RESUMO
Angioedema is a prevailing symptom in different diseases, frequently occurring in the presence of urticaria. Recurrent angioedema without urticaria (AE) can be hereditary (HAE) and acquired (AAE), and several subtypes can be distinguished, although clinical presentation is quite similar in some of them. They present with subcutaneous and mucosal swellings, affecting extremities, face, genitals, bowels, and upper airways. AE is commonly misdiagnosed due to restricted access and availability of appropriate laboratorial tests. HAE with C1 inhibitor defect is associated with quantitative and/or functional deficiency. Although bradykinin-mediated disease results mainly from disturbance in the kallikrein-kinin system, traditionally complement evaluation has been used for diagnosis. Diagnosis is established by nephelometry, turbidimetry, or radial immunodiffusion for quantitative measurement of C1 inhibitor, and chromogenic assay or ELISA has been used for functional C1-INH analysis. Wrong handling of the samples can lead to misdiagnosis and, consequently, mistaken inappropriate approaches. Dried blood spot (DBS) tests have been used for decades in newborn screening for certain metabolic diseases, and there has been growing interest in their use for other congenital conditions. Recently, DBS is now proposed as an efficient tool to diagnose HAE with C1 inhibitor deficiency, and its use would improve the access to outbound areas and family members. Regarding HAE with normal C1 inhibitor, complement assays' results are normal and the genetic sequencing of target genes, such as exon 9 of F12 and PLG, is the only available method. New methods to measure cleaved high-molecular-weight kininogen and activated plasma kallikrein have emerged as potential biochemical tests to identify bradykinin-mediated angioedema. Validated biomarkers of kallikrein-kinin system activation could be helpful in differentiating mechanisms of angioedema. Our aim is to focus on the capability to differentiate histaminergic AE from bradykinin-mediated AE. In addition, we will describe the challenges developing specific tests like direct bradykinin measurements. The need for quality tests to improve the diagnosis is well represented by the variability of results in functional assays.
Assuntos
Angioedema/diagnóstico , Angioedemas Hereditários/diagnóstico , Erros de Diagnóstico/prevenção & controle , Angioedema/sangue , Angioedema/imunologia , Angioedemas Hereditários/sangue , Angioedemas Hereditários/genética , Angioedemas Hereditários/imunologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Bradicinina/sangue , Bradicinina/imunologia , Bradicinina/metabolismo , Proteína Inibidora do Complemento C1/análise , Proteína Inibidora do Complemento C1/genética , Proteína Inibidora do Complemento C1/metabolismo , Análise Mutacional de DNA , Diagnóstico Diferencial , Teste em Amostras de Sangue Seco/métodos , Ensaio de Imunoadsorção Enzimática , Fator XII/genética , Humanos , Mutação , Plasminogênio/genética , RecidivaRESUMO
PURPOSE: Hereditary Angioedema was first described by William Osler in 1888 and it is caused by a hereditary or acquired deficiency of C1 esterase inhibitor (C1-INH). Treatment is indicated for acute attacks or prophylaxis of angioedema which occur in the subcutaneous tissue respiratory or gastrointestinal tracts. Treatment includes attenuated androgens, inhibitors of kininogen or plasminogen, like tranexamic acid or e-aminocaproic acid and the administration of C1-INH concentrate. We describe the peculiarities of the treatment chosen for 10 patients (4 families) with HAE and their evolution. METHODS: Ten patients (1-38 years old) with HAE were diagnosed by clinical history and laboratory evaluation. The following tests were performed for the complement system: C1-INH, C4 and C3 levels and hemolytic assay (CH50 and APH50) for the classic and alternative pathways. Treatment was initiated considering severity of symptoms, age, gender and therapeutic response of the patient. RESULTS: Clinical evaluation showed: 4/10 patients with recurrent subcutaneous edema; 3/10 with previous laryngeal edema and 3/10 with sporadic symptoms. Different severity of symptoms was verified in the same family. The laboratory evaluation detected: low C1-INH levels (10/10); low serum C4 level (8/10); undetectable CH50 (3/10) and low CH50 levels (6/10); low APH50 levels (2/10). Six out of ten patients did not receive any specific treatment and 2 of them had high risk of asphyxia. One adolescent had been controlled with e-aminocaproic acid, one child had been changed from danazol to tranexamic acid, a 30 year old female patient had received oxandrolone and a 38 year old man had been treated with danazol. CONCLUSIONS: Although HAE is caused by the same defect and affects members of the same family, various approaches have been taken to treat these patients. We observed different alternatives of prophylactic therapy for HAE, of which some did not require drug therapy.
