GASTROEh’TEROLOGY

1990;98:1689-1692

CASE REPORTS

Jejunal Vasculitis With Protein-Losing Enteropathy After Bone Marrow Transplantation FARRUKH RICHARD

M. JAFRI, HARVEY MENDELOW, K. SHADDUCK, and GAIL SEKAS

Departments of Medicine and Pathology and Pittsburgh Cancer Institute Adult Bone Marrow Transplant Program, Montefiore Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

for which he was treated with vancomycin and ceftazidime for 14 days. Trilinear engraftment occurred by day 15 posttransplant. He was discharged 21 days posttransplantation and was scheduled for biweekly outpatient appointments. His discharge medications included cyclosporine, 500 mg b.i.d., trimethoprim/sulfamethoxazole, 160 mg/800 mg b.i.d., prednisone, 50 mg b.i.d., and magnesium oxide, 400 mg b.i.d. Discharge laboratory data included total protein and albumin levels of 5.1 g/d1 (normal, 6.0-8.5 g/dl] and 3.3 g/d1 [normal, 3.0-5.5 g/dl), respectively. Over the next 10 days he experienced crampy periumbilical pain that was associated with nausea and a slight decrease in appetite. The pain was not related to meals and was occasionally relieved by antacids. The patient reported 1-2 formed stools per day. On readmission 31 days posttransplant, results of physical examination were unremarkable. The abdomen was nondistended, bowel sounds were present, and there was no tenderness or hepatosplenomegaly. Rectal examination rerotein loss from the gastrointestinal tract has been vealed formed, brown, heme-negative stool. The patient’s reported in a heterogeneous group of diseases total protein and albumin levels at the time were 3.8 g/d1 with or without gross anatomic lesions. Patients who and 2.6 g/dl, respectively. Endoscopy was performed and have undergone bone marrow transplantation (BMT) was notable for scattered duodenal erosions. Biopsies of the may develop protein-losing enteropathy (PLE) due to duodenum showed nonspecific inflammatory changes with epithelial denudement because of chemoradiation no evidence of viral infection or graft-vs.-host disease. conditioning therapy and/or graft-vs.-host disease (1). Cultures of duodenal biopsies were negative for herpes simplex virus and cytomegalovirus. We report a BMT recipient with hypoproteinemia The abdominal pain began to decrease after several days associated with segmental vasculitis of the jejunum in of bowel rest, and the patient resumed oral feedings. By 40 whom serum protein and albumin returned to normal days posttransplant he had developed generalized edema after resection of the involved segment. and had a weight gain of 15 lb over a 5-day period. Laboratory data included normal blood counts, electrolytes, and liver function tests; however, the serum protein and Case Report albumin levels were now 3.3 g/d1 and 2.2 g/dl, respectively. Chronic myelogenous leukemia was diagnosed in a Urinary protein excretion was 100 mg/24 h. On a loo-g-fat 37-yr-old white man. He was treated with hydroxyurea and diet, the stool weight was 450 g/24 h with a fecal fat content 9 mo later was admitted to Montefiore Hospital. Following conditioning therapy with busulfan and cyclophosphamide, he received an allogeneic human leukocyte antigen (HLA)Abbreviations used in this paper: BMT, bone marrow transplanmatched bone marrow transplant from his brother. His tation; PLE, protein-losing enteropathy. subsequent hospital course was unremarkable except for @ 1990 by the American Gastroenterological Association 0016-5085/90/$3.00 neutropenic fevers which began 5 days post-transplant and

A 37-yr-old white man experienced crampy ahdominal pain beginning 21 days after successful bone marrow transplantation for chronic myelogenous leukemia. Generalized edema and hypoproteinemia developed. Symptoms persisted until 61 days posttransplant, when the patient developed an acute abdomen. At laparotomy, an edematous segment of jejunum was resected. Pathological examination showed submucosal vasculitis and necrotizing enteritis. Serum protein and albumin levels returned to normal within a few weeks after surgery. Vasculitis of the gastrointestinal tract should be considered in the differential diagnosis of protein-losing enteropathy after bone marrow transplantation.

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of 9.8 g. An upper gastrointestinal (GI) examination with a small bowel follow-through series showed an irregular mucosal pattern, limited to the duodenum, which was consistent with duodenitis. The patient was treated with bed rest, sodium restriction, lower extremity elevation, furosemide, and supplemental hyperalimentation. Over a loday period, he lost 20 lb and was discharged with serum protein and albumin levels of 3.8 g/d1 and 2.6 g/dl, respectively. Sixty days posttransplant the patient was readmitted because of continuing crampy periumbilical pain, recurrence of lower extremity swelling, and a lo-lb weight gain.

