INTRODUCTION

Angiotensin-converting enzyme (ACE) inhibitor–induced angioedema is a well-recognised adverse drug reaction resulting from bradykinin accumulation and typically presents with non-urticarial swelling of the lips, tongue, face, or upper airway. Symptoms generally resolve within 24–72 hours following discontinuation of the offending medication [1,2]. Although persistence or recurrence following ACE inhibitor withdrawal has been described, prolonged facial oedema lasting several months is uncommon and may present a diagnostic challenge.

CASE REPORT

A 28-year-old Black African man was referred for assessment of persistent facial swelling. Six months prior to presentation, he had been admitted for investigation of nephrotic-range proteinuria and commenced on an ACE inhibitor. Shortly after initiation of the medication, he developed progressive swelling of the lips and periorbital region. The ACE inhibitor was subsequently discontinued; however, the facial swelling persisted without appreciable improvement for the following six months.

On examination, there was prominent non-pitting oedema involving the lips and periorbital regions (Fig. 1). There was no tongue involvement or evidence of airway compromise. The patient denied urticaria or pruritus and reported no respiratory symptoms or symptoms suggestive of visceral angioedema, including abdominal pain, nausea, vomiting, or diarrhoea.

Figure 1: Marked lip oedema with associated periorbital oedema at presentation.

In view of the persistent facial oedema, a broad differential diagnosis was considered, including bradykinin-mediated angioedema due to ACE inhibitor exposure or acquired C1 esterase inhibitor deficiency, as well as pseudoangioedema secondary to systemic or inflammatory conditions. These included thyroid dysfunction, connective tissue disease, orofacial granulomatous disorders, cheilitis granulomatosa, contact dermatitis and other drug-related reactions.

A detailed medication and exposure history revealed no additional new medications, topical exposures, or systemic symptoms. There was no fissuring of the tongue or evidence of facial nerve dysfunction. There was no lymphadenopathy or hepatosplenomegaly, and systemic examination revealed no features suggestive of connective tissue disease.

Laboratory investigations, including a full blood count and differential, liver function tests, thyroid function tests, C4 and C1 esterase inhibitor levels, were within normal limits. Autoimmune and haematological screening was also unremarkable. Serum albumin was reduced at 24 g/L in the context of his previously documented nephrotic-range proteinuria. Chest radiography was unremarkable. A biopsy of the lip demonstrated mild epidermal spongiosis, separation of the dermal collagen bundles and a sparse perivascular lymphocytic infiltrate, without evidence of a granulomatous or other specific inflammatory process.

Given the hypoalbuminaemia, the possibility that the facial oedema was secondary to nephrotic syndrome was also considered. Although there was no clinical evidence of anasarca, in the absence of another overt cause for the persistent facial oedema, this remained a consideration. Following correction of the serum albumin to 35 g/L, however, there was no appreciable change in the degree of facial oedema over the subsequent weeks. Renal biopsy subsequently demonstrated focal segmental glomerulosclerosis, which did not provide an alternative explanation for the persistent facial oedema. Given the absence of an overt underlying cause and concern that the initial lip biopsy might not have been representative of the affected tissue, a repeat biopsy was performed, including sampling of the lip and vermilion border. Both biopsies demonstrated the same nonspecific histopathological findings, consisting of mild epidermal spongiosis, separation of the dermal collagen bundles and a sparse perivascular lymphocytic infiltrate, without evidence of a specific inflammatory, or granulomatous process.
In the absence of clinical, laboratory, imaging or histopathological evidence supporting an alternative diagnosis, persistent ACE inhibitor-associated angioedema was considered the most likely explanation for the patient’s chronic facial oedema. The ACE inhibitor had already been discontinued, and no further pharmacological treatment was instituted in the absence of airway involvement. The patient was counselled regarding future avoidance of ACE inhibitors and related medications

DISCUSSION

ACE inhibitor–induced angioedema is a well-recognised adverse drug reaction and accounts for a significant proportion of angioedema presentations, despite its relatively low incidence [1]. It most commonly occurs during the early period following initiation of therapy, although it may develop at any stage during treatment [1,2]. Symptoms typically resolve within 24–72 hours following discontinuation of the offending medication, with most episodes resolving within the first week [1,2]. However, persistence or recurrence following withdrawal has been reported, and prolonged symptoms may occur well beyond the expected timeframe [3,4]. The mechanisms underlying this prolonged course are not fully understood, and the distinction between persistent oedema and recurrent episodes following discontinuation is clinically important [3,4].

