Cardiovascular manifestations of pheochromocytoma

Diagnostics

Cardiovascular Manifestations of Pheochromocytoma WEI-BER LIAO, MD, CHU-FENG LIU, MD, CHING-WEN CHIANG, MD, CHIA-TE KUNG, MD, AND CHI-WEI LEE, MD Pheochromocytomas are rare tumors that originate in chromaffin tissue and produce their distant variant effects by secretion of catecholamines, tending to mislead the emergency physicians to a wrong diagnosis. Therefore, we analyze the clinical cardiovascular manifestations in patients with pheochromocytoma to improve the diagnostic ability of the emergency physicians. All patients presenting to the Chang Gung Memorial Hospital between January 1993 and December 1997 with a final diagnosis of pheochromocytoma had their charts reviewed. The data of 25 patients including age, sex, adrenergic stimulation presentations, electrocardiographic changes, location of the tumor, and complications were analyzed. Hypertension was the most important major manifestation and fluctuation of blood pressure drew our attention to the possibility of pheochromocytoma. Six patients had abnormal electrocardiographic ST-T segment changes. Five of them had chest pain which prompted them to undergo coronary angiography before surgery, because acute coronary syndrome (unstable angina and acute myocardial infarction) was suspected initially. However, all of them turned out to have normal coronary arteries. Right-sided pheochromocytoma was found in three of these five patients. We should maintain high index of suspicion for pheochromocytoma in patients presenting with chest pain, fluctuating blood pressure, and ischemic electrocardiogram (ECG) changes despite any typical isoenzyme changes. Pheochromocytoma should also be included in the differential diagnosis of acute coronary syndrome because acute catecholamine secretion may induce chest pain and abnormal ECG changes mimicking an ischemic episode. The right-sided pheochromocytoma may present more striking electrocardiographic abnormalities and clinical manifestations. (Am J Emerg Med 2000;18:622625. Copyright r 2000 by W.B. Saunders Company)

Pheochromocytomas are rare tumors that originate in chromaffin tissue and produce their distant effects by secretion of catecholamines. The usual clinical findings of spells of headache, palpitation, pallor, and perspiration accompanied by hypertension are well known.1,2 Diverse electrocardiographic (ECG) abnormalities of rhythm, conduc-

From the Section of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Link, Niaosung, Kaohsiung, Taiwan, ROC. Manuscript received November 9, 1999, accepted January 20, 2000. Address reprint requests to Wei-Ber Liao, MD, Emergency Medicine, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niaosung, Kaohsiung, 833, Taiwan, ROC. Key Words: Acute coronary syndrome, pheochromocytoma, multisystem crisis, abdominal computed tomography, hypertension. Copyright r 2000 by W.B. Saunders Company 0735-6757/00/1805-0011$10.00/0 doi:10.1053/ajem.2000.7341 622

tion, and repolarization may occur in patients with pheochromocytoma. The nonspecificity and acute nature of the electrocardiographic changes associated with pheochromocytoma will often warrant coronary angiography before thrombolytic therapy.3-8 We reviewed the charts of 25 patients with pheochromocytoma and analyze their clinical manifestations. METHODS All patients presenting to the Chang Gung Memorial Hospital between January 1993 and December 1997 with a final diagnosis of pheochromocytoma had their charts reviewed. The diagnosis was made by abdominal sonography, contrast computed tomography, 131meta-iodobenzylguanidine ( 131I-MIBG), vanillylmandelic acid (VMA) of 24 hours urine (the normal range from 2 to 7 mg) and all except one were proved by pathology. The data of 25 patients including age, sex, adrenergic stimulation presentations, electrocardiographic changes, location of the tumor, and complications were analyzed. ST-T segment elevation or depression over 0.04 mv and prolonged over 0.08 seconds was assigned abnormal. QTc ⱖ 0.04 seconds was defined as prolonged. RESULTS The index number was 25 patients. There were 11 female patients and 14 male patients. The patient’s ages ranged from 16 to 68 years with mean (⫾SD) of 49 ⫾ 10 years. Hypertension (56%: 14/25) was one of the most important cardiovascular manifestations of pheochromocytoma, 8% (2/25) had labile (hypo-hyper blood pressure), 32% (8/25) persistent and 24% (6/25) paroxysmal hypertension. All tumors, except one, located on the right sides of the eight patients with clinical manifestation of labile and paroxysmal hypertension attack. The adrenergic stimulation symptoms and signs were, in decreasing order of frequency, diaphoresis (9/25; 36%), palpitation (9/25; 36%), angina (8/25; 32%), headache (7/25; 28%), abdominal pain (6/25; 24%) (which was over the site of the tumor), syncope (5/25; 20%), dyspnea (4/25; 16%), fever (3/25; 12%), blurred vision (3/25; 12%), and Raynaud’s phenomenon (2/25; 8%). Seventeen patients had normal ECG and two patients had left ventricular hypertrophy. Abnormal ST-T segment changes were recorded in six patients and five of them received emergency coronary angiography because acute coronary

