Abstract
Angiotensin-converting enzyme (ACE) inhibitors are widely used medications for managing hypertension, congestive heart failure, and diabetic nephropathy. However, a rare but potentially life-threatening adverse effect is ACE inhibitor-induced angioedema (ACEi-AE), characterized by localized, non-pitting edema involving the skin and mucous membranes, particularly of the face, tongue, lips, and upper airway. This article discusses the pathophysiology, clinical features, diagnostic approach, and management of ACEi-AE, supplemented by a real-life case example.
Introduction
ACE inhibitors, such as enalapril, lisinopril, and ramipril, are cornerstones of cardiovascular and renal disease therapy. Although generally well-tolerated, approximately 0.1%–0.7% of patients develop angioedema, often without warning, even after prolonged use. Understanding this condition is critical, as delayed recognition can result in airway compromise and fatal outcomes.
Case Example
Patient Profile
- Name: Mr. R.K.
- Age: 58 years
- Gender: Male
- Medical History: Hypertension (5 years), Type 2 Diabetes Mellitus (10 years)
- Medications: Metformin, Lisinopril (10 mg/day for 2 years)
Presentation
Mr. R.K. presented to the emergency department with a sudden onset of facial swelling, particularly involving the lips and tongue, associated with mild difficulty in swallowing but no urticaria or pruritus. He denied recent food intake changes, insect bites, or new drug exposures.
Examination
- Vitals: BP 138/86 mmHg, HR 84 bpm, RR 20/min
- Swelling of lips and anterior tongue
- No wheezing, stridor, or respiratory distress
- No skin rash or erythema
Initial Impression
- Angioedema, likely due to lisinopril
Management
- Immediate discontinuation of lisinopril
- Administration of corticosteroids (IV methylprednisolone), antihistamines (IV diphenhydramine), and monitoring
- No epinephrine given, as it was not anaphylactic
- Observation in ICU for airway compromise
- Symptoms resolved over 36 hours
Pathophysiology
Unlike allergic angioedema, which is mediated by histamine and IgE, ACEi-AE is bradykinin-mediated. ACE is responsible for degrading bradykinin, a potent vasodilator. Inhibition of ACE results in bradykinin accumulation, which increases vascular permeability, leading to localized edema.
Key Mechanisms:
- Bradykinin accumulation → Vasodilation and increased vascular permeability
- Substance P and neuropeptides may also contribute
- Not histamine-dependent → Explains poor response to antihistamines and corticosteroids in some cases
Risk Factors
- African descent
- Female gender
- Smoking
- History of seasonal allergies
- Renal dysfunction
- Previous episodes of idiopathic angioedema
Clinical Features
| Feature | Description |
|---|---|
| Onset | Can occur any time during treatment (even after years) |
| Location | Face, lips, tongue, pharynx, larynx (rarely GI tract) |
| Skin involvement | Usually no urticaria or itching |
| Respiratory symptoms | Stridor, hoarseness, dyspnea – may signal airway risk |
| GI symptoms | Nausea, abdominal pain (in cases with bowel wall edema) |
Differential Diagnosis
- Anaphylaxis (histamine-mediated angioedema)
- Hereditary angioedema (C1 esterase inhibitor deficiency)
- Idiopathic angioedema
- Food or drug allergies
- Infectious or inflammatory causes
Diagnostic Clues:
- No eosinophilia or elevated IgE
- Normal C1 esterase inhibitor levels and function
- Absence of hives/urticaria
- Temporal relation to ACE inhibitor use
Diagnosis
ACEi-AE is largely a clinical diagnosis. Investigations are used to exclude other causes.
Workup May Include:
- CBC, CRP – Usually normal
- C1 esterase inhibitor, C4 levels – To rule out hereditary angioedema
- Allergy testing – If suspicion of allergic cause
- Laryngoscopy – If airway involvement suspected
Management
Immediate Actions:
- Stop ACE inhibitor immediately.
- Airway assessment – Most crucial step.
- Hospital admission for monitoring if airway involvement suspected.
Pharmacologic Treatment:
| Medication | Use |
|---|---|
| Antihistamines | Limited role; used empirically |
| Corticosteroids | May help, though evidence is limited |
| Epinephrine | Use only if signs of anaphylaxis |
| Icatibant (bradykinin receptor antagonist) | Effective, though costly and not always available |
| Fresh Frozen Plasma (FFP) | Contains ACE enzyme – anecdotal success in severe cases |
Airway Management:
- Early intubation if signs of airway compromise
- Emergency tracheostomy may be required in rapidly progressive cases
Prognosis
- Most cases resolve within 24–72 hours after stopping the ACE inhibitor.
- Recurrence is possible if ACE inhibitors are resumed.
- Mortality is rare but increases with delayed recognition and airway obstruction.
Prevention
- Avoid re-challenge with any ACE inhibitor once angioedema has occurred.
- Angiotensin receptor blockers (ARBs) are sometimes used as alternatives but can rarely cause angioedema too. Use with caution.
- Educate patients on warning signs and instruct to seek immediate help if symptoms recur.
Conclusion
ACE inhibitor-induced angioedema is an uncommon but serious adverse effect that all clinicians prescribing these agents must be aware of. While the mechanism is bradykinin-mediated and differs from allergic angioedema, the clinical presentation can be similar. Early recognition, drug cessation, airway monitoring, and patient education are key to effective management and prevention of recurrence.
References
- Bas M, Adams V, Suvorava T, et al. Nonallergic angioedema: Role of bradykinin. Allergy. 2007.
- Beltrami L, Zingale LC, Carugo S, Cicardi M. Angiotensin-converting enzyme inhibitor-related angioedema: How to deal with it. Expert Opin Drug Saf. 2006.
- Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased risk for angioedema from ACE inhibitors. Arch Intern Med. 1996.