A Rare Case of Losartan-Induced Visceral Angioedema

Introduction

Angioedema is an infrequently encountered condition. It involves swelling of the mucosal and submucosal tissue. It can be either allergic or non-allergic in nature and is a known side effect of certain medications, including angiotensin converting enzyme inhibitors (ACEIs). Angioedema typically manifests as swelling of the face, lips, and tongue, which can lead to severe and life-threatening airway compromise. ¹ However, angioedema can be isolated to involvement of mucosal tissues in the lower digestive tract, termed visceral angioedema. ² While ACEIs are more often associated with cases of drug-induced angioedema, there have been reported cases of ARB-induced angioedema.^3,4 This case presents a scenario involving a woman who appeared to have suffered isolated visceral angioedema related to ARB medication use.

Case

An 81-year-old female with a past medical history of hypertension, chronic kidney disease stage IIIa, hyperlipidemia, anxiety, and eczema presented to the clinic to follow up with her Primary Care Provider (PCP) after 4 Emergency Room (ER) visits for abdominal pain, nausea, and a single episode of bloody diarrhea. Thorough diagnostic workup in the ER included abdominal X-rays, an abdominal and pelvic CT scan without IV contrast and an abdominal and pelvic CT scan with IV contrast were completed during these 4 visits. On the images of CT scan with IV contrast, mucosal thickening and submucosal edema of the transverse, descending, and sigmoid colon were noted (Figure 1). No definite explanation for this CT finding or explanation of her symptoms was identified in the emergency room.

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Figure 1.

CT scan with IV contrast images demonstrating thickening and edema of mucosal and submucosal tissues.

When she was seen by the PCP for follow up 2 weeks later, she was continuing to experience left lower quadrant abdominal pain. The pain fluctuated in severity, seemed to be random in nature, but may have been slightly improved with bowel movements. She continued to have intermittent loose stools. She had no recent antibiotics or known exposure to infectious illness, no personal or family history of inflammatory bowel disease or malabsorption and had never had this problem before. She had no change in diet or food intolerance in the past. Her only medication change was the introduction of losartan for hypertension 5 weeks prior to the onset of symptoms (6 weeks prior to the first ER visit). The patient had been afebrile throughout these visits and had no symptoms or lab findings suggestive of systemic infection. Additionally, her physical exam had been quite benign except for some mild tenderness in the left lower quadrant. At the time of her follow up visit in clinic, the radiologist that read her CT scan was consulted and confirmed that angioedema could be an explanation for the mucosal thickening noted on her CT images. The losartan was discontinued at that visit and the patient was followed clinically with an in-person visit in 3 weeks. Her abdominal pain had resolved within 3 days of discontinuation of the losartan. She had subsequent follow up 7 weeks and 3 months after stopping this medication and had no recurrence of abdominal pain. The onset of symptoms after beginning losartan and the resolution of symptoms within days of discontinuation are consistent with isolated visceral angioedema secondary to this medication.

Discussion

Angioedema is defined as the swelling of mucosal and sub-mucosal tissues. In the case of medication-induced non-allergic angioedema, is thought to be a bradykinin-mediated process. ¹ The likely mechanism of ACEI-induced angioedema is associated with loss of angiotensin converting enzyme (ACE) activity. ACE enhances bradykinin breakdown into inactive metabolites. When ACEIs block the action of ACE, bradykinin is not broken down into these inactive metabolites which cause vasoactive effects in the body. This increase in bradykinin causes vasodilation and increased vascular permeability, which leads to the mucosal swelling seen in angioedema. ⁵ Although ARB medication has been associated with angioedema on rare occasions, the exact mechanism is not known since ARB’s do not act directly on ACE or bradykinin. There have been postulations that ARB’s may indirectly lead to increased levels of bradykinin in some individuals. A leading theory involves a proposed feedback loop in which increased levels of angiotensin II would lead to self-inhibition of ACE, thus allowing for accumulation of bradykinin and its vasoactive effects. ⁴

Although rare, rates of drug-induced angioedema are much higher in ACEIs than ARB’s. Current literature estimates the risk of developing angioedema from an ACEI to be between 0.1% and 0.7%. ² The risk of developing angioedema from an ARB medication has been shown to be much lower and actually similar to rates seen with beta blockers and placebo in some studies.^3,4 However, actual incidence is likely to be higher due to lack of awareness of this rare medication side effect. Visceral angioedema, as depicted in this case presentation, is more rare and more difficult to identify than angioedema occurring in upper airways. Consequently, it is likely to be unrecognized and unreported. It is important for clinicians to be aware that angioedema can involve any mucosal tissue. Although it is most commonly seen in the face, mouth, and oropharynx, there can be intestinal involvement with or without any proximal tissues being affected.^2,4

The best imaging option for evaluating visceral angioedema is an IV contrast-enhanced CT. Typical findings include edematous bowel wall thickening with surrounding free fluid. In some cases, a layered pattern of edema can be seen in cross section views of the bowel, which is described as a halo or target sign.^2,6 The bowel wall thickening can be either circumferential or asymmetric. ⁶

Onset of medication-induced angioedema can occur at any time during therapy; however, it most commonly develops within the initial weeks to 1 month of starting a medication. ⁵ Treatment of angioedema primarily revolves around discontinuation of the offending agent. It is important to understand that these cases of angioedema are bradykinin mediated, not histamine, and thus will not respond to typical allergic-type angioedema treatments such as antihistamines, epinephrine, and corticosteroids. ³ There have been investigations of bradykinin targeted treatment, but to date, management is limited to discontinuing the medicine and supportive care. ³ Resolution of symptoms typically occurs within 24 to 48 h of discontinuation of the offending medication. ⁵

ACEI medication should be avoided in patients that previously developed angioedema with an ACEI. Additionally, some experts consider that there is an increased risk of developing angioedema with an ARB medication in patients that have previously had a case of angioedema related to ACEI’s.^7,8 Although the risk is still low and some articles suggest that it is reasonable to trial an ARB 4 weeks after the resolution of ACEI-induced angioedema, it seems reasonable that this should be done very cautiously and only if other classes of antihypertensive medications are not reasonable options. ⁴

Conclusion

Angioedema is a rare complication of some medications, notably ACEI’s. However, there have been several reports, including this case, of ARB-induced angioedema. Angioedema can present as swelling and edema of any mucosal surface and should be considered in situations of gastrointestinal symptoms of unclear etiology. Treatment primarily involves discontinuation of the suspected offending medication and close airway monitoring in situations where the face, mouth, or upper airway are involved. We hope that sharing this case will lead to increased awareness and identification of atypical presentations of medication-induced angioedema and that it may inspire further investigation into the mechanism of action behind ARB-induced angioedema.