A 42-year-old woman with hypertension

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Problem 6 A 42-year-old woman with hypertension

Lucia Gagliardi

You are a medical resident in a major teaching hospital. A 42-year-old woman is referred to your outpatient clinic for assessment and management of hypertension. The referral letter states that she was diagnosed with hypertension 8 years ago. She remains hypertensive (blood pressure 150/90 mmHg to 180/100 mmHg when checked by her general practitioner) despite treatment with three agents (irbesartan, indapamide and amlodipine). She was diagnosed with ‘anxiety’ several years ago, for which she has been taking diazepam. She has had no other major illnesses. There is no family history of hypertension.

Q.1

What are the possible aetiologies of hypertension in this patient?

Q.2

What questions will you ask her and what will you look for on physical examination?

She was diagnosed with hypertension 8 years ago and this has never been well controlled. She has been on the current treatment regimen for the last 3 years and is compliant. She self-monitors her blood pressure at home and obtains readings between 140/90 mmHg and 200/100 mmHg. She has no explanation for this variation.

She was diagnosed with ‘anxiety’ around the same time the diagnosis of hypertension was made. This diagnosis was based on intermittent episodes of palpitations, shortness of breath, sweating, associated with a feeling of ‘impending doom’. She has had no headaches. She has been diagnosed and managed by her local general practitioner.

In the last 2 years she has experienced central weight gain (10 kg), which has occurred despite diet and exercise. She has never had depression and has not had any problems with concentration. She has not experienced increased facial hair or acne. Her muscle strength has always been good. She slipped and fell 2 months ago and sustained a fractured radius. Her periods are regular. She has two children – aged 15 and 10. Both pregnancies were uncomplicated. She is not on the oral contraceptive and does not take any other medications. She drinks 1–2 standard drinks per week and is a non-smoker. Her mother had diabetes; her father is alive and well. There is no other family history of hypertension or endocrine or renal disease.

On examination she appears slightly anxious, and is tremulous. She is overweight, but there are no clinical features of Cushing’s. Her blood pressure is 170/90 mmHg lying and 160/85 mmHg standing. Her pulse is 110 bpm and regular. She has a forceful, non-displaced apex beat; examination of the cardiovascular system is otherwise unremarkable. There are no abdominal masses or striae visible or bruits audible. She is able to stand from a squat without difficulty. On fundoscopy there is silver wiring.

Q.3

What investigations will you perform?

The following results are available.

Investigation 6.1 Summary of results

Fasting glucose (3.8–5.5 mmol/L)	10
Urea (2.7–8.0 mmol/L)	7.3
Creatinine (50–120 µmol/L)	68
eGFR (mL/min/1.73 m²)	>60
Ionized calcium (1.1–1.25 mmol/L)	1.31
Total calcium (2.10–2.55 mmol/L)	2.75
Phosphate (0.65–1.45 mmol/L)	1.27
Plasma metanephrine	18 100 pmol/L (<500 pmol/L)
Plasma normetanephrine	9260 pmol/L (<900 pmol/L)

Q.4

Please discuss the results. What is the diagnosis? What will be your next step(s)?

Some imaging studies are arranged and a CT scan of the abdomen performed. A representative slice is shown (Figure 6.1).

Figure 6.1

Q.5

What does the scan show?

She is tolerating phenoxybenzamine well, but has been tachycardic (heart rate 110–120 bpm for the last 2 days).

Q.6

What should be done next?

She undergoes a laparoscopic adrenalectomy and the large adrenal tumour is removed intact. As soon as the adrenal vein is ligated the blood pressure falls and the anaesthetist is able to reduce the alpha blockade. The opened surgical specimen is shown (Figure 6.2).

Figure 6.2

All medications are stopped immediately postoperatively.

Q.7

What postoperative complications should she be observed for?

Over the next week her blood pressure without medication varies between 100/70 and 125/80 mmHg. The histopathology is consistent with a phaeochromocytoma.

