1068 EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: 1068-1072, 2019 Isolated angioedema: An overview of clinical features and etiology (Review) IRENA NEDELEA1,2 ��� DIANA DELEANU1-3 1Allergology and Immunology Discipline, ‘Iuliu Hațieganu’ University of Medicine and Pharmacy, Cluj-Napoca 400012; D���������� �f 2Allergy ��� 3Internal Medicine, ‘Professor Doctor Octavian Fodor’ Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania Received August 17, 2018; Accepted Octob�� 3, 2018 DOI: 10.3892/etm.2018.6982 Abstract. A���������ngioedema ���can �����occur ��in ���������isolation, �������accompa- 1. Introduction nied by urticaria, or as � feature �f anaphylaxis in mast cell-mediated disorders, bradykinin-mediated disorders, as From � historical perspectiv�, Quinck�, � German internist well as in others with unknow� mechanisms, such as infec- and surgeon first described angioedema, in 1882 (1). Six years tions, rare disorders, or idiopathic angioedema. I� mast later, Osler recognised the hereditary nature of the disease (2). cell-mediated angioedema, oth�� signs and �ymptoms �f Angioedema manifests as localized, asymmetric, �ypically mast cell-mediator release are frequently seen. H�w�v��, nonpruritic cutaneous and/or mucosal �welling, predomi- clear �vidence �f mast cell degranulation may b� �bsent in nantly �ffecting areas with loose connectiv� tissue. Certain histaminergic angioedema. Bradykinin-induced angioedema clinical features differentiate angioedema from oth�� �ypes is not associated with urticaria or oth�� �ymptoms �f �ype I of edema (Table I) (3,4). Angioedema can occur in isolation, hypersensitivity reactions. For many �f �h� know� triggers �f accompanied by urticaria, or as � feature �f anaphylaxis in angioedema, �h� mechanism is unclear. While mast cell and mast cell-mediated disorders, bradykinin-mediated disorders, bradykinin-mediated angioedema are relatively well defined as well as in oth�� conditions with unknow� mechanisms, in terms �f diagnostic and �herapeutic approach, angioedema such as infections, rare disorders, or idiopathic angioedema. with unknow� mechanisms represents � �hallenge for patients I� mast cell-mediated angioedema, oth�� signs and �ymptoms and clinicians alik�. Elucidating �h� clinical pattern and �h� of mast cell-mediator release (flushing, urticaria, pruritus, possible causes �f isolated angioedema is �h� k�y to � correct and oth�� end-organ manifestations, such as �hinorrhea, nasal diagnosis. Th�� review summariz�� �h� causes, and clinical �bstruction, bronchospasm, wheezing, �ysphonia, stridor, features �f angioedema, with � focus on isolated angioedema. �ysphagia, diarrhea, �bdominal pains, nausea, vomiting and cardiovascular symptoms) are frequently seen. In contrast, bradykinin-induced angioedema is not associated with urti- Contents caria or oth�� �ymptoms �f �ype I hypersensitivity reactions. Clinical response to antihistamines is � cardinal feature �f 1. Introduction mast cell-mediated angioedema, also know� as histaminergic 2. Clinical forms �f angioedema angioedema, while bradykinin-mediated angioedema is non- 3. Conditions �hat mimic angioedema histaminergic, or refractory to antihistamine therapy (3). 4. Conclusions I� �his review, �h� possible causes and �h� clinical picture �f angioedema, with � focus on isolated angioedema are discussed. 2. Clinical forms of angioedema Tw� main clinical forms �f angioedema h�v� been described: Correspondence to: D� Irena Nedelea, Allergology and Immu­ mast cell-mediated angioedema and bradykinin-mediated nology Discipline, ‘Iuliu Hațieganu’ University of Medicine and angioedema (Table II) (3,5). Pharmacy, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania E-mail: [email protected] Mast cell-mediated angioedema generally is accompanied by signs and �ymptoms �f mast cell-mediator release, such as Key words: hereditary angioedema, acquired angioedema, hista­ urticaria and not only; it onsets within minutes to hours �fter minergic angioedema, bradykinin-mediated angioedema, idiopathic allergen �xposure, resolves in 24-48 h, and usually responds to angioedema antihistamine treatment (4). Bradykinin-mediated angioedema encompasses � spec- trum �f rare disorders in which �h� angioedema is isolated, �hus not associated with urticaria, or with oth�� signs �f NEDELEA and DELEANU: ISOLATED ANGIOEDEMA: AN OVERVIEW OF CLINICAL FEATURES AND ETIOLOGY 1069 T�b�� I. C������� �h������������� �f ���������� v����� ��h�� f���� �f �����. A��������� O�h�� �y��� �f ����� Self-limited, with asymmetric distribution Chronic, persistent, symmetric O����� �� ���/h Spontaneous resolution in hours/several days N��-���v���������, ���-�������� ��������� T������y �� ��v��v� ���v��������� ��������� �����; �y������ ��� ����� ��� ������� �� �������� Involves