ISCHEMIC ENTEROCOLITIS IN PHEOCHROMOCYTOMA

Transcription

1 GASTROENTEROLOGY 1971 by 'The Williams & Wilkins Co. Vol. 60, No.4 Printed in U.S.A. ISCHEMIC ENTEROCOLITIS IN PHEOCHROMOCYTOMA L. A. ROSATI, M.D., AND N. A. AUGUR, JR., M.D. Department of Pathology and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan The gastrointestinal complications of pheochromocytoma are reviewed in a patient who presented with hypertension, chronic constipation, and distended bowel. It is postulated that excessive levels of blood catecholamines liberated from the pheochromocytoma produced persistent vasoconstriction and resulted in widespread hemorrhagic necrosis of the gut. Pheochromocytoma is recognized as simulating a wide variety of diseases. Gastrointestinal manifestations have commonly included nausea, vomiting, abdominal pain, and, less frequently, diarrhea and gastrointestinal bleeding. There has been only scant reference to the association of ischemic enterocolitis and pheochromocytoma. In this communication we report the particularly uncommon symptoms of obstipation and colonic distention in a woman with pheochromocytoma, and we examine the possible role of catecholamines in the pathogenesis of fatal hemorrhagic enteropathy. Case Report Patient summary. A 50-year-old woman was admitted to the University of Michigan Medical Center because of severe unrelenting constipation, colonic distention, hypertension, and skin rash. The patient had been normotensive until 2 years before admission. Eight months before admission she complained of headache, heat intolerance, and perspiration with hot flashes. Received September 15, Accepted November 23, Address requests for reprints to: Dr. L. A. Rosati, Department of Pathology, University of Michigan, 1335 E. Catherine Street, Ann Arbor, Michigan Dr. Augur's present address is: 16 Chadwick, Portland, Maine The authors gratefully wish to acknowledge the very helpful criticism given this paper by Drs. John G. Batsakis and Henry D. Appelman. Her blood pressure then was 210/130 mm Hg and her pulse was 112 per min. She was treated with a combination drug containing reserpine, hydralazine, and hydrochlorothiazide (Serapas). Her blood pressure promptly improved, but mild postural symptoms were noted. Five months before admission she began to complain of constipation. This gradually progressed to obstipation, and was associated with noncrampy postprandial pain, abdominal distention, mild borborygmus, and a weight loss of 40 lb. She was hospitalized twice for the unrelenting constipation and was found to have a dilated, fecal filled colon and a dilated atonic small bowel. She was subsequently transferred to the University Hospital for further evaluation. The woman was thin and appeared chronically ill. The blood pressure was 220/130 mm Hg supine and 80/60 standing. The pulse was 96 per min and regular. Funduscopic examination revealed grade II arteriovenous nicking and isolated arteriolar spasm. The heart was enlarged and a grade II systolic ejection murmur was audible along the left sternal border. The abdomen was distended and slow peristaltic waves were visible. A mass was palpable in the right lower quadrant. There was rectolinear erythema of the skin of the arms and legs, and bluish red patches on the fingers, knees, and feet. These areas were cool and blanched with pressure. The urine contained no protein or glucose. The sediment contained 0 to 2 red cells and 4 to 6 white cells per high power field. Culture yielded 100,000 colonies of Streptococcus veridans and Escherichia coli per ml. The hemogram was normal. Fasting blood glucose was 114 mg per 100 ml and creatinine was 1.3 mg per 100 ml. Urinary catecholamines were 7750 mg per 24 hr (normal, up to 103 mg per 24 hr), 581

