plasma electrolytes but at an historical set of results for any finding of hypokalaemia or alkalosis, also to reflect that hypokalaemia on a low-dose of thiazide is a reason for pursuing (rather than dismissing) the diagnosis of primary hyperaldosteronism.

Differential diagnosis

The hypokalaemic hypertensive is an interesting diagnostic challenge that can usually be solved by a series of logical moves. The finding of a Conn’s adenoma is the most satisfying outcome because surgical excision is most likely to lead to long-term cure. The other curable cause is liquorice which, taken in excess, inhibits the enzyme 11β‎-hydroxysteroid dehydrogenase (11HSD) and permits cortisol access to the mineralocorticoid receptor (see ‘Apparent mineralocorticoid excess’ in Chapter 16.17.4). Excess production of cortisol in Cushing’s syndrome can also mimic Conn’s. This is most likely to happen when there is ectopic ACTH production or with a malignant adrenocortical tumour, resulting in gross excess of cortisol and consequent saturation of the 11HSD enzyme (Fig. 16.17.3.2). Cosecreting, or coexisting, aldosterone- and cortisol-producing adenomas should also be considered, although generally the clinical picture is predominantly of one or the other.

Fig. 16.17.3.2 Coronal (panel A) and axial (panel B) CT scan images of a large right-sided malignant adrenocortical tumour (horizontal arrow) that is invading the liver (vertical arrows).

Fig. 16.17.3.2
Coronal (panel A) and axial (panel B) CT scan images of a large right-sided malignant adrenocortical tumour (horizontal arrow) that is invading the liver (vertical arrows).

Clinical investigation

Electrolytes

The critical tests in the investigation of hypokalaemic hypertension are plasma and urine electrolytes, and plasma renin and aldosterone. If the recommendations described above for screening tests in young patients with hypertension have been observed, all but the plasma aldosterone should already have been performed. The urine K+ (which can be performed on a spot sample) is usually in excess of 40 mmol/litre if hypokalaemia is due to increased urinary loss, but this test is valuable only when performed when plasma K+ is low. Because transient hypokalaemia is common, and hypokalaemia commonly transient even in Conn’s syndrome, it is important not to postpone urine K+ estimation and risk missing a one-off opportunity for sparing a patient the further investigations required for renal K+ loss.

Renin

Of the triad of hypokalaemia, suppressed plasma renin and elevated aldosterone, the renin is of most importance in the diagnosis of Conn’s—although still not invariable, even in untreated patients. The diagnosis should be entertained in the absence of an elevated aldosterone, especially in patients where a suppressed renin is unexpected: the younger patient (aged <45 years), particularly if already on an ACE inhibitor or angiotensin receptor blocker (ARB); and the older patient with resistant hypertension, receiving multiple drugs which normally elevate renin.

The main confounders in interpretation of the plasma renin level are drugs. A low renin in the presence of β‎-blockade is of no significance, and a β‎-blocker (which is unlikely to help with blood pressure control in Conn’s anyway) should be discontinued or substituted by an ACE inhibitor or ARB 2 weeks before renin measurement. Conversely, spironolactone or amiloride will desuppress’ of renin in most patients, and this should be borne in mind if the patient was already receiving one of these drugs prior to investigation.

Renin itself is very stable in blood, providing this is not chilled (which cryoactivates the renin precursor, prorenin). Although changes in posture and activity cause two- to threefold changes in renin, the range of renin between high- and low-renin patients is some 1000-fold, hence it is simple to interpret results taken in routine outpatient clinics or surgeries, providing the blood sample (taken into an EDTA tube) reaches the laboratory for plasma separation on the same day as the blood is taken.

Aldosterone

Plasma aldosterone is often elevated above the normal range (100–400 pmol/litre), and is generally higher in patients with macroadenomas (>1 cm) than in those with microadenomas or hyperplasia. In patients with adenomas there is an exaggerated influence of ACTH leading to pronounced diurnal variation in aldosterone levels, which are more likely to be normal when sampled in the afternoon. By contrast, patients with hyperplasia have an exaggerated response to angiotensin II, so that levels may actually rise during the day in response to activity and be normalized by drugs blocking the renin system, particularly angiotensin receptor blockade. However, the most profound influences are serum K+ and the use of calcium channel blocker treatment, which (as already stated) are probably now the commonest reason for the diagnosis of Conn’s syndrome to be missed.

Aldosterone/renin ratio

The recognition that aldosterone is often normal—even, sometimes, after correction of hypokalaemia and withdrawal of calcium channel blocker—led to the concept of the aldosterone/renin ratio. However, in practice, because renin is log-normally distributed and aldosterone distribution is normal, the aldosterone/renin ratio is always high in low-renin patients (except in the rare low-renin, low-aldosterone differential diagnoses considered above for hypokalaemic hypertension) and the vast majority of those with an elevated aldosterone/renin ratio do not have primary hyperaldosteronism, hence the key question is how to avoid unnecessary investigations in these cases. The empirical answer is that in the absence of other clues—hypokalaemia, high/high-normal plasma Na+, alkalosis—investigation be undertaken only in patients with resistant hypertension.

Secondary hypertensionSaline (fludrocortisone)

A possible dynamic test before proceeding to radiological investigations is the saline (or fludrocortisone) suppression test, which in principle is equivalent to the outpatient dexamethasone test for Cushing’s syndrome (see Chapter 13.7.1). In practice the classical test prescribes sodium and potassium loading during the 3 days of suppression by fludrocortisone 400 µg daily, and the consequent risk of severe hypertension necessitates close observation. Simplified protocols using either fludrocortisone or saline suppression alone are also sometimes followed. However, many investigators regard suppression as unreliable and unnecessary: perhaps its role in diagnosis can best be reserved for a late stage in the diagnostic algorithm, in patients where the case for surgery is borderline, and when extra certainty about diagnosis is required..

Genetic testing

This is rarely required, but if there is a family history of early-onset hypertension, and particularly of strokes at a young age, the patient should be screened for glucocorticoid remediable aldosteronism (see Chapter 16.17.4), of which there are only a few known families in the United Kingdom. Interestingly, research is increasingly providing fascinating insights into the genetics of aldosterone-producing adenomas, which in turn may lead to improved diagnosis in future, without the need for adrenal venous sampling.