Assuntos
Angioedema/tratamento farmacológico , Proteínas Inativadoras do Complemento 1/deficiência , Proteínas Inativadoras do Complemento 1/uso terapêutico , Adolescente , Adulto , Fatores Etários , Ácido Aminocaproico/uso terapêutico , Androgênios/uso terapêutico , Angioedema/sangue , Angioedema/genética , Antifibrinolíticos/uso terapêutico , Criança , Pré-Escolar , Danazol/uso terapêutico , Relação Dose-Resposta a Droga , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Masculino , Oxandrolona/uso terapêutico , Linhagem , Índice de Gravidade de Doença , Fatores Sexuais , Ácido Tranexâmico/uso terapêuticoRESUMO
Hereditary angioedema is caused by a defect in C1 inhibitor activity (C1INH). Its occurrence is rare and it is associated with an autosomal dominant mode of inheritance. We describe seven patients (4M:3F), age from 12 to 50 years old, who are affected by hereditary angioedema; four of them belong to the same family. The main clinical manifestations were: angioedema of face, hands and feet (6/7) and abdominal pain (2/7). No triggering factors were associated with symptoms in 4/7 patients and trauma (2/7) and menses (1/7) were reported in the other three ones. One patient was submitted to laparotomy for partial intestinal resection, before diagnosis. Laboratory complement analysis revealed the absence of hemolytic function of complement, reduced C4 (6/7) and low C1INH levels. All patients received Danazol (100 mg/day) with clinical control. Hereditary angioedema has to be considered in the differential diagnosis of angioedema, since an early diagnosis of this immunodeficiency, leading to specific treatment in order to decrease the complications.
Assuntos
Angioedema/genética , Proteínas do Sistema Complemento/análise , Adulto , Angioedema/sangue , Angioedema/diagnóstico , Proteínas Inativadoras do Complemento 1/análise , Complemento C3/análise , Complemento C4/análise , Ensaio de Atividade Hemolítica de Complemento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores DesencadeantesRESUMO
Hereditary angioedema (HAE), an autosomal disorder caused by a deficiency of C1 inhibitor, is characterized by attacks of localized swelling, laryngeal edema, or abdominal pain. Plasma samples from one pregnant patient were studied serially by functional and quantitative immunochemical assays as well as immunoblot assays for high molecular weight kininogen (HMWK) and/or prekallikrein/kallikrein (PK/K). An immunoblot of this patient's HMWK from plasma obtained before she became pregnant and when she was well revealed that it was mostly an intact protein of 120 kd, similar to immunoblot results of normal plasma HMWK. In plasma samples taken throughout her pregnancy, before, during, and after clinical attacks of angioedema, all of her plasma HMWK was shown to be cleaved into the 45 kd light chain form. After delivery of the infant the 120 kd form of intact plasma HMWK returned to her plasma. In comparison, immunoblot studies on 21 normal and abnormal pregnancies revealed that plasma HMWK was an intact protein at 120 kd. That this patient's plasma during her pregnancy was contact activated was determined by additional immunoblot studies for PK/K. Immunoblot assay for plasma PK/K revealed kallikrein-alpha 2-macroglobulin complexes and a 50 kd PK/K form seen only in activated plasma samples. The findings of kallikrein-alpha 2-macroglobulin complexes and a 50 kd PK/K form disappeared after delivery. These combined studies on this patient show that the structures of HMWK and prekallikrein as indicated by immunoblot assays were altered during pregnancy. Immunoblot assays for detection of changes in the structure of HMWK and prekallikrein may be objective laboratory studies for documenting clinical attacks of hereditary angioedema, their onset, and their resolution.