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Pheochromocytoma without hypertension presenting as cardiomyopathy
Pheochromecytoma as cardiomyopathy
without
hypertension
presenting
George Baker, M.D.* Nicholas H. Zeller, M.D. Stanley Weitzner, M.D. John K. Leach, M.D. Albuquerque, N. M.
P
heochromocytoma, a tumor of chromaffin tissue, is usually found in the adrenal glands, but on occasion has been located in a number of ectopic sites including sympathetic and parasympathetic ganglia and the organ of Zuckerkandl.‘s2 The tumor secretes norepinephrine and epinephrine with combined alpha- and beta-adrenergic stimulation, the former usually more prominent and accounting for the rapid onset of labile systemic hypertension.2 Occasionally a pheochromocytoma, usually malignant, secretes primarily dopamine, the action of which is similar to that of norepinephrine except for selective nonadrenergic vasodilating effects. Rarely, the dominant clinical picture of paroxysmal or sustained hypertension with associated diaphoresis, weight loss, pallor, and hyperglycemia does not become apparent until late in the clinical course.3 The patient may then present in a diffusely hypermetabolic state simulating hyperthyroidism, carcinoid syndrome, gram-negative septic shock, arteriovenous fistula, acute psychotic states, pulmonary embolism, malignant hyper-
tensive crises, or diabetic lactic acidosis.2*4 A few patients have been described in whom a very large pheochromocytoma, nearly always located in the right adrenal, secretes much larger amounts of epinephrine than norepinephrine accounting for the slow development of hypotensive episodes, catecholamine cardiomyopathy, tachycardia, arrhythmias, diaphoresis, and weakness.5 Since hypertension or hypertensive episodes typically do not appear until late in the clinical course of such patients, medical attention is initially directed to other possibilities. The presence of a pheochromocytoma may not be suspected until such time in the patient’s illness when therapy may no longer be effective. The following case illustrates such an atypical presentation in which the patient demonstrated progressive, unexplained congestive heart failure and remained normotensive until his final month of illness. It is the purpose of this paper to emphasize diagnostic pitfalls, to explore to a limited extent the pathophysiologic character of this patient’s illness, and to describe how
From
the Departments of Medicine and Pathology, University of New Mexico School of Medicine, Administration Hospital, Albuquerque, N. M. Received for publication Nov. 17, 1970. Reprint requests to: Dr. Nicholas H. Zeller, Cardiology Section, Veterans Administration Hospital, Dr., SE, Albuquerque. N. M. 87108. *Present address: Department of Cardiology, San Francisco Medical Center. Third and Parnessus, Calif.
688
American
Heart
Journal
May, 1972
and
the Veterans
2100
Ridgecrest
San
Francisco.
Vol. 83, No. 5, pp. 688493
Volume Number
83 5
Pheochromocytoma
it differs from the usual case of pheochromocytoma encountered. Case
report
A 39-year-old man was initially admitted to another hospital on March 15, 1968, because of intermittent dyspnea of two weeks’ duration, chest tightness with occasional sharp chest pain, weakness, easy fatigability, diaphoresis, pallor, and tremor. Physical examination was reported as normal. Cardiac fluoroscopy showed left ventricular and left atria1 enlargement, and the electrocardiogram (ECG) was reported as “consistent with disease of the left ventricle.” The serum cholesterol level was 240 mg. per cent, and the two-hour post prandial blood sugar was 153 mg. per cent. The patient then was referred to the Albuquerque Veterans Administration Hospital, where he was followed until his death. Admission work-up revealed a blood pressure of 130/80 mm. Hg in the arms, 140/80 mm. Hg in the legs, and mild left ventricular enlargement. A Grade I/VI systolic ejection murmur was heard along the left sternal border. ECG showed left ventricular hypertrophy and an intraventricular conduction defect. Slow progression of the disease process was noted, although he continued to be normotensive during the next several months. Marked wasting and a 31 pound weight loss ensued. During a subsequent prolonged hospitalization, elevated jugular venous pressure, progressive cardiac enlargement, a protodiastolic gallop, and hepatic enlargement indicated congestive heart failure; he was treated with digitalis with some improvement. Laboratory data revealed the following: fasting blood sugar, 124 mg. per cent; two-hour post prandial blood sugar, 158 mg. per cent; proteinbound iodine, 3.4 rg per cent. Cardiac catheterization performed on Sept. 13, 1968, disclosed no intracardiac shunts or obstructive lesions, but a left ventriculogram revealed evidence of diminished contractility. Following discharge from the hospital, his condition remained stable for about two months. He was readmitted Dec. 1, 1968, with a ten-day history of recurrent