RESUMO

Hereditary angioedema (HAE) is an autosomal dominant disease mostly due to the deficiency of C1 inhibitor (C1-INH). HAE with normal C1-INH was first described in 2000 and associated with mutations in the coagulation factor XII in 2006. Both diseases are associated with high bradykinin production, resulting in increased vascular permeability. Gastrointestinal edema due to HAE can be misdiagnosed as acute abdomen and unnecessary surgical procedures may be performed. The present study evaluates the prevalence of surgical procedures and/or acute abdomen in HAE patients with the coagulation factor XII mutation. It is a retrospective study where patients were diagnosed with recurrent angioedema without urticaria, normal C1-INH levels, and positive family history of angioedema. All patients were evaluated for the known mutations located at exon 9 of the F12 gene. Medical records were evaluated and questionnaires were applied to 52 patients with normal C1-INH levels (age range 13-76 years; 47/52, 90.38% women; 5/52, 9.61% men). F12 mutation was present in 32/52 patients (61.5%). Acute abdominal pain was diagnosed in 16/52 (30.76%) patients, appendicitis in 9/16 (56.2%), and undetermined diagnosis in 7/16 (43.7%). Among patients diagnosed with acute abdominal pain, 13/16 (81.2%) underwent surgery and 3/16 (18.7%) improved without surgical intervention. We conclude that many HAE patients with coagulation factor XII mutation were misdiagnosed with acute abdomen and subjected to unnecessary invasive procedures. It is critical to disseminate information about this rare mutation in patients with otherwise normal C1-INH activity, in order to speed up diagnosis and avoid misconduct.

Assuntos

Abdome Agudo , Angioedema , Angioedemas Hereditários , Dor Abdominal , Adolescente , Adulto , Idoso , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/genética , Proteína Inibidora do Complemento C1 , Fator XII/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem

RESUMO

Abdominal pain due to intestinal swellings is one of the most common manifestations in hereditary angioedema (HAE). Bowel swellings can cause severe abdominal pain, nausea, vomiting, and diarrhea, which may lead to misdiagnosis of gastrointestinal disorders. In rare cases, HAE abdominal attacks can be accompanied by acute pancreatitis. Here, we report 3 patients with HAE and acute pancreatitis and present a literature review of similar cases. Patients with confirmed diagnosis of HAE secondary to C1-inhibitor (C1-INH) deficiency (n = 2) and HAE with normal C1-INH and F12 mutation (F12-HAE) (n = 1) were included. Pancreatitis was diagnosed based on clinical symptoms and high lipase and amylase levels. Three HAE patients were diagnosed with acute pancreatitis based on increased amylase levels during severe abdominal swelling episodes. Two were previously diagnosed with HAE type I and one with F12-HAE. Pancreatitis was efficiently treated in two patients using Icatibant, with pain relief within hours. When conservatively treated, pancreatitis pain took longer time to resolve. Eighteen pancreatitis cases in HAE with C1-INH deficiency were previously reported and none in F12-HAE. Most patients (12/18) underwent invasive procedures and/or diagnostic methods. Although rare, severe abdominal HAE attacks could cause pancreatitis; HAE-specific treatments may be efficient for HAE-associated pancreatitis. HAE should be considered as a differential diagnosis of acute idiopathic pancreatitis. To our knowledge, this is the first report of HAE-associated pancreatitis in a F12-HAE patient treated with Icatibant.

RESUMO

Hereditary angioedema (HAE) is an autosomal dominant disease caused by C1-INH deficiency due to mutations in SERPING1 (C1-INH-HAE) in most of the cases, or by specific mutations in factor XII gene, F12 (F12-HAE). Identification of polymorphisms in the genes encoding proteins from key pathways driving HAE can help to understand how genetic diversity contributes to its phenotypic variability. Here, 15 genes related to the Kallikrein-Kinin System (KKS) were analyzed by next generation sequencing in 59 patients with C1-INH-HAE or F12-HAE from Brazil, Denmark and Spain, and 19 healthy relatives in a total of 31 families. We identified 211 variants, from which 23 occurred only in Danish subjects and 79 were found only in Brazilian individuals, resulting in 109/211 variations in common between European and Brazilian population in the HAE families analyzed. BDKRB2 and CPM presented a large number of variants in untranslated regions, 46/49 and 19/24, respectively; whereas ACE (n = 26), SERPING1 (n = 26), CPM (n = 24), and NOS3 (n = 16) genes presented the higher number of variants directly affecting amino acid sequence. Despite the large amount of variants identified, the lack of association between genotype and phenotype indicates that the modulation of HAE symptom requires a more complex regulation, probably involving pathways beyond the KKS, epigenetics and environmental factors. Considering the new HAE types recently described, molecules involved in the regulation of vasculature and in plasminogen activation become promising targets for future genetic studies.