Secondary hypertensionScanning

The adrenals are easily imaged by either CT or MRI, except when there is a dearth of intra-abdominal fat (Fig. 16.17.3.3). Under such circumstances, where the patient is very slim, skilled ultrasonography may be superior to CT or MRI. There is no proven advantage of one of these two modalities over the other, MRI may be preferred in younger patients, to spare radiation, and the fat-suppression sequence is useful for differentiating adenomas both from other adrenal masses, and sometimes the adjacent normal adrenal. Resolution may be higher with CT, but the limit for both modalities is not so much inherent resolution as the existence of 0.3–0.6-cm adenomas that do not create a discrete bulge within an adrenal limb, and even 1-cm adenomas at the bifurcation of the two limbs can be difficult to distinguish from a normal gland. It is valuable to request coronal reconstructions, which may show or confirm adenomas less evident on the axial views. Neither MRI nor CT can differentiate functional from incidental adenomas.

Fig. 16.17.3.3 Conn’s adenoma (arrow): CT transverse view (left), coronal view (middle), surgical specimen (right).

Fig. 16.17.3.3
Conn’s adenoma (arrow): CT transverse view (left), coronal view (middle), surgical specimen (right).

Functional lateralization

This is the key, but most difficult stage of diagnosis. Lateralization is essential in predicting that removal of one adrenal will have a substantial benefit, as well as indicating which adrenal to remove, although it might occasionally be omitted in younger patients (aged <35 years) with macroadenomas, or where the tumour is more than 3.5 cm in diameter and needs to be removed to exclude a mixed adrenal carcinoma.

At present, the only reliable form of lateralization available at most specialist centres is adrenal vein sampling, This is technically demanding and should be undertaken only by experienced radiologists (Fig. 16.17.3.4). On the left side, the adrenal vein is the only vein to enter the renal vein superiorly, and cannulation is relatively straightforward. On the right, however, the adrenal vein is one of several small veins (<1 mm diameter) entering the inferior vena cava posteriorly. A fish-hooked ‘Cobra’ catheter with side-holes maximizes the chances of success at 80%, providing several veins are sampled, with reference samples also taken in the inferior vena cava above and below the adrenal veins.

Fig. 16.17.3.4 Adrenal vein sampling for a right adrenal adenoma.

Fig. 16.17.3.4
Adrenal vein sampling for a right adrenal adenoma.

Secondary hypertensionAll samples need to be assayed for aldosterone and cortisol, with the ratio compared between the two sides: a ratio above 4 is usually diagnostic, and above 10 is definitive. Ratios of two- to fourfold can be compatible with lateralization, but are best confirmed on repeat sampling. In such cases accuracy might be enhanced by simultaneous sampling from both veins, or—if aldosterone levels were low on the first occasion—by prior ACTH stimulation. Some centres advocate these additional procedures as a routine, but they increase both the cost and duration of adrenal vein sampling at a time when the increased recognition of Conn’s syndrome requires increased access to tests for lateralization. When the right adrenal vein cannot be cannulated—revealed by a cortisol concentration less than 20% above that in the inferior vena cava—it is very risky to draw conclusions from the left sample alone: concentrations of aldosterone can be very high, even in a normal vein, because adrenal vein blood flow is so low.

Isotope scans can also be used for lateralization. 131I-cholesterol (or 75Se-methyl-19-norcholesterol) can be bought or generated for scanning in any nuclear medicine department, but 11C-metomidate (Fig. 17.3.5) must be synthesized on site in centres with a cyclotron and positron emission tomography (PET) scanner. The cholesterol scans rely on its role as precursor of steroid synthesis, and the scan is performed 1 week after isotope administration to permit cholesterol turnover and elimination from non-adrenal sites. However, the technique has a generally unreliable record, possibly because the dexamethasone taken during the week of investigation has variable influence on zona glomerulos as well as zona fasciculata uptake. Metomidate binds to synthetic enzymes in both the aldosterone and cortisol pathway, but appears relatively selective for those expressed in aldosterone-producing adenomas.

Fig. 16.17.3.5 11C-metomidate PET/CT scan of a right adrenal aldosteronoma. Uptake correctly differentiated hot and cold nodules, as confirmed by presence and absence of aldosterone secretion from the nodules when cultured post-operatively.

Fig. 16.17.3.5
11C-metomidate PET/CT scan of a right adrenal aldosteronoma. Uptake correctly differentiated hot and cold nodules, as confirmed by presence and absence of aldosterone secretion from the nodules when cultured post-operatively.

Uptake correctly differentiated hot and cold nodules, as confirmed by presence and absence of aldosterone secretion from the nodules when cultured postoperatively.

Treatment

Uptake correctly differentiated hot and cold nodules, as confirmed by presence and absence of aldosterone secretion from the nodules when cultured postoperatively.

Medical

Medical treatment is preferred for bilateral adrenal hyperplasia, before surgery for adenoma, in older patients with adenoma who are well controlled, or where there is any doubt about diagnosis or lateralization.

Chronic medical treatment is by K+-sparing diuretic, preferably spironolactone or amiloride. Spironolactone is a competitive antagonist of aldosterone, hence patients with very high aldosterone levels may require higher doses than used in resistant hypertension. While this is possible for preoperative use, long-term administration causes gynecomastia. High-dose amiloride (20–40 mg daily) is better tolerated but less effective. Eplerenone also avoids the gynecomastia of spironolactone, but again is less effective and currently much more expensive. A possible strategy is to combine eplerenone or a low dose of spironolactone (≤25 mg daily) with amiloride, but vigilant monitoring of plasma electrolytes is required.

It may not be possible to control blood pressure entirely by diuresis, especially in older patients with microadenomas, where calcium channel blockers or α‎-blockers can usefully be added. In patients who are difficult to control the maximum useful dose of diuretic can be found by titrating dose against plasma renin: once this is de-suppressed it becomes logical to add ACE inhibition an ARB. In patients with bilateral hyperplasia, one of these classes is often required, even when renin is suppressed. This may reflect either the resistant nature of hypertension that often ensues with long-standing hyperaldosteronism, or the increased sensitivity to angiotensin in salt-loaded patients.

Surgical

Elective surgery is indicated for younger patients with adenomas, and older patients intolerant of medical treatment, or uncontrolled by by it. A good blood pressure response to spironolactone augurs well for cure by surgery, but the opposite is not necessarily true a poor response does not exclude benefit from surgery. It is best not to promise any patient complete cure, but rather a substantial reduction in number of medicines required to control blood pressure. A bonus in many patients is alleviation of chronic fatigue, presumably attributable to total body K+ depletion.