chest pain, profuse diaphoresis, marked dyspnea, and weakness. He was noted to be nauseated and to have pedal edema, marked heat intolerance, diarrhea, and pallor. Physical examination revealed a blood pressure of 180/112 mm. Hg, sinus tachycardia with a rate of 124 beats per minute, and a normal temperature. The patient was markedly pale, tremulous, and apprehensive. Large pools of sweat collected on the surface of the examining table. Funduscopic examination revealed arteriolar narrowing and A-V nicking. Jugular venous pressure was not elevated and the chest was clear. The heart was enlarged to percussion to the right and left with a forceful left ventricular thrust. Pulmonic closure was accentuated and a protodiastolic gallop was present. A Grade I/VI systolic ejection murmur was present at the lower left sternal border. The liver was palpable 5 cm. below the right costal margin; it was smooth and slightly tender. Marked proximal wasting of both the upper and lower extremities was present. Violaceous discoloration with papular hyperkeratosis was
presenting
as cardiomyopathy
689
present over the proximal interphalangeal joints and over the periungual areas of the deeply spooned and longitudinally ridged nails. Chest x-ray on admission showed further cardiomegaly, predominantly left ventricular and left atrial. Intravenous pyelogram showed displacement of the right kidney inferiorly, attributed to enlargement of the liver. The ECG showed a left ventricular hypertrophy pattern. Laboratory data were as follows: hematocrit, 40 per cent; hemoglobin, 13.8 Gm. per cent; blood urea nitrogen, 51 mg. per cent; two-hour post prandial glucose, 136 mg. per cent; serum bilirubin, 1.5 mg. per cent; sodium, 144 mEq. per liter; chlorides, 102 mEq. per liter; Ta uptake, 12.3 per cent; free thyroxine, 3.7 fig per cent; serum glutamic oxalacetic transaminase, 810 I.U.; urinalysis, 1.034 specific gravity, negative sugar, and negative albumin. Fivehydroxyindole acetic acid was 10.6 mg. per 24 hours (normal: up to 10 mg. per 24 hours). Twenty-four hour urine collections for vanilmandelic acid completed four and eighteen days after admission, not reported until shortly before death, were 39 mg. per 24 hours and 2.5 mg. per 24 hours, respectively (normal up to 8 mg. per 24 hours). The patient did well until Dec. 8, 1968, when he developed an episode of tachycardia, dyspnea, diaphoresis, and a fever of 104” F. A right upper lobe infiltrate visible on chest x-ray was felt to represent an acute pulmonary infarction. Treatment with Mercuhydrin, penicillin, and anticoagulants effected moderate improvement. The diagnosis of dermatomyositis was suggested by a neurological consultant. Electromyography was consistent with myopathy, but muscle and skin biopsies were normal. Electroencephalogram demonstrated poorly organized activity, suggestive of a toxic or metabolic disorder. ECG showed multiple ventricular premature contractions, a wandering supraventricilar pacemaker, left axis deviation, and widenine of the ORS complex. In spite of ireatment with prednisone, lidoCaine, isoproterenol, and supportive measures, the patient became markedly hypotensive and died. Necropsy was performed one hour after death. The heart weighed 630 grams. All cardiac chambers were dilated and both ventricles were hypertrophied. There was patchy endocardial fibrosis in the left ventricle. Microscopic examination disclosed moderate enlargement of myocardial fibers in both ventricles and slight patchy interstitial fibrosis, also a broad band of fibrosis beneath the endocardium in the left ventricle. Necrosis of muscle fibers was absent. There was slight to moderate intimal atherosclerosis of the coronary arteries. A small recent infarct was present in the upper lobe of the right lung. The right adrenal gland was replaced by a large, firm, slightly nodular neoplasm measuring 10 by 7 by 3 cm. in greatest dimensions and weighing 130 grams (Fig. 1). The cut surface of the tumor had a lobular pattern and was gray red with two central, irregular cystic areas. A portion of the tumor stained dark brown after fixation in Zenker’s (dichromate) solution. Histologically, it was composed of varyingsized islands of round and polygonal cells surrounded by a richly vascular, collagenous, and reticulin stroma. The cells had eosinophilic cytoplasm. The
690
Baker et al.
Fig. 1. Hemisection of right adrenal tumor. nuclei were vesicular or hyperchromatic and varied somewhat in size (Fig. 2). There were no mitoses. A Wilder reticulin stain outlined only the islands of cells and adjacent capillaries but did not envelop individual pheochromocytes. The tumor was centrally hyalinized and cystic in places. A small amount of normal adrenal tissue was present at the periphery of the tumor. The diagnosis was pheochromocytoma. The left adrenal gland was normal grossly and microscopically. The remainder of the necropsy failed to reveal any other lesion which could explain the patient’s clinical picture.
