Clinical features of hereditary angioedema and warning signs (H4AE) for its identification

Abstract Objectives The study describes a case series of hereditary angioedema with C1 Inhibitor Deficiency (C1INH-HAE) in order to corroborate six clinical warning signs "HAAAAE (H4AE)" to enable early identification of this disease. Methods The authors analyzed the C1INH-HAE cohort to analyze the clinical aspects of the present study's patients and corroborate the six clinical warning signs of the Hereditary Angioedema Brazilian Guidelines. Data regarding demographics, the onset of disease, time to diagnosis, frequency of attacks per year, organs involved, triggers, crisis duration and their outcomes, and disease treatment were collected. Then the authors developed an acronym, H4AE, to help healthcare professionals remember the warning signs. Results The authors included 98 patients in the study, with a mean age of 38.1 years, 67.3% being female, and 75.3% with a family history of HAE. HAE diagnosis was delayed, on average, 13.7 years after its initial manifestation. Exploratory laparotomy was reported by 26.9%, and orotracheal intubation by 21.3% of the present study's patients; 61.3% and 30.3% of them were admitted at least once in the hospital and in the intensive care unit, respectively. The authors constructed an acronym "H4AE" with the six warning signs of HAE: Hereditary, recurrent Angioedema, Abdominal pain, Absence of urticaria, Absence of response to antihistamines, Estrogen association. Conclusion C1INH-HAE is still underdiagnosed and associated with high morbidity. The study showed clinical features of this disease, corroborating the warning signs, which may be useful in raising awareness and improving the diagnosis of C1INH-HAE. The authors suggest the acronym "H4AE" to remind the warning signs.

Angioedema hereditario tipo III en una embarazada: a propósito de un caso / Hereditary angioedema type III in pregnant women: case report and literature review

Resumen ANTECEDENTES: El angioedema hereditario es una enfermedad rara, caracterizada por episodios recurrentes de edema en cualquier parte del cuerpo, sobre todo en las extremidades, la cara y las vías respiratorias. Existen tres tipos de enfermedad en función de su causa, el menos frecuente es el III con un nivel y función del inhibidor de C1 normales. Su fisiopatología es poco conocida; por lo tanto, su diagnóstico es difícil. Su tratamiento ha avanzado en los últimos años, aunque queda mucho por definir, sobre todo durante el embarazo. OBJETIVO: Evaluar la bibliografía disponible relacionada con el angioedema hereditario y su atención médica en mujeres embarazadas. CASO CLÍNICO: Paciente de 30 años, en curso de su primer embarazo. El único antecedente personal destacable fue haber padecido angioedema hereditario tipo III, diagnosticado 10 años antes después de varios episodios de angioedema orofacial. A lo largo del embarazo sobrevinieron varias crisis de la enfermedad que requirieron tratamiento de los episodios agudos y de mantenimiento en el tercer trimestre. Por último, ocurrió un parto instrumentado mediante vaccum, por riesgo de pérdida de bienestar fetal con buen desenlace materno y fetal en el posparto inmediato. CONCLUSIONES: El angioedema hereditario tipo III es una enfermedad muy rara y poco conocida en la Ginecoobstetricia que requiere establecer un protocolo y estandarización de la atención clínica, sobre todo en las embarazadas, lo que ayudará a proporcionar una información y asistencia de calidad a estas pacientes.

Abstract BACKGROUND: Hereditary angioedema is a rare disease characterized by recurrent episodes of edema anywhere in the body, especially in the extremities, face and airways. There are three types of the disease depending on its cause, the most infrequent being III with normal C1 inhibitor level and function. Its pathophysiology is poorly understood; therefore, its diagnosis is difficult. Its treatment has advanced in recent years, although much remains to be defined, especially during pregnancy. OBJECTIVE: To evaluate the available literature related to hereditary angioedema and its medical care in pregnant women. CLINICAL CASE: 30-year-old female patient, during her first pregnancy. The only personal history of note was hereditary angioedema type III, diagnosed 10 years earlier after several episodes of orofacial angioedema. Throughout the pregnancy, several crises of the disease occurred, requiring treatment in acute episodes and maintenance treatment in the third trimester. Finally, one delivery was instrumented by vaccum, due to risk of loss of fetal well-being with good maternal and fetal outcome in the immediate postpartum period. CONCLUSIONS: Hereditary angioedema type III is a very rare and little-known disease that requires establishing a protocol and standardization of clinical care, especially in pregnant women, which will help to provide quality information and assistance to these patients.

Hereditary angioedema: how to approach it at the emergency department? / Angioedema hereditário: como abordar na emergência?

ABSTRACT Angioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor (ecallantide). In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes.

