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Isolated Visceral Angioedema: An Underdiagnosed Complication of ACE Inhibitors?

      Angiotensin-converting enzyme (ACE) inhibitors are known to cause potentially fatal peripheral angioedema in some patients. ACE inhibitors may also cause isolated visceral angioedema, a rarely reported complication. This article describes 2 patients who experienced this complication. Both patients came to medical attention with episodes of recurrent abdominal symptoms that had occurred while taking ACE inhibitors for hypertension. Each patient had undergone surgical procedures for symptoms that persisted after surgery and were ultimately relieved with cessation of their ACE inhibitors. These cases call attention to what may be an underappreciated cause of abdominal pain in patients presenting to emergency departments.
      ACE (angiotensin-converting enzyme), CT (computed tomographic)
      Angiotensin-converting enzyme (ACE) inhibitors, commonly used to treat hypertension and congestive heart failure, are known to cause cough, hypotension, and dizziness in some patients. Much less frequently, ACE inhibitors are associated with angioedema of the face and neck, a potentially life-threatening occurrence that warrants cessation of the medication.
      • Slater EE
      • Merrill DD
      • Guess HA
      • et al.
      Clinical profile of angiocdema associated with angiotensin-convcrting enzyme inhibition.
      • Jain M
      • Armstrong L
      • Hall J
      Predisposition to and late onset of upper airway obstruction following angiotensin-converting enzyme inhibitor therapy.
      Herein we describe 2 cases that demonstrate a rare complication of ACE inhibitor therapy—isolated visceral angioedema of the small bowel.

      REPORT OF CASES

      Case 1

      A 67-year-old woman came to the emergency department in October 1996 having experienced in 1 day 2 episodes of severe mid-epigastric pain associated with nausea and vomiting. She was afebrile (35.9°C), and examination revealed moderate epigastric tenderness and hypoactive bowel sounds. No guarding or rebound tenderness was present. Findings on cardiac and pulmonary examinations were unremarkable. She was neurologically intact and clinically euvolemic. Comprehensive metabolic panel results, complete blood cell count, and amylase and lipase levels were normal except for mild leukocytosis. An abdominal computed tomographic (CT) scan showed dilated and thickened loops of small bowel and ascites (Figure 1). The C1 inhibitor level, determined after the initial blood tests, was normal as well.
      Figure thumbnail gr1
      Figure 1Case1. Abdominal computed tomographic scand emonstrating marked small bowel edema.
      The patient had a history of chronic hypertension and on questioning reported previous episodes of tongue swelling during a 3-year period of therapy with fosinopril. After a 6-month hiatus, she had resumed fosinopril treatment 3 days prior to this presentation. The patient had also experienced similar episodes of abdominal pain 3 years earlier while taking fosinopril. Work-up at the time included abdominal ultrasonography that showed gallstones but no evidence of ductal dilatation. Cholecystectomy was performed, and pathologic analysis revealed stones with only mild chronic cholecystitis. An intraoperative cholangiogram was normal, and the patient continued to have similar episodes in the months following surgery. Her only other current medications were aspirin because of known right carotid stenosis with 1 previous transient ischemic attack and oral estrogen because she had undergone hysterectomy and bilateral oophorectomy 30 years previously.
      The patient was admitted to the hospital for observation. She was given intravenous prochlorperazine for nausea and placed on maintenance saline infusion. The fosinopril was discontinued. The known right carotid artery stenosis raised concern for occult intestinal ischemia, and mesenteric angiography was performed. Findings were normal, and without any other measures, the patient's symptoms completely resolved by the following morning. A barium x-ray study of the small bowel was performed at this time, and findings were normal (Figure 2). The patient was discharged and has had no further episodes of abdominal pain in the subsequent 36 months since discontinuing fosinopril.
      Figure thumbnail gr2
      Figure 2Case 1. Normal-appearing small bowel on barium x-ray image. The study was performed on the morning after the patient presented to the emergency department. The patient was symptom- free at the time of this study.