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syndrome was suspected. As in case 1, the patient presented with syncope, chest pain with wide QRS tachycardia, evolutional ECG changes mimicking acute myocardial infarction, as well as, fluctuation of blood pressure (from 240/167 to 49/33 mmHg), had undergone electrocardioversion, and lidocaine and procainamide treatment (Figure 1). The ECG changed from nonspecific ST-T changes (Figure 1A) to ST-T segment convex elevation and QTc prolongation (Figure 1B) and then to diffuse ST-T segment wide elevation (Figure 1C). The total level of lactic dehydrogenase (LDH; 2,293 U/L) and creatine phosphokinase (CPK; 7,288 U/L) were abnormal, whereas isoenzyme ratios were normal (LDH1/ LDH2:7.0/9.3 and CPK-MB/CPK-MM:0/100). After right adrenalectomy (8.5 ⫻ 7.8 ⫻ 6.5 cm3 with extensive hemorrhage and necrosis), QTc prolongation reverted to normal 3 months later. This patient also had high fever of 40°C during

FIGURE 2. Electrocardiogram of case 2. (A) Four years ago; showing sinus tachycardia, ST-T segment elevation in V1-2 suggesting acute anterior myocardial infarction. QTc ⫽ 0.46 seconds. (B) At arrival at the ED; showing junctional tachycardia, diffuse ST-T segment depression. QTc ⫽ 0.36 seconds. (C) Four hours later at ED; showing sinus tachycardia, diffuse horizontal ST-T segment depression. QTc ⫽ 0.48 seconds.

FIGURE 1. Electrocardiogram of case 1. (A) At beginning with syncope; showing sinus tachycardia, left axis deviation, prominent P wave in II,III,aVF, clockwise rotation and diffuse ST-T changes. QTc ⫽ 0.42 seconds. (B) Five hours later; showing sinus tachycardia, left axis deviation, clockwise rotation and diffuse ST-T segment convex elevation. QTc ⫽ 0.46 seconds. (C) Sixteen hours later; showing sinus tachycardia, and acute myocardial infarction pattern. (Body temperature ⫽ 40°C, blood pressure fluctuating)

attacks. His complications included hyperglycemic hyperosmolar nonketotic acidosis, acute respiratory failure, acute renal failure, acute pulmonary edema, rhabdomyolysis, and hypoxic encephalopathy. The second patient presented with chest pain, syncope, fever, cold sweating, dyspnea, ST-T segment elevation, junctional or sinus tachycardia during attacks and diffuse downsloping ST-T segments depression in the ECG recorded 4 years ago (Figure 2A-C). Her isoenzymes were normal. During her last visit (Figure 2B,C), pheochromocytoma was eventually diagnosed and left adrenalectomy was performed (4.5 ⫻ 4.0 ⫻ 3.0 cm3 ). The third patient presented with chest pain and his ECG showed sinus rhythm with prominent ST elevation and T wave inversion mimicking acute anterior infarction (Figure 3), the total LDH level was elevated but the isoenzymes were normal: LDH 116 U/L (LDH1/LDH2: 26.2/41.1) and

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AMERICAN JOURNAL OF EMERGENCY MEDICINE 䊏 Volume 18, Number 5 䊏 September 2000

FIGURE 3. Electrocardiogram of case 3 showing sinus tachycardia, diffuse ST-T changes mimicking acute anterior myocardial infarction. QTc ⫽ 0.62 seconds.

