Eu ropea n. Journal of. En docrino logy. Clinical Study. A Riester and others. Life- threatening events in pheochromocytoma. – Pheochromocytomas vary in presentation, tumor size, and in catecholamine production. Whether pheochromocytoma size correlates with hormone levels. The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 6, . Definition of pheochromocytoma and paraganglioma (PPGL).

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Pheochromocytomas are rare neuroendocrine tumors with a highly variable clinical presentation, but they most commonly present as spells of headaches, sweating, palpitations, and hypertension. Patients with pheochromocytoma may develop complicated and potentially lethal cardiovascular and other complications, especially in the setting of diagnostic or interventional procedures e.

The serious and potentially lethal nature of such complications is due to the potent effect of paroxysmal release of catecholamines. Because this warrants prompt diagnosis and treatment, the physician should be aware of the clinical manifestations and complications of catecholamine excess and be able to provide proper preoperative management to minimize catecholamine-related pre- intra- and postoperative adverse events.

The following clinical scenario and discussion aim to enhance the knowledge of the physician regarding the behavior of pheochromocytoma and to outline current approaches to comprehensive preoperative management of patients suffering from this tumor. A yr-old white male presented to the community hospital emergency room with a 3-wk history of presyncopal and syncopal episodes, as well as abdominal pain with intermittent nausea.

The patient had reported brief feelings of light-headedness and fainting upon standing on three separate occasions before his admission. The third episode resulted in an injury to his head. At the emergency room, he also complained of abdominal pain associated with nausea. In the past, other symptoms and problems included episodes of sweating lasting 1—2 min, palpitations, and dizziness all three usually occurring once every 1—2 wk for the past 6 monthsand blurred vision for the last 2—3 months.

Past medical history was also significant for labile and difficult-to-control hypertension [treated with amlodipine Norvasc 10 mg and metoprolol Toprol XL 50 mg once a day] for the past 5 yr. He also had a history of severe weight gain over pounds during the last 2 yr, compounded by low energy level. A few months before hospitalization, the patient was put on a diet and a weight loss medication phentermine, 30 mg once a day for 2 months resulting in a pound weight loss; however, he continued to be hypertensive.

Biochemical Diagnosis of Pheochromocytoma, a Rediscovered Catecholamine-Metabolizing Tumor

In addition, he was previously diagnosed to have uncomplicated umbilical hernia, benign prostate hypertrophy, and bilateral knee osteoarthritis. At the emergency room, in view of the recurrent episodes of syncope and recent history of abdominal pain associated with nausea, a work-up for cardio- and cerebrovascular events and a possible small bowel obstruction was initiated.

Computed tomography CT of the abdomen pheochromoocytoma a 6. Magnetic resonance imaging confirmed the diagnosis of the left adrenal mass that appeared heterogeneous with a bright signal on T2-weighted images. It also showed moderately distended loops of the small bowel.

Electrocardiogram ECG did not show any ischemia. The patient was taken to the operating room for urgent umbilical hernia repair. Therefore, surgery pheochhromocytoma immediately aborted. The patient was subsequently transferred to the intensive care unit, and an endocrinology consult was requested for suspicion of a possible pheochromocytoma. Pheochromocytima patient was discharged on phenoxybenzamine Dibenzylinemetoprolol, and amlodipine.

Subsequently, the patient was referred to the National Institutes of Health NIH for further evaluation of his left adrenal pheochromocytoma. Three weeks before surgery, the patient was started on phenoxybenzamine 10 mg per day by mouth, which was gradually titrated up to 30 mg three times a day.

A transthoracic echocardiogram showed a mildly dilated left atrium and ventricle. Therefore, a cardiology consult was obtained; but no further recommendations were given. At midnight, the patient was given an extra dose of 40 mg of phenoxybenzamine, During the surgery the following morning, there was no significant change in blood pressure during tumor manipulation and removal.

Histopathological examination confirmed the diagnosis pheochhromocytoma pheochromocytoma. The World Health Organization defines pheochromocytoma as a tumor arising from catecholamine-producing chromaffin cells in the adrenal medulla—an intraadrenal paraganglioma 12. Closely related tumors of extraadrenal sympathetic catecholamine producing and parasympathetic rarely catecholamine producing paraganglia are classified as extraadrenal jurrnal.

