C1抑制物基因突变提前形成终止密码子导致遗传性血管水肿

目的 检测7例来自不同遗传性血管水肿家系患者进行C1抑制物（C1 inhibitor,C1 INH）基因突变.方法 2011 至2012年北京协和医院变态反应科诊断为Ⅰ型HAE的7例来自不同HAE家系的先证者及53名健康成人为研究对象,采集外周静脉血,提取基因组DNA,聚合酶链反应扩增C1 INH基因的8个外显子及其相邻序列并进行序列检测.将检测结果与GenBank公布的C1 INH 基因序列相比较,确定突变及基因多态性.结果 7例患者C1 INH基因序列中均鉴定到致病突变,分别为c.289 CA,g.3248T〉C,g.3493T〉C,g.5755 G〉A,g.9498 T〉C,g.15193 A〉G,g.18012 G〉A.结论 本研究鉴定的7种不同C1 INH基因突变中有5种为国内外首次报道,丰富了中国C1 INH基因突变数据库.     

比色法检测C1抑制物功能及其在遗传性血管水肿诊断中的应用

目的采用比色法检测C1抑制物功能并评价此方法对诊断遗传性血管水肿(hereditary angioedema,HAE)的敏感性和特异性,以及标本的储存时间和温度对检测结果的影响。方法将血浆标本加入过量的C1酯酶中,然后加入染色底物C2H5CO-Lys-Gly-Arg-pNA,与剩余的C1酯酶发生反应,通过分光光度仪检测与受试者血浆反应后剩余的C1酯酶与底物反应的吸光度,得出C1INH的功能活性。通过对65名健康对照者和21例已明确诊断的HAE患者C1抑制物功能的检测,得出该方法的正常值范围以及在HAE诊断中的敏感性和特异性。同时将9份健康对照者血浆样本分别存放于不同的温度(室温、4℃、-20℃)和时间(收集血浆后立即、4、8和24h),评价标本存放时间和温度对检测结果的影响。结果比色法检测C1抑制物的正常范围为(0.56～1.58)UC1 INH/ml,诊断HAE的特异性(65/65)和敏感性(21/21)均为100%。室温保存24h后,C1INH功能检测会显著下降;保存于-20℃,对检测结果无影响。结论比色法检测C1抑制物功能对HAE的诊断具有极高的敏感性和特异性,但易受标本保存的温度和时间影响。推荐采血后立即分离血浆检测,或存放于-20℃24h或以内检测,否则可能产生假阳性结果。     

Safety and Efficacy of Prophylactic Nanofiltered C1-inhibitor in Hereditary Angioedema

ObjectiveNanofiltered C1-inhibitor (C1INH-nf) is approved for prophylactic treatment of hereditary angioedema. This study assessed the efficacy and safety of C1INH-nf as prophylactic therapy in a large cohort of patients with hereditary angioedema.MethodsAn open-label multicenter extension study was performed involving 146 subjects with hereditary angioedema who were treated with C1INH-nf for up to 2.6 years in centers throughout the United States. Subjects were to be treated with C1INH-nf 1000 units every 3 to 7 days. The primary efficacy variable was the number of attacks of angioedema experienced.ResultsSubjects experienced a 93.7% reduction in attacks while taking prophylactic C1INH-nf (0.19 attacks per month; interquartile range, 0.00-0.64) compared with the historical rate of attacks. Some 87.7% reported an attack frequency of 1 or less attack per month during prophylactic C1INH-nf and 34.9% had no attacks during the study. Some 7.5% of subjects experienced relatively frequent attacks despite twice-weekly C1INH-nf. Although twice-weekly dosing was highly effective in most subjects, once-weekly dosing provided adequate control in a subgroup of subjects. No clinical characteristics predicted the response to prophylactic C1INH-nf, including historical attack frequency. C1INH-nf was well tolerated.ConclusionProphylactic C1INH-nf is highly effective and safe, and provides durable prophylaxis in the majority of patients with hereditary angioedema. The recommended dose of C1INH-nf 1000 units twice weekly is supported by this open-label study. Individual patients may benefit from further dose adjustment on the basis of response to therapy and individual treatment goals.     

Hereditary Angioedema: An Infrequent Cause of Abdominal Pain with Ascites

Patients with hereditary angioedema have episodes of local swelling, usually affecting the face, extremities, upper airway, and gastrointestinal tract. Only infrequently does it cause recurrent abdominal pain (with or without ascites); however, because it has potentially life-threatening complications, an early diagnosis is important. We describe a case of type I hereditary angioedema (a quantitative deficit of Cl inhibitor), the sole initial symptom of which was severe recurrent and self-limited abdominal pain, accompanied by ascites during these episodes. During a 4-yr period of treatment with danazol, the patient was virtually asymptomatic, despite levels of C4 and C1 inhibitor that remained below normal limits, and there have been no major side effects that could be attributed to treatment with androgens.     

Hereditary Angioedema Due to C1-Inhibitor Deficiency in Romania: First National Study,Diagnostic and Treatment Challenges

Background: Hereditary angioedema (HAE) is a rare genetic potentially life-threatening disease characterized by episodic non-pruritic subcutaneous and submucosal edema attacks in different parts of the body. Objective: To assess the status of Romanian HAE patients after the recent introduction of a new therapy through a nationwide program. Methods: This cross-sectional observational study included patients from the Romanian HAE Registry. Results: The study included 84 patients with HAE type I (91.7%) and type II (8.3%). The mean delay in diagnosis was 2.4 years in children and 16.7 years in adults (p=0.019). Stress and tiredness were the most frequent trigger factors. The majority of the HAE episodes involved subcutaneous (89.3%), abdominal (77.4%), genital (51.2%), facial (41.7%), and laryngeal (39.3%) symptoms during the preceding 12 months. One or several misdiagnoses were reported in 83.33% patients and 44.1 % of the patients were subjected to or proposed unnecessary surgery during abdominal episodes. Plasma-derived C1-INH (pdC1-INH) and recombinant C1-INH (rhC1-INH) were respectively used in 10 (11.9%) and 13 (15.5%) of the HAE patients for life-threatening attacks over the past 12 months. Fortythree (51.19%) patients practiced home treatment with subcutaneous injection of the bradykinin B2-receptor antagonist for acute HAE attacks. Conclusion: The significantly lower delay observed in children suggests an improvement in the awareness of C1-INH-HAE among physicians in recent years. The management of HAE in Romania has been somewhat enhanced as the majority of HAE patients have recently gained access to pdC1-INH, rhC1-INH, and bradykinin B2-receptor antagonist.     

Angioedema in a patient with C1 esterase inhibitor deficiency

Angioedema is characterized by recurrent, circumscribed, solitary or multiple subcutaneous and mucosal swelling, involving the extremities, face, larynx, bowel wall. Angioedema is due to hereditary or acquired varieties of C1 esterase inhibitor (C1INH) deficiency.A case of atypical acquired angioedema in a 49-year old man, responding favourably to cinnarizine and alcohol abstinence, is presented in this article. Cinnarizine was prescribed due to presumed alcoholic liver disease. The clinical significant amelioration was not associated with concomitant good laboratory result, which is a relatively common occurrence.     

Hereditary angioedema with normal C1 inhibition

Until recently, it was assumed that hereditary angioedema was a disease resulting exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity, and protein in plasma were described. Since then, numerous patients and families with this condition have been reported. Most of the patients were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. In some families, mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected persons.     

Increased Risk of Recurrent Gout Attacks with Hospitalization

Background

Although anecdotal evidence suggests that the risk of recurrent gout attack increases with hospitalization, no study has formally tested this hypothesis.

Methods

We conducted an online case-crossover study of individuals with gout. We obtained information on gout attacks over a 1-year period, including onset date, symptoms and signs, medications, and exposure to potential risk factors, including hospitalization, during the 2-day hazard period before each gout attack. The same exposure information also was obtained over 2-day intercritical gout control periods. We performed conditional logistic regression to examine the relationship of hospitalization with recurrent gout attacks and whether such a relationship was modified by concomitant use of anti-gout medications.

Results

Of 724 participants (mean age, 54.5 years; 78.5% male), 35 hospitalizations occurred during a hazard or control period. The adjusted odds of gout attacks was increased 4-fold with hospitalization (odds ratio, 4.05; 95% confidence interval, 1.78-9.19) compared with no hospitalization. The effect of hospitalization tended to attenuate with the use of allopurinol, colchicine, or nonsteroidal anti-inflammatory drugs, but not statistically significantly.

Conclusions

Our study confirmed that the risk of gout attacks increases among patients with gout during hospitalization. Appropriate measures should be considered for prevention of gout attacks during hospitalization for patients with preexisting gout.     

Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course

Purpose

A new type of hereditary angioedema was described recently. It was characterized by recurrent bouts of angioedema in various organs and normal C1 inhibitor and was observed mainly in women. Our aim was to conduct a detailed study of the clinical features of this condition.

Methods

A total of 138 patients with hereditary angioedema and normal C1 inhibitor who belonged to 43 unrelated families were examined through the use of standardized questionnaires.

Results

A majority of patients with hereditary angioedema and normal C1 inhibitor had skin swellings (92.8%), tongue swellings (53.6%), and abdominal pain attacks (50%). Laryngeal edema (25.4%) and uvular edema (21.7%) also were frequent, whereas edema episodes of other organs were rare (3.6%). Facial swellings and tongue involvement occurred considerably more frequently compared with hereditary angioedema caused by C1 inhibitor deficiency. The number of patients with recurrent edema of only 1 organ was higher than in classic hereditary angioedema. The number of patients with disease onset in adulthood was significantly higher in hereditary angioedema with normal C1 inhibitor compared with classic hereditary angioedema. Erythema marginatum was not observed. A subgroup of patients from families with coagulation factor XII mutations showed the same symptoms as the other patients.

Conclusions

Hereditary angioedema with normal C1 inhibitor levels shows a characteristic pattern of clinical symptoms. The main clinical features include skin swellings, tongue swellings, and abdominal pain attacks. There are many differences in the clinical symptoms and course of disease between this type of hereditary angioedema and classic hereditary angioedema caused by a genetic C1 inhibitor deficiency.     

Bowman-Birk Inhibitor Concentrate: A Novel Therapeutic Agent for Patients with Active Ulcerative Colitis

Bowman-Birk inhibitor concentrate (BBIC), a soy extract with high protease inhibitor activity, is efficacious in the treatment of colitis in mice and has been used in numerous clinical trials. A randomized, double blind, placebo-controlled trial was performed to investigate the safety and possible benefits of BBIC in patients with active ulcerative colitis. The Sutherland Disease Activity Index (SDAI) was used to assess disease activity, response (Index decrease ≥ 3), and remission (Index ≤ 1 with no rectal bleeding) in patients receiving 12 weeks of therapy. The Index scores of patients receiving BBIC decreased more than those of the patients receiving placebo (P = 0.067). Beneficial trends were observed in the rates of remission (P = 0.082) and clinical response (P = 0.22). No severe adverse events were observed. This trial suggests a potential benefit over placebo for both achieving clinical response and induction of remission in patients with active ulcerative colitis without apparent toxicity.