CPK 16 U/L (MB: MM: 0/100). After right adrenalectomy (6.0 ⫻ 6.0 ⫻ 5.0 cm3 ), the ECG reverted to normal. The fourth patient presented with chest pain and her ECG showed T inversion in V4-6 . Her blood pressure dropped from 211/156 mmHg to 81/50 mmHg after right adrenalectomy (3.0 ⫻ 3.0 ⫻ 2.0 cm3 ). The fifth patient presented with cold sweating, chest tightness, and fluctuation of blood pressure. His ECG showed left ventricle hypertrophy with strain and QTc ⫽ 0.62 seconds. VMA ⫽ 19.5 mg. A pelvic mass about 5.0 ⫻ 6.0 ⫻ 7.0 cm3 was removed. His blood pressure became stable after surgery. Coronary angiogram of these five patients were all normal. The QTc prolongation over 0.44 seconds were recorded in four of these five patients. The tumors were located at the right side in three of these patients. The tumors were detected by the computed tomography in all 25 patients, and were located at the right side in 12 patients (of which one was malignant, two showed recurrence), at the left side in nine patients (of which one is malignant, one showed recurrence); at both sides in one patient and extrarenal in three patients (pelvis, prostate, and stomach respectively). The mean tumor size was 4.9 ⫻ 5.7 ⫾ 1.1 ⫻ 1.7 cm2 (ranged from 3 ⫻ 3 to 10 ⫻ 15 cm2 ). Hypertension could be elicited in 20% (5/25) of these patients on manipulation of the tumor. The mean value of VMA was 17.4 ⫾ 7.7 mg (ranged from 7.1 to 42.2 mg). Acute renal failure occurred in one patient, chronic renal failure in one patient. Hyperglycemia (more than 126 mg/dL) was noted in 11 patients and one had hyperglycemic hyperosmolar nonketotic acidosis. Acute respiratory failure, rhabdomyolysis, and pulmonary edema were found in one, and two patients respectively. DISCUSSION ECG abnormalities in patients with pheochromocytoma may result from stimulation of the myocardium by excessively high plasma catecholamine levels.9-11 In our series, five patients had striking ECG changes and received coronary angiography before surgery. These changes were transient, and the ECG reverted to normal after the removal of the tumor.3,4,8,9 Catecholamines, particularly norepinephrine are known to have a toxic effect on the myocardium, and this may account for many of the ECG changes commonly reported. Excessive norepinephrine causes myocardial in-

jury in part by decreasing coronary blood flow attributable to vasoconstriction and in part by increasing the cardiac oxygen demand, ischemic damage may result (Figures 1-3).10 Rapid reversal of the ECG changes after surgery suggested a toxic myocarditis rather than true transmural infarction (Figure 1).4 Rapid catecholamine injection before complete intravascular mixing, as well as, brief stimulation of nerves with localized cardiac distribution are likely to have localized cardiac effects.10 The striking paroxysmal abnormalities of repolarization, consisting of marked prolongation of the Q-T interval, as well as deep and wide symmetrically inverted T waves, are frequently observed in patients with pheochromocytoma and may give rise to dangerous ventricular arrhythmias.3,4,7,8 A preoperative QTc interval longer than 0.44 seconds was found in four of five patients who received coronary angiography, 16% (4/25) in our series. Surgical removal of the pheochromocytoma resulted in normalization of the QTc intervals. Hypertension is one of the most important cardiovascular manifestations in our patients (56%). Blood pressure fluctuation sometimes help to distinguish it from the other forms of hypertension. In our series, 32% had fluctuating hypertension. One patient with labile blood pressure presented as pheochromocytoma multisystem crisis.12 Hypertensionhypotension, fever, hyperglycemic hyperosmolar nonketotic acidosis, mental status changes, renal dysfunction, respiratory dysfunction, cardiac dysfunction, and lactic acidosis had been found in this patient. Although emergency tumor removal was performed (8.5 ⫻ 7.8 ⫻ 6.5 cm3 ), he was left with hypoxic encephalopathy. Successful treatment of this kind of patient demands prompt diagnosis, vigorous preoperative medical treatment, and emergency tumor removal. The tumors of such patients were usually large, located in the right adrenal gland.12 A combination of sudden release of catecholamines, epinephrine’s relatively greater beta effect on peripheral vessels, and a net reduction in viable myofibrils may explain the atypical manifestation, hypotension as well as hypertension.12-15 In these circumstances the heart may show evidence of myocarditis. Blood volume is also reduced in these cases and it is thought to be the result of a high sympathetic tone or a state of autonomic dysfunction, and may provoke hypotension.16 Tumor necrosis caused by ischemia secondary to vasoconstriction and a massive