      Case 2

      A 41-year-old woman presented to the emergency department in January 1998 with a 48-hour history of worsening crampy abdominal pain with intermittent nausea and vomiting. She denied fever, chills, hematochezia, and melena, and there were no genitourinary complaints. Her last menstrual period had been 1 week earlier. The patient had undergone cholecystectomy 1 month before this presentation after experiencing similar abdominal pain. No gallbladder wall thickening, ductal dilatation, or pericholecystic fluid was noted intraoperatively, and findings on limited bowel inspection were unremarkable. Her only medication was lisinopril (20 mg/d for the past 2 years), and her history, other than essential hypertension, was noncontributory. There was no family history of angioedema or inflammatory bowel disease.
      Examination findings at this presentation included tachycardia (128 beats/min) and an obese, distended abdomen that was tender to deep palpation in both lower quadrants. Comprehensive metabolic panel and complete blood cell count revealed mild leukocytosis with left shift; serum lactate and amylase levels were normal. An abdominal CT scan revealed marked thickening of the small bowel extending to the distal ileum, as well as a small amount of ascites around the liver and in the pelvis (Figure 3).
      Figure thumbnail gr3
      Figure 3Case 2. Computed tomographic scan performed at the time of the patient's presentation. Note diffuse small bowel edema.
      The patient was taken to surgery where an inflamed, edematous small intestine was found (Figure 4). The area of inflammation began 15 cm proximal to the ileocecal valve and extended (proximally) some 160 cm. Mesentery had normal pulsation, and as the bowel appeared viable throughout, no resection was performed. Diagnosis of ACE inhibitor-induced visceral angioedema was entertained, and lisinopril was not resumed postoperatively. Stool cultures obtained on admission were negative, and the patient was ultimately discharged. Thus far, she has had no recurrence of her symptoms, with more than 1 year of follow-up.
      Figure thumbnail gr4
      Figure 4Case 2. Intraoperative photograph of edematous, inflamed small intestine. The bowel was judged to be viable, however, as was mesenteric circulation. No resection was performed.

