Hereditary angioedema (HAE) is a rare,unpredictable,autosomal dominant disorder characterized by recurrent swelling in subcutaneous and submucosal tissue.In recent years,the pathophysiology and pathogenesis of HAE have been continuously studied and elucidated.In addition to the genes encoding complement 1 esterase inhibitors,new pathogenic variants have been identified in the genes encoding coagulation factor Ⅻ,plasminogen,angiopoietin-1,kininogen,heparan sulfate 3-O-sulfotransferase 6,and myoferlin in HAE.Moreover,different pathogenic variants have different mechanisms in causing HAE.In addition,the pathogenic genes of some patients remain unknown.This review summarizes the recent progress in the classification,epidemiology,pathophysiology,and pathogenesis of HAE,aiming to provide ideas for further fundamental research,clinical diagnosis,and drug development of HAE.
Humans ; Angioedemas, Hereditary/diagnosis* ; Angiopoietin-1/metabolism* ; Plasminogen/metabolism* ; Kininogens/metabolism* ; Complement C1 Inhibitor Protein/metabolism*

Hereditary angioedema is a disease of congenital deficiency or functional defect in the C1 esterase inhibitor (C1-INH) consequent to mutation in the SERPING1 gene, which encodes C1-INH. This disease manifests as recurrent, non-pitting, non-pruritic subcutaneous, or submucosal edema as well as an erythematous rash in some cases. These symptoms result from the uncontrolled localized production of bradykinin. The most commonly affected sites are the extremities, face, gastrointestinal tract, and respiratory system. When the respiratory system is affected by hereditary angioedema, swelling of the airway can restrict breathing and lead to life-threatening obstruction. Herein, we report a case of a 24-year-old woman with type 2 hereditary angioedema who presented with recurrent episodic abdominal pain and swelling of the extremities. She had no family history of angioedema. Although her C4 level was markedly decreased (3.40 mg/dL; normal range: 10-40 mg/dL), she presented with a very high C1-INH level (81.0 mg/dL; normal range: 21.0-39.0 mg/dL) and abnormally low C1-INH activity (less than 25%; normal range: 70%-130%). The SERPING1 gene mutation was confirmed in this patient. She was treated with prophylactic tranexamic acid, as needed, and subsequently reported fewer and less severe episodes. To our knowledge, this is the first reported case of type 2 hereditary angioedema in Korea that was consequent to SERPING1 mutation and involved a significantly elevated level of C1-INH as well as a low level of C1-INH activity.
Abdominal Pain ; Angioedema ; Angioedemas, Hereditary* ; Bradykinin ; Complement C1 Inhibitor Protein ; Edema ; Exanthema ; Extremities ; Female ; Gastrointestinal Tract ; Humans ; Korea ; Reference Values ; Respiration ; Respiratory System ; Tranexamic Acid ; Young Adult

Hereditary angioedema (HAE) is a rare autosomal dominant disease that usually occurs in adolescence and early adulthood. It is characterized by recurrent non-pitting edema involving the skin and intestinal tract, especially the extremities and face. It is not associated with urticaria and pruritus. The cause is known to be the deficiency of C1 inhibitor. We herein report a 7-year-old girl with HAE who had recurrent episodes of swelling of the extremities and face without urticaria and pruritus. Her great grandmother had suffered from the same symptoms. The level of serum C4 was 8.01 mg/dL (normal: 10-40 mg/dL). The level of C1 inhibitor was 5.0 mg/dL (normal: 18-40 mg/dL). To our knowledge, this is the first pediatric case with typical clinical symptoms of HAE and C1 esterase inhibitor deficiency in Korea.
Adolescent ; Angioedema ; Angioedemas, Hereditary ; Complement C1 Inhibitor Protein ; Edema ; Extremities ; Humans ; Korea ; Pruritus ; Skin ; Urticaria

Hereditary angioneurotic laryngeal edema (HALE) is an autosomal dominant hereditary disease in which there is a decrease or defect in the C1 inhibitor (C1-INH). The pathophysiology of HALE is characterized by recurrent spontaneous episodes of transient edema of the laryngeal mucose and submucosal tissue with remission at irregular. Patients may die because of a life-threatening acute upper airway obstruction caused by laryngeal edema. HALE was diagnosed on the clinical symptoms, family history, and markedly decreased serum C1-INH activity and C1-INH protein.
Angioedemas, Hereditary ; diagnosis ; Complement C1 Inactivator Proteins ; analysis ; metabolism ; Complement C1 Inhibitor Protein ; Humans ; Laryngeal Edema ; diagnosis ; Recurrence

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.
Adult ; Angioedemas, Hereditary/*complications/diagnosis/*genetics ; Brain/radionuclide imaging ; Complement C1 Inhibitor Protein/*genetics/metabolism ; Danazol/therapeutic use ; Estrogen Antagonists/therapeutic use ; Humans ; Magnetic Resonance Angiography ; Male ; Migraine Disorders/*diagnosis/drug therapy/*etiology ; Piperidines/therapeutic use ; Tryptamines/therapeutic use ; Vasoconstrictor Agents/therapeutic use