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release of catecholamines also contributes to the initial hypertension and the subsequent hypotension and myocardial impairment.17-18 Fever presented in 12% of our patients. The sudden outpouring of epinephrine has been postulated as causing an elevation in body temperature by a combination of inducing hypermetabolism and impairing heat dissipation as a consequence of cutaneous vasoconstriction.19-20 The possible mechanism for acute renal failure may be caused by intense renal vasoconstriction induced by catecholamines and cardiovascular shock.21-22 Lactic acidosis, although rare in patients with pheochromocytoma, could result from increased lactate production in the liver secondary to glycogenolysis and by creation of anaerobic tissue conditions secondary to vasospasm.23 Catecholamine induced vasospasm, platelet aggregation, and thrombosis may play a role in the mental status changes and pulmonary edema.24-25 Hypoxic encephalopathy may be attributable to persistent hypotension or to direct effects of catecholamines or other vasoactive factors. CONCLUSION We should maintain high index of suspicion for pheochromocytoma in patients presenting with chest pain, fluctuating blood pressure, and ischemic ECG changes. Pheochromocytoma should also be included in the differential diagnosis of acute coronary syndrome because acute catecholamine secretion may induce chest pain and abnormal ECG changes mimicking acute myocardial infarction. For these patients, the associated hypersympathetic symptoms and signs of catecholamine release should be sought. The right-sided pheochromocytoma may present more striking electrocardiographic abnormalities and clinical manifestations. Abdominal computed tomography may help to detect this lesion and should be undertaken as soon as possible. Early recognition and surgical treatment of an underlying pheochromocytoma may prevent the development of complications. REFERENCES 1. Newell KA, Prinz RA, Pickleman J, et al: Pheochromocytoma multisystem crisis. Arch Surg 1988;123:956-959 2. Abildskov JA: Adrenergic effects on the QT interval of the electrocardiogram. Am Heart J 1976;92:210-216 3. Sayer WJ, Moser M, Mattingly TW: Pheochromocytoma and the abnormal electrocardiogram. Am Heart J 1954;48:42-53 4. Simons M, Downing SE: Coronary vasoconstriction and catecholamine cardiomyopathy. Am Heart J 1985;109:297-304 5. Stenstrom G, Swedberg K: QRS amplitudes, QTc intervals and ECG abnormalities in pheochromocytoma patients before, during and after treatment. Acta Med Scand 1988;224:231-235

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6. Shimizu K, Miura Y, Meguro Y, et al: QT prolongation with torsade de pointes in pheochromocytoma. Am Heart J 1992;124:235239 7. Hass GJ, Tzagournis M, Boudoulas H: Pheochromocytoma: Catecholamine-mediated electrocardiographic changes mimicking ischemia. Am Heart J 1988;116:1363-1365 8. McManus BM, Fleury TA, Roberts WC: Fatal catecholamine crisis in pheochromocytoma: Curable cause of cardiac arrest. Am Heart J 1981;102:930-932 9. Goldbaum TS, Henochowicz S, Mustafa M, et al: Pheochromocytoma presenting with prinzmetal’s angina. Am J Med 1986;81:921922 10. Radtke WE, Kazmier FJ, Rutherford BD, et al: Cardiovascular complications of pheochromocytoma crisis. Am J Cardiol 1975;35:701705 11. Cheng TO, Bashour TT: Striking electrocardiographic changes associated with pheochromocytoma masquerading as ischemic heart disease. Chest 1976;70:397-399 12. Van Vliet PD, Burchell HB, Titus JL: Focal myocarditis associated with pheochromocytoma. N Engl J Med 1966;274:1102-1108 13. Sardesai SH, Mourant AJ, Sivathandon Y, et al: Phaeochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure. Br Heart J 1990;234-237 14. Shaw TRD, Raffery P, Tait GW: Transient shock and myocardial impairment caused by phaeochromocytoma crisis. Br Heart J 1987;57:194-198 15. Quezado ZN, Keiser HR, Parker MM: Reversible myocardial depression after massive catecholamine release from a pheochromocytoma. Crit Care Med 1992;20:549-551 16. Brunjes S, Johns VJ Jr, Crane MG: Pheochromocytoma: Postoperative shock and blood volume. N Engl J Med 1960;262:393396 17. Jones DJ, Durning P: Phaeochromocytoma presenting as an acute abdomen: report of two cases. Br Med J 1985;291:1267-1268 18. Gordon DL, Atamian SD, Brooks MH, et al: Fever in pheochromocytoma. Arch Intern Med 1992;152:1269-1272 19. Fukumoto S, Matsumoto T, Harada SI, et al: Pheochromocytoma with pyrexia and marked inflammatory signs: A paraneoplastic syndrome with possible relation to interleukin-6 production. J Clin Endocrinol Metab 1991;73:877-881 20. Smithwick RH, Green WER, Robertson CW, et al: Pheochromocytoma: A discussion of symptoms, signs and procedures of diagnostic value. N Engl J Med 1950;242:252-257 21. Sutton MG St J, Sheps SG, Lie JT: Prevalence of clinically unsuspected pheochromocytoma: Review of a 50-year autopsy series. Mayo Clin Proc 1981;56:354-360 22. Borneman M, Hill SC, Kidd II GS: Lactic acidosis in pheochromocytoma. Ann Intern Med 1986;105:880-882 23. Takabatake T, Kawabata M, Ohta H, et al: Acute renal failure and transient massive, proteinuria in a case of pheochromocytoma. Clin Nephrol 1985;24:47-49 24. Shemin D, Cohn PS, Zipin SB: Pheochromocytoma presenting as rhabdomyolysis and acute myoglobinuric renal failure. Arch Intern Med 1990;150:2384-2385 25. Hill JB, Schwartzman RJ: Cerebral infarction and disseminated intravascular coagulation with pheochromacytoma. Arch Neurol 1981;38:395