2 582 CASE REPORTS Vol. 60, No.4 and vanillylmandelic acid was 136 mg per 24 hr (normal, 0.7 to 6.8 mg per 24 hr). The electrocardiogram demonstrated left axis deviation, left ventricular hypertrophy, and poor progression of the R-waves across the precordial leads. Chest X-ray revealed a small nodule in the right lower lung field. Abdominal X-ray films demonstrated a markedly distended colon with a large amount of fecal material and retained barium from a previous upper gastrointestinal series. Enemas were successful in evacuating the bowel, and the mass in the right lower quadrant disappeared. Nevertheless, the abdomen remained distended and the patient did not have a spontaneous bowel movement. The skin lesions were considered typical of livido reticularis. On the 7th hospital day the patient suddenly became apneic, vomited coffee-ground material, and had a cardiac arrest. Resuscitation was unsuccessful. Necropsy Findings. Postmortem examination revealed a 525-g neoplasm, 13 cm in diameter, in the right adrenal gland and massive dilation of the bowel from duodenum to rectum. Scattered segments of small intestine had an intense violaceous hue. Small amounts of purulent exudate covered the serosa of isolated loops of small bowel but no perforation was found. The mucosa of much of the small and proximal large intestine was hemorrhagic and covered by a shaggy gray-green membrap.e. A small amount of dark blood was present in the lumen. Thin linear ulcers were present in the lower esophagus. The stomach was moderately distended and contained dark blood; no mucosal ulcers or hemorrhages were found. The microscopic findings supported the gross impression of ischemic enterocolitis (figs. 1, 2, and 3). There was hemorrhage and necrosis of the small and large intestinal mucosa, and in focal areas these changes involved all layers of the wall. Multiple fibrin thrombi were present in the capillaries and venules of the lamina propria and submucosa. In addition, several larger mixed thrombi were found in the small veins of the muscularis propria, serosa, and adjacent mesentery. Vessels not occupied by thrombi were engorged with red blood cells. The small caliber distal radicles of the superior mesenteric artery and the vasa recta were thickened as a result of edema and degeneration, with focal necrosis of smooth muscle in the media (fig. 4). These changes diminished the caliber of the lumen of these vessels but did not cause occlusion. FIG. 1. Whole thickness of small intestine and adjacent mesentery showing numerous fibrin thrombi (phosphotungstic acid-hematoxylin, X 3).

3 April 1971 CASE REPORTS 583 The right adrenal medulla contained an ovoid boggy tumor which compressed the cortex. The central portion contained approximately 50 ml of bloody fluid in a yellow-tan loculated matrix. This was surrounded by a rim of gray-red tissue which showed a positive chromaffin reaction. Microscopically, the central area was characterized by necrosis and recent hemorrhage with extensive fibrin deposition. The typical histopathological features of pheochromocytoma were evident in tumor tissue taken from the periphery (fig. 5). Additional studies were performed on frozen tumor tissue and tumor fluid: Fluid from tumor Total catecholamines Tumor tissue Norepinephrine Epinephrine 4000 Ilg per liter 14 Ilg per g < Ilg per g Other significant necropsy findings included cardiomegaly (550 g) with concentric hypertrophy of the left ventricular myocardium. Microscopic features of catecholamine-induced cardiomyopathy were not present. Old, partly calcified granulomas were present in lung, liver, and spleen. Discussion This patient died suddenly after a long history of nonparoxysmal hypertension and chronic constipation which progressed to obstipation and severe colonic distention. We consider these symptoms and the postmortem findings of ischemic enterocolitis a result of catecholamines produced by the pheochromocytoma. The gastrointestinal manifestations of pheochromocytoma are diverse. Nausea, vomiting, and abdominal pain are well recognized symptoms of this disease; others, such as obstipation and megacolon, are infrequent and likely to be clinically misleading, as they were in this case. Pheochromocytoma is not listed as a cause of obstipation and megacolon in major textbooks of gastroenterology. A review of the literature, however, reveals one study in which a 5% incidence of constipation was noted in patients with pheochromocytoma and nonparoxysmal hypertension. 1 Melmom 2 has stated that severe constipation, albeit an unusual manifestation of pheochromocytoma, has led to the erroneous FIG. 2. Small intestine: necrotic mucosal villi and numerous fibrin thrombi in mucosal capillaries and submucosal venules (phosphotungstic acid-hematoxylin, X 105). FIG. 3. Colon: extensive mucosal necrosis with fibrin thrombi and subadjacent zone of acute purulent inflammation (hematoxylin and eosin, X 128).

4 584 CASE REPORTS Vol. 60, N o. 4 FIG. 4. Cross section of a branch of distal mesenteric artery showing fragmentation, edema, and focal necrosis (hematoxylin and eosin, X 165). FIG. 5. Pheochromocytoma composed of polygonal and spindled cells in clusters with sinusoidal spaces (hematoxylin and eosin, X 165). diagnosis of Hirschprung's disease. Only scattered case reports, however, have appeared in which pheochromocytoma has been associated with megacolon. 3-5 The catecholamines influence gastro- intestinal physiology through relaxation of intestinal smooth muscle, decrease in frequency and intensity of peristalsis, and vasoconstriction of splanchnic arterioles. 6 When these drugs are administered in nonphysiological amounts to experimental animals or to patients in shock, massive colonic dilation and various gastrointestinal disorders may be produced such as abdominal pain, ileus, massive colonic dilation, bleeding, intestinal infarction, and perforation. The associated pathological lesions have included hemorrhagic necrosis, intramural vascular thrombosis, and structural alteration of splanchnic arterioles. 7-9 Identical lesions have been described in patients with pheochromocytoma. Roach 8 and Brown et al. 4, 7 were among the first to correlate the elevated catecholamines with serious gastrointestinal complications of pheochromocytoma. One of the patients, described by Brown et al. 4, 7 was a woman with recurrent pheochromocytoma and progressive abdominal distention; another was a child with multiple pheochromocytomas, intestinal bleeding, and perforation. In both instances, necropsy revealed typical changes of ischemic enterocolitis; in addition, an associated proliferative arteritis of splanchnic arterioles was found in the latter patient.