Discussion Although nonspecific and consistent with other disorders, paroxysms of palpitation, anxiety, tremulousness, diaphoresis, weakness, and weight loss, associated with progressive myocardial disease, are compatible with pheochromocytoma.6 Various authors have discussed myocardial lesions secondary to chronically elevated levels of catecholamines when used therapeutically, or when produced by experimentally, pheochromocytoma. 7-gA review by Szakacs and Cannon’ of the autopsy material at the Armed Forces Institute of Pathology yielded 17 cases of pheochromocytoma which demonstrated acute myocarditis with no evidence of significant coronary artery disease. Similar findings have been noted in patients without pheochromocytoma treated with catecholamine preparations for a significant length of time-usually eight hours or more. Szakacs and Cannon’ induced similar changes in dogs with I-norepinephrine. These changes were somewhat more severe than in man. Myocardial hemorrhages were seen accompanied by endocardial proliferation, thickening, and
Am. Heart I. May, 1972
edema. Degenerating myofibrils and cellular infiltration were also present. During their studies, cardiac arrhythmias were frequently observed. Handforth induced similar lesions in the hearts of hamsters by means of subcutaneous injections of isoproterenol. Dosages of drugs used by the two groups of investigators usually exceeded concentrations encountered in clinical situations. Van Vliet, Burchell, and Titus10 concluded that the myocardial fibrosis observed after longstanding exposure to catecholamines probably represented the healed stage of active myocarditis. Engelman and Sjoerdsmall correlated regression of clinically recognized cardiomyopathy induced by catecholamines with resection of the pheochromocytoma. Therefore, the myocardial lesions observed in our patient were probably due to the direct toxic effects of catecholamines on the heart. Catecholamine-secreting tumors usually arise from the adrenal areas, although they have been described in every area of chromaffin tissue in the body.1*2t4The rare, predominantly epinephrine-secreting tumor, however, rarely occurs in an extraadrenal location.5J3 Page, Raker, and Berberich,6 in a recent article describing a patient similar to ours, emphasized that determination of the free catecholamine or normetanephrine-metanephrine excretion rather than total catecholamines or vanilmandelic acid “may provide a clue as to the presence and location of a pheochromocytoma.” The division of catecholamine effects into alpha and beta types is well known.2J3 Norepinephrine acts on beta-adrenergic receptors in the heart to cause increased contractility and on alpha receptors in arteries and veins to cause vasoconstriction. The resultant effect, therefore, is elevation of blood pressure, the usual manifestation of predominantly norepinephrine-secreting tumors. Epinephrine, on the other hand, while having beta-stimulatory effects on the heart, exhibits both alpha and beta effects on peripheral vessels. With usual clinical doses, the beta effect predominates and total peripheral resistance decreases. Patients with predominantly epinephrinesecreting tumors present with tachycardia, sweating, pallor, abdominal pain, nausea,
Volume Number
83 5
Fie. 2. Reoresentative stroma. (Hematoxylin
Pheochromocytoma
section of oheochromocvtoma and eosin.*X40.)
vomiting, hyperglycemia, and hypotension. Although urinary catecholamine patterns were not obtained in our patient, the symptomatology and clinical course seem to us consistent with a predominantly epinephrine-secreting tumor. The usual case of pheochromocytoma becomes clinically manifest when the tumor is still small with rapid synthesis and excretion of active catecholamines directly into the circulation.2 Some tumors, however, maintain a high concentration of catecholamines as bound amines within the tumor substance. Metabolism within the tumor results in proportionately greater release of metabolites than free catecholamines. The appearance of symptoms is then delayed until sufficient quantities of metabolically active catecholamines have been released. Tumors producing such a clinical picture are usually over 50 grams in weight. Unusually high levels of inactive metabolites are then present and easily detected by standard chemical analyses.14J5The ratio of vanilmandelic acid metabolites to epinephrine and norepinephrine in the urine is consequently high under these conditions, indicating the probability of a large tumor more easily localized by intravenous pyelography and simultaneous nephrotomography. The occurrence of hypotensive crises has been attributed to sudden beta stimulation
presenting
as cardiomyopathy
691
showing islands of cells bordered by an abundant vast :ular
causing decreased peripheral vascular resistance and acute myocardial failure secondary to catecholamine-induced cardiomyopathy. Sustained hypotension is common during surgery for pheochromocytoma and is a recognized fatal complication of anesthesia for these tumors.ls It has been emphasized that careful attention to fluid replacement during surgery is necessary to prevent this complication.4 Due to the difficulties inherent in making a definitive diagnosis of pheochromocytoma, a number of provocative pharmacologic tests have been devised. The histamine stimulation test is frequently inconclusive and potentially dangerous.” The tyramine test, which stimulates direct release of catecholamines from nerve endings, is reportedly a safer and more specific procedure.‘* The glucagon test, which stimulates release of catecholamines from adrenal medullary tissue, has fewer side effects, is more specific than the histamine test, and is easier to perform than the tyramine test.1ss20 With sustained hypertension, phentolamine may be employed to block alpha stimulation producing a prompt and dramatic fall in blood pressure. However, this procedure may result in severe prolonged hypotension related to the postulated reduction in blood volume associated with long-term effects of catecholamines. This
692
Am. Heart J. May, 1972
Baker et al.
