FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study.
FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study.
复制标题
DOI：
10.1016/s1474-4422(11)70155-7
复制
发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Tyynismaa H
中科院分区：
文献类型：
--
作者：
Suomalainen A;Elo JM;Pietiläinen KH;Hakonen AH;Sevastianova K;Korpela M;Isohanni P;Marjavaara SK;Tyni T;Kiuru-Enari S;Pihko H;Darin N;Õunap K;Kluijtmans LA;Paetau A;Buzkova J;Bindoff LA;Annunen-Rasila J;Uusimaa J;Rissanen A;Yki-Järvinen H;Hirano M;Tulinius M;Smeitink J;Tyynismaa H
由于血清中缺乏敏感的生物标志物，肌肉活检是诊断线粒体疾病的金标准。成纤维细胞生长因子 21 (FGF-21) 是一种在脂质代谢和饥饿反应中具有调节作用的生长因子，在线粒体呼吸链缺陷的小鼠骨骼肌和血清中浓度升高。我们在一项回顾性诊断研究中调查了 FGF-21 是否可以作为人类线粒体疾病的生物标志物。我们评估了来自欧洲和美国七个研究中心的患有线粒体疾病或非线粒体神经系统疾病（疾病对照）的成人和儿童样本，并从同一中心招募了年龄尽可能匹配的健康志愿者（健康对照）。我们使用 ELISA 测量血清或血浆样本中的 FGF-21 浓度（异常值定义为 >200 pg/mL）。我们将这些浓度与血清或血浆中的乳酸、丙酮酸、乳酸与丙酮酸比率和肌酸激酶的值进行比较，并计算所有生物标志物的敏感性、特异性以及阳性和阴性预测值。我们分析了 67 名线粒体疾病患者（41 名成人和 26 名儿童）、34 名疾病对照者（22 名成人和 12 名儿童）和 74 名健康对照者的血清或血浆。成人血清中 FGF-21 的平均浓度为 820 (SD 1151) pg/mL，呼吸链缺陷儿童患者为 1983 (1550) pg/mL，健康对照者为 76 (58) pg/mL。在患有影响骨骼肌的线粒体疾病的患者中，FGF-21 浓度较高，但在疾病对照组（包括营养不良患者）中则不然。在血清中 FGF-21 浓度异常的患者中，患有肌肉表现的线粒体疾病的比值比为 132·0 (95% CI 38·7–450·3)。对于肌肉表现的线粒体疾病的识别，敏感性为 92·3% (95% CI 81·5–97·9%)，特异性为 91·7% (84·8–96·1%)。 FGF-21 的阳性和阴性预测值为 84·2% (95% CI 72·1–92·5%) 和 96·1 (90·4–98·9%)。 FGF-21 正确识别肌肉表现的呼吸链疾病的准确性优于所有传统生物标志物。 FGF-21 的受试者工作特征曲线下面积为 0·95；相比之下，其他生物标志物的值为 0·83 乳酸（p=0·037、0·83 丙酮酸（p=0·015）、0·72 乳酸与丙酮酸比率（p=0·0002）和 0·77 肌酸激酶（p=0·013）。 血清中 FGF-21 浓度的测量 确定了成人和儿童的原发性肌肉表现呼吸链缺陷，并且可能作为这些疾病的一线诊断测试是可行的，以减少肌肉活检的需要。 Sigrid Jusélius 基金会、Jane 和 Aatos Erkko 基金会、芬兰分子医学研究所、赫尔辛基大学、赫尔辛基大学中央医院、芬兰科学院、诺和诺德、Arvo 和 Lea Ylppö 基金会。
Muscle biopsy is the gold standard for diagnosis of mitochondrial disorders because of the lack of sensitive biomarkers in serum. Fibroblast growth factor 21 (FGF-21) is a growth factor with regulatory roles in lipid metabolism and the starvation response, and concentrations are raised in skeletal muscle and serum in mice with mitochondrial respiratory chain deficiencies. We investigated in a retrospective diagnostic study whether FGF-21 could be a biomarker for human mitochondrial disorders. We assessed samples from adults and children with mitochondrial disorders or non-mitochondrial neurological disorders (disease controls) from seven study centres in Europe and the USA, and recruited healthy volunteers (healthy controls), matched for age where possible, from the same centres. We used ELISA to measure FGF-21 concentrations in serum or plasma samples (abnormal values were defined as >200 pg/mL). We compared these concentrations with values for lactate, pyruvate, lactate-to-pyruvate ratio, and creatine kinase in serum or plasma and calculated sensitivity, specificity, and positive and negative predictive values for all biomarkers. We analysed serum or plasma from 67 patients (41 adults and 26 children) with mitochondrial disorders, 34 disease controls (22 adults and 12 children), and 74 healthy controls. Mean FGF-21 concentrations in serum were 820 (SD 1151) pg/mL in adult and 1983 (1550) pg/mL in child patients with respiratory chain deficiencies and 76 (58) pg/mL in healthy controls. FGF-21 concentrations were high in patients with mitochondrial disorders affecting skeletal muscle but not in disease controls, including those with dystrophies. In patients with abnormal FGF-21 concentrations in serum, the odds ratio of having a muscle-manifesting mitochondrial disease was 132·0 (95% CI 38·7–450·3). For the identification of muscle-manifesting mitochondrial disease, the sensitivity was 92·3% (95% CI 81·5–97·9%) and specificity was 91·7% (84·8–96·1%). The positive and negative predictive values for FGF-21 were 84·2% (95% CI 72·1–92·5%) and 96·1 (90·4–98·9%). The accuracy of FGF-21 to correctly identify muscle-manifesting respiratory chain disorders was better than that for all conventional biomarkers. The area under the receiver-operating-characteristic curve for FGF-21 was 0·95; by comparison, the values for other biomarkers were 0·83 lactate (p=0·037, 0·83 for pyruvate (p=0·015), 0·72 for the lactate-to-pyruvate ratio (p=0·0002), and 0·77 for creatine kinase (p=0·013). Measurement of FGF-21 concentrations in serum identified primary muscle-manifesting respiratory chain deficiencies in adults and children and might be feasible as a first-line diagnostic test for these disorders to reduce the need for muscle biopsy. Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, Molecular Medicine Institute of Finland, University of Helsinki, Helsinki University Central Hospital, Academy of Finland, Novo Nordisk, Arvo and Lea Ylppö Foundation.