RESUMO As crises de angioedema são causas comuns de atendimentos nas emergências, e devido ao potencial de gravidade, é importante que os profissionais que atuam nesses serviços conheçam suas causas e abordagem. Os mecanismos envolvidos no angioedema sem urticas podem ser histaminérgicos ou mediados por bradicinina. As causas mais comuns de angioedema mediado por histamina são alimentos, medicamentos, ferroada de insetos e idiopática. Quando o mediador é a bradicinina, os desencadeantes são os inibidores da enzima conversora de angiotensina e fatores relacionados ao angioedema adquirido com deficiência do inibidor de C1 ou angioedema hereditário que são menos comuns, mas muito importantes pela possibilidade de desfecho fatal. O angioedema hereditário é uma doença rara, caracterizada por crises de edema que acometem o tecido subcutâneo e mucosas de vários órgãos, manifestando-se principalmente por crises de angioedema e dor abdominal. Esse tipo de angioedema não responde ao tratamento usual com adrenalina, anti-histamínicos e corticosteroides. Assim, se não identificados e tratados adequadamente, esses pacientes têm risco de morte por edema de laringe estimado em 25% a 40%. O tratamento do angioedema hereditário mudou drasticamente nos últimos anos, com o desenvolvimento de novos e eficientes fármacos para as crises: inibidor de C1 derivado de plasma, inibidor de C1 recombinante humano, antagonista do receptor B2 da bradicinina (icatibanto) e o inibidor da calicreína (ecalantide). No Brasil, até o momento, estão liberados para uso o inibidor de C1 derivado de plasma e o icatibanto. O manejo correto desses pacientes na emergência evita cirurgias desnecessárias e, principalmente, desfechos fatais.

Hereditary angioedema caused by C1-esterase inhibitor deficiency: a case report with literature-based analysis

Hereditary angioedema (HAE) caused by C1-esterase inhibitor deficiency is an autosomal-dominant disease caused by a mutation in the C1-inhibitor gene. It is a rare disease that is often worsened during pregnancy and childbirth. HAE, though uncommon but if untreated it may lead to maternal death.  The case report presents the successful management of a 24 years old, G2P1, with hereditary angioedema caused by C1-esterase inhibitor deficiency. This patient was managed with a multidisciplinary approach by an obstetrician, an immunologist, an anaesthesiologist and a pediatrician. She had an uneventful antenatal period, labor was induced. She had precipitate delivery and soon after delivery had a flare up of the disease. It was successfully managed with fresh frozen plasma and close observation.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Outcomes of long term treatments of type I hereditary angioedema in a Turkish family

Abstract: Background: Hereditary angioedema is a rare autosomal dominantly inherited immunodeficiency disorder characterized by potentially life-threatening angioedema attacks. Objective: We aimed to investigate the clinical and genetic features of a family with angioedema attacks. Methods: The medical history, clinical features and C1-INH gene mutation of a Turkish family were investigated and outcomes of long-term treatments were described. Results: Five members had experienced recurrent swellings on the face and extremities triggered by trauma. They were all misdiagnosed as familial Mediterranean fever (FMF) depending on frequent abdominal pain and were on colchicine therapy for a long time. They had low C4 and C1-INH protein concentrations and functions. A mutation (c.1247T>A) in C1-INH gene was detected. They were diagnosed as having hereditary angioedema with C1-INH deficiency (C1-INH hereditary angioedema) for the first time. Three of them benefited from danazol treatment without any significant adverse events and one received weekly C1 esterase replacement treatment instead of danazol since she had a medical history of thromboembolic stroke. Study limitations: Small sample size of participants. Conclusion: Patients with C1-INH hereditary angioedema may be misdiagnosed as having familial Mediterranean fever in regions where the disorder is endemic. Medical history, suspicion of hereditary angioedema and laboratory evaluations of patients and their family members lead the correct diagnoses of hereditary angioedema. Danazol and C1 replacement treatments provide significant reduction in hereditary angioedema attacks.

Treatment of hereditary angioedema due to C1 inhibitor deficiency in Argentina

The benefits of the worldwide approval of new drugs for the treatment of acute C1-INH-HAE attacks may still not reach all patients. Identifying the current barriers in the access to medication, as well as conducting a detailed assessment of the progress in this area, is essential to achieve universal treatment. Two hundred and twenty five patients registered in the Argentina Hereditary Angioedema Patient Association (AHAEPA) were randomly selected and invited to participate in a web based questionnaire on accessibility to icatibant and pdC1-INH, self-treatment, delay to treatment, and coverage. The data retrieved was compared to our previous reports in 2008 and 2013. We collected 156/225 answers. One hundred and eighteen (76%) patients have either pdC1-INH (n = 86), icatibant (n = 10) or both (n = 22), while 38 (24%) do not have access to treatment. In 2008, 26% had access while 82% had it in 2013. Thirty-two subjects (22%) self-inject themselves, similar to 29% in 2013, even though between studies, widespread self-injection training activities have taken place. However, considering injections by proxy, home treatment reached 56%. Only half of the patients decide to receive treatment early during the attack. Ninety-nine patients (63%) have full coverage, thirty (19%) have no coverage at all and the rest only obtain partial reimbursement. Twenty-nine families (31%) share a single treatment dose of the medication, better than 36% in 2013. Argentina's C1-INH-HAE patients had a sustained improvement in their access to medication. Efforts should continue to further improve accessibility and optimal management of HAE acute attacks to all patients in the country.