hypovolemia with hemoconcentration is thought to be due in part to fluid transudation from the intravascular compartment accompanying profuse sweating.21 In addition to pharmacologic tests, various chemical analytic tests of serum or urine are commonly employed. They are considered necessary for definitive diagnosis but have not proved to be 100 per cent accurate. Vanilmandelic acid determinations are inexpensive and accurate but measure substances commonly found in urine other than the metabolic products of catecholamines.22 A number of patients have been reported in whom urinary vanilmandelic acid determinations were normal but normetanephrine and metanephrine as well as free catecholamine levels were elevated, indicating the presence of a pheochromocytoma. Measurement of metanephrine and normetanephrine excretion has thus proved superior to measurement of vanilmandelic acid excretion in diagnostic accuracy.5*16 Specific treatment is available for medical preparation prior to surgical excision. Phenoxybenzamine and phentolamine have been employed as alpha blockers to reduce hypertensive effects of primarily norepinephrine-secreting tumors. Page, Raker, and Berberichs emphasize that these agents may be somewhat dangerous in epinephrine-secreting tumors “since by blocking alpha adrenergic receptors they may further sensitize the patient to beta adrenergic effects of epinephrine.” It seems reasonable to conclude, also, that loss of peripheral vasoconstriction might induce a hypotensive episode in the presence of the usual hypovolemia and muscular vascular dilatation of beta stimulation. Other agents including hydralizine, guanethidine, and alpha-methyldopa have been employed but with less success than phenoxybenzamine or phentolamine. Alpha-methylparatyrosine has been shown to be of benefit in medical management of patients with a predominantly dopamine-secreting tunior.23 Propranolol also has been suggested for the therapy of primarily epinephrine-secreting tumors but might be dangerous due to the drug’s propensity to aggravate congestive heart failure. At present, it is employed chiefly for the correction of arrhythmias
during surgery and not as a specific betaadrenergic blocker in epinephrine-secreting tumors. This remains an area which might bear fruitful exploration. Summary Characteristically, a patient with pheochromocytoma presents with paroxysmal or sustained hypertension and related symptoms. Occasionally the predominant manifestation of such a tumor may be congestive heart failure associated with primary myocardial disease, and hypertension may be absent. A patient with pheochromocytoma \\hose symptoms and clinical course related to a primary cardiomyopathy, and who remained normotensive until the final month of illness, has been presented. nlechanisms implicated in the development of primary myocardial disease by a pheochromocytoma have been reviewed. Diagnostic and therapeutic measures have been briefly outlined. The physician must be alert to the relatively rare occurrence of a pheochromocytoma in a patient who presents with a primary cardiomyopathy or unexplained congestive heart failure, since removal of the tumor allows for regression, if not cure, of the associated heart disease. REFERENCES 1. Kirkendall, W. M., Liechty, R. D., and Gulp, D. A.: Diagnosis and treatment of patients with pheochromocytoma, Arch. Intern. Med. (Chicago) 115:525, 1965. K. L. : Catecholamines and the adrenal 2. Melmon, medulla, in Williams, R. H., editor: Textbook of endocrinology, Philadelphia, 1968, W. B. Saunders Company, p. 379. 3. Henry, M. U.: A case of pheochromocytoma without hypertension, Brit. Med. J. 2:344, 19.54. 4. Engelman, K., and Sjoerdsma, A.: Clinical Staff Conference. Pheochromocytoma: Current concepts of diagnosis and treatment, Ann. Intern. Med. 65:1302, 1966. 5. Page, L. B., Raker, J. W., and Berberich, F. R.: Pheochromocytoma with predominant epinephrine secretion, Amer. J. Med. 47:648, 1969. G.: Present status 6. Von Euler, U. S., and Strom, of diagnosis and treatment of pheochromocvtoma, Circulation 15:5, 19.57. 7. Szak&, J. E., and Cannon, A.: L-norepinephrine mvocarditis. Amer. 1. Clin. Path. 30:425. 19.58. ’ 8. Handforth, C. P.: Isoproterenol-induced myo”
Volwne Number
83 5
Pheochromocytoma
cardial infarction in animals, Arch. Path. (Chicago) 173:161, 1962. 9. Kline, I. K.: Myocardial alterations associated with pheochromocytomas, Amer. J. Path. 38:539, 1961. 10. Van Vliet, P. D., Burchell, H. B., and Titus, J. L.: Focal myocarditis associated with nheochromocvtoma. New Enc. 1. Med. 274: i102, 1966. 11. Engelman, K., and Sjoerdsma, A.: Chronic medical therapy for pheochromocytoma, Ann. Intern. Med. (Chicago) 61:229. 1964. 12. Crout, J. R.,‘ and Sjoerdsma,’ A.: Catecholamines in the localization of pheochromocytoma, Circulation 22:516, 1960. 13. Koelle, G. B.: Neurohumoral transmission and the autonomic nervous system, in Goodman, L. S., and Gilman, A., editors: The pharmacological basis of therapeutics, New York, 1965. The Macmillan Comnanv. D. 399. 14. Grout, J. R.: Catecholamines’ in urine, in Seligson, D., editor: Standard methods of clinical chemistry, New York, 1961, Academic Press, Vol. III, p. 62. J. R., and Sjoerdsma, A.: Turnover and 15. Crout, metabolism of catecholamines in patients with -
”
16. 17.
18.
19.
20.
21.
22.
23.
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as cardiomyopathy
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pheochromocytoma, J. Clln. Invest. 48:94, 1964. Page, L. B., and Copeland, R. B.: Pheochromocytoma, Disease of the Month, January, 1968. Roth, G. M., and Kvale, W. F.: Tentative test for pheochromocytoma, Amer. J. Med. Sci. 210:653, 1945. Engelman, K., and Sjoerdsma, A.: A new test for pheochromocytoma. Pressor responsiveness to tyramine, J.A.M.A. 189:81, 1964. Lawrence, A. M.: Glucagon provocative test for pheochromocytoma, Ann. Intern. Med. (Chicago) 66:1091, 1967. Sheps, S. G., and Maher, F. T.: Histamine and glucagon tests in diagnosis of pheochromocvtoma. T.A.M.A. 205:895. 1968. Pelkondn: R., and Ditkanen, E.: Unusual electrocardiographic changes in pheochromocytoma, Acta Med. Stand. 173:41, 1963. Pisana, J. J., Crout, J. R., and Abraham, D.: Determination of 3-methoxy-4 hydroxy-mandelic acid in urine, Clin. Chem. 7:285, 1962. Jones, N. F., Walker, G., Ruthven, C. R. J., and Sandler, M.: Alpha-methyl-para-tyrosine in the management of pheochromocytoma, Lancet 2:1105, 1968.
without
hypertension
presenting
George Baker, M.D.* Nicholas H. Zeller, M.D. Stanley Weitzner, M.D. John K. Leach, M.D. Albuquerque, N. M.
