本文關(guān)鍵詞： 線粒體病 GDF15 生物標(biāo)記物　出處：《山東大學(xué)》2016年碩士論文　論文類型：學(xué)位論文

【摘要】：背景線粒體病是由于線粒體DNA (mtDNA)或核DNA突變導(dǎo)致的原發(fā)性線粒體呼吸鏈氧化磷酸化障礙的一組遺傳代謝性疾病,在人群中患病率約為1：5000。該病在各個(gè)年齡段均可發(fā)病,而且臨床表現(xiàn)各異。所有器官均可受累,臨床上以能量需求旺盛的腦、心、腎、眼、耳及肌肉等多見。線粒體病根據(jù)臨床表現(xiàn)可分為不同的臨床綜合征,臨床上以線粒體腦肌病伴高乳酸血癥和卒中樣發(fā)作(MELAS),肌陣攣癲癇伴破碎紅纖維(MERRF)和慢性進(jìn)行性眼外肌麻痹(CPEO)、亞急性壞死性腦脊髓病(Leigh綜合征)等多見。也可表現(xiàn)為多種癥狀的非特異性組合或者多種綜合征的疊加,或者僅僅表現(xiàn)單一的癥狀,如聽力下降或者糖尿病等。線粒體病非特異性的臨床表現(xiàn)和缺乏可靠的生物標(biāo)記物給臨床診斷造成了很多困難。在臨床工作中,我們常用的線粒體病標(biāo)記物包括：乳酸,丙酮酸,肌酸激酶。然而,這些生物學(xué)標(biāo)記物在診斷線粒體疾病方面效能較低,因此,目前診斷的標(biāo)準(zhǔn)仍然依靠病史和肌肉活檢酶組織化學(xué)染色。肌肉病理診斷需要先進(jìn)的實(shí)驗(yàn)室設(shè)施、熟練技術(shù)人員及大量資金的投入,因此限制了肌肉病理工作的普及。對(duì)于廣大不能開展肌肉活檢酶組織化學(xué)染色的醫(yī)院,通過結(jié)合患者病史和可靠性的血清生物學(xué)標(biāo)志物來提示我們進(jìn)行基因診斷或肌肉病理診斷是十分必要的。生長分化因子15(Growth Differentiation Factor 15),也稱為巨噬細(xì)胞抑制因子,是轉(zhuǎn)化生長因子-β超家族成員之一,最早在活化的巨噬細(xì)胞中發(fā)現(xiàn)其mRNA表達(dá)升高。人體許多組織均能分泌GDF15,例如：在炎癥、氧化應(yīng)激,低氧等情況下心肌組織,肝組織的GDF15表達(dá)量明顯升高。近幾年國外有研究表明：G DF15可以作為心臟病、肝病、腫瘤等患者的非特異性血清生物學(xué)標(biāo)記物。有趣的是：最近Kalko和Saskia Koene等指出血清GDF15與線粒體功能損害相關(guān),可能是診斷線粒體病的潛在生物學(xué)標(biāo)記物且與疾病臨床嚴(yán)重程度相關(guān)。目的：本研究旨在探討中國人群血清生長分化因子(GDF15)在線粒體病診斷篩查中的價(jià)值,同時(shí)探究血清GDF15水平與Newcastle線粒體病評(píng)分量表(Newcastle Mitochondrial Disease Adult Scale, NMDAS)的相關(guān)關(guān)系。方法：線粒體病患者42例,其平均年齡28.8±14歲。我們根據(jù)線粒體病患者年齡和性別選取了我院健康體檢中心健康人與確診的非線粒體相關(guān)的神經(jīng)肌肉病作為正常對(duì)照組和對(duì)照組作為對(duì)照。20例非線粒體性神經(jīng)肌肉病患者,其平均年齡39+18.9歲。正常對(duì)照組50例,平均年齡29.5±12.4歲。選取部分線粒體病患者的肌肉標(biāo)本作為線粒體病組,確診為非神經(jīng)肌肉患者的肌肉標(biāo)本作為正常對(duì)照組。兩組之間性別、年齡比較差異無統(tǒng)計(jì)學(xué)意義(P0.05)。對(duì)所有入選者均抽取空腹外周靜脈血5ml,3000g/min離心10分鐘,留取1ml血清標(biāo)本分裝、編碼后于-80℃冰箱保存用于GDF15測(cè)定。比較每個(gè)生物標(biāo)記物水平(GDF15, FGF21、乳酸、肌酸激酶)在不同組間的差異；通過診斷性比值比(OR)、敏感性、特異性、陽性預(yù)測(cè)值、陰性預(yù)測(cè)值、診斷性O(shè)R、ROC曲線等比較GDF、FGF21、乳酸、肌酸激酶在線粒體病診斷方面的價(jià)值。結(jié)果：1.線粒體病患者血清GDF15水平均明顯高于病例對(duì)照組和正常組。2.血清GDF15的診斷比值比(OR)明顯高于FGF21,乳酸和肌酸激酶。3.線粒體病患者肌肉中GDF15的mRNA表達(dá)量明顯升高。4.血清GDF15水平與線粒體病患者肌肉病理中破碎紅纖維的比例呈正相關(guān)。5.血清GDF15水平與線粒體病患者臨床嚴(yán)重程度(NMDAS評(píng)分)呈正相關(guān)。6.ROC曲線下的面積(AUC):GDF15:AUC 0.998 [95% CI 0.993-1], p0.001), FGF21:AUC 0.925 ([95%CI 0.860-0.966], p0.001),乳酸：AUC 0.870 (95% CI [0.794-0.926], P＜0.001),肌酸激酶：AUC 0.553 (95% CI [0.452-0.650], p= 0.3774).結(jié)論：血清GDF15是線粒體病的敏感標(biāo)記物,可以作為首要檢查方法來輔助診斷線粒體病。
[Abstract]:The background of mitochondrial disease is due to mitochondrial DNA (mtDNA) is a group of inherited metabolic diseases or nuclear DNA mutations in primary oxidative phosphorylation of the mitochondrial respiratory chain disorders, prevalence rate is about 1:5000. of the disease in all ages can occur in the crowd, but with different clinical manifestations. All the organs can be involved in clinical, energy the demand for the brain, heart, kidney, eye, ear and muscle rare. Mitochondrial disease according to the clinical manifestations can be divided into different clinical syndrome, clinically with mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS), muscle clonic epilepsy with ragged red fibers (MERRF) and chronic progressive extraocular muscle paralysis (CPEO), subacute necrotizing encephalomyelopathy (Leigh syndrome) and other rare. Also could be expressed in a variety of symptoms or a combination of a variety of non-specific syndrome superimposed, or just single symptoms, such as hearing loss or Diabetes. Mitochondrial disease nonspecific clinical manifestations and lack of reliable biomarkers has caused many difficulties for clinical diagnosis. In clinical work, we used mitochondrial disease markers including: lactate, pyruvate, creatine kinase. However, these biological markers