La aprobación mundial de los medicamentos para el ataque agudo del angioedema hereditario (HAE) no beneficia a todos los pacientes. Es necesario conocer las barreras de acceso a la medicación para el tratamiento universal. Doscientos veinticinco pacientes, registrados en la Asociación de Pacientes con Angioedema Hereditario (AHAEPA), fueron encuestados por internet acerca de su accesibilidad al icatibant y al concentrado del inhibidor de C1 (pdC1-INH), a la auto inyección de la medicación, al retraso del tratamiento y a la cobertura del medicamento. Comparamos esta información con la obtenida en nuestros estudios de 2008 y 2013. Recolectamos 156/225 respuestas. Ciento dieciocho (76%) pacientes tienen pdC1-INH (n = 86), icatibant (n = 10) o ambos (n = 22), mientras que 38 (24%) no tienen medicación. En 2008, 26% tenían acceso y en 2013, 82%. Treinta y dos (22%) se autoinyectan la medicación, similar al 29% en 2013. Sumando las aplicaciones por profesionales de la salud o familiares en la casa, el tratamiento fuera de las instituciones médicas alcanza el 56%. Solo la mitad decide tratarse tempranamente. Noventa y nueve (63%) tiene cobertura del 100%, 30 (19%) no tiene ningún tipo de cobertura, y el resto la tiene en forma parcial. Veintinueve familias (31%), solo tienen una dosis de tratamiento para todos, mejor que el 36% en 2013. Los pacientes con C1-INH-HAE han tenido una mejoría sustancial en el acceso a la medicación. Igualmente, los esfuerzos deben continuar para mejorar la accesibilidad y tratamiento óptimo de todos.

Angioedema hereditario / Hereditary angioedema

El angioedema hereditario es una enfermedad poco frecuente, con herencia autosómica dominante que se caracteriza por presentar edemas en piel y en la mucosa de diferentes órganos, fundamentalmente el tubo digestivo y el aparato respiratorio. Las manifestaciones clínicas pueden ser ligeras o graves, en dependencia de su intensidad y localización. Las formas más graves son el edema de la glotis y del tubo digestivo, que llegan a ocasionar síntomas como deshidratación intensa y dolor abdominal, el que puede confundirse con un abdomen agudo y llevar a una intervención quirúrgica innecesaria. El edema se caracteriza por no ser pruriginoso, no presentar aumento de la temperatura, no dejar godet al presionarlo y generalmente existen antecedentes familiares. No tiene predilección por sexo, ni por el color de la piel. Para su diagnóstico es necesario hacer un interrogatorio minucioso y exámenes complementarios del sistema complemento. Se han descrito dos formas clásicas denominadas angioedema hereditario tipo I y tipo II, el primero es el más frecuente. Recientemente se ha descrito el tipo III que se presenta solo en mujeres, sin alteración cuantitativa o cualitativa de C1-inhibidor y se asocia con el consumo de medicamentos o anticonceptivos orales que contienen estrógenos. El tratamiento se basa fundamentalmente en el uso de andrógenos atenuados o de los antifibrinolíticos, así como evitar los factores de riesgo en caso de que estos se conozcan. En los casos que presenten cuadros agudos se puede utilizar el plasma fresco congelado y un concentrado purificado de C1- inhibidor (Berinert-500) de uso endovenoso y de respuesta rápida; aunque sin ser muy efectiva se puede usar la epinefrina subcutánea. Los esteroides y los antihistamínicos no tienen ninguna efectividad en el tratamiento de estos pacientes(AU)

Hereditary angioedema is a rare disease with autosomal dominant inheritance that is characterized by edema in skin and mucosa of various organs, mainly gastrointestinal tract and the respiratory system. Clinical manifestations may be mild or severe, depending on their location and intensity. The most severe forms are edema of the glottis, and the edema of gastrointestinal tract which can cause severe dehydration and abdominal pain that can be confused with an acute abdomen and unnecessary surgery. The edema is characterized by not being itchy, no temperature rise, non-marking when pressed and usually have a family history. No predilection for sex, or skin color. Its diagnosis is necessary to make a thorough examination and additional tests of the complement system. They described two classic forms called HAE type I and type II, type I is the most common. Recently it described the type III that occurs only in females, without quantitative or qualitative alteration of C1 inhibitor and is associated with the consumption of drugs or oral contraceptives containing estrogen. The treatment is based primarily on the use of attenuated androgens or antifibrinolytic and avoiding risk factors if they are known. In cases of acute conditions present you can use fresh frozen plasma and purified C1 inhibitor concentrate (Berinert-500) for intravenous use and rapid response; but the use of subcutaneous epinephrine may not be very effective. Steroids and antihistamines have no effectiveness when used in these patients(AU)

Angioedema hereditario en Medellín, Colombia: evaluación clínica y de la calidad de vida / Hereditary angioedema in Medellín (Colombia): Clinical evaluation and quality of life appraisal