Secondary hypertensionSurgery should be undertaken by a surgeon experienced in laparoscopic adrenalectomy, but patients warned that anatomical anomalies—or peroperative eventualities such as tear of the inferior vena cava—may necessitate conversion to open adrenalectomy in about 1/20 procedures. No special preoperative care is required although it is sensible to undertake assessment to exclude hypercortisolism in those patients with large adenomas. Diuretics should be withdrawn from the time of surgery, but any additional antihypertensive treatment continued until any change in blood pressure becomes clear over the following weeks. In the future, alcohol ablation of adenomas is looking a viable option, preserving the adjacent normal adrenal gland. Left-side adenomas, sitting close to the stomach, are accessible for both diagnostic fine-needle aspiration, and therapeutic ablation, delivered using endoscopic ultrasound. This development should lower the bar at which intervention for a benign tumour is considered. Alcohol ablation also opens up the possibility of cure for the increasing number of patients found to have bilateral aldosterone-producing adenomas but in whom bilateral adrenalectomy would never be considered an option.

Prognosis

Most (70–80%) younger patients with adenomas are cured of hypertension and hypokalaemia. Older patients are less likely to come off all antihypertensive treatment, but hypokalaemia is rarely persistent if they have been well selected for surgery, and the average number of medicines is more than halved, with improved blood pressure control in the remainder. The lesser success of surgery in older patients is due to a mixture of longer duration of hypertension, associated essential hypertension, and lingering suspicion that the smaller adenomas are part of the bilateral hyperplasia spectrum, with residual disease in the contralateral adrenal. Residual hypertension can be exquisitely sensitive to low doses of an angiotensin receptor blocker ARB, and there may be a role for routine prophylactic treatment of older patients to prevent hyperplasia of the remaining adrenal.

Renal hypertension

The principal curable cause is renovascular hypertension. This is usually due to a stenosis in one or both renal arteries, but can be due to a suprarenal aortic stenosis. Other curable causes include renal tumours (hypernephroma and, the rarest of all secondary causes, a juxtaglomerular renin-secreting tumour); a unilateral, poorly functioning scarred or hydronephrotic kidney which hypersecretes renin, and can be removed without unacceptable loss of renal function (so-called Page kidneys; Fig. 16.17.3.6); and various causes of acute/subacute glomerulonephritis, some associated with systemic disorders whose treatment by immunosuppression cures the hypertension and underlying disorder. Interestingly, aortic dissection, often itself a complication of arterial hypertension, may extend into the renal arteries and thereby exacerbate hypertension by causing increased secretion of renin.

Fig. 16.17.3.6 A Page kidney. CT scan image showing a left-sided neuroblastoma compressing the kidney (arrow). The compression impedes renal blood flow, resulting in excess secretion of the hormone renin and consequently hypertension. Named after Irvine Page (1901-89) who demonstrated that wrapping cellophane tightly around an animal’s kidney caused arterial blood pressure to rise. The patient’s hypertension was cured after surgery to remove the tumour.

Fig. 16.17.3.6
A Page kidney. CT scan image showing a left-sided neuroblastoma compressing the kidney (arrow). The compression impedes renal blood flow, resulting in excess secretion of the hormone renin and consequently hypertension. Named after Irvine Page (1901-89) who demonstrated that wrapping cellophane tightly around an animal’s kidney caused arterial blood pressure to rise. The patient’s hypertension was cured after surgery to remove the tumour.

Renovascular hypertension

This is most commonly due to intrinsic disease of the intima (acquired-atherosclerosis) or media (congenital-fibromuscular dysplasia). Extrinsic narrowing can be caused by ligamentous bands or by tumours (e.g. neurofibromas).

Fibromuscular dysplasia (FMD) accounts for only 10 to 20% of all patients with renovascular hypertension, but is the commonest cause under the age of 40. It is a nonatherosclerotic and noninflammatory disease of small and medium arteries, usually affecting the media, less commonly the adventitia (<25%), and rarely the intima. The classical ‘string of beads’ appearance seen at arteriography results from proliferation of the extracellular matrix and disruption of the internal elastic lamina, causing multiple stenoses and poststenoticsaccular aneurysms. The condition affects women more often than men, and there is usually no family history of hypertension. FMD involves extrarenal arteries in about one-quarter of patients, with cerebral infarction recorded due to relative hypotension and hypoperfusion of FMD-affected carotid arteries following successful renal angioplasty.

The typical medial form of FMD does not affect the proximal part of the renal arteries and is bilateral in about one-third of cases. Other vascular beds, e.g. the cerebral arteries, can be affected. Complications (other than renal ischaemia) are rare, whereas dissection or thrombosis can ensue in the rarer intimal or adventitial form of FMD. Rupture of renal artery aneurysms is rare.

Atheromatous renal artery stenosis has the same risk factors as atheromatous disease of other arteries, which often coexists. It is thus commoner in older men, and whereas FMD rarely causes renal impairment, atheromatous disease often presents with impaired renal function rather than hypertension, with intervention undertaken to protect renal function as much as to lower blood pressure. Apart from the obvious difference in biology of FMD and atheromatous renovascular hypertension, there is a difference in location of the stenosis, which is more likely to be proximal in atheromatous disease (Fig. 16.17.3.7).

Fig. 16.17.3.7 MR angiogram demonstrating fibromuscular dysplasia of the right renal artery causing stenosis (arrow).

Fig. 16.17.3.7
MR angiogram demonstrating fibromuscular dysplasia of the right renal artery causing stenosis (arrow).

Mechanism of hypertension

Unilateral renal artery stenosis gives rise to an endocrine disorder, because reduced pressure in the afferent arteriole causes juxtaglomerular hyperplasia and increased renin secretion. The consequent increase in angiotensin II formation causes hypertension, partly by vasoconstriction and partly through increased aldosterone secretion. Although secondary hyperaldosteronism is not usually a marked feature of renal artery stenosis, the combination of hypokalaemia and hyponatraemia should raise suspicion of the diagnosis, the latter being dilutional and due to the inhibition by angiotensin II of free water clearance. The effect on renin secretion is less predictable when renal artery stenosis affects both renal arteries: sometimes it is high, but sometimes bilateral reduction in GFR leads to sufficient sodium retention that renin is suppressed.