Q.8

What follow-up is necessary for this patient?

Answers

A.1 In this patient, secondary hypertension should be suspected because she has refractory/resistant hypertension – remaining hypertensive despite three antihypertensive drugs – and has no family history of hypertension. The possible causes of secondary hypertension in this patient include:

• Endocrine (phaeochromocytoma, Cushing’s syndrome, Conn’s syndrome).

• Renal (renovascular disease, primary renal disease).

• Other (coarctation of the aorta, oral contraceptive pill).

She must be investigated for a secondary cause of hypertension.

A.2 The following components of the history should be clarified:

• Hypertension – previous treatment; compliance with medications.

• Diagnosis of ‘anxiety’ – how diagnosis made – including whether psychiatric or psychological evaluation was performed; description of symptoms (chest pain, shortness of breath, increased respiratory rate, sweating, symptoms persistent or episodic, precipitating factors).

Specific enquiry should be made regarding:

• Symptoms of phaeochromocytoma (see Table 6.1).

• Symptoms of Cushing’s syndrome (see Table 6.2).

• Symptoms of Conn’s syndrome (see Box 6.1).

• Previous renal disease – infections, haematuria, renal calculi.

• Full drug, alcohol and smoking history.

• Family history – hypertension, renal or endocrine diseases.

Table 6.1 Phaeochromocytoma – catecholamine excess

Symptoms	Signs
‘Classic triad’ – episodic headache, sweating, tachycardia (palpitations)	Hypertension (essential or paroxysmal)
	Diaphoresis
	Tremor
	Tachycardia

Table 6.2 Cushing’s syndrome – hypercortisolism

Symptoms	Signs
Central (centripetal) obesity (abdominal weight gain, sparing of arms and legs)

Truncal obesity, thin arms and legs (‘lemon on a toothpick’)

Moon face, buffalo hump (dorsocervical fat pad); temporal and supraclavicular fossae fullness

Poor or delayed wound healing

Thinning of skin

Skin infections

Non-healing wounds

Atrophic, fragile skin; skin tears

Facial plethora; broad reddish-purple abdominal striae; acne

Fungal infections – nails, skin

Increased facial hair, thinned scalp hair

Oligomenorrhoea, amenorrhoea

Muscle weakness – difficulty climbing stairs, combing hair

Osteoporosis – minimal trauma fractures

Glucose intolerance – polyuria, polydipsia

Psychological changes – labile mood, depression, anxiety, psychosis, memory impairment, difficulty concentrating

Increased facial hair; thinned scalp hair

Proximal muscle wasting and weakness – unable to stand from a squat

Box 6.1

Conn’s syndrome – primary aldosteronism

Symptoms and Signs

The classic presentation of Conn’s syndrome is hypertension and hypokalaemia. Severe hypokalaemia (serum potassium <2.5 mmol/L) may result in muscle weakness.

The physical examination should include inspection both for signs of a secondary cause of hypertension and for complications of longstanding hypertension.

• General inspection – Cushingoid features (see Table 6.2); tremor (phaeochromocytoma).

• Examination of the cardiovascular system:

– blood pressure – lying and standing

– pulses – radial pulse rate (tachycardia with phaeochromocytoma); radiofemoral delay (coarctation of the aorta); peripheral pulses

– praecordium – apex beat – quality and location (forceful – left ventricular hypertrophy; displaced – left ventricular enlargement)

– signs of left ventricular failure which may occur with longstanding hypertension – elevated jugular venous pulse, pulmonary crepitations

– fundal examination – hypertensive changes – silver wiring, AV nipping, haemorrhages/exudates, papilloedema.

• Abdominal examination – Cushing’s – striae, bruising; abdominal masses; renal artery stenosis – abdominal bruit.

• Examination of proximal muscle bulk and strength – stand from a squat; strength of shoulder abduction.

