□ CASE REPORT □

Drug-induced Isolated Visceral Angioneurotic Edema

Masahiro ARAKAWA, Yaeko MURATA, Yuya RIKIMARU* and Yasuhiko SASAKI

Abstract no reports of isolated visceral angioneurotic edema induced by an ACE-I and/or ARB in patients on maintenance hemo- A44-year-old woman on maintenance hemodialysis dialysis. was admitted to our hospital because of severe abdominal pain. The patient had been medicated with and Case Report for hypertension for one month prior to admis- sion. An abdominal computerized scan (CT) showed a di- A 44-year-old woman was admitted to our hospital on lated and thickened loop of the small bowel with massive September 1, 2004 with acute onset of abdominal pain. A ascites and a small nodule in the jejunum. The patient’s renal histological diagnosis of mesangial proliferative abdominal pain was thought to be due to isolated visceral glomerulonephritis had been made on October 15, 1984. She angioneurotic edema induced by lisinopril and/or valsar- had undergone living donor renal transplantation on June 24, tan, and medication of these two drugs was therefore 1992. However, maintenance hemodialysis three times a stopped. Her symptoms resolved and an abdominal CT week was started on June 10, 2004 because of renal trans- demonstrated almost complete resolution of ascites and plant rejection. She had no known allergies to drugs or envi- of small bowel edema except for a small nodule in the je- ronmental agents and had no travel history. Her family junum. A laparoscopic operation was performed to excise history was unremarkable. One month before admission to the small nodule of the jejunum, and a histological diag- our hospital, lisinopril (10 mg daily) and valsartan (80 mg nosis of accessory pancreas of the jejunum was made. daily) were substituted for hydrochloride (20 mg This is the first report of isolated visceral angioneurotic daily), which she had been receiving for about 12 years for edema induced by lisinopril and/or valsartan in a patient hypertension. On admission, pertinent findings on physical on maintenance hemodialysis and, moreover, with the as- examination included a fever of 38.5°C, blood pressure of sociation of accessory pancreas of the jejunum. 130/80 mmHg, and left lower abdominal tenderness with (Internal Medicine 44: 975–978, 2005) signs of peritonitis. Results of cardiac and pulmonary exami- nations were unremarkable. No facial or oropharyngeal Key words: -converting enzyme inhibitor, angio- swelling was noted. Laboratory findings on admission are tensin II receptor blocker, lisinopril, valsartan shown in Table 1. Leukocytosis and anemia were recog- nized. C-reactive protein was 0.3 mg/dl. Results of viral serology (hepatitis B and C) were negative, and no infectious organisms were isolated from stool specimens. An abdomi- Introduction nal computerized tomographic scan (CT) at admission showed diffuse small bowel thickening, ascites and a small Angiotensin-converting enzyme inhibitors (ACE-Is) and nodule in the jejunum (Fig. 1). Ascitic fluid had a clear angiotensin II receptor blockers (ARBs) are known to cause yellow appearance with an exudative pattern (Table 1), and potentially fatal peripheral angioedema and isolated visceral microbiological cultures were negative for pathogens. The angioneurotic edema in patients with or without renal failure. C1 esterase inhibitor level was normal. Complement levels We did a computerized search of MEDLINE for English- were as follows: CH50, 19.6 CH50/ml; C3, 54 mg/dl; C4, 13 language articles using the PubMed search engine with vari- mg/dl. The levels of serotonin and tumor markers (CEA, ous combinations of the following medical subject heading CA19-9, AFP) were within normal limits. Upper endoscopy terms: ‘visceral angioneurotic edema’, ‘ACE-Is’, ‘ARBs’, and colonoscopy results were normal. We suspected that the ‘intestine’, ‘abdominal pain’ and ‘hemodialysis’. We found patient had drug-induced isolated visceral angioneurotic

From the Department of Internal Medicine and *the Department of Radiology, Ishinomaki Red Cross Hospital, Ishinomaki Received for publication December 14, 2004; Accepted for publication May 11, 2005 Reprint requests should be addressed to Dr. Masahiro Arakawa, the Department of Internal Medicine, Ishinomaki Red Cross Hospital, 1-7-10 Yoshino-cho, Ishinomaki 986-8522

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Table 1. Laboratory Findings on Admission