5 April 1971 CASE REPORTS 585 Ischemic enterocolitis lo has been described under a variety of headings including hemorrhagic enteropathy, terminal hemorrhagic necrotizing enteropathy,l1 and hemorrhagic necrosis of the gastrointestinal tract. This disorder, which may involve all or only a segment of the gut, is characterized grossly by intense mucosal congestion and varying degrees of mucosal necrosis with ulcers. Microscopically, the affected segments reveal mucosal hemorrhage and necrosis. Fibrin thrombi are common in mucosal capillaries, and, in severe cases, they may extend into venules and small veins in all layers of the bowel wall. Several theories have been proposed to explain the pathogenesis of ischemic enterocolitis. Many factors may be involved but ischemia is considered to be a basic prerequisite. 10, 11 In patients with pheochromocytoma, it seems likely that ischemic enterocolitis is a result of splanchnic circulatory derangement induced by high levels of catecholamines. These alterations are characterized by vasoconstriction and, occasionally, veno-occlusive disease. Characteristically, structural alteration of the arteries and arterioles are thought not to occur in ischemic enterocolitis. Brown et ai.,4 however, described a form of proliferative arteritis in a case associated with pheochromocytoma, and we observed edema and focal smooth muscle necrosis in the media of the distal splanchnic arteries in this case. These may represent catecholamine-induced lesions. However, as neither arteriopathy nor vascular occlusion need be present in cases of ischemic enterocolitis associated with pheochromocytoma, we assume that catecholamineinduced vascoconstriction is the major factor in the pathogenesis of this condition. The widespread venous and capillary thrombi and the splanchnic arteriopathy in this case, however, provide definite anatomical evidence of a structurally altered circulation. These lesions, superimposed on a prolonged and intense vasoconstriction which likely preceded them, provide the mechanism for the severe ischemia and subsequent enterocolitis observed in this patient. The chronic constipation, distended bowel, and sudden death of our patient undoubtedly reflect not only chronic elevation of catecholamines, but also the acute release of a large amount of these potent amines as judged by their levels in the bloody fluid contained in the neoplasm. We feel that hemorrhage into the neoplasm, releasing massive amounts of catecholamines, initiated the terminal events. The findings at necropsy of a hemorrhagic pheochromocytoma and ischemic enterocolitis suggest that these events evolved rapidly over a short period of time. REFERENCES 1. Gifford RW, Kvale WF, Maher FT, et al: Clinical features, diagnoses and treatment of pheochromocytoma: a review of 76 cases. Mayo Clin Proc 39: , Melmom KL: Textbook of Endocrinology. Edited by RH Williams. Philadelphia, WB Saunders Co, 1968, p Bernstein A, Wright AC, Spencer D: Pheochromocytoma as a cause of gastrointestinal distention. Postgrad Med 43:80-183, Brown RB, Borowsky M: Further observation on intestinal lesions associated with pheochromocytoma. Ann Surg 151: , Surgical grand rounds. Hypertension and ileus. Dlinois Med J 34: , Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics. New York, Macmillan, 1965, p Brown RB, Rice BH, Szakas JE: Intestinal bleeding and perforation complicating treatment with vasoconstrictors. Ann Surg 150: , Roach PJ: Gastrointestinal bleeding in pheochromocytoma and following the administration of norepinephrine (arterenol). Arch Intern Med (Chicago) 104: , Blachett RB, Pickering GW, Weber GM: The effects of prolonged infusions of noradrenaline and adrenaline in the arterial pressure of the rabbit. Clin Sci 9: , McGovern VJ, Goulston SJM: Ischemic enterocolitis. Gut 6: , Bhagwatt HG, Hawk WA: Terminal hemorrhagic necrotizing enteropathy (THNE). Arner J Gastroent 45: , 1966