For simplification, in this report, the term pheochromocytoma will be used to refer to both adrenal and sympathetic ganglia-derived extraadrenal tumors. Practically all pheochromocytomas produce catecholamines with considerable variation in their content, depending on expression of biosynthetic enzymes as depicted in Fig. Murnal extraadrenal pheochromocytomas produce predominantly NE.


The concentrations of catecholamines in pheochromocytoma tissues are enormous 6potentially creating a volcano that can erupt at any time. At such levels, any direct tumor stimulation may lead to abrupt and significant catecholamine release that exceeds normal plasma values times or more 78.

These differences in catecholamine content and release explain different clinical presentations and ultimately necessitate specific treatment for each patient. Adapted from Eisenhofer et al.

Diagram illustrating the main pathways of catecholamine synthesis, release, and metabolism in pheochromocytoma. Numbers in squares indicate sites of: Nevertheless, most of these silent tumors synthesize and metabolize catecholamines to metanephrines elevated either in plasma or urine and show elevations in plasma catecholamines only during paroxysmal attacks possessing the same danger as other pheochromocytomas 11 In addition to catecholamines, pheochromocytomas are known to produce other vasoactive substances neuropeptide Y, adrenomedullin, and atrial natriuretic peptide that may cause hypertension 9.

The adrenoceptors are the final pheochromochtoma for catecholamines that are found in excess in most patients with pheochromocytoma Fig. However, the proximity of sites of NE and EPI release to adrenoceptors and the resulting concentrations at effector sites are also important determinants of adrenoceptor-mediated responses to these two catecholamines 13 SA, Sinoatrial; AV, atrioventricular. Adapted from Pacak et al.

In patients with pheochromocytoma, both NE and EPI behave as hormones as they are released into circulation. Furthermore, EPI is important as a metabolic hormone In particular, EPI stimulates lipolysis, ketogenesis, thermogenesis, and glycolysis, and raises plasma glucose levels by stimulating glycogenolysis and gluconeogenesis.

Thus, patients with EPI-secreting pheochromocytomas more frequently show episodic symptoms and signs with palpitations, light-headedness or syncope, anxiety, and hyperglycemia than patients with tumors that secrete mainly NE, who more often have continuous symptoms and signs including hypertension, sweating, and headache 317 These catecholamine-specific effects on adrenoceptors explain the wide range of clinical presentations of patients with pheochromocytomas and serve as the basis for appropriate preoperative adrenergic blockade.

Although some patients need significant amounts of adrenoceptor blockers, some may not, despite high circulating catecholamine concentrations often seen in patients with metastatic pheochromocytoma. This mechanism prevents, at least partially, a patient from the harmful effects of catecholamines, which often favor the administration of lower doses of adrenoceptor blockers and catecholamine synthesis inhibitors to minimize drug-related side effects.

The panel of experts at the First International Symposium on Pheochromocytoma recommended that all patients with a biochemically positive pheochromocytoma should receive appropriate preoperative medical management to block the effects of released catecholamines 2. Wide-ranging practices, international differences in available or approved therapies 22 — 29and a scarcity of evidence-based studies comparing different therapies led to a lack of consensus regarding the recommended drugs for preoperative blockade.

The main goal of preoperative management of a pheochromocytoma patient is to normalize pheochromocyfoma pressure, heart rate, and function of other organs; restore volume depletion; and prevent a patient from surgery-induced catecholamine storm and its consequences on the cardiovascular system. Therefore, when preoperative adrenergic blockade is started, drug doses are usually much higher, the combination of various drugs is often necessary, and targets for cardiovascular indices are much stricter than they would be pheochromocgtoma no operation was performed.

Currently, there is no consensus for when adrenergic blockade should be started when preparing a patient for surgery. In most medical centers, adrenergic blockade usually starts 7—14 d preoperatively to have adequate time to normalize blood pressure and heart rate and to expand the contracted blood volume 2732 — In some patients who have organ damage from long-standing jural excess e.

At other institutions, the target blood pressure is either lower 37 or higher 9depending on institutional experience.

Pheochromocytoma: clinical review based on a rare case in adolescence

Nevertheless, recommendations regarding blood pressure and heart rate are supported by observational nonsystematic studies and personal experience rather than properly conducted prospective clinical studies.

