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Correspondence:
Dr. Y. Chowers, Dept. of Gastroenterology, Sheba
Medical Center, Tel Hashomer 52621, Israel. Phone: (972-3) 530-2679 Fax: (972-3) 530-3160 email:
[email protected]
Pheochromocytoma: A Disease with Many Faces Marina Shargorodsky MD 1
1,3
2,3
and Reuven Zimlichman MD 2
3
Department of Endocrinology and Hypertension, Department of Internal Medicine, and Institute of Physiologic Hygiene, Wolfson Medical Center, Holon, Israel
Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
Key words:
pheochromocytoma, cardiovascular disease, catecholamines, metanephrines, normetanephrines IMAJ 2002;4:817±818
Catecholamine-secreting tumors are frequently sought but rarely
pheochromocytomas when paroxysmal symptoms are evident, but
diagnosed. In many cases their presence is associated with
pheochromocytomas are usually not the most common cause of
spectacular cardiovascular disturbances. When diagnosed and
hypertension-related spells.
treated properly, however, these tumors are mostly curable.
In their article in this issue of
IMAJ ,
Hamdan et al. [1] report a
Pheochromocytomas provide clinicians with a unique treatment
rare manfestation of a rare disease ± low back pain with vertebral
opportunity since the response to either surgery or pharmacologic
lytic lesion. In another article in the current issue, Liel et al. [2]
therapy is dramatic, but incorrect diagnosis and treatment can have
describe a confusing pheochromocytoma that appears together
catastrophic consequences.
with meningiomas and mimics meningioma in the base of the skull.
Catecholamine-secreting tumors are extremely rare, with an incidence of 2±8 cases per million people. Despite their rarity, they
These are only two of the many faces of the diverse clinical presentations of this peculiar disease.
should be considered in patients with hypertension, panic attacks,
A "rule of 10" has been described for catecholamine-secreting
adrenal incidentalomas, autonomic disturbances or familial dis-
tumors: 10% are multiple or bilateral, 10% recur after surgical
eases with a predisposition to develop pheochromocytoma.
removal, 10% are familial, and 10% are malignant. Several
Identification of pheochromocytomas is essential because the
syndromes have been associated with phechromocytoma, such as
associated hypertension is curable upon diagnosis, localization and
MEN II a and II b, neurofibromatosis, and von Hippel-Lindau
surgical resection of the tumor. In contrast, undiagnosed cases are
disease [3]. It is obvious that before any attempt to localize the
at risk of lethal paroxysms and about 10% of cases are malignant.
pheochromocytoma, excess of catecholamine levels in the plasma
Patients with catecholamine-secreting tumors may be asympto-
or urine should be sought.
matic, however symptoms usually arise from the pharmacologic
The diagnostic approach, which in the 1940s was based on
effect of excess catecholamines in the circulation. Hypertension
clinical impression, exploratory laparotomy, histamine stimulation
may be sustained or paroxysmal, and spells may occur sponta-
and phentolamine suppression tests, progressed to catecholamine
neously or can be precipitated by postural change, medications,
measurements and intravenous pyelograms in the 1960s. In most
anxiety, increase in abdominal pressure, exercise, or manual
laboratories today, plasma or urinary catecholamines are measured
compression of the tumor. A spell usually lasts from several
by high pressure liquid chromatography, usually with electroche-
minutes up to one hour. Clinicians usually screen patients for
mical detection. However, despite these developments, the
IMAJ . Vol 4 . October 2002
Pheochromocytoma
817
Editorials
diagnosis of pheochromocytoma continues to be a diagnostic
In patients with inconclusive tests for plasma metanephrine
challenge in many cases. The most practical screening tests are still
levels, namely patients with mild to moderate elevations, two
24 hour urine collections for measuring catecholamines or their
additional tests are useful and recommended. The first is the
metabolites.
clonidine suppression test, which is based on the fact that clonidine
The present approach to biochemical diagnosis of pheochro-
suppresses plasma catecholamine levels in sympathetic over-
mocytoma has several limitations. Catecholamines are secreted in
activity, while such an effect is not seen in patients with
excess not only in patients with pheochromocystoma, and vice
pheochromocytoma. It should be stressed that this test, usually
versa ± pheochromocytomas do not always secrete enough
reliable, loses its sensitivity in patients with a small or intermit-
catecholamines to produce typical symptoms and diagnostic
tently secreting pheochromocytoma. The second, the glucagon
plasma levels. In many cases pheochromocytomas secrete catecho-
stimulation test, is especially useful in patients with elevated
lamines periodically, and between the episodes catecholamine
plasma metanephrines but normal plasma catecholamines. When
levels may be normal. In other cases, tumors of small size produce
this test is performed, a positive response has high specificity, while
low amounts of catecholamines that are not high enough to confirm
a negative test has low sensitivity and does not exclude
a solid diagnosis of pheochromocytoma. Thus the commonly used
pheochromocytoma.
tests to measure plasma catecholamines and their metabolites do
To summarize, pheochromocytoma, with its many faces,
not absolutely confirm or exclude the possibility of pheochromo-
continues to pose a diagnostic challenge in many patients.
cytoma.
However, a major tool had been added to our armamentarium for
The most prominent progress in recent years in the area of
diagnosis of the disease ± the measurement of plasma and urine
pheochromocytoma diagnosis was the introduction of tests to
metanephrines and normetanephrines. A positive test, as defined
measure plasma levels of normetanephrine and metanephrine. A
above, definitively diagnoses the condition. A negative test
normetanephrine level above 2.5 pmol/ml and a metanephrine level
excludes pheochromocytoma unequivocally. However, as with many
above 1.4 pmol/L ± more than 4 and 2.5-fold the upper reference
tests, the ``gray area'' that lies in the middle of the spectrum
limits ± indicate a pheochromocytoma with 100% specificity. The
remains problematic for clinicians in their attempt to reach the
development of tests for measuring plasma metanephrine and
correct diagnosis.
normetanephrine is a groundbreaking achievement. Finally, after many years of having to compromise with tests of partial sensitivity
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IMAJ
2002;4:827±8.
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Correspondence:
Dr. R. Zimlichman, Chief, Dept. of Medicine, Wolfson
Medical Center, P.O. Box 5, Holon 58100, Israel.
metanephrine. One of the medications that can cause a false
Phone: (972-3) 502-8614
positive test is recent ingestion of paracetamol, a frequently used
Fax: (972-3) 503-2693
drug.
email: zimlich@post,tau.ac.il
Capsule Signaling in sepsis Normally, the activated protein C has a protective role in sepsis,
provides insights into the signaling pathway of immune
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the thrombin receptor (protease activated receptor, or PAR1) is
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IMAJ . Vol 4 . October 2002
