Education Resource from the Society for Endocrinology
R T Peaston
Clinical Biochemistry Department, Newcastle upon Tyne NHS Hospitals Trust.
Summer School 5-8 July 2005
St Aidan’s College, Durham University, Durham, UK
Phaeochromocytomas are rare tumours of chromaffin cells that are generally characterised by the autonomous production of catecholamines. Phaeochromocytomas vary considerably in the relative and total amounts of catecholamines produced and stored, in the overall rates of synthesis and in individual-to individual differences in sensitivities to catecholamines. It is these differences that contribute to the diversity of presenting signs and symptoms that can include hypertension, diaphoresis, anxiety or panic attacks, headaches, tachycardia. However, some 10% of patients may be completely asymptomatic. Several clinical disorders mimic the signs and symptoms of phaeochromocytoma and a clinical strategy for patients with phaeochromocytoma was aptly summarised by Ross 1 “Think of it, confirm it, find it and remove it”. Thus diagnosis depends on a high index of clinical suspicion and the biochemical conformation of excessive catecholamine production by the measurement of plasma or urinary catecholamines and metabolites.
Biochemical testing is typically performed as part of the evaluation for secondary causes of hypertension, incidental adrenal masses or in patients with a family history associated with phaeochromocytoma. Despite significant advances in the development of sensitive and specific biochemical test for the diagnosis of catecholamine secreting tumours, a number of issues still remain unresolved. These include the optimum sample collection techniques, use of urine or plasma samples, the merits of measuring catecholamines or metabolites, and the need for additional testing strategies such as suppression testing. Biochemical diagnosis of phaeochromocytoma in most patients is straightforward when urinary catecholamines (noradrenaline, adrenaline) or their methylated metabolites (normetadrenaline, metadrenaline) are well above the levels for patients with essential hypertension or normal subjects. The problem arises in trying to differentiate the presence of phaeochromocytoma in patients with only moderate biosynthetic activity of the tumour from patients with non-specific stimulated sympathetic nervous system activity. This becomes particularly relevant when trying to detect the tumour in individuals with inherited conditions such as Von Hippel-Lindau (VHL) or multiple endocrine neoplasia type 2 (MEN-2). Because phaeochromcytomas are a heterogeneous group of hormone-secreting tumours, no single biochemical test can achieve 100% diagnostic accuracy.
At present the most frequently employed biochemical tests include 24-hour
urinary fractionated catecholamines (noradrenaline, adrenaline, dopamine),
24-hour fractionated metadrenalines (normetadrenaline, metadrenaline) and in
some centres plasma catecholamines (noradrenaline, adrenaline) all analysed
by HPLC. A simple and more convenient approach is the use of overnight urine
samples 2. Since catecholamines exhibit diurnal variation in excretion, the
elimination of environmental and emotional stimuli in association with recumbency
results in a decline in catecholamine secretion in normal subjects. Recently
the measurements of plasma metadrenalines (metanephrines) have been advocated
as the test of choice for the detection and exclusion of the presence of a
phaeochromocytoma 3. Whilst plasma metadrenalines have a high diagnostic sensitivity
(>98%), the variable specificity
(82-90%) can lead to false positive rates of up to 18%, particularly in patients
without a genetic predisposition to the disease. The choice of biochemical
tests in any centre will by necessity determine the strategy for the diagnosis
of phaeochromocytoma. A reliable screening approach is the use of urinary free
metadrenalines in combination with urinary catecholamines. With borderline
increases in urinary metadrenaline and catecholamine excretion or when clinical
suspicion indicates the possible presence of a phaeochromocytoma, the use of
plasma metadrenalines can readily exclude the diagnosis in such patients.
In summary, for populations with low probability of phaeochromocytoma, measure urinary catecholamines and especially fractionated urinary metadrenalines. Apply plasma metadrenalines if inconclusive urine results and clinical suspicion of phaeochromocytoma, and in patients with elevated urine catecholamines and metadrenalines levels. Plasma metadrenalines should be applied as a screening test in patients with a genetic syndrome that increases the risk for phaeochromocytoma. In these high probability clinical settings, plasma metadenalines has a superior sensitivity to either urinary catecholamines or metadrenalines.
The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society
Revised:
28-Jul-2005