Uncharted Territory

By Pierre Jacomet, Chile

The experiences in my own family with pheochromocytomas have led me to some conclusions that are only hinted at in the literature, but which I feel it is important for families and physicians to hear. We have all read the warnings in the VHL Handbook and in previous articles in the VHL Family Forum about the potential dangers of untreated pheos, and the need for testing. In families that are aware that they are at risk for pheos, and who are careful about screening, the worst repercussions of pheos will likely never occur. But there are family members who are "hiding out" from VHL, who do not want to get tested, or who may be unaware that they are at risk for VHL. It is for them that I am writing.

Of the 16 people in my family who have had pheos, only three have been diagnosed in time to prevent their deaths. The rest were diagnosed after their deaths, during the autopsy. They were not diagnosed because their symptoms were misunderstood. I did not understand how this could happen until I learned a great deal more about pheos. Let me explain.

Pheochromocytomas¹  (pheos for short) are relatively rare, usually benign tumors. Most arise from the adrenal medulla (90%) and the organs of Zuckerkandl (8%). They occur rarely in extra-adrenal sites (outside the adrenal glands) in the abdomen, chest (less than 2%) and neck (less than 0.1%). A number of pheos in or around the heart have been reported; these are usually located in the left atrial region. In the general population, pheos occur at all ages with a peak of incidence in the third and fourth decades. In adults, the tumor occurs with equal frequency in both sexes, whereas 60% of the affected children are male. Multiple tumors (adrenal and extra-adrenal) are more common in children (35% of the cases) than in adults (8%). Approximately 10% are familial and more than 70% are bilateral. Less than 10% are malignant. These are more often outside the adrenal glands and actively secreting a hormone called dopamine.

Pheos are not exclusively associated with VHL. Some otherwise healthy family groups may present with them as an isolated occurrence. Other families present with them in association with Multiple Endocrine Neoplasia (MEN types II and III), and von Recklinghausen disease (Neurofibromatosis). But a number of VHL families do develop pheos, adrenal or extra-adrenal. Most pheos secrete a number of hormones: epinephrine, norepinephrine, dopamine, VMA (vanylmandelic acid), and metanephrines.

Rarely they have been found to contain other hormones.² The diverse symptoms produced by release of these drugs can confuse the diagnosis.

It is a known fact that no disease entity can cause more diverse manifestations than pheo. Some of these manifestations are associated with an increase in catecholamine levels. Exclusion of most of these conditions can be done by combining clinical and biochemical tests. The addition of plasma metanephrine assay gives us one more tool, but it is still a complex process of confirming the existence of the pheo and then locating where it is hiding in the body. CT and MIBG can be used to locate the pheo.

As there is no prevention for pheo, all patients with severe or episodic high blood pressure and associated symptoms should be screened, especially if they do not respond to treatment. Other indications for screening include:

• All hypertensive children
• All individuals with VHL, MEN II, or MEN III and their first-degree relatives even if they have normal blood pressure and no particularly suspicious symptoms. Cases of low blood pressure and pheos have been reported in our family. It is especially important to test people with VHL prior to any surgery, or before or during pregnancy, or before labor and delivery.
• Individuals having episodes of high blood pressure during labor, exercise, anesthesia or radiological procedures.

Medical texts and articles stress the need to distinguish pheo symptoms from those of other conditions, a process called differential diagnosis. Among others, the following conditions can present similar symptoms. Pheochomocytomas might be misdiagnosed as any of these conditions:

1. Anxiety, tension states, psychoneurosis, psychosis, or erectile dysfunction in males
2. Hypoglycemia
3. Menopause
4. Vasodilating headaches, ophthalmic migraines and cluster headaches
5. Suspected drug abuse: amphetamines, cocaine, LSD, phenylpropanolamine, caffeine
6. Known drug effects: interaction of monoamine oxidase inhibitors with certain food and beverages (beer, wine, cheese), clonidine withdrawal symptoms, atropine administration, nasal decongestants, tricyclic antidepressants⁴
7. Lesions of the nervous system: trauma, tumor, stroke, focal arterial insufficiency, autonomic hyperreflexia, diencephalic seizure and syndrome
8. Dysfunctions of the central and peripheral nervous system: cardiogenic hypertensive reflex in angina pectoris; exaggerated response to hypovolemia or infection, paroxysmal tachycardia, familial dysautonomia.