Complete blood cell count Blood chemistory White blood cell 13,300/mm3 Total protein 7.1 g/dl neutrophils 92.5% Total bilirubin 1.2 mg/dl lymphocytes 5.5% AST 20 IU/l monocyte 1.0% ALT 12 IU/l eosinophils 0% LDH 460 IU/l basophils 0.5% Blood urea nitrogen 30.4 mg/dl Red blood cell 29,900,000/mm3 Serum creatinine 6.4 mg/dl Hemoglobin 9.9 g/d Sodium 143 mmol/l Hematocrit 30.2% Potassium 3.9 mmol/l Platelet 170,000/mm Chloride 109 mmol/l Calcium 9.9 mg/dl Ascitic fluid Phosphate 3.5 mg/dl Total protein 2.5 g/dl CPK 43 IU/l Glucose 91 mg/dl Amylase 230 IU/l Chloride 110 mmol/l Glucose 81 mg/dl LDH 195 IU/l C-reactive protein 0.3 mg/dl Amylase 140 IU/l Cell counts 100/l Occult blood of stool (–) Neutrophils 3% Lymphocytes 61% Monocytes 22% Histocytes 14%

AST: L-asparate: 2 oxoglutarate aminotransferase, ALT: L-alanine: 2 oxoglutarate amino- transferase, CPK: creatinine phosphokinase, LDH: lactate dehydrogenase.

Figure 1. CT obtained on admission shows loops of bowel with Figure 2. CT obtained 3 days after stopping medications of thick walls and narrow lumens and a small nodule of the lisinopril and valsartan shows an almost normal small intestine. jejunum (→). Arrow (→) shows a small nodule of the jejunum. edema, and we therefore stopped medication of lisinopril and Discussion valsartan on October 5, 2004. Her abdominal symptoms and abnormal swelling of the small intestine on CT images were We thought that ischemia, infection, mechanical obstruc- resolved (Fig. 2). A laparoscopic operation was performed tion, inflammatory bowel disease, vasculitis, and acquired or on October 22, 2004 to excise the small nodule of the jeju- hereditary C1 inhibitor deficiency should be considered as num, and a histological diagnosis of accessory pancreas of differential diagnoses in the present case (1). A diagnosis of the jejunum was made. drug-induced isolated visceral angioneurotic edema was

976 Internal Medicine Vol. 44, No. 9 (September 2005) Isolated Visceral Angioneurotic Edema made because our patient became symptom-free with no ab- the free rather than the total circulating plasma drug concen- normal swelling of the small intestine on CT images without tration (12). It has also been reported that lisinopril has a having undergone any specific therapy other than stopping poor ability to bind to plasma protein and that quinapril hy- treatment with an angiotensin-converting enzyme inhibitor drochloride and valsartan have a good ability to bind to (ACE-I) and angiotensin II receptor blocker (ARB). plasma protein (9–11) and it has been shown that the half- We thought that leukocytosis might be due to dehydra- life of lisinopril is longer than that of quinapril hydrochloride tion, because serum total protein and white blood cell counts (9, 10). We accordingly thought that lisinopril had a greater became 5.8 g/dl and 8,600/mm3, respectively, on September potential to induce adverse effects, such as angioedema, than 3 after drip infusion and fasting treatments. Although the ori- did quinapril hydrochloride in the present case with severe gin of the fever on admission was not clear, the fever was not renal impairment, because increased bradykinin levels ap- thought to be an important sign for diagnosis because her pear to be one of the mechanisms underlying the develop- body temperature returned to normal the next day without ment of ACE-I-associated angioedema. special treatment. When the renal biopsy was performed on It has been reported that co-administration of drugs can October 15, 1984, the patient’s complement levels were nor- result in the displacement by a strongly bound drug of a less- mal (CH50, 32.8 CH50/ml; C3, 92 mg/dl; C4, 25 mg/dl). strongly bound drug from its binding sites, and this leads to Although laboratory data showed hypocomplementemia in greater amounts of free, non-protein-bound, drug available the clinical course of visceral angioneurotic edema, we could for distribution to the sites of action, and since free drug is not determine the origin of hypocomplementemia. The ab- a major determinant of pharmacologic effects, these drug in- normal complement levels returned to normal levels (CH50, teractions could result in toxicity and/or enhanced efficacy 25.8 CH50/ml; C3, 69 mg/dl; C4, 15 mg/dl) on February 8, (13). We thought that since valsartan, which has a strong 2005. binding activity to plasma protein, was administered with The pathophysiologic mechanism of ACE-I-induced lisinopril, which has weak binding activity to plasma protein, angioedema is unknown, but several possible mechanisms the amount of unbound lisinopril in the plasma increased and have been reported. These include antigen-antibody interac- the adverse effect of lisinopril might have been accentuated tions (2), bradykinin accumulation (3), and ACE-I-induced in the present case. However, since a search of articles in C1 inhibitor deficiency (4). We thought that other unknown MEDLINE over the past 20 years showed no report of a case factors might also be involved because various durations in which angioedema was induced by ACE-Is-ARBs interac- from ACE-I exposure to development of symptoms have tions, we will make efforts to study further cases that are the been reported (5). same as our case and examine the plasma levels of drugs and ARB-related angioedema has occurred in patients not bradykinin in each case. having previously been exposed to an ACE-I and in patients Attention should be given to the possibility of visceral having previously received an ACE-I and not having devel- angioneurotic edema induced by medication of ACE-Is and/- oped angioedema (6). The exact mechanism of ARB-related or ARBs in patients taking these drugs who have abdominal angioedema is unknown. It has also been reported that ARBs pain. cause an increase in plasma angiotensin II levels, which may The histological diagnosis of the small nodule of the jeju- lead to a negative feedback inhibition of ACE activity, thus num in the present case was accessory pancreas. It has been predisposing individuals to developing angioedema (5). reported that the favored sites for accessory pancreas are the One month before admission, lisinopril and valsartan were stomach and duodenum followed by the jejunum and that substituted for quinapril hydrochloride. Although cases of about 20% of islet cell tumors arise in ectopic pancreatic tis- angioedema induced by quinapril hydrochloride have been sues (14). Histological diagnosis of the accessory pancreas reported (7), it is not clear that angioedema did not appear was benign, and we thought that the accessory pancreas of during medication with quinapril hydrochloride in the pres- the jejunum had no relation to the clinical course in the pres- ent case. ent case. In patients with renal impairment, pharmacokinetics stud- To the best of our knowledge, this is the first report in the ies of drugs for which the main route of elimination is uri- English language literature on isolated visceral angioneurotic nary excretion have demonstrated that the time to peak edema induced by lisinopril and/or valsartan in a patient on concentration was longer, the peak concentration was higher, hemodialysis and, moreover, associated with accessory pan- and the decline in serum concentration slower than these in creas of the jejunum. patients with normal renal function (8). It has been reported that lisinopril and quinapril hydrochloride are primarily References eliminated in urine and that valsartan is not eliminated in urine (9–11). 1) Schmidt TD, McGrath KM. Angiotensin-converting enzyme inhibitor It has been reported that many drugs circulate in the angioedema of the intestine: A case report and review of the literature. plasma partly bound to plasma protein, and since only the Am J Med Sci 324: 106–108, 2002. 2) Yeung JH, Coleman JW, Park BK. Drug-protein conjugates—IX. uncombined or free drug can distribute to the site of pharma- Immunogenicity of captoril-protein conjugates. Biochem Pharmacol cologic action, the therapeutic response should be related to 34: 4005–4012, 1985.