OBJECTIVE: The etiology and pathogenesis of moyamoya disease remain unclear. Furthermore, the definitive diagnostic protein-biomarkers for moyamoya disease are still unknown. The present study analyzed serum proteomes from normal controls and moyamoya patients to identify novel serological biomarkers for diagnosing moyamoya disease. METHODS: We compared the two-dimensional electrophoresis patterns of sera from moyamoya disease patients and normal controls and identified the differentially-expressed spots by matrix-assisted laser desorption/ionization-time-of flight mass spectrometry and electrospray ionization quadruple time-of-flight mass spectrometry. RESULTS: We found and analyzed 22 differently-expressed proteomes. Two proteins were up-regulated. Twenty proteins were down-regulated. Complement C1 inhibitor protein and apolipoprotein C-III showed predominantly changed expressions (complement C1 inhibitor protein averaged a 7.23-fold expression in moyamoya patients as compared to controls, while apolipoprotein C-III averaged a 0.066-fold expression). CONCLUSION: Although our study had a small sample size, our proteomic data provide serologic clue proteins for understanding moyamoya disease.
Apolipoprotein C-III ; Biomarkers ; Complement C1 Inhibitor Protein ; Electrophoresis ; Humans ; Mass Spectrometry ; Moyamoya Disease ; Proteins ; Proteome ; Sample Size

Angioedemas, Hereditary ; genetics ; Complement C1 Inhibitor Protein ; genetics ; Female ; Humans ; Middle Aged ; Mutation

Adult ; Angioedemas, Hereditary ; therapy ; Complement C1 Inhibitor Protein ; therapeutic use ; Female ; Humans ; Plasma

Complement 1 (C1) inhibitor is an acute phase protein with anti-inflammatory properties. The aim of the present study was to elucidate the relationship between brachial ankle pulse wave velocity (baPWV), the parameter of arterial stiffness, and C1 inhibitor. One hundred subjects were randomly enrolled in this study. Data about baPWV, age, gender, hypertension, smoking, and body mass index (BMI) were measured. Blood tests for total cholesterol, low density lipoprotein, high density lipoprotein, triglycerides, hemoglobin A1c, erythrocyte sedimentation rate, C-reactive protein, complement 3, and C1 inhibitor were performed. Based on the Pearson correlation, the C1 inhibitor showed a positive relation to the baPWV (P<0.001). Multiple regression analysis revealed the significant predictors of baPWV were not only the conventional risk factors of arteriosclerosis and/or atherosclerosis, such as age (P<0.001), gender (P<0.001), hypertension (P<0.001), and BMI (P=0.006), but also the acute phase protein, C1 inhibitor (P=0.025). In conclusion, C1 inhibitor is associated with arterial stiffness through its association with increased inflammation.
Adolescent ; Adult ; Age Factors ; Aged ; Ankle/blood supply ; Ankle Brachial Index ; Blood Flow Velocity/physiology ; Blood Pressure/physiology ; Body Mass Index ; Brachial Artery/*physiology ; Complement C1 Inhibitor Protein/*metabolism ; Elasticity ; Female ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Regression Analysis ; Risk Factors ; Sex Factors

BACKGROUND AND OBJECTIVES: Angioedema is a localized, nonpitting edema resulting from extravasation of fluid into the interstitial space. It usually develops suddenly and fades during the course of 24 to 48 hours. However, angioedema of the upper respiratory tract can result in serious acute respiratory distress, airway obstruction, and death. The purpose of this study was to analyze clinical characteristics of angioedema in the head and neck. SUBJECTS AND METHOD: A review of 144 patients with angioedema of the head and neck over 3-year period was conducted. RESULTS: The presumptive causes were 115 allergic reactions to food, drug, or environmental exposure, 3 losses of C1 esterase inhibitor, 1 angiotensin-converting enzyme inhibitor use, and 25 idiopathic conditions. The main locations of the edema were 100 face/lips, 4 oral cavity/oropharynx, 5 larynx/hypopharynx, and 35 multiple sites of the head and neck. Most of patients were treated with steroids and H1 and H2 blockers. All of 7 patients with low oxygen saturation and 14 out of 18 patients with hypotension on arrival were improved within 24 hours. There were 4 patients with airway distress treated with urgent airway intervention, three of them were completely recovered within 110-240 hours but one of them died of the disease. Patients with the cause of idiopathic and loss of C1 esterase inhibitor were found to stay longer in the hospital over 48 hours (p<0.05). CONCLUSION: Angioedema of the head and neck usually responds well to the treatment. However, there might be cases with life-threatening airway obstruction.
Airway Obstruction ; Angioedema ; Complement C1 Inhibitor Protein ; Edema ; Environmental Exposure ; Head ; Humans ; Hypersensitivity ; Hypotension ; Neck ; Oxygen ; Respiratory System ; Steroids