P
heochromocytoma, a tumor of chromaffin tissue, is usually found in the adrenal glands, but on occasion has been located in a number of ectopic sites including sympathetic and parasympathetic ganglia and the organ of Zuckerkandl.‘s2 The tumor secretes norepinephrine and epinephrine with combined alpha- and beta-adrenergic stimulation, the former usually more prominent and accounting for the rapid onset of labile systemic hypertension.2 Occasionally a pheochromocytoma, usually malignant, secretes primarily dopamine, the action of which is similar to that of norepinephrine except for selective nonadrenergic vasodilating effects. Rarely, the dominant clinical picture of paroxysmal or sustained hypertension with associated diaphoresis, weight loss, pallor, and hyperglycemia does not become apparent until late in the clinical course.3 The patient may then present in a diffusely hypermetabolic state simulating hyperthyroidism, carcinoid syndrome, gram-negative septic shock, arteriovenous fistula, acute psychotic states, pulmonary embolism, malignant hyper-
tensive crises, or diabetic lactic acidosis.2*4 A few patients have been described in whom a very large pheochromocytoma, nearly always located in the right adrenal, secretes much larger amounts of epinephrine than norepinephrine accounting for the slow development of hypotensive episodes, catecholamine cardiomyopathy, tachycardia, arrhythmias, diaphoresis, and weakness.5 Since hypertension or hypertensive episodes typically do not appear until late in the clinical course of such patients, medical attention is initially directed to other possibilities. The presence of a pheochromocytoma may not be suspected until such time in the patient’s illness when therapy may no longer be effective. The following case illustrates such an atypical presentation in which the patient demonstrated progressive, unexplained congestive heart failure and remained normotensive until his final month of illness. It is the purpose of this paper to emphasize diagnostic pitfalls, to explore to a limited extent the pathophysiologic character of this patient’s illness, and to describe how
From
the Departments of Medicine and Pathology, University of New Mexico School of Medicine, Administration Hospital, Albuquerque, N. M. Received for publication Nov. 17, 1970. Reprint requests to: Dr. Nicholas H. Zeller, Cardiology Section, Veterans Administration Hospital, Dr., SE, Albuquerque. N. M. 87108. *Present address: Department of Cardiology, San Francisco Medical Center. Third and Parnessus, Calif.
688
American
Heart
Journal
May, 1972
and
the Veterans
2100
Ridgecrest
San
Francisco.
Vol. 83, No. 5, pp. 688493
Volume Number
83 5
Pheochromocytoma
it differs from the usual case of pheochromocytoma encountered. Case
report
A 39-year-old man was initially admitted to another hospital on March 15, 1968, because of intermittent dyspnea of two weeks’ duration, chest tightness with occasional sharp chest pain, weakness, easy fatigability, diaphoresis, pallor, and tremor. Physical examination was reported as normal. Cardiac fluoroscopy showed left ventricular and left atria1 enlargement, and the electrocardiogram (ECG) was reported as “consistent with disease of the left ventricle.” The serum cholesterol level was 240 mg. per cent, and the two-hour post prandial blood sugar was 153 mg. per cent. The patient then was referred to the Albuquerque Veterans Administration Hospital, where he was followed until his death. Admission work-up revealed a blood pressure of 130/80 mm. Hg in the arms, 140/80 mm. Hg in the legs, and mild left ventricular enlargement. A Grade I/VI systolic ejection murmur was heard along the left sternal border. ECG showed left ventricular hypertrophy and an intraventricular conduction defect. Slow progression of the disease process was noted, although he continued to be normotensive during the next several months. Marked wasting and a 31 pound weight loss ensued. During a subsequent prolonged hospitalization, elevated jugular venous pressure, progressive cardiac enlargement, a protodiastolic gallop, and hepatic enlargement indicated congestive heart failure; he was treated with digitalis with some improvement. Laboratory data revealed the following: fasting blood sugar, 124 mg. per cent; two-hour post prandial blood sugar, 158 mg. per cent; proteinbound iodine, 3.4 rg per cent. Cardiac catheterization performed on Sept. 13, 1968, disclosed no intracardiac shunts or obstructive lesions, but a left ventriculogram revealed evidence of diminished contractility. Following discharge from the hospital, his condition remained stable for about two months. He was readmitted Dec. 1, 1968, with a ten-day history of recurrent chest pain, profuse diaphoresis, marked dyspnea, and weakness. He was noted to be nauseated and to have pedal edema, marked heat intolerance, diarrhea, and