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3) Basran GS, Morley J, Paul W, Turner-Warwick M. Evidence in man of 9) Kelly JG, Doyle GD, Carmody M, Glover DR, Cooper WD. Pharma- synergistic interaction between putative mediators of acute inflamma- cokinetics of lisinopril, and in renal failure: effects tion and asthma. Lancet 24: 935–937, 1982. of haemodialysis. Br J Clin Pharmacol 26: 781–786, 1988. 4) Ohsawa I, Satomura A, Fuke Y, et al. Worsening fluid retention in a 10) Blum RA, Olson SC, Kohli RK, Horvath AM, Sedman AJ, Posvar EL. patient with hereditary angioedema and end-stage renal disease. Intern Pharmacokinetics of quinapril and its active metabolite, quinaprilat, in Med 43: 708–712, 2004. patients on chronic hemodialysis. J Clin Pharmacol 30: 938–942, 1990. 5) Oudit G, Girgrah N, Allard J. ACE inhibitor-induced angioedema of 11) Brookman LJ, Rolan PE, Benjamin IS, et al. Pharmacokinetics of the intestine: Case report, incidence, pathophysiology, diagnosis and valsartan in patients with liver disease. Clin Pharmacol Ther 62: 272– management. Can J Gastroenterol 15: 827–832, 2001. 278, 1997. 6) Sica DA, Gehr TW. The pharmacokinetics and pharmacodynamics of 12) Oates JA, Wilkinson GR. Principles of drug therapy. In: Harrison’s angiotensin-receptor blockers in end-stage renal disease. J Principles of Internal Medicine. 13th ed. Isselbacher KJ, Braunwald E, Angiotensin Aldosterone Syst 3: 247–254, 2002. Wilson JD, et al, Eds. McGraw-Hill, New York, 1994: 399–400. 7) Mchaourab A, Sarantopoulos C, Stowe DF. Airway obstruction due to 13) DeVane CL. Clinical significance of drug binding, protein binding, and late-onset angioneurotic edema from angiotensin-converting enzyme binding displacement drug interactions. Psychopharmacol Bull 36:5– inhibition. Can J Anaesth 46: 975–978, 1999. 21, 2002. 8) Soo Hoo GW, Dao HT, Klaustermeyer WB. Severe angioedema and 14) Crawford JM, Cotran RS. Ectopic pancreas. In: Robin’s Pathologic respiratory distress associated with lisinopril use. West J Med 158: Basis of Disease. 6th ed. Cotran RS, Kumar V, Collins T, Eds. WB 412–417, 1993. Saunders Company, Philadelphia, 1999: 904.

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