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Pseudopheochromocytoma

Mackenzie, Isla S; Brown, Morris J

doi: 10.1097/HJH.0b013e3282f0fdbc
Editorial commentaries
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Introduction

Pseudopheochromocytoma is a rare but often disabling syndrome of paroxysmal severe hypertension and symptoms of catecholamine excess, including feelings of anxiety, tremor, sweating and palpitations [1]. In some patients, other features are also present including chest pain, headache, nausea, dizziness, pseudoseizures and paradoxically low blood pressures. Episodes tend to have rapid onset and last from a few minutes up to a few hours and be followed by intense fatigue that can last for several days. During episodes, many patients feel as though they ‘might die’. Although many of the presenting features of pseudopheochromocytoma resemble those of pheochromocytoma, the main difference is that there is no definite anatomical or biochemical abnormality, although evidence of mild to moderate catecholamine excess may be present, particularly during paroxysms. Other reported biochemical abnormalities in pseudopheochromocytoma include elevated peripheral plasma dopamine sulphate levels [2] but these are not present in all patients. Pseudopheochromocytoma has clinical similarities with both Page's syndrome [3] (‘hypertensive diencephalic syndrome’) which was first described in 1935, and autonomic epilepsy which is occasionally associated with tumours or cysts in the thalamic region [4] but can occur as an unexplained entity. To date, no anatomical thalamic abnormalities have been confirmed in patients with pseudopheochromocytoma.

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Psychological aspects

Pseudopheochromocytoma is largely a diagnosis of exclusion, which requires careful screening for any treatable pheochromocytoma before the diagnosis is made. There is considerable overlap between pseudopheochromocytoma and panic disorder conditions and it is not known to what extent psychological factors can influence the often severe acute rise in blood pressure seen in patients with pseudopheochromocytoma during paroxysms. Indeed, pseudopheochromocytoma has been associated with a history of traumatic psychological experiences during childhood or a tendency to suppress distressing emotions, and psychotherapy has been useful in relieving symptoms in many patients [5].

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Multifactorial causes

Increasingly, we are realizing that in most complex disorders, including hypertension, it is the exception to find a unifactorial cause and in the vast majority of cases, a large number of factors act together to influence the development of the condition in any one individual. The same is likely to be true in pseudopheochromocytoma, where many different factors, including both somatic and supratentorial elements, probably interplay in any one patient to cause the clinical syndrome. It is also likely that there is heterogeneity among patients, with differences in the severity and clinical features which lead to the label of pseudopheochromocytoma.

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Secondary causes of pseudopheochromocytoma-like symptoms

When assessing a patient with pseudopheochromocytoma-like symptoms, it is important to ascertain whether the syndrome may be secondary to another condition, e.g. obstructive sleep apnoea [6] or drug therapy, e.g. tricyclic antidepressants, sympathomimetic agents or reboxetine [7] all of which can raise sympathetic activity. Other conditions aside from pheochromocytoma that can present in a similar way to pseudopheochromocytoma include systemic mastocytosis, cocaine use and reninoma.

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Sympathoadrenal function in pseudopheochromocytoma

In the current issue of the Journal, Sharabi et al. [8] have published one of the largest series of patients with pseudopheochromocytoma in the literature to date and have attempted to unravel some of the mechanisms underlying the condition, by studying the role of the sympathetic nervous system and adrenal function in pseudopheochromocytoma. This was a difficult study to do, partly due to difficulty recruiting patients with the true condition but also due to uncertainty as to what the primary endpoint should be, according to which the study should be powered. As a result of this, many measurements were made, with no single primary outcome measure defined. Plasma catecholamine levels and haemodynamic parameters were measured following the administration of various pharmacological manipulators of the sympathetic nervous system and adrenal function in a group of 11 patients with pseudopheochromocytoma and 14 healthy controls. Baseline levels of plasma catecholamines and metanephrine, the O-methylated metabolite of epinephrine, were also measured and functional imaging of the adrenal medulla was performed using the positron emission tomography (PET) radiotracer [18F]fluorodopamine.

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Pharmacological manipulation of sympathoadrenal function

The pharmacological agents administered in the study were as follows: the ganglion blocker trimethaphan, which is a competitive antagonist at nicotinic cholinergic receptors at autonomic ganglia and inhibits both sympathetic and parasympathetic outflow; yohimbine, which is a competitive α2-adrenoceptor antagonist, which increases adrenal production of epinephrine and norepinephrine by binding to preganglionic α2-adrenoceptors and blocking the negative feedback inhibition of catecholamine production; isoproterenol which is a β-adrenoceptor agonist; and glucagon which stimulates epinephrine production.