Once again there was no nausea, vomiting, or diarrhea. Examination showed moderate edema of the lower extremities with some edema of the abdominal wall. Laboratory studies were notable for a protein level of 4.1 g/d1 and an albumin level of 2.7 g/dl. Results of a repeat upper endoscopy were normal. Biopsies of the stomach and duodenum did not show any evidence of viral infection or graft-vs.-host disease. The patient again started a regimen of bed rest, sodium restriction, and diuretic therapy. The day after admission, he developed marked worsening of the pain which became intense, steady, and nonradiating. There was no associated fever, chills, or diarrhea. Examination showed exquisite direct and rebound tenderness in both lower quadrants and in the epigastrium. There was no rigidity or distension. Plain films of the abdomen did not show any free air or bowel distension. The white blood cell count was 14,900/mm3 with 40% neutrophils and 40% bands. Exploratory laparotomy showed an edematous 2%cm segment of mid jejunum which was resected with an end-to-end anastomosis. Gross examination of the specimen showed striking serosal injection and edema of the jejunal wall but no significant serosal exudate. The attached segment of mesentery was similarly edematous and injected. The mucosa was extensively denuded and ulcerated with patches of yellow-white adherent pseudomembranous exudate overlying the ulcerated areas [Figure 1A). On microscopic examination, the mucosa had zones of deeply penetrating ulceration filled with acute inflammatory exudate and fibrin. The surrounding mucosa displayed marked glandular epithelial atypia strongly suggestive of prior episodes of focal ulceration followed by mucosal regeneration. The submucosa was markedly edematous. Several medium-sized and small arteries in the submucosa displayed prominent focal fibrinoid necrosis of their walls with a surrounding collar of mixed inflammatory exudate. The focal and segmental nature of this necrotizing vasculitis was quite prominently displayed by smaller branches of larger, otherwise intact arteries (Figure 1B) and by involvement of only one of a pair of identical sized, adjacent vessels (Figure lC]. No emboli were found. Immunoperoxidase studies of microscopic sections for cytomegalovirus and herpes simplex virus were negative. Silver stains for fungi were also negative. The patient’s postoperative course was uneventful, and he was discharged 2 wk later. At discharge, serum protein and albumin levels were 4.6 g/d1 and 3.0 g/dl, respectively, with increases to 6.0 g/d1 and 4.2 g/d1 within several weeks. Twenty-three months after successful bone marrow trans-

plantation, the patient has had no recurrences of abdominal pain and has returned to full-time employment.

Discussion Protein-losing enteropathy has been reported in a variety of diseases associated either with increased mucosal permeability to protein caused by surface cell damage or increased cell loss, or with mucosal erosion or ulceration, or lymphatic obstruction (2) or leakage at the zona occludens (3). Proteinlosing enteropathy has been reported following both solid-organ transplantation and BMT (4,5) and was suspected as a cause of hypoproteinemia in our patient because of maintenance of normal hepatic synthetic function, absence of proteinuria, and lack of evidence of malnutrition. The pathological demonstration of necrotizing vasculitis involving a localized segment of jejunum, as well as normalization of the serum albumin after resection of this segment, further supports the supposition that this patient’s protein loss occurred in the intestine. Initially, several etiologies of this patient’s PLE were considered. Protein-losing enteropathy is a frequent finding during the conditioning period in patients undergoing BMT (1). Cytoreductive chemoradiation therapy has been shown to cause extensive denudement of gastrointestinal tract epithelium (5). Of the drugs frequently used, cyclophosphamide usually has minimal intestinal toxicity [S), but severe enterocolitis has been reported after its use (7). Cyclophosphamide and vincristine have been shown to cause increased intestinal protein loss in rats. In addition to damaging the cells, these agents change the physicochemical characteristics of the glycocalix, contributing to a loss of the barrier function of the mucosa (8). Although our patient did undergo chemotherapy with cyclophosphamide, his symptoms began several weeks later. His hypoproteinemia was probably not secondary to chemotherapy because enteritis lasting beyond 20 days after cessation of therapy is unlikely to result from conditioning toxicity (5). The development of graft-vs.-host disease of the intestine following BMT is a well-recognized complication of transplantation. Protein-losing enteropathy following graft-vs.-host disease has been reported previously both in animal (9) and human subjects (1). The primary event may be a direct T-lymphocytemediated crypt cell lysis. Epithelial stem cells as well as differentiated cells may also be damaged (5). These events may lead to epithelial necrosis and consequent PLE. In our patient there was no histological evidence of graft-vs.-host disease of the intestine in specimens obtained at either of the endoscopies or in the surgical specimen. Prednisone has been suggested as a cause of PLE. A

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Figure 1. A. Acute nectrotizing enteritis in the jejunum. B. Segmental arteritis in the branch of larger artery of the submucosa (original magnification x200). C. Focal arteritis in one of two small submucosal arteries (original magnification x 200).