Introducción. El angioedema hereditario es una inmunodeficiencia primaria de carácter autosómico dominante, debida a un déficit en la proteína inhibidora del factor C1 y caracterizada por episodios recurrentes de edema subcutáneo y de las mucosas. Las impredecibles y frecuentes crisis de angioedema afectan la calidad de vida de los individuos que las padecen. Objetivo. Analizar las características clínicas de una familia con un caso índice de angioedema hereditario y determinar el impacto de la enfermedad en la calidad de vida. Materiales y métodos. En el estudio se incluyeron 26 miembros de la familia, a 25 de los cuales se les midieron los niveles sanguíneos del factor C4 del complemento y del inhibidor de C1 antigénico y funcional. Se utilizaron dos instrumentos, el SF-36 para evaluar la salud del adulto y el KIDSCREEN-27 para la calidad de vida de niños y adolescentes. Resultados. El 83 % de los individuos que reportaron síntomas cumplían con los criterios serológicos del angioedema hereditario de tipo I: valores bajos del factor C4 del complemento y del inhibidor de C1 cuantitativo (antigénico) y cualitativo (funcional). Se encontró que la calidad de vida en cuanto al bienestar psicológico y el desempeño emocional de los pacientes, se veía considerablemente afectada por los síntomas de la enfermedad. Conclusión. Este estudio provee información sobre la primera familia caracterizada con angioedema hereditario de tipo 1 en el Valle de Aburrá, Colombia. Aunque para ello se usó un instrumento genérico, se confirmó, además, el efecto negativo de la enfermedad en la calidad de vida de los individuos que la padecen.

Introduction: Hereditary angioedema is an autosomal dominant primary immunodeficiency caused by a deficiency of the C1 inhibitor protein and characterized by recurrent episodes of subcutaneous and mucosal edema. Unpredictable and frequent crisis of angioedema affect the quality of life of individuals suffering this kind of disorder. Objective: To analyze the clinical characteristics of a family with an index case of hereditary angioedema and to determine the impact of this disease on their quality of life. Materials and methods: Twenty six members of the family were included in the trial; 25 of them were analyzed for C4 complement and antigenic and functional C1 inhibitor blood levels. Two instruments (SF-365 and KIDSCREEN-27) were used to evaluate adult health quality and children and teenagers quality of life, respectively. Results: Eighty three percent (83%) of individuals reporting symptoms of the condition exhibited serological criteria of hereditary angioedema type I: low levels of both C4 complement and quantitative (antigenic) and qualitative (functional) C1 inhibitor. In relation to patients' psychological and emotional performance, their quality of life was significantly affected by the symptoms of hereditary angioedema. Conclusion: This study provides evidence of the first family in Valle de Aburrá (Colombia) characterized as having hereditary angioedema type I. Despite the use of a generic instrument, the negative impact on the quality of life of individuals suffering this disease was also confirmed.

Icatibant, an inhibitor of bradykinin receptor 2, for hereditary angioedema attacks: prospective experimental single-cohort study / Icatibanto, um inibidor de receptor 2 de bradicinina, para ataques de angioedema hereditário: estudo experimental prospectivo de coorte sem grupo controle

CONTEXT AND OBJECTIVE: Hereditary angioedema (HAE) with C1 inhibitor deficiency manifests as recurrent episodes of edema involving the skin, upper respiratory tract and gastrointestinal tract. It can be lethal due to asphyxia. The aim here was to evaluate the response to therapy for these attacks using icatibant, an inhibitor of the bradykinin receptor, which was recently introduced into Brazil. DESIGN AND SETTING: Prospective experimental single-cohort study on the efficacy and safety of icatibant for HAE patients. METHODS: Patients with a confirmed HAE diagnosis were enrolled according to symptoms and regardless of the time since onset of the attack. Icatibant was administered in accordance with the protocol that has been approved in Brazil. Symptom severity was assessed continuously and adverse events were monitored. RESULTS: 24 attacks in 20 HAE patients were treated (female/male 19:1; 19-55 years; median 29 years of age). The symptoms were: subcutaneous edema (22/24); abdominal pain (15/24) and upper airway obstruction (10/24). The time taken until onset of relief was: 5-10 minutes (5/24; 20.8%); 10-20 (5/24; 20.8%); 20-30 (8/24; 33.4%); 30-60 (5/24; 20.8%); and 2 hours (1/24; 4.3%). The time taken for complete resolution of symptoms ranged from 4.3 to 33.4 hours. Adverse effects were only reported at injection sites. Mild to moderate erythema and/or feelings of burning were reported by 15/24 patients, itching by 3 and no adverse effects in 6. CONCLUSION: HAE type I patients who received icatibant responded promptly; most achieved improved symptom severity within 30 minutes. Local adverse events occurred in 75% of the patients. .