Diagnosis

Most cases of renovascular hypertension are probably not diagnosed because of the absence of sensitive clinical or biochemical markers. Lack of a family history of hypertension in younger patients, or recent onset (or exacerbation) of hypertension in older patients is more likely than in essential hypertension. Acute shortness of breath, due to flash pulmonary oedema, can be the presenting feature of bilateral renal artery stenosis. However, the main clinical clue is the finding, in about one-half of the patients, of a bruit anteriorly or posteriorly over a renal area. It is important to remember, however, that such a bruit is never diagnostic: normal abdominal arteries can give rise to innocent flow murmurs in younger patients and in older patients a bruit could arise from any of a number of arteries within the abdomen. The response to antihypertensive drugs can also give clues: in particular poor response to β‎-blockade in younger patients, or rapid worsening of renal function in older patients.

The diagnosis of renal artery stenosis is made radiologically. The cheapest investigation is a nuclear medicine scan using technetium-labelled MAG3, both the uptake and elimination of this being delayed on the ischaemic side, with the difference in excretion rate between sides greatly increased following a single dose of captopril (25 mg) because of dilatation of the efferent arterioles in glomeruli and consequent reduction in filtration fraction. For this reason the scan is best performed initially with captopril; if abnormal, it is repeated on a subsequent visit without captopril, with partial or complete normalization being evidence that the previous abnormality was due to vascular rather than renal parenchymal disease. However, the MAG3 scan is not always positive, with chronic use of ACE inhibitors being a cause of some false negatives and it may also miss bilateral renal artery stenoses that do not cause significant asymmetry between the kidneys.

Partly for these reasons, nuclear imaging is not performed for suspected renal artery stenosis in most centres, with investigation proceeding to direct imaging of the renal arteries by CT or MR angiography (Fig. 16.17.3.7). In patients under 20 years of age some form of angiography should always be undertaken, except in those with low-renin syndromes, because of the high likelihood of a secondary cause being present, and that this will be a vascular abnormality. As well as providing an accurate estimate in most patients of the severity of any stenosis, angiography will also detect suprarenal aortic stenoses. False-positive and false-negative diagnoses still occur; e.g. the poststenotic dilatations of FMD can-if they expand proximally around the artery-be a cause of stenoses being missed. However, the risk of diagnostic error can be reduced by careful review of images taken in more than one projection, and it is useful to remember that stenoses are not usually isolated lesions in both FMD and atheromatous disease (Fig. 16.17.3.8).

Fig. 16.17.3.8 MRI scan image showing a concomitant left renal artery stenosis (arrow) and left subclavian artery stenosis (arrow).

Fig. 16.17.3.8
MRI scan image showing a concomitant left renal artery stenosis (arrow) and left subclavian artery stenosis (arrow).

Some centres use Doppler flow measurements for diagnosis, but these are more user-dependent than angiography, which is still required subsequently for anatomical diagnosis. On the other hand, there are some patients in whom an anatomical diagnosis is made first, but the severity is in question. Here it can be useful to perform Doppler or MAG3 scan as the second investigation before proceeding to treatment. Another investigation that is sometimes helpful at this stage is renal vein sampling for renin determination, the main use for which is before removing a kidney thought responsible for causing hypertension through elevated renin secretion. The contralateral-anatomically normal-kidney has often sustained microvascular damage as a consequence of prolonged hypertension and renin excess, and is found to secrete as much renin as (or more than) the diseased kidney. Nephrectomy should not normally be contemplated where significant renal function remains, but in any circumstance there would rarely be an indication for removing a kidney showing less than 25% excess renin secretion compared to the contralateral side.

Treatment

There are several options, one of which is simply to continue optimal drug treatment if for any reason the risks of other intervention appear excessive. Among interventions, the options are as for any other arterial stenosis, namely angioplasty, stenting or surgery. For FMD, angioplasty is usually curative, and about three-quarters can discontinue antihypertensive treatment. In atheromatous disease, angioplasty is much less likely to be successful, especially for lesions at the origin of the artery, and restenosis can occur. It is reasonable to recommend stenting as a backup procedure when angioplasty has failed. Complete cure of hypertension is very much less likely than in FMD. In the past, the purpose of intervention was often to protect or improve renal function. The ASTRAL trial has largely rebutted this objective, although some argue that patients were excluded from this trial where clinicians were certain of benefit from intervention.

Sometimes angioplasty is unsuccessful because balloon inflation fails to dent the stenosis. Surgery is required in this situation, or when failure can be predicted because stenosis is due to external compression or there is complete occlusion. As renovascular surgery is not common today outside the transplant arena, a favoured surgical procedure is autotransplantation to the pelvis.

Coarctation of the aorta

Coarctation of the aorta, a congenital cause of hypertension, was described pathologically in the 1700s and recognized clinically in the early 1900s. The term describes a constriction of the aorta at the point where the fetal arterial duct originates, and the condition should ideally be diagnosed in early childhood, with most cases treated before hypertension develops. Coarctation represents 5 to 8% of all causes of congenital heart disease, but less than 1% of all cases of hypertension. However, sometimes diagnosis is delayed until the patient presents in adulthood with hypertension, and high blood pressure can sometimes develop even after surgical cure of the coarctation. Coarctation may also develop at a much lower level in the aorta secondary to long-standing aortitis. The mechanism of hypertension is predominantly the relative renal ischaemia consequent on low perfusion pressure in the aorta beyond the coarctation.

The classical clinical finding in coarctation is radiofemoral pulse delay or weak lower limb pulses, confirmed by measurement of reduced blood pressure in the legs. Of greater sensitivity and specificity in the clinic is a bruit-systolic or continuous-over the front and back of the praecordium, which arises in the intercostal collaterals.

The diagnosis should be confirmed by two-dimensional (2D) echocardiography (suprasternal view) or by CT or MR angiography (Figs 16.17.3.9 and 16.17.3.10). Treatment is by surgery, balloon dilatation, or stenting. Surgery or balloon dilation are the preferred approaches in childhood, balloon dilation and stent implantation in adolescents and adults. Although upper limb hypertension is usually cured, recurrence has been attributed to a variety of unproven factors, including a systemic vasculopathy.

