Pheochromocytoma

Pheochromocytoma is a notorious clinical entity. Although suspicion is aroused by severe hypertension in young patients, this sign is often absent. We present a case in which early absence of hypertension and nonspecific signs and symptoms led to failure of prompt diagnosis. The delay proved fatal when the patient developed fulminant pheochromocytoma crisis. This case illustrates a variety of clinical features seen from the vantage of the evolution of the disease as it went unrecognized. The patient's course underscores the importance of familiarity with the gamut of manifestations for timely diagnosis, and the priority of the latter given the looming risk of overwhelming complications.

(CHEST 2000; 118:1221-1223)

Key words: cardiomyopathy; hypertension; marijuana; myocarditis; noncardiogenic pulmonary edema; pheochromocytoma; pheochromocytoma crisis

Pheochromocytoma is a tumor of special renown in clinical medicine. Its hallmark--severe, labile BP elevation--leads to its frequent consideration as a potential etiology in young hypertensive patients, despite the low prevalence of the condition.[1] Yet, pheochromocytoma commonly does not behave in the classic manner, and the nonspecific nature of its manifestations may render prompt recognition elusive.[1] Detailed knowledge of the protean presentations of pheochromocytoma provides the best chance at early detection. Failure may lead to a catastrophic outcome.

CASE PRESENTATION

A 28-year-old man presented to our emergency department with headache, epigastric discomfort, nausea, and vomiting. One year earlier, he had visited another emergency department, complaining of nausea, vomiting, and headache. He was noted to have mild glucose intolerance and was discharged with "gastroenteritis." Four months later, he came to our emergency department with complaints of a right temporal headache. A diagnosis of sinusitis was made prior to discharge. Two months thereafter, the patient returned after awakening with "heart pounding" and vomiting. He received volume repletion for postural hypotension and was released with "gastritis." Ten days before admission, recurrent symptoms led to an upper GI series. Detection of mild reflux esophagitis prompted omeprazole treatment.

On the night of admission, the patient noted a throbbing right occipital headache. After playing basketball, he developed bilious vomiting and presented to our emergency department. He complained of lightheadedness, dull abdominal pain, and precordial discomfort without radiation or pleurisy. Initial examination showed labile hypertension and epigastric tenderness, but the patient soon became pale, diaphoretic, and dyspneic. Following 100 ml of hemoptysis, he required intubation for hypoxia. Chest radiography revealed diffuse bilateral alveolar infiltrates.

The patient denied smoking or drinking, but admitted to marijuana use. Examination (ICU) showed a sedated, profusely diaphoretic man. BP ranged from 85/55 to 290/170 mm Hg, pulse was 140 to 180 beats/rain, and temperature was 40.1. [degrees] C (104.1 [degrees] F). He required 100% fraction of inspired oxygen and positive end-expiratory pressure of 15 mm Hg. A pulmonary artery catheter yielded the following: right atrial pressure, 9 mm Hg; pulmonary artery pressure, 30/22 mm Hg; mean pulmonary capillary wedge pressure, 22 mm Hg; and cardiac index, 2.1 L/min/[m.sup.2]. Lungs had diffuse crackles bilaterally. There was a soft systolic murmur at the left sternal border. Abdomen was soft; no discrete masses were appreciated. Laboratory values included the fbllowing: bicarbonate, 22 mg/dL; anion gap, 18 mg/dL; urea nitrogen, 15 mg/dL; creatinine, 1.2 mg/dL; glucose, 270 mg/dL; creatine kinase, 385 mg/dL; MB fraction, 14.7 mg/dL; and leukocyte count, 14,800 cells/[micro]L. Room-air arterial blood gas measurements (preintubation) revealed a pH of 7.4; [Pco.sub.2], 32 mm Hg; [Po.sub.2], 61 mm Hg; and bicarbonate, 21 mg/dL. Toxicology screens were positive for tetrahydrocannabinol. ECG showed sinus tachycardia. Echocardiography revealed normal left and right ventricular size and wall thickness, but severe biventricular dysfunction (left ventricular ejection fraction, 20%).

The patient continued to have marked swings in BP and pulmonary capillary wedge pressure requiring titration of sodium nitroprusside. Abdominal ultrasonography (Fig 1) and CT (Fig 2) showed a hemorrhagic 12-cm left suprarenal mass. The patient received normal saline solution, 4 L IV, followed by phenoxybenzamine, 30 mg nasogastrically, and phentolamine boluses of 0.5 to 1.0 mg IV, totaling 7 mg. On his second hospital day, however, the patient suffered a terminal bradyasystolic arrest. Spot urine analysis subsequently showed the following: epinephrine, 4,520 [micro]g/L (normal range, 0 to 25 [micro]g/d); norepinephrine, 8,760 [micro]g/L (normal range, 0 to 100 [micro]g/d).

