This includes catecholamine secreting tumours of the adrenal medulla, extra-adrenal paragangliomas, familial phaeochromocytoma, Von Hippel Lindau and succinate dehydrogenase mutations. Diagnosis is usually made by measuring elevated urine metanephrines.

Urine metanephrines negative

Reassure no sign of phaeochromocytoma and discharge

Other diagnoses that may be considered include thyrotoxicosis for generalised anxiety, menopause for flushing and sweating attacks, spontaneous hypoglycaemia for fasting associated attacks, carcinoid syndrome for episodic flushing and diarrhoea. 

Alternative diagnoses such as anxiety and agitated depression, or cardiac arrythmia, should also be considered and appropriate referral for further investigation considered.

Urine metanephrines borderline/positive (<3x upper limit of normal)

Thorough clinical assessment is necessary looking particularly for sleep apnoea or depression

Both of these may cause chronic increases in catecholamine release and lead to false positive screening tests, though results are unlikely to be >3x the upper limit of normal.

Check drug history thoroughly including depot psychotropics

Many drugs, particularly psychotropic agents which interfere with serotonin and catecholamine uptake or metabolism, may cause false positive screening.

Check plasma metanephrines

If the clinical picture is unclear, or is consistent with a phaeochromocytomaormal, proceed to check plasma metanephrines. Most experts agree that normal plasma levels should be considered reassuring and allow reassurance and discharge in most cases, since the test is highly sensitive and specific.

If the clinical picture is not convincing and OSA is likely, arrange investigation and treatment prior to repeating investigations.

This may take some months, but catecholamine release should fall and normalise after treatment of OSA.

 Clonidine suppression test

Clonidine testing is occassionally useful in cases where there is hypertension and modest elevations of urine metanephrines (<4xULN). These grey cases can usually be resolved by taking a careful medication history, seeking evidence of sleep apnoea or by checking serum metanephrines as a normal result will effectively exclude a phaeochromocytoma. If no cause has been found, the clonidine test may be useful though it is expensive, timely and poorly tolerated by most patients. Clonidine acts via the alpha preganglionic receptors and should reduce catecholamine secretion. This test confirms the absence of phaeochromocytoma if noradrenaline levels suppress to normal and less than 50% basal, and metanephrines have fallen by greater than 40% or to within the normal range.

Doubts persist, for example about interfering medications

Discuss with a biochemist.

Urine metanephrine strongly positive or plasma metanephrine positive

Ensure full investigation has been performed at baseline

This should include the following in all patients: thorough family history and documented family tree; 1x plasma metanephrine; chest radiograph; CT adrenals; MIBG scan; baseline pituitary function; fasting gut hormones; calcitonin; and, further cross sectional imaging depending on results of MIBG scan.

Explain results and treatment options

Patients need to understand their diagnosis and the importance of adhering to medical treatment.

This is particularly important because the medication may not be well tolerated, but non compliance can have fatal consequences.

Initiate medical treatment with alpha blockade

Usual treatment starts with phenoxybenzamine. This may be started at a low dose eg 10mg daily, and should be gradually uptitrated to a usual maximum of 40-60mg in divided doses daily. Close BP monitoring is required and patients must be advised to keep up a high fluid intake.

This may have unpleasant side effects, for example dizziness, malaise and swollen ankles.

Doxazosin, usually in a sustained release preparation, may be used if phenoxybenzamine is unavailable or not tolerated. Dose should be titrated to the maximum tolerated.

Once a date is set for surgery, the dose of phenoxybenzamine should be uptitrated further until the patient develops significant hypotension and nasal congestion. This may require hospital admission, intravenous fluids or even blood transfusion for haemodilution and postural hypotension.

Add beta blockade for symptomatic tachycardia

Once a patient is fully alpha blocked, typically after about several weeks in an out patient setting, initiate beta blockade, for example with propranolol if they develop significant and symptomatic tachycardia.

This is not always necessary and must only be given after the patient is fully alpha blocked. Close BP monitoring is again required and the dose should be increased to the maximum tolerated or 240mg in divided doses.

Arrange surgery

Ideally patients will have been fully alpha and beta blocked over a period of at least six weeks prior to surgery.

Peri operative management

Ideally, patients should be admitted preoperatively for intravenous alpha blockade prior to surgery.

If the patient is already on full oral treatment, administer intravenous phenoxybenzamine over three days prior to surgery.

Monitor postural blood pressure and haemoglobin over successive days.

Patients frequently require intravenous fluid support for dramatic falls in blood pressure. Full blood count should be checked daily, as a dramatic fall in haemoglobin may occur, which should be treated with pre operative blood transfusions if necessary. This occurs due to haemodilution as the vascular bed dilates and the intravascular volume expands. This preparation should prevent dramatic changes in blood pressure peri operatively, although an anaesthetist experienced in this procedure is essential.

If iv phenoxybenzamine is unavailable, the patient will require uptitration of their oral phenoxybenzamine in the week prior to surgery. This may also require admission and the dose should be increased by 10mg every 24hours until significant hypotension and nasal stuffiness occur. Patients may require intravenous fluid support as above, and ALL patients should start on iv fluids overnight before planned surgery to minimise the chance of significant perioperative hypotension.

Emergency management

In the acutely unwell patient, or one presenting with a crisis, the first priority should be fluid resuscitation. This should prevent a catastrophic fall in blood pressure occurring when alpha blockade is initiated.

Beta blockade is added only after the patient appears to be fully alpha blocked which may take several days.

Post operative management

All medication may be stopped routinely.

Blood pressure should be closely monitored.

Arrange for urinary metanephrines to be repeated at six to 12 weeks.

Follow up

Reasssess symptoms, blood pressure and metanephrines approximately three months post operatively.

Review and discuss the histological findings: malignant or benign.

Arrange oncology multidisciplinary review for future management of malignant disease. This may include resumption of alpha and beta blockade, MIBG therapy, chemotherapy or repeat surgery.

Discuss genetic testing, family screening and future surveillance imaging where a syndrome is suspected, for example in the presence of other suggestive features, extra-adrenal disease or phaeochromocytomas occurring at a young age (<45 years).

For benign disease apparently cured by surgery, long term follow up is still required.

Annual follow up must include a review of symptoms, blood pressure, family history and 2x24hr urinary collections for metanephrines in all patients with a history of phaeochromocytoma

Further investigations are required in patients with familial syndromes.

Imaging should only be repeated where clinically indicated by a rise in metanephrines, symptom recurrence or if indicated in the presence of a familial syndrome.