In our family, all too often the pheo presented psychotic symptoms. The patient was then sent to a psychiatrist or psychoanalyst and treated with no success, the cause of his or her condition being physical. This is dangerous and sometimes fatal, as pheos can be highly lethal tumors.

In order for a person to evolve through life it requires a certain stability, a sense of self. Pheos, with their abundant secretion of unexpected drugs, alter the balance. In so doing, they alter mental functions, producing attacks of panic, anguish, anxiety, rage, and sometimes, erectile dysfunction in males.

In our family group, pheos have been responsible for a number of deaths at ages that vary from 14 to 54. Most of them happened in males aged 30. They invariably presented the same symptoms: anxiety, anguish, rage, drug use, alcoholism, poor decision making capabilities and extended periods of sexual impotence. All were treated unsuccessfully with psychotherapeutic methods before dying. Their pheos were detected post mortem. This state of affairs is serious because it neglects a physical, organic cause of a supposed neurosis. In our family group only three pheos have been detected and removed. The patients, although labeled neurotics prior to surgery, after a period of adjustment were able to lead normal lives. Two of them were alcoholics before surgery. Pheo removal ended the alcohol abuse without need of special therapies for that particular symptom.

Based on my experience, I feel that there can be a direct relationship between pheos and psychiatric conditions. This is not to say that all psychiatric patients have pheos, nor that all people with pheos display psychotic behaviors. Rather, I suggest that patients with pheos can present symptoms akin to neurotic or psychotic states. This may sound exaggerated. But we all know that drugs we take (alcohol, cocaine, and so forth) do alter consciousness. Why should it be different with chemicals produced in error by our own bodies?

This seems to be uncharted territory. Because there often is not a great deal of communication between a patient’s physicians and psychologists, the relationship may go undetected. In my opinion, this state of affairs is dangerous. VHL families need to be vigilant and remember to test for pheos when any of these misleading symptoms appear in the family.

1. See: Denise A. Morris and James R. Sowers, "Pheochromocytoma: An Update" in Manual of Endocrinology and Metabolism, Norman Lavin, ed., Little Brown & Co. New York.

2. Hormones reported associated with pheos include vasoactive intestinal peptide, serotonin, ACTH, somatostatin, opioid peptides, alpha-MSH, calcitonin (particularly in MEN II and III), parathyroid-like hormone, and neuropeptide Y (a potent vasoconstrictor).

3. Bahemuka, M. "Correspondence: Pheochromocytoma with schizophreniform psychosis." British Journal of Psychiatry 142(1983) 422-429.

4. "Tricyclic antidepressants (which block neuronal uptake of norepinephrine) represent another drug category with effects that can either mimic pheochromocytoma or can provoke an attack in patients with a pheo -- in addition these drugs complicate differential diagnosis since in addition to blood pressure disturbances they can cause false-positive biochemical test results. They are more commonly used than MAO inhibitors. In particular, there are a lot of VHL patients who are on these drugs." -- Graeme Eisenhofer, Ph.D., NIH.

References:

Manger & Gifford, "Pheochromocytoma", Blackwell-Science, 1996

Owen et al, "Increased dopamine-receptor sensitivity in schizophrenia" Lancet (1978) ii, 223-5

Schildkraut, J.J. "The catecholamine hypothesis of affective disorders: a review of supporting evidence." American Journal of Psychiatry, 122(1965)509-22.

As printed in the VHL Family Forum  9:1, March 2001.  For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.