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Results

The main findings of the current study were of increased adrenal epinephrine release and increased circulatory responses to catecholamines in the patients with pseudopheochromocytoma. In the current study, patients with pseudopheochromocytoma had higher baseline plasma epinephrine levels but similar norepinephrine levels to controls. In contrast, a previous study showed no difference between baseline plasma epinephrine or norepinephrine levels in patients with pseudopheochromocytoma and controls [9]. No abnormality in adrenomedullary function was observed on [18F]fluorodopamine PET scanning in the patients with pseudopheochromocytoma.

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Ganglion blockers

When interpreting the effects of the ganglion blockade by trimethaphan, it is worth bearing a few points in mind. First, trimethaphan, in addition to blocking the autonomic ganglia, causes histamine release, unlike the alternative ganglion blocker, pentolinium. Trimethaphan also has a shorter half-life than pentolinium. Pentolinium is sometimes used as a diagnostic suppression test in the investigation of patients with possible pheochromocytoma [10]. The effects of ganglion blockade depend upon the level of preganglionic stimulation. Pentolinium is good at suppressing physiological elevations of epinephrine but has less effect if epinephrine levels are normal at baseline. In contrast, clonidine, which is also used as a suppression test in the diagnosis of pheochromocytoma, is not very effective in suppressing epinephrine, but suppresses norepinephrine levels well. The authors did not include the pentolinium suppression test as an evaluation of the pseudopheochromocytoma patients included in this study. In the current study, the results in response to trimethaphan are somewhat surprising in that there was a lesser fall in norepinephrine levels in patients with pseudopheochromocytoma than in controls. This could be explained by the fact that the pseudopheochromocytoma patients started with significantly lower baseline levels of norepinephrine than the controls and ganglion blockers are less effective at lowering norepinephrine levels from a lower baseline level. With regard to epinephrine levels, if as the authors suggest, there are higher baseline epinephrine levels in patients with pseudopheochromocytoma, one might expect to see an exaggerated drop in epinephrine levels in response to trimethaphan administration; however, the authors did not report the changes in epinephrine levels with trimethaphan.

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Potential role of dopamine in pseudopheochromocytoma

The role of dopamine in pseudopheochromocytoma was not directly assessed in this study. Dopamine sulphate levels were found to be three-fold elevated in patients with pseudopheochromocytoma in one study [2] but in patients in the current study, plasma dopamine levels were normal. It is also known that dopamine antagonists can induce hypertensive crisis in patients with pheochromocytoma by blocking the presynaptic negative inhibition of norepinephrine release. Anecdotally, we have had some success in improving the symptoms of pseudopheochromocytoma by using low doses of the dopamine agonist cabergoline; however, the unproven benefits would need to be weighed against the reported association between some dopamine agonists and cardiac valvular fibrosis when used at high doses.

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Role of adrenoceptor sensitivity in pseudopheochromocytoma

A previous study by Hamada et al. [9] showed that patients with pseudopheochromocytoma had a significantly greater systolic blood pressure response to a valsalva manoeuvre than patients with pheochromocytoma, essential hypertension or normal controls. The systolic blood pressure rise was suppressed by the prior administration of non-selective β-blockade or α1-blockade. They concluded that patients with pseudopheochromocytoma had β and α1-adrenoceptor hypersensitivity. It is known that β-blockers and α1-blockers relieve symptoms in some patients with pseudopheochromocytoma. Interestingly, while α-blockers are the mainstay of medical therapy for pheochromocytoma (sometimes combined with β-blockade depending on the degree of tachycardia on α-blockade, which is often related to the amount of epinephrine production), patients with pseudopheochromocytoma tend to have a slightly better response to β-blockade, although often α1-blockade is used in combination. Antidepressants may also have a role in the management of pseudopheochromocytoma.

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Conclusions

While the current study represents an important addition to the limited literature on pseudopheochromocytoma, unfortunately it has not yet fully explained the mechanisms of pseudopheochromocytoma or provided any specific diagnostic test for the condition. The findings support the use of α-blockade and β-blockade in the management of patients with pseudopheochromocytoma but have not suggested any other possible treatments. The authors should, however, be congratulated on ascertaining and studying a cohort of patients with this rare but important condition. Further publications of well-phenotyped series of patients with pseudopheochromocytoma should be encouraged to help improve our understanding and treatment of the condition.

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References

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2 Kuchel O. Increased plasma dopamine in patients presenting with the pseudopheochromocytoma quandary: retrospective analysis of 10 years' experience. J Hypertens 1998; 16:1531–1537.
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8 Sharabi Y, Goldstein DS, Bentho O, Saleem A, Pechnik S, Geraci MF, et al. Sympathoadrenal function in patients with paroxysmal hypertension – pseudopheochromocytoma. J Hypertens 2007; 25:2286–2295.
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© 2007 Lippincott Williams & Wilkins, Inc.