pallor. Physical examination revealed a blood pressure of 180/112 mm. Hg, sinus tachycardia with a rate of 124 beats per minute, and a normal temperature. The patient was markedly pale, tremulous, and apprehensive. Large pools of sweat collected on the surface of the examining table. Funduscopic examination revealed arteriolar narrowing and A-V nicking. Jugular venous pressure was not elevated and the chest was clear. The heart was enlarged to percussion to the right and left with a forceful left ventricular thrust. Pulmonic closure was accentuated and a protodiastolic gallop was present. A Grade I/VI systolic ejection murmur was present at the lower left sternal border. The liver was palpable 5 cm. below the right costal margin; it was smooth and slightly tender. Marked proximal wasting of both the upper and lower extremities was present. Violaceous discoloration with papular hyperkeratosis was
presenting
as cardiomyopathy
689
present over the proximal interphalangeal joints and over the periungual areas of the deeply spooned and longitudinally ridged nails. Chest x-ray on admission showed further cardiomegaly, predominantly left ventricular and left atrial. Intravenous pyelogram showed displacement of the right kidney inferiorly, attributed to enlargement of the liver. The ECG showed a left ventricular hypertrophy pattern. Laboratory data were as follows: hematocrit, 40 per cent; hemoglobin, 13.8 Gm. per cent; blood urea nitrogen, 51 mg. per cent; two-hour post prandial glucose, 136 mg. per cent; serum bilirubin, 1.5 mg. per cent; sodium, 144 mEq. per liter; chlorides, 102 mEq. per liter; Ta uptake, 12.3 per cent; free thyroxine, 3.7 fig per cent; serum glutamic oxalacetic transaminase, 810 I.U.; urinalysis, 1.034 specific gravity, negative sugar, and negative albumin. Fivehydroxyindole acetic acid was 10.6 mg. per 24 hours (normal: up to 10 mg. per 24 hours). Twenty-four hour urine collections for vanilmandelic acid completed four and eighteen days after admission, not reported until shortly before death, were 39 mg. per 24 hours and 2.5 mg. per 24 hours, respectively (normal up to 8 mg. per 24 hours). The patient did well until Dec. 8, 1968, when he developed an episode of tachycardia, dyspnea, diaphoresis, and a fever of 104” F. A right upper lobe infiltrate visible on chest x-ray was felt to represent an acute pulmonary infarction. Treatment with Mercuhydrin, penicillin, and anticoagulants effected moderate improvement. The diagnosis of dermatomyositis was suggested by a neurological consultant. Electromyography was consistent with myopathy, but muscle and skin biopsies were normal. Electroencephalogram demonstrated poorly organized activity, suggestive of a toxic or metabolic disorder. ECG showed multiple ventricular premature contractions, a wandering supraventricilar pacemaker, left axis deviation, and widenine of the ORS complex. In spite of ireatment with prednisone, lidoCaine, isoproterenol, and supportive measures, the patient became markedly hypotensive and died. Necropsy was performed one hour after death. The heart weighed 630 grams. All cardiac chambers were dilated and both ventricles were hypertrophied. There was patchy endocardial fibrosis in the left ventricle. Microscopic examination disclosed moderate enlargement of myocardial fibers in both ventricles and slight patchy interstitial fibrosis, also a broad band of fibrosis beneath the endocardium in the left ventricle. Necrosis of muscle fibers was absent. There was slight to moderate intimal atherosclerosis of the coronary arteries. A small recent infarct was present in the upper lobe of the right lung. The right adrenal gland was replaced by a large, firm, slightly nodular neoplasm measuring 10 by 7 by 3 cm. in greatest dimensions and weighing 130 grams (Fig. 1). The cut surface of the tumor had a lobular pattern and was gray red with two central, irregular cystic areas. A portion of the tumor stained dark brown after fixation in Zenker’s (dichromate) solution. Histologically, it was composed of varyingsized islands of round and polygonal cells surrounded by a richly vascular, collagenous, and reticulin stroma. The cells had eosinophilic cytoplasm. The
690
Baker et al.
Fig. 1. Hemisection of right adrenal tumor. nuclei were vesicular or hyperchromatic and varied somewhat in size (Fig. 2). There were no mitoses. A Wilder reticulin stain outlined only the islands of cells and adjacent capillaries but did not envelop individual pheochromocytes. The tumor was centrally hyalinized and cystic in places. A small amount of normal adrenal tissue was present at the periphery of the tumor. The diagnosis was pheochromocytoma. The left adrenal gland was normal grossly and microscopically. The remainder of the necropsy failed to reveal any other lesion which could explain the patient’s clinical picture.