ACE inhibitor–induced angioedema is mediated primarily by accumulation of bradykinin as a consequence of impaired degradation by angiotensin-converting enzyme, resulting in increased vascular permeability and localised tissue oedema [1,2]. Unlike histamine-mediated angioedema, it is characteristically non-pruritic and occurs without urticaria, and conventional therapies directed at histamine-mediated disease, including antihistamines and corticosteroids, are generally ineffective [2,5]. Recognised risk factors include Black ethnicity, female sex, older age, smoking and concomitant treatment with dipeptidyl peptidase-4 inhibitors [1,2,5]. The anatomical distribution is variable, but the lips, tongue, face and upper airway are commonly affected, with airway involvement representing the principal acute complication [1,2].

The atypical persistence of facial oedema following ACE inhibitor withdrawal can create substantial diagnostic uncertainty because chronic facial swelling has a broad differential diagnosis. Conditions that may clinically mimic angioedema include thyroid disease, autoimmune and connective tissue disorders, granulomatous disease and other inflammatory or drug-related disorders [5]. In patients with persistent facial oedema, distinguishing true angioedema from pseudoangioedema is therefore important. The absence of urticaria and pruritus may provide an important clinical clue towards a bradykinin-mediated process, although these features alone are not diagnostic [2,5]. Recognition of the potential for a prolonged course is particularly relevant when the clinical phenotype remains compatible with ACE inhibitor-associated angioedema despite an apparently inappropriate duration of symptoms.

Failure to recognise prolonged ACE inhibitor-associated angioedema may result in repeated referrals, extensive investigations and unnecessary invasive procedures as alternative diagnoses are pursued. This is particularly relevant in patients with persistent facial swelling in whom the temporal relationship with ACE inhibitor exposure may be overlooked or considered insufficiently convincing because the medication has already been discontinued [3,4]. A careful and comprehensive medication history therefore remains central to the assessment of unexplained non-urticarial facial oedema [1,2]. Once ACE inhibitor-associated angioedema is suspected, permanent avoidance of ACE inhibitors is recommended because subsequent exposure may result in recurrent angioedema and potentially life-threatening airway compromise [1,2]. Awareness of this atypical natural history may facilitate earlier recognition, reduce unnecessary diagnostic procedures and ensure appropriate counselling regarding future ACE inhibitor exposure.

LEARNING POINTS

CONCLUSION

ACE inhibitor–induced angioedema is a well-recognised adverse drug reaction that typically resolves within days of discontinuing the offending medication. However, persistence or recurrence after withdrawal may occur, and prolonged facial oedema can present a significant diagnostic challenge. This case highlights the importance of recognising that ACE inhibitor-associated angioedema may occasionally follow an atypically prolonged course and mimic other causes of chronic facial swelling. Maintaining awareness of this possibility and taking a careful medication history may facilitate earlier recognition, avoid unnecessary investigations and procedures, and ensure appropriate counselling regarding future ACE inhibitor exposure

Consent

The examination of the patient was conducted according to the principles of the Declaration of Helsinki.

The authors certify that they have obtained all appropriate patient consent forms, in which the patients gave their consent for images and other clinical information to be included in the journal. The patients understand that their names and initials will not be published and due effort will be made to conceal their identity, but that anonymity cannot be guaranteed.

REFERENCES

1.  Brown T, Gonzalez J, Monteleone C. Angiotensin-converting enzyme inhibitor-induced angioedema:A review of the literature. J Clin Hypertens (Greenwich). 2017;19:1377-82.

2.  Ameer MA, Mushtaq J, Chaudhry H, Patel N, Khan SI. Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema:A Case Report With a Review of Management Options. Cureus. 2023;15:e40250.

3.  Beltrami L, Zanichelli A, Zingale LC, Vacchini R, Carugo S, Cicardi M. Long-term follow-up of 111 patients with angiotensin-converting enzyme inhibitor-related angioedema. J Hypertens. 2011;29:2273-7.

4.  Bezalel S, Mahlab-Guri K, Asher I, Werner B, Sthoeger ZM. Angiotensin-converting enzyme inhibitor-induced angioedema. Am J Med. 2015;128:120-5.

5.  Kaplan AP. Angioedema. World Allergy Organ J. 2008;1:103-13.