[Figures 1-2 ILLUSTRATION OMITTED]

DISCUSSION

This report illustrates the devastating course of an unrecognized case of pheochromocytoma. Perhaps the most difficult aspect of the diagnosis lay in the lack of hypertension prior to hospitalization. Hypertension, either sustained or paroxysmal, is the cardinal feature of pheochromocytoma.[1] Reviews, however, have placed its frequency at 72.4%, with that of sustained hypertension at only 47.9%.[1] These figures emphasize the modest sensitivity of hypertension for diagnosis; its absence cannot be relied on to exclude the condition.

In the absence of hypertension, early diagnosis hinges on recognizing the clustering of alternative, individually nondistinctive, manifestations.[1] The classic triad of headache, palpitations, and diaphoresis, when present, is a strong clue.[1] In the above case, the coexistence of headache and palpitations should have aroused suspicion. Yet the patient's recurrent GI complaints diverted attention from the diagnosis. Nausea and vomiting, which occur in [is less than] 20% of cases,[1] led to discovery of mild reflux esophagitis--a red herring. GI symptoms also obscured the significance of the patient's orthostatic hypotension--another manifestation of catecholamine excess.[1] Furthermore, the patient's glucose intolerance, which in a nonobese male subject in his third decade was an additional signpost,[1] was importantly overlooked.

The late course ultimately provided strong support for pheochromocytoma. In fact, the panoply of characteristic features documented in this single patient has little precedent in the literature: (1) severe, labile hypertension; (2) abdominal and chest pain,[1-2] likely secondary to hemorrhage into the tumor and vasospasm-induced myocardial ischemia, respectively; (3) cardiomyopathy of recent onset (myocyte necrosis with inflammatory infiltration and hemorrhage is a long-recognized pathologic feature of catecholamine excess)[3,4]; (4) pulmonary edema, both cardiogenic and noncardiogenic, the latter resulting from pulmonary-capillary membrane damage and catecholamine constriction of postcapillary venules[5]; (5) fever, thought secondary to tumor secretion[1] of interleukin-6; (6) anion gap metabolic acidosis, reflecting likely lactic acidosis from organ-tissue hypoperfusion.[6] The trigger to the crisis may have involved either marijuana,[1,6] or a blow to the abdomen during basketball.[2]

The initial step in the workup of clinically suspected pheochromocytoma (once medications known to alter levels are discontinued) is a 24-h urine collection for epinephrine, norepinephrine, vanillylmandelic acid, and metanephrines.[7] If levels are normal, detection may require repetition during the occurrence of a spell. Localization--with a view toward surgical excision--then relies on abdominal CT or MRI, supplemented as needed by 1231-metaiodobenzylguanidine scintigraphy.[7]

The diagnosis in this case rested with detection of the hemorrhagic suprarenal mass, later confirmed by massive elevation of urinary catecholamines. We sought to stabilize the patient prior to surgical resection through a-blockade and volume expansion.[2] Nevertheless, he succumbed to the hemodynamic collapse that can occur during pheochromocytoma crisis, attributed to sudden depletion of catecholamines in the setting of downregulated vascular receptors.[1] Pheochromocytoma is often lethal when unsuspected[8]; earlier diagnosis would have improved the odds of a favorable outcome.

ACKNOWLEDGMENT: The authors thank Jeffrey A. Solomon, MD, for his valuable assistance in preparing and interpreting the radiographic images.

REFERENCES

[1] Werbel SS, Ober KP. Pheochromocytoma: update on diagnosis, localization and management. Med Clin North Am 1995; 79:131-153

[2] Shapiro B, Fig LM. Management of pheochromocytoma. Endocrinol Metab Clin North Am 1989; 18:443-481

[3] Szakacs JE, Cannon AL. Noreprinephrine myocarditis. Am J Clin Pathol 1958; 30:425-434

[4] Van Vliet PD, Burchell HB, Titus JL. Focal myocarditis associated with pheochromocytomas. N Engl J Med 1966; 274:1102-1108

[5] Suga K, Tsukamoto K, Nishigauchi K, et al. Iodine-123-MIBG imaging in pheochromocytoma with cardiomyopathy and pulmonary edema. J Nucl Med 1996; 37:1351-1364

[6] Bergland BE. Pheochromocytoma presenting as shock. Am J Emerg Med 1989; 7:44-48

[7] Young WF. Pheochromocytoma and primary aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am 1997; 26:801-827

[8] St John Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma: review of 50-year autopsy series. Mayo Clin Proc 1981; 56:354-360

(*) From the Cardiovascular (Drs. Kizer and St. John Sutton) and Pulmonary and Critical Care Divisions (Drs. Koniaris and Edelman), Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, PA.

Manuscript received January 31, 2000; revision accepted March 21, 2000.

Correspondence to: Jorge R. Kizer, MD, MSc, Cardiovascular Division, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104; e-mail: kizer@mail.med.upenn.edu

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