A.3 She needs to be investigated for endocrine causes of hypertension – phaeochromocytoma, Cushing’s and Conn’s syndrome.

Investigations:

• Phaeochromocytoma – plasma or urine metanephrines or catecholamines.

• Cushing’s syndrome – urinary free cortisol or dexamethasone suppression test.

• Conn’s syndrome – direct renin concentration, plasma aldosterone and serum K.

• Simple screening tests for renal disease (EUC and urinalysis) and a baseline ECG are also appropriate.

A.4 The elevated plasma metanephrine levels are diagnostic of phaeochromocytoma. Further biochemical testing (e.g. clonidine suppression testing) is not required. Elevated blood glucose may occur in phaeochromocytoma – a result of insulin resistance produced by the elevated catecholamines. This often resolves after treatment of the phaeochromocytoma. The elevated plasma calcium may be seen in phaeochromocytoma due to catecholamine-induced volume contraction/dehydration or to primary hyperparathyroidism – which may be sporadic (although unusual in this age group) or associated with the phaeochromocytoma as part of a multiple endocrine neoplasia syndrome.

The priority of management of this patient is treatment of the phaeochromocytoma.

With appropriate endocrine consultation the principles of management are:

• Blood pressure and heart rate self-monitoring twice daily.

• Initiation of alpha-blockade to control blood pressure (phenoxybenzamine is most commonly used, although prazocin is a suitable alternative). Alpha-blockade results in vasodilatation. The dose of phenoxybenzamine should be gradually titrated up according to blood pressure (aims of treatment should be individualized – but in this patient a seated blood pressure of 120/80 mmHg is a reasonable goal, provided that this does not induce postural hypotension). In view of the potential orthostatic hypotension, she should be advised to liberalize her salt intake 2–3 days after commencing phenoxybenzamine (to expand circulating blood volume).

• The physiological response to vasodilatation (and therefore to alpha-blockade) is tachycardia (pulse rate >100 bpm). On development of a tachycardia, beta-blockade should be initiated. Beta-blockade should never be started first because blockade of vasodilatory peripheral beta-receptors with unopposed alpha-adrenergic stimulation can lead to a further increase in blood pressure, and could even precipitate a hypertensive crisis.

• Localization of the phaeochromocytoma – she should be referred for a non-contrast (ionic contrast can precipitate a hypertensive crisis) CT scan of the adrenal glands.

A.5 The scan shows a well-circumscribed heterogeneous mass behind the liver in the region of the right adrenal gland. The lesion is 10 cm diameter.

A.6 She is consistently tachycardic so a beta-blocker should be introduced (e.g. metoprolol). The definitive management of this patient is adrenalectomy and she should be referred to an experienced adrenal surgeon and anaesthetist.

A.7 Postoperative hypotension may occur which can be managed with fluid loading. Hypoglycaemia may sometimes occur because of the loss of catecholamine-induced suppression of insulin secretion. Other complications include the surgically related problems of atelectasis, infection and deep vein thrombosis.

A.8 Serum metanephrines should be checked to determine whether she has been cured. There is a risk of recurrence – which is highest in younger patients, those with extra-adrenal or familial disease, or bilateral and/or large tumours. Recommendations are increasingly being made that patients with phaeochromocytoma should undergo long-term surveillance (10 years in sporadic phaeochromocytoma and indefinitely in familial disease) (Lenders et al. 2005). This patient will also need a fasting blood glucose and serum calcium levels checked, as both were elevated preoperatively. If she remains hypercalcaemic then she will need investigation for primary hyperparathyroidism. If a repeat fasting blood glucose level is elevated, then this is diagnostic of diabetes mellitus.

Revision Points

Phaeochromocytomas are catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla (80–85%) or extra-adrenal paraganglia (10–15%; paraganglioma). Phaeochromocytomas are rare, accounting for 0.1–0.6% of all hypertension. Approximately 25% are diagnosed during the investigation of the ‘adrenal incidentaloma’ (an adrenal tumour >1 cm in diameter discovered incidentally by radiological investigations performed for another purpose).