      DISCUSSION

      Our review of the literature yielded 8 previously reported cases of visceral angioedema related to ACE inhibitor exposure.
      • Abdelmalek ME
      • Douglas DD
      Lisinopril-induced isolated visceral angioedema: review of ACE-inhibitor-induccd small bowel angio-edema.
      • Farraye FA
      • Peppercorn MA
      • Steer ML
      • Joffe N
      • Rees M
      Acute small-bowel mucosal edema following enalapril use [letter].
      • Matsumura M
      • Haruki K
      • Kajinami K
      • Takada T
      Angioedema likely related to angiotensin converting enzyme inhibitors.
      • Jacobs RL
      • Hobermun LJ
      • Goldstein HM
      Angioedema of die small bowel caused by an angiotensin-converting enzyme inhibitor.
      • Gregory KW
      • Davis RC
      Images in clinical medicine: angiocdema of the intestine.
      • Dupasquier E
      A rare clinical form of angioneurotic edema caused by enalapril: acute abdomen (in French].
      • Mullins RJ
      • Shanahan TM
      • Dobson RT
      Visceral angioedema related to treatment with an ACE inhibitor.
      • Guy C
      • Cathebras P
      • Rousset H
      Suspected angioedema of abdominal viscera [letter].
      Conclusions about this phenomenon are difficult to draw from such a limited cohort, but interestingly, all cases reported so far have involved women, and in most, the symptoms occurred within 2 days of exposure to an ACE inhibitor (Table 1). There is no known sex predilection for reported cases of peripheral ACE inhibitor-associated angioedema or for hereditary angioedema. In case 1, the first report to involve fosinopril, the patient's history of tongue swelling while taking the drug, the onset of her current presentation within 3 days of resuming it, and the rapid reversal of signs and symptoms on withdrawal of the medication strongly implicates small bowel angioedema from fosinopril exposure as the cause of her episode. The similar improvement experienced by the patient in case 2—without specific therapy other than cessation of lisinopril—also supports our diagnosis. Both patients had undergone prior surgical procedures for symptoms that subsequently failed to resolve until withdrawal of their ACE inhibitors. Clinically, these cases present with acute abdominal symptoms, and a correct diagnosis depends on a high index of suspicion in patients taking ACE inhibitors.
      Table 1Previously Reported Cases of Visceral Angioedema Related to Angiotensin-Con verting Enzyme Inhibitor Exposure
      SourceAge (yj/sexMedicationDuration of use prior to onset of symptomsPresentation
      Abdelmalek & Doug] as,
      • Abdelmalek ME
      • Douglas DD
      Lisinopril-induced isolated visceral angioedema: review of ACE-inhibitor-induccd small bowel angio-edema.
      1997
      41/FLisinopril2 dPain, ascites, small bowel edema
      Farraye et al,
      • Farraye FA
      • Peppercorn MA
      • Steer ML
      • Joffe N
      • Rees M
      Acute small-bowel mucosal edema following enalapril use [letter].
      1988
      41/FEnalapril1 dPain, small bowel edema
      Matsumura et al,
      • Matsumura M
      • Haruki K
      • Kajinami K
      • Takada T
      Angioedema likely related to angiotensin converting enzyme inhibitors.
      1993
      48/FCaptopril2 dPain, ascites
      Jacobs etal,
      • Jacobs RL
      • Hobermun LJ
      • Goldstein HM
      Angioedema of die small bowel caused by an angiotensin-converting enzyme inhibitor.
      1994
      51/FEnalapril9 wkPain, ascites, small bowel edema
      Gregory & Davis,
      • Gregory KW
      • Davis RC
      Images in clinical medicine: angiocdema of the intestine.
      1996
      58/FLisinoprilUnspecifiedPain, cmesis, small bowel edema
      Dupasquier,
      • Dupasquier E
      A rare clinical form of angioneurotic edema caused by enalapril: acute abdomen (in French].
      1994
      43/FEnalapril1 dPain, emesis, diarrhea
      Mullinsetal,
      • Mullins RJ
      • Shanahan TM
      • Dobson RT
      Visceral angioedema related to treatment with an ACE inhibitor.
      1996
      59/FEnalapril2 dPain, emesis, diarrhea
      Guy eta],
      • Guy C
      • Cathebras P
      • Rousset H
      Suspected angioedema of abdominal viscera [letter].
      1994
      29/FLisinopril16 wkPain, ascites
      Angioneurotic edema may be caused by certain drugs as well as by hereditary or acquired Cl inhibitor deficiency. It may also be idiopathic. The incidence of angioedema related to the use of ACE inhibitors appears to be between 0.1% and 0.2%
      • Israili ZH
      • Hall WD
      Cough and angioneurotic edema associated with angiolensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology.
      and typically involves the upper respiratory tract and face. The exact pathophysiologic mechanism for ACE inhibitor-induced angioedema is unknown, but several possible mechanisms have been described. These include antibody-antigen interactions,
      • Yeung JH
      • Coleman JW
      • Park BK
      Drug-protein conjugates-IX: immunogenicity of captopril-protein conjugates.
      bradykinin accumulation,
      • Skidgcl A, R
      • Erdos EG
      Cleavage of peptide bonds by angiotensin 1 converting enzyme.
      and ACE inhibitor-induced C1 inhibitor deficiency in patients with borderline C1 inhibitor values.
      • Israili ZH
      • Hall WD
      Cough and angioneurotic edema associated with angiolensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology.
      Support for the bradykinin model is compelling in that several features of angioedema, including altered vascular permeability and inflammation, can be linked to bradykinin experimentally.
      • Oyvin TA
      • Gaponyuk PY
      • Volodin VM
      • Oyvin VI
      • Takaryer OY
      Mechanisms of blood vessel permeability derangement under the influence of permeability factors (histaminc, serotonin, kinins) and inflammatory agents.
      • Basran GS
      • Morley J
      • Paul W
      • Tumer-Warwick M
      Evidence in man of syncrgistic interaction between putative mediators of acute inflammation and asthma.
      Definitive evidence of causation, however, is lacking, and the short duration from ACE inhibitor exposure to development of abdominal symptoms in most reported cases suggests other factors may be involved.
      Visceral angioedema should be considered in patients using ACE inhibitors with unexplained abdominal pain. Differential diagnosis includes ischemia, infection, mechanical obstruction, inflammatory bowel disease, and vasculitis, all of which may present similarly. Acquired or hereditary C 1 inhibitor deficiency should also be considered, as either may present with isolated gastrointestinal angioedema.
      • Eck SL
      • Morse JH
      • Janssen DA
      • Emerson SG
      • Markovitz DM
      Angioedema presenting as chronic gastrointestinal symptoms.
      That these 2 patients have remained symptom-free without specific therapy except stopping their ACE inhibitors argues against these other processes.
      We hope this report increases awareness of what may well be an underdiagnosed complication of ACE inhibitor therapy. The occurrence of either peripheral or visceral angioedema in patients taking ACE inhibitors should prompt cessation of the drug. Failure to consider this condition may lead to unnecessary medical and surgical investigations, as appears to have occurred in these 2 cases.

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