Logical Approach to a Patient Presenting with Recurrent Angioedema Attacks

Abstract

Abstract

Angioedema is described as local, restricted noninflammatory edema as a result of augmented plasma leakage fromthe capillaries situated in the profound layers of the skin andthe mucosae. The major mediators such as histamine and bradykinin play a role in the pathophysiology of most of the angioedema cases. According to these mediators, angioedema is essentially classified as histaminergic or bradykininergic. Angioedema can be observed with wheals as anindicator of urticaria, and this type is often associated withhistaminergic (allergic, IgE-mediated) type. Histaminergicangioedema is the most common type of angioedema. Angioedema is categorized into either acute (symptoms lasting less than 6 weeks) or chronic (lasting more than 6 weeks) form. It is further characterized into angioedema manifesting with or without wheals. Angioedema with wheals may be acute, chronic, spontaneous or inducible. Angioedema without wheals (AEWOW) is still seen in approximately 10% of urticaria patients, but it can also take place as a discrete entity. In 2014 Hereditary Angioedema International Working Group classification, AEWOW is mainly categorized into hereditary and acquired types. Hereditary AEWOW forms are as follows: Hereditary angioedema (HAE) with genetic C1 inhibitor (C1-INH) deficiency,HAE with normal C1-INH but with Factor XII gene mutation, and unknown HAE; acquired forms of AEWOW have4 subtypes. Acquired C1-INH deficiency, angiotensin converting enzyme inhibitor (ACE-i) induced, idiopathic histaminergic and idiopathic non-histaminergic angioedema. From these types, just idiopathic histaminergic is histaminergic, the others are bradykininergic angioedemas. Hereditary angioedema is a rare congenital disease mainly attributable to the SERPING1 gene mutations, programmingthe C1-INH protein that yields to plasma deficiency, resulting in recurrent attacks of severe angioedema. As of 2018,over 490 different mutations were demonstrated in the region of C1-INH gene (SERPINGI). It is now known thatC1-INH deficiency excites the plasma contact (kallikreinkinin) system, which ultimately results in bradykininover production. After the year 2000, the most recent development in the field of HAE, 3 new types of HAE with “normal” C1-INH were reported. Several abnormalities in thegenes of Factor XII, Angiopoietin-1 and Plasminogen havebeen identified in this novel disease entity. Due to obviousin consistency of clinical pictures, complete understanding of recurrent angioedema phenotypes and the underlying mediator of symptoms are essential for precise diagnosis andselecting the appropriate therapy options. Although the main therapies of histaminergic angioedema are antihistamines,corticosteroids, and epinephrine, these medications will notwork in especially hereditary angioedema and some typesof acquired angioedema. In this present review, the distinctive epidemiology, pathophysiology and clinical spectrumof histaminergic and bradykininergic angioedema, and differential diagnosis are discussed under the light of recent literature, along with our case scenarios.

Keywords

• histaminergic angioedema,urticaria,hereditary angioedema,C1 inhibitor,factorXII,angiopoietin-1,plasminogen

Tekrarlayan Anjiyoödem Atakları İle Başvuran Hastaya Akılcı Yaklaşım

Öz

Öz

Anjiyoödem mukoza ve cildin derin tabakalarında bulunan kapillerlerden artmış plaz-ma sızmasına bağlı lokal, enflamatuar olmayan ve kendini sınırlayan bir ödem olaraktanımladır. Histamin ve bradikinin gibi iki ana mediatör, anjiyoödem vakalarının çoğu-nun patofizyolojisinde rol oynarlar.  Bu mediatörlere göre, anjiyoödem esas olarak his-tamin- ve bradikinin-aracılı hastalık olarak sınıflandırılır. Anjiyoödem ürtikerin bir be-lirtisi olarak kabarıklıkla beraber olabilir ve bu şekli çoğunlukla histaminerjik (allerjik,IgE-aracılı) tiple ilişkilidir. Histaminerjik anjiyoödem en sık anjiyoödem tipidir. Anji-yoödem, akut (semptomlar 6 haftadan kısa sürerse) veya kronik (semptomlar 6 hafta-dan uzun sürerse) olarak iki şekilde ayrılabilir. Anjiyoödem, ürtikerle (kaşıntılı kaba-rıklık) beraber olup olmamasına göre de daha ileri sınıflanabilir. Kaşıntılı kabarıkla be-raber olan anjiyoödem, akut ya da kronik, spontan ya da indüklenebilir bir ürtikerin gös-tergesidir. Kabarıkla olmayan anjiyoödem, ürtikerli hastaların yine de %10’un da gö-rülebilir fakat ayrı bir semptom olarak da oluşabilir. Kabarıklık oluşmayan (kabarcık-sız) anjiyoödemin herediter şekilleri şöyledir: genetik C1 inhibitor (C1-INH) eksikli-ğiyle giden herediter anjiyoödem (HAÖ), faktör XII gen mutasyonu olup normal C1-INH ile giden HAÖ ve nedeni bilinmeyen HAÖ. Kabarıklık oluşmayan anjiyoödeminakkiz şekilleri 4 alttiptir. Akkiz C1-INH eksikliği, anjiyotensin konverting enzim inhi-bitor (ACE-i)’ün indüklediği, idiyopatik histaminerjik ve idiyopatik histaminerjik ol-mayan anjiyoödem. Bu tiplerden sadece idiyopatik histaminerjik olan histamin aracı-lı, diğerleri ise bradikinin aracılığıyla oluşan anjiyoödemlerdir. Herediter anjiyoödem,C1-INH kodlayan SERPING1 genindeki mutasyonlar sonucunda plazma düzeyinde düş-meye bağlı tekrarlayan ciddi şişme (anjiyoödem) ataklarıyla seyreden nadir görülen ge-netik bir bozukluktur. 2018 itibarıyla, C1-INH (SERPINGI) geninde 490’den fazla de-ğişik mutasyon bildirilmiştir. Günümüzde C1-INH eksikliğinin plazma kontakt (kallik-rein-kinin) sisteminin aktivasyonuna ve nihai olarak bradikinin aşırı üretimine yol aç-tığı bilinmektedir. 2000 yılı sonrasında, HAÖ hastalığı hakkındaki en yeni gelişme, C1-INH’in düzeyinin “normal” olduğu 3 yeni HAÖ tipinin bildirilmesidir. Faktör XII, An-jiyopoietin-1 ve Plazminojen gibi birkaç gende bazı anomaliler hastalığın bu yeni tipin-de tanımlanmıştır. Doğru teşhis ve uygun tedaviyi seçmek için, klinik tablonun bariz he-terojenliğinden dolayı, anjiyoödem fenotipinin ve semptomların altında yatan medya-törün iyi bilinmesi esastır. Histamin-aracılı anjiyoödemin asıl tedavisi antihistaminik,kortikosteroit ve epinefrin olmakla beraber, bu ilaçlar herediter ve bazı akkiz anjiyoö-dem tiplerinde işe yaramayacaktır. Bu derlemede, histaminerjik ve bradikinerjik anji-yoödeme özgün epidemiyoloji, patofizyoloji ve klinik spektrum ve bu hastalıkların ayı-rıcı tanısı olgu senaryoları eşliğinde son literatür verileri ışığında detaylı olarak tartışıl-maktadır.

Anahtar Kelimeler

• histaminerjik anjiyoödem,ürtiker,herediter anjiyoödem,C1inhibitor,faktör XII,anjiyopoietin-1,plazminojen

References

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