Phaeochromocytoma

Aetiology and pathology

Catecholamine biochemistry

Catecholamine biochemistry is summarized in Fig. 16.17.3.11. The final step in the biosynthetic pathway is the N-methylation of noradrenaline (norepinephrine) to adrenaline (epinephrine), which outside the brain occurs only in the adrenal medulla because the enzyme phenylethanolamine N-methyltransferase in the adrenal is dependent for induction on glucocorticoids, secreted at high concentration into the adrenal portocapillary circulation. The clinical importance of this is that extra-adrenal phaeochromocytomas rarely produce adrenaline.

Fig. 16.17.3.11 The biosynthetic pathway for epinephrine and norepinephrine (upper panel), and for metabolism of norepinephrine (lower panel). COMT, catechol-O-methyltransferase; DOPA, dihydroxyphenylalanine; MAO, monoamine oxidase; VMA, vanillylmandelic acid.

Fig. 16.17.3.11
The biosynthetic pathway for epinephrine and norepinephrine (upper panel), and for metabolism of norepinephrine (lower panel). COMT, catechol-O-methyltransferase; DOPA, dihydroxyphenylalanine; MAO, monoamine oxidase; VMA, vanillylmandelic acid.

The metabolism of catecholamines is different from normal in phaeochromocytoma in that adrenaline and noradrenaline are liberated directly into the bloodstream, rather than mainly into the synaptic gap around sympathetic nerve endings. Noradrenaline released from these is largely recaptured by neuronal and extraneuronal uptake, and metabolized before any free amine escapes into the bloodstream. Consequently, the proportion of parent amine (noradrenaline) to metabolite (adrenaline) is usually higher in blood and urine in the presence of a phaeochromocytoma than in any other cause of elevated catecholamine production.

Pathology

Phaeochromocytomas arise in chromaffin tissue and their anatomical distribution closely parallels the sites where this tissue is present at the time of birth. The term phaeochromocytoma reflects the dusky colour of the cut surface of the tumour, whereas the term chromaffin refers to the brownish colour caused by contact with dichromate salts, which oxidize the catecholamines.

Secondary hypertensionMost phaeochromocytomas are benign, but the pathologist can rarely provide a clear distinction between those that are benign and those that are malignant: benign tumours can appear to be invading the capsule of the tumour, which is often ill-defined, while malignant tumours may show no mitoses because of their slow rate of division. Yearly surveillance, or earlier if indicated clinically, with measurement of plasma metanephrine levels is recommended.

Genetics

Several mutations cause syndromes that include phaeochromocytoma (Table 16.17.3.2), the clinical and biochemical features of which are variable. Only tumours associated with mutations of succinate dehydrogenase (SDH, subunits B or D) commonly occur outside the adrenal, where they are sometimes referred to as paragangliomas rather than extra-adrenal phaeochromocytomas, and parangangliomas in the head or neck are restricted to SDHD (or rarely SDHC) mutations. VHL and RET mutations may cause multiple tumour types, the site of these being determined by the site of mutation in the gene: e.g. VHL type 2c missense mutations cause only phaeochromocytoma, while the gene deletions of type 1 cause renal cell carcinoma but not phaeochromocytoma. The main value of genotyping has become prediction of multiple (but usually benign) extra-adrenal phaeochromocytomas in patients with SDHD mutations, while patients with SDHB mutations have a high incidence of malignancy.

Table 16.17.3.2 Genes associated with familial forms of phaeochromocytoma

Gene

Chromosome

Exons

Protein

Frequency of germ-line mutations in apparent sporadic phaeochromocytoma (%)

Frequency of malignant disease (%)

VHL

3p25–26

3

pVHL19 and pVHL30

2–1

5

RET

10qll.2

21

Tyrosine-kinase receptor

<5

3

NF1

17qll.2

59

Neurofibromin

Unknown

11

SDHB

1P36.13

8

Catalytic iron-sulphur protein

3–10

50

SDHD

Hq23

4

CybS (membrane-spanning subunit)

4–7

<3

VHL, von Hippel–Lindau syndrome; RET, a proto-oncogene encoding a receptor tyrosine kinase; NF1, neurofibromatosis type 1; SDHB, succinate dehydrogenase B; SDHD, succinate dehydrogenase D.

Some of the mutations in VHL or SDH also occur in sporadic tumours. This observation, together with the biochemical connection between VHL and SDH, has suggested that one underlying cause of phaeochromocytoma is failure to suppress hypoxia-induced cell proliferation. Oxygen detection by prolyl hydroxylases normally leads to degradation of hypoxia inducible factors in a process that requires the VHL protein: if VHL is defective, or prolyl hydroxylases are inhibited by accumulation of succinate, then the degradation of hypoxia inducible factors is altered and cell proliferation is stimulated.

Epidemiology

Phaeochromocytoma is a rare tumour, responsible for probably 0.1 to 1% of hypertensives, although it is possible that some of its non-blood-pressure presentations are overlooked and that we selectively detect patients in whom pressure natriuresis no longer compensates for the effect of vasoconstriction upon blood pressure. However, despite its rarity, phaeochromocytoma justifies the disproportionate interest that it commands among physicians, combining the potential for being lethal if not diagnosed and treated, and for cure in most patients if diagnosed. The need for maintaining a high awareness of the condition is emphasized by the small number of deaths each year due to undiagnosed phaeochromocytoma in both anaesthetic and obstetric practice.

Clinical features

Hypertension is the most common presentation of phaeochromocytoma in clinical practice, but other rare presentations include unexplained heart failure or paroxysmal arrhythmias. Patients with large tumours occasionally remain asymptomatic, and this is the norm for small phaeochromocytomas detected through regular screening of patients with a genetic diagnosis.

In hypertensive patients a spontaneous history or direct enquiry will usually reveal at least one of a group of characteristic symptoms. The classical triad comprises headache, sweating, and palpitations; less frequent are episodes of pallor, a feeling of ‘impending doom’, and paraesthesiae. Spontaneous haemorrhage and infarction in the tumour can be associated with local pain and (on occasion) systemic features of tissue necrosis, and rarely the patient can present with the features of full-blown retroperitoneal haemorrhage, coupled to a pathognomonic swinging blood pressure.