CONTEXTO E OBJETIVO: O angioedema hereditário (AEH) com deficiência de inibidor de C1 manifesta-se por episódios recorrentes de edema envolvendo pele, trato respiratório superior e gastrointestinal. Pode ser letal por asfixia. O objetivo foi avaliar a resposta à terapia dos ataques com icatibanto, inibidor do receptor de bradicinina, recentemente introduzido no Brasil. TIPO DE ESTUDO E LOCAL: Estudo experimental prospectivo de coorte, sem grupo controle, da eficácia e segurança do icatibanto em paciente com AEH. MÉTODOS: Pacientes com diagnóstico confirmado de AEH foram incluídos de acordo com os sintomas, independentemente do tempo de início do ataque. Icatibanto foi administrado segundo protocolo aprovado no Brasil. A gravidade do sintoma foi estabelecida continuamente e os eventos adversos foram monitorados. RESULTADOS: 24 ataques em 20 pacientes com AEH foram tratados (19 F:1 M; 19-55 anos; mediana 29 anos). Os sintomas foram: edema subcutâneo (22/24), dor abdominal (15/24) e obstrução de vias aéreas superiores (10/24). O tempo para o início do alívio foi: 5-10 minutos, 5/24 (20,8%); 10-20, 5/24 (20,8%); 20-30, 8/24 (33,4%); 30-60, 5/24 (20,8%) e 2 horas, 1/24 (4,3%). O tempo para a resolução completa variou de 4,3-33,4 horas. Somente efeitos adversos nos locais das injeções foram relatados. Eritema leve a moderado e/ou sensação de ardor foram relatados por 15/24 pacientes, prurido em 3, e 6 não tiveram efeitos adversos. CONCLUSÃO: Pacientes com AEH tipo I receberam icatibanto com pronta resposta; a maioria teve melhora na gravidade dos sintomas em 30 minutos. Eventos adversos locais ocorreram em 75% dos pacientes. .

Angioedema hereditario: Tratamiento del ataque agudo en la Argentina / Hereditary angioedema: Treatment of acute attacks in Argentina

En el mundo, el angioedema hereditario (HAE) afecta a 1 de cada 50 000 personas. Produce episodios de angioedema cutáneo, abdominal y laríngeos que generan gran incapacidad. La mortalidad por la enfermedad oscila entre 15 y 50%. Aunque en Argentina un concentrado plasmático de C1 inhibidor (pdC1INH) ha estado aprobado y disponible por décadas para el tratamiento del ataque agudo, solo 15 (26%) de 58 pacientes había recibido pdC1INH alguna vez hasta el año 2008, y solo 2(3.4%) lo usaban regularmente. Luego de la aprobación de los nuevos medicamentos para HAE, incluido el icatibant en Argentina y de la publicación de las guías terapéuticas, 42 (82%) de 51 pacientes del grupo original tienen pdC1INH para tratar el próximo ataque. Sin embargo, 16 (18%) de estos pacientes continúan sin acceso a la medicación y otros 15 (35.7%) acceden a través de otro enfermo en forma espuria. Solo 12 (28.6%) de los pacientes con el medicamento puede auto tratarse en su domicilio. La mejora en el acceso a la medicación es importante pero debe extenderse a todos los afectados y facilitarse el auto-tratamiento.

In the world, hereditary angioedema (HAE) affects 1every 50 000 persons. It is characterized by highly disabling and recurrent episodes of cutaneous, abdominal and laryngeal episodes of angioedema. Asphyxia related mortality ranges from 15 to 50%. In Argentina a plasma derived C1 inhibitor concentrate (pdC1INH) has been available for the treatment of acute attacks for many decades, however, only15 (26%) out of 58 patients had received pdC1INH at least once until 2008, and only2 (3.4%) had used it regularly. After worldwide approval of the new drugs for the treatment of acute HAE attacks, adding icatibant to pdC1INH in Argentina, and after publication of the therapeutic guide for the country, 42 (82%) out of 51 patients from the original group has pdC1INH available to treat their next attack. However, 16 (18%) patients continue without access to medication and other 15 (35.7%) obtain their therapy spuriously through some other affected relative in their environment. Only 12 (28.6%) patients of the group self-treated at home. Access to treatment has greatly improved, but needs to be extended to all patients and self-treatment at home should be encouraged.

Clinical Significance of Plasma Protease C1 Inhibitor in Latent Autoimmune Diabetes in Adults / 天津医药

Objective To examine plasma levels of protease C1 inhibitor (SERPING1) in adult patients with latent autoimmune diabetes (LADA), and their clinical significance thereof. Methods The levels of SERPING1 were detected and compared between LADA, type 1 diabetes (T1DM), type 2 diabetes (T2DM) and healthy control groups. The correlation between plasma levels of SERPING1 and other clinical indicators such as age, disease course, glycosylated hemoglobin (HbA1c), fasting blood glucose (FPG), 2 h postprandial plasma glucose (2 hPG), fasting c-peptide (FCP) and 2 h postprandi-al C peptide (2 hCP) was analyzed. Multi-factor regression analysis and receiver operating characteristic (ROC) were used to evaluate the predictive effect of SERPING1 in LADA at the early stage. Results The level of SERPING1 was significantly higher in LADA group than that of T2DM group and control group (P < 0.05). There was a negative correlation between SERPING1 and FCP, and a positive correlation between SERPING1 and HbA1c, FPG and 2 hPG (P<0.05). There were no significant correlation between SERPING1 and age, disease course and 2 hCP. FCP was analyzed by regression equation (P<0.05), and which was the main influence factor of the plasma level of SERPING1. The area under the ROC curve (AUC) of SERPING1 was 0.613 (P<0.05), 95%CI 0.514-0.712. The optimal cut-point of SERPING1 for early prediction of LADA was 289.71 mg/L, and the sensitivity and specificity were 69%and 48%respectively. Conclusion SERPING1 combined with other indicators will be useful for identifying LADA from T2DM at the early stage.