Discussion Although nonspecific and consistent with other disorders, paroxysms of palpitation, anxiety, tremulousness, diaphoresis, weakness, and weight loss, associated with progressive myocardial disease, are compatible with pheochromocytoma.6 Various authors have discussed myocardial lesions secondary to chronically elevated levels of catecholamines when used therapeutically, or when produced by experimentally, pheochromocytoma. 7-gA review by Szakacs and Cannon’ of the autopsy material at the Armed Forces Institute of Pathology yielded 17 cases of pheochromocytoma which demonstrated acute myocarditis with no evidence of significant coronary artery disease. Similar findings have been noted in patients without pheochromocytoma treated with catecholamine preparations for a significant length of time-usually eight hours or more. Szakacs and Cannon’ induced similar changes in dogs with I-norepinephrine. These changes were somewhat more severe than in man. Myocardial hemorrhages were seen accompanied by endocardial proliferation, thickening, and
Am. Heart I. May, 1972
edema. Degenerating myofibrils and cellular infiltration were also present. During their studies, cardiac arrhythmias were frequently observed. Handforth induced similar lesions in the hearts of hamsters by means of subcutaneous injections of isoproterenol. Dosages of drugs used by the two groups of investigators usually exceeded concentrations encountered in clinical situations. Van Vliet, Burchell, and Titus10 concluded that the myocardial fibrosis observed after longstanding exposure to catecholamines probably represented the healed stage of active myocarditis. Engelman and Sjoerdsmall correlated regression of clinically recognized cardiomyopathy induced by catecholamines with resection of the pheochromocytoma. Therefore, the myocardial lesions observed in our patient were probably due to the direct toxic effects of catecholamines on the heart. Catecholamine-secreting tumors usually arise from the adrenal areas, although they have been described in every area of chromaffin tissue in the body.1*2t4The rare, predominantly epinephrine-secreting tumor, however, rarely occurs in an extraadrenal location.5J3 Page, Raker, and Berberich,6 in a recent article describing a patient similar to ours, emphasized that determination of the free catecholamine or normetanephrine-metanephrine excretion rather than total catecholamines or vanilmandelic acid “may provide a clue as to the presence and location of a pheochromocytoma.” The division of catecholamine effects into alpha and beta types is well known.2J3 Norepinephrine acts on beta-adrenergic receptors in the heart to cause increased contractility and on alpha receptors in arteries and veins to cause vasoconstriction. The resultant effect, therefore, is elevation of blood pressure, the usual manifestation of predominantly norepinephrine-secreting tumors. Epinephrine, on the other hand, while having beta-stimulatory effects on the heart, exhibits both alpha and beta effects on peripheral vessels. With usual clinical doses, the beta effect predominates and total peripheral resistance decreases. Patients with predominantly epinephrinesecreting tumors present with tachycardia, sweating, pallor, abdominal pain, nausea,
Volume Number
83 5
Fie. 2. Reoresentative stroma. (Hematoxylin
Pheochromocytoma
section of oheochromocvtoma and eosin.*X40.)
vomiting, hyperglycemia, and hypotension. Although urinary catecholamine patterns were not obtained in our patient, the symptomatology and clinical course seem to us consistent with a predominantly epinephrine-secreting tumor. The usual case of pheochromocytoma becomes clinically manifest when the tumor is still small with rapid synthesis and excretion of active catecholamines directly into the circulation.2 Some tumors, however, maintain a high concentration of catecholamines as bound amines within the tumor substance. Metabolism within the tumor results in proportionately greater release of metabolites than free catecholamines. The appearance of symptoms is then delayed until sufficient quantities of metabolically active catecholamines have been released. Tumors producing such a clinical picture are usually over 50 grams in weight. Unusually high levels of inactive metabolites are then present and easily detected by standard chemical analyses.14J5The ratio of vanilmandelic acid metabolites to epinephrine and norepinephrine in the urine is consequently high under these conditions, indicating the probability of a large tumor more easily localized by intravenous pyelography and simultaneous nephrotomography. The occurrence of hypotensive crises has been attributed to sudden beta stimulation
presenting
as cardiomyopathy
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showing islands of cells bordered by an abundant vast :ular
causing decreased peripheral vascular resistance and acute myocardial failure secondary to catecholamine-induced cardiomyopathy. Sustained hypotension is common during surgery for pheochromocytoma and is a recognized fatal complication of anesthesia for these tumors.ls It has been emphasized that careful attention to fluid replacement during surgery is necessary to prevent this complication.4 Due to the difficulties inherent in making a definitive diagnosis of pheochromocytoma, a number of provocative pharmacologic tests have been devised. The histamine stimulation test is frequently inconclusive and potentially dangerous.” The tyramine test, which stimulates direct release of catecholamines from nerve endings, is reportedly a safer and more specific procedure.‘* The glucagon test, which stimulates release of catecholamines from adrenal medullary tissue, has fewer side effects, is more specific than the histamine test, and is easier to perform than the tyramine test.1ss20 With sustained hypertension, phentolamine may be employed to block alpha stimulation producing a prompt and dramatic fall in blood pressure. However, this procedure may result in severe prolonged hypotension related to the postulated reduction in blood volume associated with long-term effects of catecholamines. This