Most of the symptoms of phaeochromocytoma can be readily ascribed to the expected effects of catecholamine excess, and disappear rapidly on initiation of appropriate treatment. Because large tumours principally secrete noradrenaline, even when arising within the adrenal gland, tachycardia is usually only modest, and can be replaced altogether by reflex bradycardia when episodes of hypertension are triggered by release of noradrenaline alone. The bradycardia can be severe enough—if the hypertension is high enough—to be misdiagnosed as asystolic cardiac arrest, and the correct treatment is not atropine but phentolamine to reduce the blood pressure. Severe bradycardia is also recorded in response to the paradoxical rise in blood pressure when patients with phaeochromocytoma are inadvertently given a nonselective β‎-blocker such as propranolol. Often, however, the clinical features are less impressive than might be expected, possibly because the adrenoceptors have been down-regulated by years of exposure before the diagnosis is first entertained.

Examination may reveal a bruit over the tumour. A Raynaud’s type of discolouration over the extremities and the larger joints in the limbs can be caused by ischaemia.

Clinical investigation

The diagnosis of phaeochromocytoma is usually not difficult once the possibility has been entertained; often more difficult is excluding the diagnosis in patients who have clinical and/or biochemical features of physiological catecholamine excess. There are two distinct questions to ask in order. ‘Does the patient have a phaeochromocytoma?’, and ‘Where is it’. It is unwise to use radiological tests to answer the first question because of the risk of false positives and false negatives.

Biochemical analyses of catecholamines and their metabolites

Twenty-four-hour urine samples measure integrated catecholamine release and provide a useful screening test, with catecholamine metabolites less temperamental to assay than the more unstable catecholamines themselves. Vanillylmandelic acid (VMA) measured by high-performance liquid chromatography (HPLC) is least prone to interference, l-DOPA and paracetamol being the main concerns, and although now regarded as less sensitive than some alternatives it is still the exception for VMA to be entirely normal in a patient with hypertension due to a phaeochromocytoma. Metanephrines (sometimes called metadrenalines) measured by radioimmunoassay or gas chromatography–mass spectrometry (GCMS) are more sensitive and more specific than VMA, with the assay of ‘fractionated metanephrines’ permitting separate evaluation of noradrenaline and adrenaline secretion, 24-h urinary metanephrine measurements also do not require the addition of acid preservatives to the bottles. The ability to differentiate physiological release of noradrenaline from sympathetic nerve endings from pathological secretion from a phaeochromocytoma arises because of the presence of two different enzymes in the two locations: monoamine oxidase (MAO) in sympathetic nerves, and catechol-O-methyltransferase (COMT) in the adrenal medulla and phaeochromocytoma (see Fig. 16.17.3.11).

The measurement of free catecholamines in plasma (which have a very short half-life) by HPLC with electrochemical detection allows short bursts of secretion during a possible phaeochromocytoma crisis to be detected. However, the technique is susceptible to interference, especially in the adrenaline peak, and the finding of an adrenaline concentration that is higher than that of noradrenaline should be regarded as suspect. Dopamine levels are usually undetectable in plasma, whereas it is the major catecholamine in urine as a product of renal decarboxylation of plasma dihydroxyphenylalanine. Only several-fold increases in urinary dopamine are of diagnostic value, and are more likely to indicate neuroblastoma (in a child) or melanoma (which secretes dopamine as a by-product of melanin synthesis) than phaeochromocytoma.

Most adrenal phaeochromocytomas secrete adrenaline (and therefore metadrenaline), the exceptions being patients with very large tumours, which completely disrupt the portocapillary supply of cortisol required to induce phenylethanolamine N-methyltransferase, and patients with von Hippel-Lindau syndrome, who often have normal adrenaline levels even when their tumour is small. By contrast, in patients with multiple endocrine neoplasia (MEN) an elevated plasma adrenaline concentration is the first biochemical abnormality. Usually the normal adrenal predominance of adrenaline over noradrenaline is reversed as the tumour enlarges. Occasionally even large tumours secrete mainly adrenaline if either the tumour’s centre is infarcted leaving a rim still exposed to cortical cortisol supply, or the tumour itself is secreting ACTH or corticotrophin releasing factor (CRF). This secretion may be triggered by α‎--blocker therapy, and typical Cushing’s features are then absent (as with any ectopic ACTH tumour).

Phaeochromocytomas often secrete one or more neuropeptides: somatostatin may exaggerate the episodic nature of catecholamine discharge by inhibiting catecholamine release as soon as a discharge starts, and it may also contribute to a reversible form of diabetes in phaeochromocytoma.

Suppression tests

The use of plasma or urine metanephrine measurements, in a reliable laboratory, has reduced the number of patients with ambiguous results. In deciding which of the ‘grey zone’ patients need further investigations, it is also helpful to remember that modest increases in noradrenaline secretion are usually insufficient to cause severe hypertension. This is partly because of receptor (and postreceptor) desensitization, and partly volume depletion consequent on pressure natriuresis. Where doubt about the diagnosis remains, a pharmacological suppression test can be performed prior to imaging. Whereas physiological elevations of noradrenaline release are temporarily suppressed by administration of the ganglion-blocking drug pentolinium, or the centrally acting α‎2-agonist clonidine, these drugs do not suppress autonomous secretion by tumour.

Pentolinium should not be used in patients with an eGFR less than 60 ml/min. After the patient has rested supine for 30 min, plasma catecholamines are measured in two baseline samples taken 5 min apart from an intravenous cannula, and in two further samples taken 10 and 20 min after an intravenous bolus of pentolinium 2.5 mg. Patients should remain supine for a further 60 min, and their erect arterial pressure checked before they are allowed to leave the clinic. A normal response to pentolinium is a fall of both plasma noradrenaline and adrenaline concentrations into the normal range, or by 50% from baseline. However, there may be little fall in plasma catecholamine values when the basal levels are already within the normal range.

In the clonidine test, blood is taken hourly for 3 h before and after oral administration of clonidine 300 µg. Plasma noradrenaline or normetanephrine should fall by 50%, but adrenaline is little affected. Clonidine is more useful than pentolinium for patients with normal basal levels of noradrenaline or normetanephrine.

Localization of phaeochromocytomas

A substantial clue to localization is provided by measurement of plasma adrenaline (or metadrenaline) or fractionated urinary metanephrines (as stated previously, extra-adrenal tumours rarely produce adrenaline). CT or MRI scanning provides, where 90% of phaeochromocytomas are found (Fig. 16.17.3.12). CT (left) and m-iodobenzylguanidine (mIBG) scan (right) of a patient with a left adrenal phaeochromocytoma. Both scans illustrate typical nonhomogeneous appearance due to large area of haemorrhage/infarction at the centre of the tumour.