Angioedema hereditario: Guía de tratamiento / Hereditary angioedema: A therapeutic guide

El angioedema hereditario (HAE) es una enfermedad rara, autosómica dominante, caracterizada por episodios que comprometen la piel, el tracto gastrointestinal y la laringe. Tiene una mortalidad histórica por asfixia del 15 al 50%. Es producida por la deficiencia funcional del C1 inhibidor. La identificación de la bradiquinina como mediador principal ha estimulado el desarrollo de nuevos medicamentos para tratar la enfermedad. El tratamiento del HAE se establece en consensos internacionales. El desarrollo de guías para el tratamiento de la enfermedad permite ordenar el uso de procedimientos diagnósticos y drogas. Describimos aquí algunas características farmacológicas de los medicamentos utilizados en el tratamiento del HAE en la Argentina: el concentrado plasmático de C1 inhibidor, el antagonista de la bradiquinina, icatibant, el andrógeno atenuado danazol y los agentes anti-fibrinolíticos ácidos épsilon aminocaproico (EACA) y tranexámico. Asimismo, se describe su forma de uso y del control de los eventos adversos más frecuentes, así como las recomendaciones del último consenso internacional, aplicables para conformar una primera guía de tratamiento del HAE en la Argentina.

Hereditary angioedema (HAE) is a rare autosomal dominant disease, characterized by episodes of edema involving the skin, gastrointestinal tract and larynx. HAE has a historical asphyxia mortality of 15% to 50%. It is the consequence of functional C1 inhibitor deficiency. The identification of bradykinin as the principal mediator of the disease has lead to the development of new drugs for its treatment. HAE management and treatment are agreed by international consensus decision. A therapeutic guide for the treatment of the disease is important to improve diagnosis and treatment. We here describe the pharmacology of drugs available for the treatment of HAE in Argentina: plasma derived C1 Inhibitor, the bradykinin antagonist: icatibant, the attenuated androgen danazol and the anti-fibrinolytic agents epsilonaminocaproic acid and tranexamic acid. Furthermore, we describe drug use and adverse effects control, as well as the last international consensus document recommendations applicable to Argentina to conform a first guide to HAE treatment in our country.

Angioedema hereditario / Hereditary angioedema

Se presenta el caso de una mujer de 46 años, quien consulta por lesiones dérmicas episódicas de 28 años de evolución, consistentes en edema doloroso ocasionalmente pruriginoso, súbito, recurrente, familiar, que compromete varias regiones corporales incluyendo la laringe. Por la gravedad de los episodios ha requerido repetidas hospitalizaciones en las que se ha recuperado mediante tratamiento sintomático. Se encuentran valores séricos de C3 165.5 mg/dL, C4 1 mg/dL, CH50 < 256 U, e inhibidor de C1 38 mg/dL. Se realiza diagnóstico de angioedema hereditario tipo I y se inicia tratamiento con antifibrinolíticos y andrógeno con mejoría de los síntomas. Se hace énfasis en la necesidad de sospechar la enfermedad clínicamente en pacientes con episodios recurrentes de angioedema sin urticaria con el fin de instaurar el tratamiento adecuado, por falla en dicha sospecha, dos de los familiares de la paciente infortunadamente fallecieron. (Acta Med Colomb 2012; 37: 34-37).

A 46 year-old woman affected by familiar, recurrent episodes of skin lesions with painful, occasionally pruriginous angioedema who had been hospitalized because of laryngeal compromise is presented. Laboratory results include C3: 165.5 mg/dL, C4: 1 mg/dL, CH50 < 256 Units, and C1 inhibidor 38 mg/dL. Hereditary angioedema Type I is diagnosed, patient is currently on treatment with anti-fibrynolytic and androgen, obtaining clinical improvement. A clinical emphasis in the diagnosis of Hereditary angioedema is performed since misdiagnosis of this disease may lead to death as it happened to two patients's relatives. (Acta Med Colomb 2012; 37: 34-37).

