Title: A Decade-Long Silent Threat: Isolated Unilateral Tongue Edema from ACE Inhibitor-Induced AngioedemaMizuki Seki1, Takaaki Kobayashi2, Cynthia Young2, Saburo Minami1, Akihito Yoshida3Department of Emergency and Trauma, Kameda Medical Center, Kamogawa, Chiba, JapanDepartment of Internal Medicine, University of Kentucky, Lexington, KYDepartment of General Internal Medicine, Kameda Medical Center, Kamogawa, Chiba, JapanKey clinical message: Recognize that angioedema induced by ACE inhibitors can present in atypical forms and may occur years after initiating therapy.Keyword: Angioedema, tongue edema, ACE-inhibiter, drug adverse eventCorresponding author: Mizuki Seki Department of Emergency and Trauma, Kameda Medical Center, Kamogawa, Chiba, Japan Email seki.mizuki@kameda.jpCase Illustrated (496 of 500 words)An 84-year-old Japanese woman with a history of hypertension and myocardial infarction presented to the emergency department with progressive, isolated left-sided tongue swelling that had developed over several days. She denied dyspnea, dysphagia, or symptoms suggestive of airway compromise. She also reported no recent changes in diet, medications, allergen exposure, sick contacts, or travel history. Her vital signs were unremarkable, and physical examination revealed non-tender, localized swelling of the left side of the tongue without erythema, induration, or other signs of inflammation (Figure 1). Following her emergency department visit, the patient underwent evaluation at an oral surgery clinic to exclude alternative diagnoses, including malignancy. No other pathologies were identified. The patient had been taking enalapril, an angiotensin-converting enzyme inhibitor (ACE-I), for hypertension management for over 10 years. Based on her clinical presentation and exclusion of other potential etiologies, ACE-I-induced angioedema was strongly suspected. Enalapril was promptly discontinued, leading to complete resolution of the tongue edema within 48 hours, confirming the diagnosis (Figure 2).ACE-I-induced angioedema is an uncommon but potentially serious adverse reaction, with an incidence of 0.1–1%. ACE-Is, along with NSAIDs and β-lactam antibiotics, are significant causative agents of drug-induced angioedema [1]. This condition is mediated by bradykinin accumulation due to ACE inhibition, resulting in increased vascular permeability and localized edema. Unlike histamine-mediated angioedema, which presents as transient superficial swelling, bradykinin-mediated reactions are characterized by deep swelling involving the dermis, subcutaneous tissues, and submucosa. Established risk factors for ACE-I-induced angioedema include African-American ethnicity, previous drug-induced rash, advanced age, history of seasonal allergies, and concurrent NSAID use [2]. In this case, the patient exhibited none of these risk factors except advanced age. The typical clinical presentation involves diffuse lip or facial swelling, while isolated unilateral tongue edema is rare, with only a few similar cases reported in the literature. The onset of ACE-I-induced angioedema is highly variable, ranging from days to over a decade after starting therapy [3]. The delayed onset observed in this case, after more than a decade of ACE-I use, raises the hypothesis that bradykinin accumulation occurs gradually or that enzymatic activity may change with advancing age. However, the precise pathophysiological mechanism remains unclear. This delayed onset often complicates diagnosis, particularly in long-term users. Management requires immediate discontinuation of the ACE inhibitor, which is usually sufficient to resolve symptoms. Severe cases with airway involvement may necessitate advanced airway management, such as intubation or tracheostomy. For patients requiring continued antihypertensive therapy, alternatives such as calcium channel blockers or angiotensin receptor blockers (ARBs) should be considered. Although ARBs have a lower incidence of angioedema compared to ACE-Is, cross-reactivity has been documented in approximately 10% of cases. In this case, the patient was transitioned to an ARB and has remained asymptomatic, with no recurrence of angioedema to date. In conclusion, ACE-I-induced angioedema can present in atypical, localized forms, such as isolated unilateral tongue swelling, even after years of medication use. Awareness of these diverse presentations and timely drug discontinuation are critical to ensuring patient safety and preventing severe complications.Funding: None Patient consent: The patient’s written consent was obtained. Ethical approval: The local ethical committee approval does not apply in this case. Conflict of interest: No disclosureAcknowledgments: None Authors’ contributions: MS wrote a first draft of the manuscript. TK and AY critically reviewed and revised the manuscript. All authors read and approved the final paper.ReferencesLerch, M., et al., Drug-Induced Angioedema. Adverse Cutaneous Drug Eruptions, Chemical Immunology and Allergy, 2012. 97:98-105.Inomata N., et al., Isolated angioedema: An overview of clinical features and etiology (Review). Exp Ther Med. 2019. 17(2):1068-1072.Al-Hoqani ZK., et al., Unilateral Tongue Angioedema Induced by Angiotensin Converting Enzyme Inhibitor: A Case Report. Oman Med J. 2020;35(1):e92.【Figure】Tongue appearance at initial visit and two days after discontinuation of ACE inhibitor.Figure 1 Figure 2