Although phaeochromocytomas are usually sporadic, they may occur as a component of a familial syndrome (neurofibromatosis 1 (NF1), von Hippel–Lindau (VHL), multiple endocrine neoplasia 2 (MEN2), succinate dehydrogenase (SDH) syndromes). Features suggestive of familial disease include young age at diagnosis (age <30), bilateral phaeochromocytomas, family history, associated manifestations of NF1, VHL, MEN2, SDH.

The clinical presentation of phaeochromocytoma is variable. The classic presentation is with episodic headache, sweating and tachycardia. Hypertension may be sustained or paroxysmal. Other symptoms include: palpitations, dyspnoea, anxiety, pallor, orthostatic hypotension, weight loss, polyuria, polydipsia. The initial presentation of a phaeochromocytoma may be with an adrenal incidentaloma – such patients are frequently normotensive and asymptomatic – because the phaeochromocytoma is either non-secretory or secreting only low levels of catecholamines.

Measurements of either plasma-free or 24-hour urine metanephrines are increasingly thought to be among the most sensitive of tests for the diagnosis of phaeochromocytoma. Metanephrines are formed as a result of catecholamine metabolism (most of which occurs within the tumour) – and hence increased sensitivity of metanephrine testing is due to the continuous production of these metabolites. Conversely, the production of catecholamines from phaeochromocytomas is highly variable.

Interpretation of investigations can be made difficult because of medications which alter metanephrine or catecholamine levels (e.g. tricyclic antidepressants, phenoxybenzamine, stimulants – caffeine, nicotine, amphetamines). Where possible medications should be stopped prior to repeat testing.

In the clonidine suppression test clonidine is administered to suppress catecholamine release; plasma catecholamines or metanephrines are measured. This should be able to distinguish increased catecholamine levels due to a phaeochromocytoma from increased levels due to sympathetic activation.

Once a biochemical diagnosis is made, imaging (CT abdomen and pelvis) is needed to localize the tumour. If the imaging is negative then there are two possibilities: (a) the diagnosis of phaeochromocytoma is incorrect or (b) the tumour is extra-adrenal (paraganglioma). Nuclear imaging using a tracer compound, MIBG, can help localize the tumour. MIBG is a compound resembling noradrenaline and is taken up by adrenergic tissue. MIBG scanning can also be useful in detecting metastatic disease.

Once the diagnosis has been established and the tumour localized there are several steps in management:

• Control hypertension using alpha- (always first) and beta-blockade (also controls tachycardia).

• Coordinated care with a surgical and anaesthetics team experienced in the surgical and anaesthetic management of phaeochromocytoma.

• Assessment for cure.

• Postoperative surveillance for recurrence – there is no consensus on how this is best done, and to an extent this depends on the type of phaeochromocytoma. For example, in sporadic solitary phaeochromocytoma, annual clinical (blood pressure) and biochemical screening for a few years may suffice, as a proportion of patients with phaeochromocytoma also have essential hypertension. One group has suggested annual follow-up for 10 years for sporadic phaeochromocytoma. All patients with paraganglioma, bilateral or familial phaeochromocytoma should be followed up indefinitely.

• Families with familial phaeochromocytoma should be referred to a clinician/geneticist for screening and follow-up.

Issues to Consider

• What advice should you give to a patient with an incidental finding of an adrenal adenoma?

• What are the risks of non-operative management of a phaeochromocytoma in a patient with easily controlled hypertension?

Further Information

Alderazi Y., Yeh M.W., Robinson B.G., et al. Phaeochromocytoma: current concepts. Medical Journal of Australia. 2005;183:201-204. Available online at http://www.mja.com.au/public/issues/183_04_150805/ald10166_fm.html

Lenders J.W.M., Eisenhofer G., Mannelli M. Phaeochromocytoma. Lancet. 2005;366:665-675.

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