Migraine-like Headache in a Patient with Complement 1 Inhibitor Deficient Hereditary Angioedema

We report on an angioedema patient with a genetic defect in complement 1 inhibitor, manifesting migraine-like episodes of headache, effective prophylaxis with Danazol, and triptan for a treatment of acute clinical episode. The patient was 44-yr-old Korean man with abdominal pain and headache, who was brought into the Emergency Department of Seoul National University Hospital, Seoul. He suffered from frequent attacks of migraine-like headache (3-7 per month), pulsating in nature associated with nausea. Severities were aggravated by activity and his headache had shown recent progression with abdominal pain. No remarkable findings were observed on radiologic examination, brain magnetic resonance images and intracranial and extracranial magnetic resonance angiography. Danazol 200 mg every other day was subsequently used. Following administration of Danazol, symptoms showed improvement and the patient was discharged. While taking Danazol, the migraine-like episodes appeared to be prevented for about 2 yr. At the eighth month, he suffered a moderate degree of migraine-like headache; however, administration of naratriptan 2.5 mg resolved his problem. A case of genetic defect of C1-INH deficiency presented with headache episodes, and was controlled by Danazol and triptan. It suggests that pathogenic mechanism of headache in hereditary angioedema may be mediated by the neurogenic inflammatory-like physiology of migraine.

Brazilian guidelines for the diagnosis and treatment of hereditary angioedema

Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with multiple organ involvement. It is caused by a quantitative or functional deficiency of the C1 inhibitor, which is a member of the serine protease inhibitor family. Hereditary angioedema is unknown to many health professionals and is therefore an underdiagnosed disease. The causes of death from hereditary angioedema include laryngeal edema with asphyxia. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40 percent. In addition to edema of the glottis, hereditary angioedema often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. It is estimated that patients with hereditary angioedema experience some degree of disability 20-100 days per year. The Experts in Clinical Immunology and Allergy of the "Associação Brasileira de Alergia e Imunopatologia -ASBAI" developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema.

Angioedema hereditario: Historia familiar y manifestaciones clínicas en 58 pacientes / Hereditary angioedema: Family history and clinical manifestations in 58 patients

El angioedema hereditario (AEH) es una enfermedad rara, autosómica dominante, caracterizada por episodios de angioedema que comprometen la piel, el tracto gastrointestinal y la laringe. Analizamos las características epidemiológicas y clínicas en una serie de 58 pacientes, 53 (91%) con diagnóstico de AEH tipo I y 5 (9%) con tipo II. La edad media al inicio fue de 10.8 ± 9.5 años (0.1 a 59) y de 25.8 ± 16.2 años (2 a 77) en el momento del diagnóstico, con un retraso diagnóstico de 15.3 ± 14.3 años. El promedio de ataques en los 6 meses previos a la consulta fue de 7.4 ± 7.6 (0 a 40). Cincuenta y cuatro (93%) presentaron ataques cutáneos, 50 (86%) abdominales, 24 (41%) laríngeos y 24 (41%) cutáneos y abdominales combinados. Veintisiete (46.5%) nunca utilizaron medicación preventiva para la enfermedad y 17 (29%) recibieron danazol en diferentes dosis por diferentes periodos de tiempo. Durante los ataques, 15 (26%) pacientes recibieron C1 inhibidor endovenoso alguna vez, 7 (12%) recibieron plasma fresco y 40 (69%) tratamiento sintomático. Ansiedad o situaciones de estrés y traumatismos fueron los desencadenantes más frecuentes. Identificamos a 6 (10%) pacientes como primera mutación y a 52 (90%) con historia familiar previa. Analizamos 20 troncos familiares identificando 205 individuos en riesgo de heredar la enfermedad, 109 (53%) de ellos con síntomas o diagnóstico AEH. El total de individuos con síntomas de AEH fue de 145, de los cuales 19 (13%) murieron por asfixia. Disminuir el retraso diagnóstico y ofrecer una terapéutica adecuada son desafíos a afrontar en el AEH.

Hereditary angioedema (HAE) is a rare autosomal dominant disease, characterized by episodes of edema typically involving the skin, gastrointestinal tract and larynx. We here describe the epidemiologic and clinical characteristic of a series of 58 patients with diagnosis of HAE, 53 (91%) type I and 5 (9%) type II. The mean age at first symptom was 10.8 ± 9.5 years and the mean age at diagnosis was 25.8 ± 16.2 years old, with a diagnosis delay of 15.3 ± 14.3 years. The mean number of attacks in the previous 6 months was 7.4 ± 7.6 range 0 to 40. Fifty four (93%) had cutaneous attacks, 50 (86%) abdominal attacks, 24 (41%) laryngeal attacks and 24 (41%) combined cutaneous and abdominal attacks. Twenty seven (46.5%) patients never received preventive treatments and 17 (29%) received danazol in different doses for different periods of time. During the attacks, 15 (26%) patients were treated with C1 inhibitor at least once, 7 (12%) with fresh frozen plasma and 40 (69%) received only supportive treatment. Stress and trauma were identified as attacks triggers. Six (10%) patients were first mutation and 52 (90%) had HAE ancestors. We reconstructed 20 kindred, identifying 205 individuals at risk of inheriting the disease, 109 (53 %) of them had signs or laboratory diagnosis of HAE. The total number of identified HAE individuals was 145, 19 (13%) died with asphyxia. So, shortening of diagnosis delay and appropriate treatment of HAE are a challenge to be fulfilled.

