Zeerleder Sacha, Levi Marcel
a Department of Immunopathology, Sanquin Research and Landsteiner Laboratory of the AMC , Amsterdam , The Netherlands ;
b Department of Hematology , Academic Medical Center, University of Amsterdam , The Netherlands ;
Ann Med. 2016;48(4):256-67. doi: 10.3109/07853890.2016.1162909. Epub 2016 Mar 26.
Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. A decreased activity of C1-inhibitor is the hallmark of C1-INH-HAE (types 1 and 2) due to a mutation in the C1-inhibitor gene, whereas the deficiency in C1-inhibitor in C1-INH-AAE is the result of autoimmune phenomena. In HAE with normal C1-inhibitor, a significant percentage of patients have an increased activity of factor XIIa due to a FXII mutation (FXII-HAE). Treatment of C1-inhibitor-dependent angioedema focuses on restoring control of BK generation by inhibition of CP proteases by correcting the balance between CP inhibitors and BK breakdown or by inhibition of BK-mediated effects at the BKR2 on endothelial cells. This review will address the pathophysiology, clinical picture, diagnosis and available treatment in C1-inhibitor-dependent angioedema focusing on BK-release and its regulation. Key Messages Inadequate control of bradykinin formation results in the formation of characteristic subcutaneous and submucosal edemas of the skin, upper airways, facial structures, abdomen and extremities as seen in hereditary and acquired C1-inhibitor-dependent angioedema. Diagnosis of hereditary and acquired C1-inhibitor-dependent angioedema may be troublesome as illustrated by the fact that there is a significant delay in diagnosis; a certain grade of suspicion is therefore crucial for quick diagnosis. Submucosal edema formation in hereditary and acquired C1-inhibitor-dependent angioedema is potentially life threatening and can occur at any age. To date effective therapies for acute and prophylactic treatment are available.
由于控制接触相（CP）激活的蛋白酶抑制剂水平不足、CP蛋白活性增加和/或缓激肽（BK）降解为无活性肽不充分，导致BK不受控制地生成，通过BK受体2（BKR2）增加血管通透性，进而导致皮下和粘膜下水肿形成。由于C1抑制剂缺乏导致的遗传性和获得性血管性水肿（C1-INH-HAE和-AAE），其特征是上呼吸道、面部结构、腹部和四肢的皮下和粘膜下水肿发作严重且可能致命，原因是BK生成控制不足。C1抑制剂活性降低是C1-INH-HAE（1型和2型）的标志，这是由于C1抑制剂基因突变所致，而C1-INH-AAE中C1抑制剂缺乏是自身免疫现象的结果。在C1抑制剂正常的遗传性血管性水肿中，相当一部分患者由于因子XIIa（FXII）突变导致因子XIIa活性增加（FXII-HAE）。C1抑制剂依赖性血管性水肿的治疗重点是通过抑制CP蛋白酶来恢复对BK生成的控制，方法是纠正CP抑制剂与BK分解之间的平衡，或抑制BK在内皮细胞上的BKR2介导的效应。本综述将阐述C1抑制剂依赖性血管性水肿的病理生理学、临床表现、诊断及现有治疗方法，重点关注BK释放及其调节。关键信息缓激肽形成控制不足会导致皮肤、上呼吸道、面部结构、腹部和四肢出现特征性的皮下和粘膜下水肿，如遗传性和获得性C1抑制剂依赖性血管性水肿所见。遗传性和获得性C1抑制剂依赖性血管性水肿的诊断可能很棘手，诊断存在显著延迟这一事实就说明了这一点；因此，一定程度的怀疑对于快速诊断至关重要。遗传性和获得性C1抑制剂依赖性血管性水肿中的粘膜下水肿形成可能危及生命，可发生于任何年龄。迄今为止，已有针对急性和预防性治疗的有效疗法。