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hypovolemia with hemoconcentration is thought to be due in part to fluid transudation from the intravascular compartment accompanying profuse sweating.21 In addition to pharmacologic tests, various chemical analytic tests of serum or urine are commonly employed. They are considered necessary for definitive diagnosis but have not proved to be 100 per cent accurate. Vanilmandelic acid determinations are inexpensive and accurate but measure substances commonly found in urine other than the metabolic products of catecholamines.22 A number of patients have been reported in whom urinary vanilmandelic acid determinations were normal but normetanephrine and metanephrine as well as free catecholamine levels were elevated, indicating the presence of a pheochromocytoma. Measurement of metanephrine and normetanephrine excretion has thus proved superior to measurement of vanilmandelic acid excretion in diagnostic accuracy.5*16 Specific treatment is available for medical preparation prior to surgical excision. Phenoxybenzamine and phentolamine have been employed as alpha blockers to reduce hypertensive effects of primarily norepinephrine-secreting tumors. Page, Raker, and Berberichs emphasize that these agents may be somewhat dangerous in epinephrine-secreting tumors “since by blocking alpha adrenergic receptors they may further sensitize the patient to beta adrenergic effects of epinephrine.” It seems reasonable to conclude, also, that loss of peripheral vasoconstriction might induce a hypotensive episode in the presence of the usual hypovolemia and muscular vascular dilatation of beta stimulation. Other agents including hydralizine, guanethidine, and alpha-methyldopa have been employed but with less success than phenoxybenzamine or phentolamine. Alpha-methylparatyrosine has been shown to be of benefit in medical management of patients with a predominantly dopamine-secreting tunior.23 Propranolol also has been suggested for the therapy of primarily epinephrine-secreting tumors but might be dangerous due to the drug’s propensity to aggravate congestive heart failure. At present, it is employed chiefly for the correction of arrhythmias
during surgery and not as a specific betaadrenergic blocker in epinephrine-secreting tumors. This remains an area which might bear fruitful exploration. Summary Characteristically, a patient with pheochromocytoma presents with paroxysmal or sustained hypertension and related symptoms. Occasionally the predominant manifestation of such a tumor may be congestive heart failure associated with primary myocardial disease, and hypertension may be absent. A patient with pheochromocytoma \\hose symptoms and clinical course related to a primary cardiomyopathy, and who remained normotensive until the final month of illness, has been presented. nlechanisms implicated in the development of primary myocardial disease by a pheochromocytoma have been reviewed. Diagnostic and therapeutic measures have been briefly outlined. The physician must be alert to the relatively rare occurrence of a pheochromocytoma in a patient who presents with a primary cardiomyopathy or unexplained congestive heart failure, since removal of the tumor allows for regression, if not cure, of the associated heart disease. REFERENCES 1. Kirkendall, W. M., Liechty, R. D., and Gulp, D. A.: Diagnosis and treatment of patients with pheochromocytoma, Arch. Intern. Med. (Chicago) 115:525, 1965. K. L. : Catecholamines and the adrenal 2. Melmon, medulla, in Williams, R. H., editor: Textbook of endocrinology, Philadelphia, 1968, W. B. Saunders Company, p. 379. 3. Henry, M. U.: A case of pheochromocytoma without hypertension, Brit. Med. J. 2:344, 19.54. 4. Engelman, K., and Sjoerdsma, A.: Clinical Staff Conference. Pheochromocytoma: Current concepts of diagnosis and treatment, Ann. Intern. Med. 65:1302, 1966. 5. Page, L. B., Raker, J. W., and Berberich, F. R.: Pheochromocytoma with predominant epinephrine secretion, Amer. J. Med. 47:648, 1969. G.: Present status 6. Von Euler, U. S., and Strom, of diagnosis and treatment of pheochromocvtoma, Circulation 15:5, 19.57. 7. Szak&, J. E., and Cannon, A.: L-norepinephrine mvocarditis. Amer. 1. Clin. Path. 30:425. 19.58. ’ 8. Handforth, C. P.: Isoproterenol-induced myo”
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cardial infarction in animals, Arch. Path. (Chicago) 173:161, 1962. 9. Kline, I. K.: Myocardial alterations associated with pheochromocytomas, Amer. J. Path. 38:539, 1961. 10. Van Vliet, P. D., Burchell, H. B., and Titus, J. L.: Focal myocarditis associated with nheochromocvtoma. New Enc. 1. Med. 274: i102, 1966. 11. Engelman, K., and Sjoerdsma, A.: Chronic medical therapy for pheochromocytoma, Ann. Intern. Med. (Chicago) 61:229. 1964. 12. Crout, J. R.,‘ and Sjoerdsma,’ A.: Catecholamines in the localization of pheochromocytoma, Circulation 22:516, 1960. 13. Koelle, G. B.: Neurohumoral transmission and the autonomic nervous system, in Goodman, L. S., and Gilman, A., editors: The pharmacological basis of therapeutics, New York, 1965. The Macmillan Comnanv. D. 399. 14. Grout, J. R.: Catecholamines’ in urine, in Seligson, D., editor: Standard methods of clinical chemistry, New York, 1961, Academic Press, Vol. III, p. 62. J. R., and Sjoerdsma, A.: Turnover and 15. Crout, metabolism of catecholamines in patients with -
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pheochromocytoma, J. Clln. Invest. 48:94, 1964. Page, L. B., and Copeland, R. B.: Pheochromocytoma, Disease of the Month, January, 1968. Roth, G. M., and Kvale, W. F.: Tentative test for pheochromocytoma, Amer. J. Med. Sci. 210:653, 1945. Engelman, K., and Sjoerdsma, A.: A new test for pheochromocytoma. Pressor responsiveness to tyramine, J.A.M.A. 189:81, 1964. Lawrence, A. M.: Glucagon provocative test for pheochromocytoma, Ann. Intern. Med. (Chicago) 66:1091, 1967. Sheps, S. G., and Maher, F. T.: Histamine and glucagon tests in diagnosis of pheochromocvtoma. T.A.M.A. 205:895. 1968. Pelkondn: R., and Ditkanen, E.: Unusual electrocardiographic changes in pheochromocytoma, Acta Med. Stand. 173:41, 1963. Pisana, J. J., Crout, J. R., and Abraham, D.: Determination of 3-methoxy-4 hydroxy-mandelic acid in urine, Clin. Chem. 7:285, 1962. Jones, N. F., Walker, G., Ruthven, C. R. J., and Sandler, M.: Alpha-methyl-para-tyrosine in the management of pheochromocytoma, Lancet 2:1105, 1968.