Fig. 16.17.3.12 CT (left) and m-iodobenzylguanidine (mIBG) scan (right) of a patient with a left adrenal phaeochromocytoma. Both scans illustrate typical nonhomogeneous appearance due to large area of haemorrhage/infarction at the centre of the tumour.

Fig. 16.17.3.12
CT (left) and m-iodobenzylguanidine (mIBG) scan (right) of a patient with a left adrenal phaeochromocytoma. Both scans illustrate typical nonhomogeneous appearance due to large area of haemorrhage/infarction at the centre of the tumour.

Secondary hypertensionIt is best to withhold CT/MRI scanning for extra-adrenal phaeochromocytomas until the radiologist can be given some clue as to where to concentrate. This can be achieved by radioisotope scanning with the iodinated analogue of noradrenaline, m-iodobenzylguanidine (mIBG), in about 85% of patients. This may carry either an [123I] or [131I] label, the former being more sensitive but also more expensive, and may be misinterpreted if users are unaware that normal adrenal glands also accumulate mIBG. There is a case for undertaking mIBG scanning in addition to CT, even for patients found to have an adrenal phaeochromocytoma, to identify extra-adrenal secondary deposits when tumours are malignant, and because there may be coexisting adrenal and extra-adrenal phaeochromocytomas. PET scans have been used and may be positive when mIBG is unhelpful, 18F-DOPA appears to be the most accurate of these ut available only when there is a centre doing neurological research for which a routine supply of this radiotracer is required. 68Ga-DOTANOC, a somatostatin receptor analogue, is acquiring a reputation for higher sensitivity than mIBG, with good specificity.

Selective venous sampling remains of occasional value when diagnostic problems persist. About 25 samples of blood are collected under fluoroscopic guidance from various sites, with an arterial sample invaluable for interpreting the results because it enables sites with a positive venoarterial difference to be readily detected. Because of the short half-life of catecholamines in the circulation (c.1 min), the concentration at the tumour site is usually several-fold greater than elsewhere. This procedure should not usually be used for adrenal phaeochromocytomas, an exception being patients with von Hippel–Lindau syndrome with small adrenal masses, in whom all other biochemical tests may be normal, and the diagnosis of phaeochromocytoma is suggested by a reversal of the normal excess of adrenaline to noradrenaline in the adrenal vein.

Because phaeochromocytomas are vascular tumours, they provide a good tumour blush, and occasionally angiography is required to resolve equivocal scans. Patients must be fully α‎-blocked and preferably also β‎-blocked prior to angiography.

Other investigations

It is important to check blood glucose in every patient as there may be α‎-mediated inhibition of insulin release prior to effective treatment, and all patients should be screened for an associated medullary carcinoma of the thyroid (see Chapter 13.5). Routine slit lamp examination of the fundi has resulted in more frequent diagnosis of von Hippel–Lindau syndrome, sometimes as a de novo occurrence.

Treatment

Medical management before surgery

The definitive treatment for phaeochromocytoma is surgical, with laparoscopic surgery possible for most adrenal tumours. Even the small number of phaeochromocytomas that are recognized to be malignant preoperatively (e.g. by the presence of bone or liver metastases) may still benefit from resection of the primary tumour. The task for the physician is to make surgery safe, for which the mainstay of medical treatment is α‎-blockade, but not all patients—especially those without elevated plasma adrenaline levels—require β‎-blockade. The objective of treatment is not solely control of blood pressure, but also the expansion of blood volume, which is invariably reduced. Indeed, phaeochromocytoma represents the pure vasoconstriction end of the vasoconstriction-volume spectrum, and the hypertensive patient is best seen as the exception where pressure natriuresis has failed to compensate adequately for vasoconstriction. Normotension is an indication, not contraindication, for the use of α‎ -blockade to restore volume preoperatively.

The α‎-blocker of choice is phenoxybenzamine, which is an irreversible blocker that actually destroys the α‎-receptor by alkylation. More modern α‎-blockers, such as doxazosin, and the mixed α‎- and β‎-blocker labetalol (a much stronger β‎-blocker than it is β‎--blocker), cause competitive blockade, which can be overcome by a surge of noradrenaline release from the tumour. An additional advantage of phenoxybenzamine is that it will block both α‎1- and α‎2-receptors, with blockade of the latter possibly advantageous because extrasynaptic α‎2-receptors mediate some of the direct vasoconstriction caused by circulating (non-neuronal) catecholamines. The diabetogenic effect of catecholamines is also an α‎2-mediated response. The starting dose of phenoxybenzamine is 10 mg once or twice daily, with increases titrated against blood pressure up to a maximum of 90 mg daily. The effect of irreversible antagonists is cumulative, with the effect of the drug—and each subsequent dose increment—taking several days to reach maximum.

There is rarely any urgency for surgery, which should not normally be considered in less than 1 month after initiation of treatment in patients with symptomatic phaeochromocytomas. Indeed, the more severe the initial clinical picture, the greater the need for prolonged α‎-blockade to expand intravascular volume. In most patients there is a low filling pressure at presentation, evident clinically as a jugular venous pressure visible only when the patient lies flat, and any postural hypotension should be assumed to reflect continuing hypovolaemia, not excessive α‎-blockade, until the venous pressure is normalized. Usually volume expansion will occur spontaneously with phenoxybenzamine treatment, but expansion should be achieved with intravenous saline if there is persistent hypovolaemia when patients are admitted a few days before surgery. During the preoperative admission the dose of phenoxybenzamine should be increased until there is at least a 10 mmHg postural fall in blood pressure.

The need for β‎-blockade is indicated by tachycardia, which may become apparent only after treatment with phenoxybenzamine, and the dose of β‎-blocking drug necessary is generally lower than that used in the treatment of hypertension. It is usually better to use a β‎1-selective agent so that the peripheral vasodilatation mediated by β‎2-receptors is not affected. Occasionally, pronounced β‎2-receptor mediated effects, including tachycardia or tremor, can oblige use of a nonselective β‎-blocker, although blood pressure control may then be more difficult and require addition of a calcium blocker. The reason for using as low a dose of β‎-blocker as possible is that there may be a period of hypotension immediately upon removal of the phaeochromocytoma, despite the preoperative preparation that has been outlined. This hypotension should normally be offset by the ability to mount a tachycardia. The correct treatment is by volume replacement, supplemented if necessary by β‎-agonists, most vasoconstrictor drugs being ineffective because of the slow washout of phenoxybenzamine.