case of reversible PLE, which was temporally related to prednisone administration, has been reported following renal transplantation (4). Prednisone did not appear responsible for the PLE in our patient, who remained on the same dose after resection of the affected segment of jejunum and had continued improvement of the serum albumin level. A further consideration for PLE in our patient was infection. Bacterial and fungal infections are common during the early transplant phase (days l-20),but because the recovery of lymphocyte mediated immunity is delayed for several months, most viral infections occur during this later period (10). Viruses implicated in enteritis have included cytomegalovirus, herpes simplex virus, coxsackievirus, rotavirus, and

adenovirus. Cytomegalovirus has been reported to cause PLE (lo], with severe enteritis resulting in hypoproteinemia (ll,12). Neither viral cultures nor histology of the biopsy and surgical specimens showed any evidence of viral infection in our patient. Thus, previously reported causes of PLE following BMT were absent and a previously unreported cause was implicated in this patient. Protein-losing enteropathy has been reported in association with jejunal vasculitis in a patient with systemic lupus erythematosus (13). The jejunum was described as having a severe, diffuse vasculitis involving the venules of the submucosa and muscularis externa, but the arteries were not affected. In contrast, our patient had segmental vasculitis of the jejunum with involvement of

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medium-sized and small arteries. This pattern of focal and segmental necrotizing arteritis bears a striking resemblance to that seen in the isolated variants of classical polyarteritis nodosa found as single-organ lesions (14). Our patient had no other evidence of cutaneous or systemic vasculitis, his hepatitis B serologies were negative, and he had no manifestations of autoimmune disease. This patient’s clinical symptoms and histological findings were consistent with a process that occurred over many weeks. Segmental intestinal vasculitis with PLE following BMT should be considered in the differential diagnosis of PLE in patients who have undergone BMT. References 1. Weisdorf S. Salati L, Longsdorf J, Ramsay N, Sharp H. Graft-vs.-

2.

3. 4.

5.

host disease of the intestine: A protein losing enteropathy characterized by fecal cu,-antitrypsin. Gastroenterology 1983;85: 10761081. Jeffries G. Protein losing gastroenteropathy. In: Sleisenger MH. Fordtran JS, eds. Gastrointestinal disease; pathophysiology, diagnosis and management. Volume 1. 4th ed. Philadelphia: Saunders, 1989:283-290. Madara JL. Loosening tight junctions, Lessons from the intestine. J Clin Invest 1989;83:1089-1094. Robson RA, Clark M, Chapman BA, Lynn KL, Bailey RR. Protein losing enteropathy following transplantation. N Z Med J 1984;97:52-53. McDonald G, Shulman H, Sullivan K, Spencer G. Intestinal and hepatic complications of human bone marrow transplantation, part I. Gastroenterology 1986;90:460-477.

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6. Shaw M, Monroe S, Ladman AJ. Effects of cancer, radiotherapy and cytotoxic drugs on intestinal structure and function. Cancer Treat Rev 1979;6:141-151. 7. Spencer G, Shulman H, Myerson D, Thomas D, McDonald G. Diffuse intestinal ulceration after marrow transplantation: a clinicopathologic study of 131 patients. Hum Path01 1986;17:621633. 8. Bero T, Javor T. The effect of cyclophosphamide and vincristine on intestinal protein loss in rats. Arch Toxic01 1985:[suppl 8):117-121. 9. Cornelius E. Protein losing enteropathy in the graft-vs.-host reaction. Transplantation 1970;9:247-252. 10. McDonald G, Shulman H, Sullivan K, Spencer G. Intestinal and hepatic complications of human bone marrow transplantation, part II. Gastroenterology 1986;90:770-784. 11. Tajima T. An autopsy case of primary cytomegalic inclusion enteritis with remarkable hypoproteinemia. Acta Path01 Jpn 1974;24:151-162. 12. Underwood JCE, Corbett CL. Persistent diarrhea and hypoalbuminemia associated with cytomegalovirus enteritis. Br Med J 1978;1:1029-1030. 13. Weiser M, Giuseppe A, BrentJens J, Evans J, Reichlin M. Systemic lupus erythematosus and intestinal venulitis. Gastroenterology 1981;81:570-579. 14. Lie JT. Systemic and isolated vasculitis. In: Rosen PP, Fechner RE, eds. Pathology annual. Volume 24. Part 1. Norwalk, Conn.: Appleton and Lange, 1989:25-114.

Received September 1,1989. Accepted December 20,1989. Address requests for reprints to: Gail Sekas, M.D., Ph.D., Gastrointestinal Unit, Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213. The authors thank Loretta Malley and Helen Gibson for secretarial assistance.

Jejunal vasculitis with protein-losing enteropathy after bone marrow transplantation.

A 37-yr-old white man experienced crampy abdominal pain beginning 21 days after successful bone marrow transplantation for chronic myelogenous leukemi...
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