Expression Change of Complement Regulator Genes of the Human Astrocytoma Cell Line after A beta1-42 and Interferon Gamma Administration

BACKGROUND: We determined the changes of complement regulator gene expression in the amyloid-beta1-42(A beta1-42) and interferon-gamma(IFN-gamma)-stimulated human astrocytoma cell line. METHODS: The human astrocytoma cell line, U373MG, was stimulated with IFN-gamma(62.5-1,000U/ml) in the presence or absence of aggregated A beta1-42(1-20micrometer) for 24 hours. Messenger RNA expression of C1 inhibitor(C1-INH), complement factor I(CFI), clusterin, vitronectin, decay accelerating factor(DAF), membrane cofactor protein(MCP), and CD59 was measured by quantitative real-time reverse transcriptase-PCR. RESULTS: IFN-gamma(final concentration, 500U/ml) markedly increased the expression of mRNA for C1-INH in a time dependent fashion. A beta1-42(final concentration, 2micrometer) induced a slight increase in the expression of C1-INH. Messenger RNAs for CFI and clusterin were minimally increased, but other regulators were unchanged or decreased by either A beta1-42 or IFN-gamma. IFN-gamma overrode A beta1-42-induced mRNA expression of C1-INH when the cells were treated with these two reagents together. CONCLUSION: Among the complement regulator genes in the human astrocytoma cell line, U373MG, only C1-INH was significantly up-regulated by IFN-gamma with or without A beta1-42 administration.

Reactive Oxygen Species Production, Expression of Complement Regulator Genes and Phagocytosis in the Murine Microglial Cell after Administration of Beta-Amyloid(A beta1-42) Protein

BACKGROUND: Microglia is a primary cellular component of neuritic plaques in Alzheimer's disease. Beta amyloid deposits attract microglia and activate them to produce inflammatory mediators. The objectives of this study were to characterize activation of the microglia; production of reactive oxygen species (ROS), constitutive and upregulated expression of complement regulators, and intracellular localization of amyloid by phagocytosis. METHODS: BV-2 cells, mouse microglia cell line, were incubated for 3~18 hours with a single dose of 20 micro M of aggregated A beta1-42. ROS measurement was done with FACScan. Messenger RNA expressions of C1-INH, vitronectin, CD59, clusterin, factor H, and superoxide dismutase (SOD) were detected by RT-PCR. The intensity of bands from 6% polyacrylamide electrophoretic gel was analyzed by a bioimage analyzer. The intracellular localization of A beta in the phagocytosed microglia was observed by transmission electron microscope. RESULTS: A beta1-42 activates microglia with an increase of ROS production. Expression of mRNA for SOD was also increased. Messenger RNA for C1-INH and vitronectin were upregulated. A beta fibrils were located in the phagosome of microglia. CONCLUSIONS: A beta activated microglia are playing dual roles as effector and scavenger cell, which as a result, may contribute to the chronic neuroinflammation of Alzheimer's disease.

Androgênios atenuados e o tratamento do angioedema hereditário / Attenuated androgens and the treatment of hereditary angioedema

o angioedema hereditário (AEH) é uma patologia de curso crônico, que resulta da deficiência do inibidor de Cl (Cl-INH). Esta deficiência pode ser quantitativa (AEH tipo I) ou qualitativa (AEH tipo Ir). É caracterizado por edema recorrente, não pruriginoso, que pode acometer qualquer região do corpo: face,. laringe (levando a risco de morte por asfixia), extremidades, genitália, órgãos intra-abdominais (causando dor abdominal, vômitos, diarréia). O tratamento divide-se em profilático, a curto ou longo prazo, e sintomático, baseando-se sempre no impacto da doença na qualidade de vida e/ou risco de fatalidade para o paciente. As medicações utilizadas para uso crônico são os antifibrinolíticos e os androgênios atenuados. Estes últimos são geralmente mais eficazes. Esta revisão tem por objetivo abordar as principais opções terapêuticas para o tratamento do AEH, dando ênfase aos androgênios atenuados, que permanecem como drogas de primeira escolha pela sua eficácia e perfil de segurança. Para a realização deste artigo, foram consultadas publicações científicas nacionais e internacionais distribuídas em periódicos e livros-texto. As referências bibliográficas foram obtidas através da base de dados Pubmed, abrangendo o período de 1974 a 2007.

Hereditary Angioedema (AEH) is a long course pathology, which results from Cl-inhibitor (Cl-INH) deficiency. It can be a quantitative (AEH type I) or qualitative (AEH type Ir) deficiency. It is characterized by non-pruritic recurrent swellings in any part of the body: face, larynx (which could lead to death by asphyxia), extremities, genital area, abdominal organs (Ieading to abdominal pain, vomiting, diarrhea). Treatment is divided into prophylactic, short term or long term, and symptomatic, always based on the disease's impact on patient's quality of life and/or the risk of fatality. Medications used for long-term treatment are antifibrino/ytic agents and attenuated androgens. The latter usually are more effective. The aim of this review is to approach the main therapeutic options to be used in the treatment of AEH, emphasizing the attenuated androgens, which are still the first line option because of its efficacy and security.