The initial dose of phenoxybenzamine is usually 10 mg twice a day and is increased until the clinical manifestations are controlled or side effects appear. Some patients, however, may require much larger doses that, at our institution, are usually increased in increments of 10 to 20 mg every 2 to 3 d. If the initial dosage is too high, the patient will have significant postural hypotension with reflex tachycardia, dizziness, syncope, nasal congestion, and other side effects, and dose titration is warranted.

As the correct dose is approached, paroxysmal hypertensive episodes are brought under control, and when the right dose is achieved the patient becomes normotensive or mildly hypotensive. Additionally, the prolonged action of phenoxybenzamine can contribute to hypotension in the first 24 h after tumor removal Another option is to administer phenoxybenzamine by infusion 0.


This approach, however, requires that the patient be admitted to the hospital and closely monitored; this period is usually too short to start catecholamine synthesis inhibitors to achieve maximum effect as discussed below.

Two studies reported no correlation between duration of treatment less than 1 wk vs.

These drugs have therapeutic or diagnostic use in pheochromocytoma, but usually only after pretreatment with appropriate antihypertensives e. Prazosin is administered in doses of 2 to 5 mg two or three times a day, terazosin is given in doses of 2 to 5 mg per day, and doxazosin in doses of 2 to 8 mg per day.

However, all three have the potential for severe postural hypotension immediately after the first dose; thus, they should be given just as the patient is ready to go to bed. Thereafter, the dosage can be increased as needed; titration can be achieved more quickly with much less side effects no reflex tachycardia, less postoperative hypotension compared with phenoxybenzamine.

Although some studies suggest that these drugs can control blood pressure pre- intra- and postoperatively as effectively as phenoxybenzamine, other studies do not support such conclusions 2545 Atenolol Tenormin is administered in doses of Carvedilol Coreg is another new antihypertensive drug with similar effects as labetalol. These drugs block NE-mediated calcium influx into vascular smooth muscle, thereby controlling hypertension and tachyarrhythmias.

It is the view of the author and others that currently, there are three main roles of these drugs in pheochromocytoma patients 9 Calcium channel blockers do not cause hypotension or orthostatic hypotension during normotensive period These agents may also prevent catecholamine-associated coronary spasm; therefore, they may be useful when pheochromocytoma is associated with catecholamine-induced coronary vasospasm.

In some medical institutions, calcium channel blockers are the primary preoperative treatment of choice in normotensive patients with pheochromocytoma Amlodipine Norvasc is given in a dose from 10—20 mg, and nicardipine Cardene in a dose from 60—90 mg per day.

Both nifedipine and verapamil have extended-release action. A good correlation exists between the perioperative cardiovascular instability and catecholamine release Therefore, the administration of drugs that block catecholamine synthesis, thereby decreasing the stimulation of various adrenoceptors by lowering circulating catecholamine levels, is an important component of preoperative management.

It significantly but not completely depletes catecholamine stores with maximum effect after about 3 d of treatment Fig. The drug is usually used to control high blood pressure in patients with pheochromocytoma, particularly those with extensive metastatic disease or preoperatively in patients with biochemically active tumors 65 — It is preferably used together with other adrenergic blockers due to incomplete depletion of catecholamine stores regardless of the dose used 273767 Despite the well-documented effect of metyrosine on catecholamine synthesis, this treatment has been adopted by only a few institutions 3766 This is partially due to the limited availability of this drug and its side effects evident at high doses.

Pheochromocytoma and Paraganglioma – Endotext – NCBI Bookshelf

Metyrosine facilitates blood pressure control both before and during surgery, especially during the induction of anesthesia and surgical manipulation of the tumor when extensive sympathetic activation or catecholamine release occurs 66 At our institution, treatment is started in all surgical candidates at a dose of mg orally every 8 to 12 h and, thereafter, the dose is increased by to mg every 2 to 3 d or as necessary up to a total dose of 1. Pheochromkcytoma treat for 1—3 wk before surgery depending on blood pressure and heart rate normalization.

Thus, it inhibits catecholamine synthesis in the brain as well as in the periphery, frequently causing sedation often sleepinessdepression, anxiety, and galactorrhea, and rarely causes extrapyramidal signs e.

If these side effects do not resolve quickly when the dosage is lowered, the drug should be discontinued. Metyrosine also causes diarrhea and crystalluria, especially when doses are higher than 4 g per day, although such a dose is rarely used.

At some medical institutions metyrosine is given to all patients, and at others only to those patients who have highly active tumors associated with difficult-to-treat symptoms and pheochrojocytoma of catecholamine excess.