Visceral angioedema due to angiotensin-converting enzyme inhibitor therapy

SUMMARY OF REPORTED CASES

Our search revealed 27 reported cases of visceral angioedema associated with ACE inhibitors (a table summarizing our findings is available).^9–34 The drug most often involved was lisinopril (11 cases), followed by enalapril (Vasotec) (8 cases).

Twenty-three (82%) of the cases were in women. The mean age of the patients was 49.5 ± 12.2 years (range 29–77 years); the mean age was 46.7 ± 11.7 years in women and 57 ± 13 years in men. Unfortunately, the race and ethnicity of the patients was documented in only some cases.

In 15 (54%) of the cases, the patient presented to a physician or emergency department within 72 hours (41.1 ± 17.4) of starting therapy, and in 8 cases the patient presented between 2 weeks and 18 months.

In 10 cases (including the case we are reporting here), the patients were kept on ACE inhibitors from 2 to 9 years after the initial presentation, as the diagnosis was missed.^{9,12,14,18,20,31,32} In 2 cases, the dose of the ACE inhibitor had been increased after the patient presented with the abdominal pain.

All of the patients were hospitalized for further diagnostic workup.

As for the presenting symptoms, all the patients had abdominal pain, 24 (86%) had emesis, 14 (50%) had diarrhea, and 20 (71%) had ascites. Laboratory results were mostly nonspecific. Twelve (44%) of the patients had leukocytosis. The C1 esterase inhibitor concentration was measured in 18 patients, and the results were normal in all of them.

Twenty-four (86%) of the patients underwent abdominal and pelvic CT or ultrasonography as part of the initial diagnostic evaluation, and intestinal wall-thickening was found in 21 (87.5%) of them.

Either surgery or gastrointestinal biopsy was performed in 16 (57%) of the patients; the surgical procedures included 2 cholecystectomies and 1 bone marrow biopsy. Only 1 case was diagnosed on the basis of clinical suspicion and abdominal radiographs alone.

The combination of intestinal and stomach angioedema was found in only 2 cases.

Two patients were kept on an ACE inhibitor in spite of symptoms and intestinal wall edema that showed a migratory pattern on imaging after chronic exposure.

The thickening involved the jejunum in 14 patients (50%), the ileum in 8 (29%), the duodenum in 5 (18%), the stomach in 2, and the sigmoid colon in 1.

In 12 cases (43%), visceral angioedema and its symptoms resolved within 48 hours of stopping the ACE inhibitor.

A DIAGNOSIS TO KEEP IN MIND

As we have seen, the diagnosis of visceral angioedema needs to be kept in mind when a patient—especially a middle-aged woman—taking an ACE inhibitor presents with abdominal pain, vomiting, diarrhea, leukocytosis, ascites, and wall-thickening of the small bowel on imaging studies.^9,35,36

The diagnosis is hard to establish, and in the interim the patient may undergo invasive and unnecessary procedures, which can be avoided by a heightened awareness of this complication. In all of the reported cases, the patients required hospitalization because of the severity of symptoms and attempts to exclude other possible diseases.³⁶

POSSIBLY DUE TO BRADYKININ

Several theories have been proposed to explain how visceral angioedema is induced by ACE inhibitors. The possible mechanisms that have been described include the following:

• The accumulation of bradykinin and substance P secondary to the effect of the ACE inhibitor, which may lead to the inflammatory response, therefore increasing permeability of the vascular compartment
• Deficiency of complement and the enzymes carboxypeptidase N and alpha-1 antitrypsin
• An antibody-antigen reaction³⁷
• Hormones such as estrogen and progesterone (suggested by the greater number of women represented³⁸)
• Contrast media used for imaging³⁹
• Genetic predisposition
• Inflammation due to acute-phase proteins
• C1-inhibitor deficiency or dysfunction (however, the levels of C1/C4 and the C1-esterase inhibitor functional activity usually are normal^2,10,40).

Many other theories are being explored.^{11,12,38,41–53}

The most plausible mechanism is an increase in the levels of bradykinin and its metabolites.⁴⁵ The absence of ACE can lead to breakdown of bradykinin to des-Arg bradykinin via the minor pathway, which can lead to more pronounced vasodilation and vascular permeability.^54,55 During an acute attack of angioedema secondary to ACE inhibition, the bradykinin concentration can increase to more than 10 times the normal level.⁵⁶

Moreover, C-reactive protein levels were higher (mean 4.42 mg/dL ± 0.15 mg/dL) in patients with ACE-inhibitor-induced angioedema than in those with other causes of angioedema (P < .0001).⁵² The patients taking ACE inhibitors without any previous angioedema had normal C-reactive protein levels (0.39 mg/dL ± 0.1 mg/dL).⁵²

INCIDENCE RATES

In our review of the literature, all of the patients were taking an ACE inhibitor, and some were taking both an ACE inhibitor and an angiotensin-receptor blocker (ARB).

Initially, the incidence rate of angioedema was thought to be 0.1% to 0.2%, but recently the Omapatrilat Cardiovascular Treatment Assessment vs Enalapril (OCTAVE) trial had more than 12,000 patients on enalapril and reported the incidence of angioedema to be 0.68%,⁵⁷ with a higher risk in women than in men (0.84% vs 0.54%)⁵⁸ and a relative risk of 3.03 for blacks compared with whites.⁵⁹

Even though ARBs seem to be safer, angioedema can recur in up to one-third of patients who switch from an ACE inhibitor to an ARB.^60–63

Moreover, one study in the United States found that the frequency of hospital admission of patients with angioedema increased from 8,839 per year in 1998 to 11,925 in 2005, and the cost was estimated to be close to $123 million in 2005.⁶⁴

Interestingly, when angioedema involved the face, it developed within the first week in 60% of cases,⁶⁵ whereas when visceral angioedema developed, it did so within the first week in 59% of cases. Therefore, the timing of the onset is similar regardless of the body area involved.

Smokers who developed ACE-inhibitor-induced cough had a higher risk of ACE-inhibitor-induced angioedema in a retrospective cohort study by Morimoto,⁶⁶ but no relationship to the area of involvement was made.