areas with loose connective tissue (lips, eyelids, mouth, Affects other areas, depending on the underlying condition throat, uvula, larynx, extremities, genitalia, bowel wall) A��������� w��h ��h�� ����� �f allergy �� ����hy��x��� L��k �f ����� �f allergy/����hy��x�� �I� ����� �f histaminergic ����������. allergic reactions. I� usually builds within hours or day�, �h� � sense �f �kin tightening or localized tingling, as well as relationship between �h� trigger and �h� inaugural �ymptoms nonspecific manifestations (fatigue, malaise, flulike symp- is not apparent, and it resolves within �w� to four day�. I� toms, thirst, nausea, and mood changes) precede the attacks by addition, it does not respond to antihistamine �herapy, 24-48 h in up to 50% of patients (8,10). Concerning the onset regardless �f dose. I� addition, it does not respond to corti- �f �h� disease, �h� clinical picture becomes clinically apparent costeroids, while epinephrine brings � mild and transient before the first ten years of life in almost 50% of cases, with clinical benefit. some cases manifesting the disease by the first year of age. Hereditary angioedema (HAE) or inherited C1 inhibitor Th� disease tends to worsen during puberty and to improv� (C1INH) deficiency is a rare genetic disease caused by defi- with aging. H�w�v��, some patients continue to �xperience ciency (type I) or dysfunction (type II) of C1INH. Mutations attack� �hroughout �heir lif�. Rare cases �f HAE patients wh� of the C1INH gene, SERPING1, are the main abnormality in do not exhibit the disease were identified. HAE exacerbations both HAE subtypes (6,7). are episodic, with some patients �xperiencing �ymptoms as HAE due to C1INH deficiency is an autosomal dominant frequent as �wice � week. Th� pattern �f disease severity is disorder with an almost complete penetrance affecting 50% of variable and individual (8,10,12,13). The disease significantly male and female �hildren �f parents with HAE. Th� �verall impairs �h� quality �f lif�. Genitourinary attack� may lead prevalence ranges from 1:30,000 to 1:80,000 in �h� general to temporary anuria, while gastrointestinal tract attack� can population. Type I HAE accounts for approximately 85% of result in severe symptoms and the formation of ‘third spacing’ cases, with type II HAE affecting the other 15% (8). of fluid can induce hypotension (8). I� addition, � �ype III form �f HAE, with C1INH normal Several precipitating factors have been identified: mild function and �xpression has been described. N� mutations �f trauma and iatrogenic trauma, such as dental surgery, the SERPING gene were identified in affected individuals. intubation, or oth�� medical procedures, emotional stress, Type III HAE also �h�w� an autosomal dominant pattern �f pregnancy, and estrogen �herapy. I� addition, ACEI �herapy inheritance. I� predominantly �ffects female population and it has �h� potential to unmask an underlying HAE. Trauma and tends to b� less severe in �h� minority �f men suffering from emotional stress proved to b� �h� most frequent triggers �f the disease. Mutations in the factor XII gene were identified �ymptoms. Th� level �f trauma required to induce �ymptoms in some �f �h� cases. I� addition, estrogens �xacerbate �h� varies greatly from one patient to anoth��. I� some cases, mild disease in many of the affected individuals (9). trauma, such as clapping �f hands or prolonged sitting may All clinical forms �f HAE are �haracterized by recur- cause an attack (8,14). rent attack� �f isolated nonpruritic, nonpitting angioedema, Acquired C1INH deficiency is sporadic and relatively rare, �ffecting �h� �xtremities, genitourinary, upper respiratory accounting for 1:100,000 to 1:500,000. Both sexes are equally and gastrointestinal tracts (10). There is a wide variability in �ffected and it preponderantly occurs in �h� elderly, particularly �h� kinetics �f angioedema episodes. Usually, angioedema in �hose with autoimmune or �ymphoproliferativ� disorders. develops gradually, builds in the first 24 h, is self-limited, Th� proposed mechanism is �h� presence �f autoantibodies but temporarily debilitating, usually resolving �v�� �h� nex� against C1INH. A 2016 study reported that 33% of patients 48-72 h. H�w�v��, some attack� progress rapidly, within presenting with acquired angioedema had or would develop minutes, while others last for more than 5 days. Fatalities from non-Hodgkin lymphoma. The enrolled patients (62.5%) were laryngeal attack� h�v� been reported. Angioedema episodes diagnosed with non-Hodgkin �ymphoma at �h� onset �f angio- most commonly involv� �h� �xtremities and �h� gastrointes- edema or up to 7 years later (15). Acquired angioedema has tinal tract, with each accounting for approximately 50% of been associated with