Malignant phaeochromocytomas

The treatment of malignant phaeochromocytomas remains uncertain and unsatisfactory. The rate of growth is usually slow, but the prognosis for affected individuals can vary between the extremes of local recurrence at intervals of many years, and rapid demise sometimes precipitated by surgery. The tumours are not particularly sensitive either to chemotherapy or to radiotherapy, although the variability of response may still make them worth trying. There has been interest in the use of therapeutic doses of mIBG as a means of targeting high doses of radioactivity to the tumour: some patients show considerable regression after such treatment, but long-term results are less certain.

It is rare for the pharmacological effects of the tumour to be the principal problem if the primary tumour has been removed or debulked. High doses of phenoxybenzamine are preferable to α‎-methyltyrosine, used as an inhibitor of noradrenaline synthesis. There is anecdotal evidence that therapy with high doses of an angiotensin receptor blocker ARB might slow progression through reflex activation of renin and hence AT2-receptor mediated apoptosis.

Prognosis and genetic screening

Most (90%) phaeochromocytomas are benign, and the proportion is probably even higher for adrenal tumours, whereas those that are extra-adrenal have a greater than 10% likelihood of proving malignant. The latter should be screened for mutations in the SDHB gene, which carry greater than 50% risk of malignancy. Other genetic screening will be influenced by a mixture of clinical features and cost considerations. A history (or family history) of other relevant tumours will lead to a search for von Hippel-Lindau syndrome or MEN type 2. There is some consensus that all patients presenting under the age of 45 years should have structured genetic counselling and screening, and this is particularly important in much younger patients. All patients should be followed indefinitely with at least an annual measurement of arterial pressure and analysis of one of the indices of catecholamine secretion as mentioned previously. The removal of a phaeochromocytoma cures hypertension in most patients, especially those that are young.

Other endocrine causes of hypertension

Conn’s syndrome and phaeochromocytoma have been singled out for attention in this chapter as the two endocrine conditions most likely to present as hypertension. However, hypertension is a feature of several other endocrinopathies: Cushing’s syndrome (Chapter 13.7.1), acromegaly (Chapter 13.2), hyperparathyroidism (Chapter 13.6), and is a common complication of type 2 diabetes. The hypertension of Cushing’s syndrome is usually modest, except in ectopic ACTH where there is saturation by high cortisol levels of 11β‎-hydroxysteroid dehydrogenase 2 (which normally converts cortisol to the inactive cortisone). The cause of the hypertension in other syndromes is less clear cut and often not corrected by surgical cure of the primary problem.

Further reading

Primary hyperaldosteronism

Choi M, et al. (2011). K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science, 331(6018), 768-72.Find this resource:

Brown MJ, Hopper RV (1999). Calcium-channel blockade can mask the diagnosis of Conn’s syndrome. Postgrad Med J, 75, 235–6.Find this resource:

Dluhy RG, Lifton RP (1999). Glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab, 84, 4341–4.Find this resource:

Ganguly A (1998). Primary aldosteronism. N Engl J Med, 339, 1828–34.Find this resource:

Gordon RD, et al. (1994). High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol, 21, 315–18.Find this resource:

Hood SJ, et al. (2007). The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) double-blind crossover trial in patients with low-renin hypertension and elevated aldosterone-renin ratio. Circulation, 116, 268–75.Find this resource:

Kaplan NM (2004). The current epidemic of primary aldosteronism: causes and consequences. J Hypertens, 22, 863–9.Find this resource:

Rossi GP, et al. (2006). A prospective study of the prevalence of primary aldosteronismin 1,125 hypertensive patients. J Am Coll Cardiol, 48, 2293-300.Find this resource:

Mulatero P, et al. (2006). Comparison of confirmatory tests for the diagnosis of primary aldosteronism. J Clin Endocrinol Metab, 91, 2618–23.Find this resource:

Stewart PM (1999). Mineralocorticoid hypertension. Lancet, 353, 1341–7.Find this resource:

Stowasser M, et al. (2003). High rate of detection of primary aldosteronism, including surgically treatable forms, after ‘non-selective’ screening of hypertensive patients. J Hypertens, 21, 2149–57.Find this resource:

Young WF Jr (2007). The incidentally discovered adrenal mass. N Engl J Med, 356, 601–10.Find this resource:

Renovascular hypertension and coarctation

Caliezi C, Reber P (2006). Images in clinical medicine. Fibromuscular dysplasia of the renal artery. N Engl J Med, 355, 2131.Find this resource:

Rosenthal E (2005). Coarctation of the aorta from fetus to adult: curable condition or lifelong disease process? Heart, 91, 1495-502.Find this resource:

Safian RD, Textor SC (2001). Renal-artery stenosis. N Engl J Med, 344, 431-42.Find this resource:

White CJ (2006). Catheter-based therapy for atherosclerotic renal artery stenosis. Circulation, 113, 1464-73.Find this resource:

Phaeochromocytoma

Allison DJ, et al. (1983). Role of venous sampling in locating a phaeochromocytoma. BMJ, 286, 1122–4.Find this resource:

Brown MJ, et al. (1981). Increased sensitivity and accuracy of phaeochromocytoma diagnosis achieved by use of plasma epinephrine estimations and a pentolinium suppression test. Lancet, i, 174–7.Find this resource:

Brown MJ et al. (2009). Pheochromocytoma. Horm Metab Res, 41, 655–7.Find this resource:

Col V, et al. (1999). Laparoscopic adrenalectomy for phaeochromocytoma: endocrinological and surgical aspects of a new therapeutic approach. Clin Endocrinol (Oxf), 50, 121–5.Find this resource:

Manger WM (1997). Pheochromocytoma. Springer Verlag, Berlin.Find this resource:

    Richards FM, et al. (1998). Molecular genetic analysis of von Hippel-Lindau disease. J Intern Med, 243, 527–33.Find this resource:

    Sisson JC, Shulkin BL (1999). Nuclear medicine imaging of pheochromocytoma and neuroblastoma. Q J Nucl Med, 43, 217–23.Find this resource: