Noris M, Ruggenenti P, Perna A, Orisio S, Caprioli J, Skerka C, Vasile B, Zipfel P F, Remuzzi G
Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Italy.
J Am Soc Nephrol. 1999 Feb;10(2):281-93. doi: 10.1681/ASN.V102281.
Familial hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) carry a very poor outcome and have been reported in association with decreased serum levels of the third complement component (C3). Uncontrolled consumption in the microcirculation, possibly related to genetically determined deficiency in factor H--a modulator of the alternative pathway of complement activation--may account for decreased C3 serum levels even during disease remission and may predispose to intravascular thrombosis. In a case-control study by multivariate analysis, we correlated putative predisposing conditions, including low C3 serum levels, with history of disease in 15 cases reporting one or more episodes of familial HUS and TTP, in 25 age- and gender-matched healthy controls and in 63 case-relatives and 56 control-relatives, respectively. The relationship between history of disease, low C3, and factor H abnormalities was investigated in all affected families and in 17 controls. Seventy-three percent of cases compared with 16% of controls (P < 0.001), and 24% of case-relatives compared with 5% of control-relatives (P = 0.005) had decreased C3 serum levels. At multivariate analysis, C3 serum level was the only parameter associated with the disease within affected families (P = 0.02) and in the overall study population (P = 0.01). Thus, subjects with decreased C3 serum levels had a relative risk of HUS or TTP of 16.56 (95% confidence interval [CI], 1.66 to 162.39) within families and of 27.77 (95% CI, 2.44 to 314.19) in the overall population, compared to subjects with normal serum levels. Factor H abnormalities were found in four of the cases, compared with three of the healthy family members (P = 0.02) and none of the controls (P = 0.04) and, within families, factor H abnormalities were correlated with C3 reduction (P < 0.05). Reduced C3 clusters in familial HUS and TTP is likely related to a genetically determined deficiency in factor H and may predispose to the disease. Its demonstration may help identify subjects at risk in affected families.
家族性溶血性尿毒症综合征（HUS）和血栓性血小板减少性紫癜（TTP）的预后很差，并且已有报道称其与血清中第三补体成分（C3）水平降低有关。微循环中补体的失控消耗，可能与遗传性因子H缺乏有关——因子H是补体激活替代途径的一种调节剂——这可能是导致疾病缓解期C3血清水平降低的原因，并且可能易引发血管内血栓形成。在一项多变量分析的病例对照研究中，我们将包括低C3血清水平在内的假定易感因素，分别与15例报告有一次或多次家族性HUS和TTP发作的病例、25例年龄和性别匹配的健康对照、63例病例亲属以及56例对照亲属的疾病史进行了关联分析。在所有受影响的家庭和17名对照中，研究了疾病史、低C3和因子H异常之间的关系。73%的病例C3血清水平降低，而对照中这一比例为16%（P < 0.001）；24%的病例亲属C3血清水平降低，而对照亲属中这一比例为5%（P = 0.005）。在多变量分析中，C3血清水平是受影响家庭中（P = 0.02）以及整个研究人群中（P = 0.01）与疾病相关的唯一参数。因此，与血清水平正常的受试者相比，C3血清水平降低的受试者在家族中患HUS或TTP的相对风险为16.56（95%置信区间[CI]，1.66至162.39），在总体人群中为27.77（95%CI，2.44至314.19）。在4例病例中发现了因子H异常，而在3名健康家庭成员中也发现了因子H异常（P = 0.02），对照中则未发现（P = 0.04），并且在家族中，因子H异常与C3降低相关（P < 0.05）。家族性HUS和TTP中C3水平降低可能与遗传性因子H缺乏有关，并且可能易引发该疾病。其证实可能有助于识别受影响家族中的高危个体。