of efficacy in diagnosis of mitochondrial disease is low, therefore, at present, the standard of diagnosis still depends on the history and muscle biopsy histochemical staining. The muscle pathological diagnosis need advanced laboratory facilities, skilled technical personnel and a large number of funds, thus limiting the popularity of muscle pathological work. For the majority of the hospital can not carry out muscle biopsy histochemical staining, by combining with the history and reliability of biochemiccal the marker to prompt us to perform gene diagnosis or pathological diagnosis is very necessary. The growth differentiation factor 15 (Growth Differe Ntiation Factor 15), also known as macrophage inhibition factor, transforming growth factor beta superfamily, most found that the increased expression of mRNA in activated macrophages. Many human tissues can secrete GDF15, for example: in inflammation, oxidative stress, myocardial tissue hypoxia condition, the expression of GDF15 in liver tissue volume increased obviously. In recent years, foreign studies have shown that: G DF15 can be used as heart disease, liver disease, nonspecific serum biomarkers for tumor patients. It is interesting: recently Kalko and Saskia Koene indicated that the correlation between serum GDF15 and mitochondrial dysfunction may be potential biomarkers for diagnosis of mitochondrial diseases and with the severity of clinical disease. Objective: This study aimed to investigate Chinese serum growth differentiation factor (GDF15) in the diagnosis of mitochondrial disease screening. At the same time, to explore the level of serum GDF15 and N Ewcastle mitochondrial disease rating scale (Newcastle Mitochondrial Disease Adult Scale, NMDAS) of the relationship. Methods: 42 cases of patients with mitochondrial disease, the average age of 28.8 + 14 years. According to the age and sex of patients with mitochondrial disease from healthy people and diagnosed in our hospital health examination center of non mitochondrial related neuromuscular disease as normal the control group and the control group as the control cases of non.20 patients with mitochondrial neuromuscular disease, the average age of 39+18.9 years. 50 cases of normal control group, mean age 29.5 + 12.4 years. Patients were part of mitochondrial diseases as the underlying muscle mitochondrial disease were diagnosed as non neuromuscular patients with muscle specimens as the control group. Sex between the two groups, no significant age difference (P0.05). All the subjects were fasting peripheral venous blood 5ml, 3000g/min centrifuge for 10 minutes, take the 1ml standard serum The packaging and encoding in -80 DEG C refrigerator for determination of GDF15. The comparison of each biomarker levels (GDF15, FGF21, creatine kinase, lactic acid) differences in different groups; through the diagnostic odds ratio (OR), sensitivity, specificity, positive predictive value, negative predictive value, diagnosis of OR, ROC curve comparison of GDF, FGF21, lactate, creatine kinase value in the diagnosis of mitochondrial diseases. Results: 1. patients with mitochondrial disease serum GDF15 levels were significantly higher than the diagnostic ratio of case control group and normal group.2. serum GDF15 ratio (OR) was significantly higher than that of FGF21, GDF15 lactic acid and creatine kinase.3. in muscle of patients with mitochondrial disease mRNA the expression of.4. significantly increased serum GDF15 level and mitochondrial disease in patients with muscle pathology in ragged red fiber ratio of.5. was positively correlated with serum GDF15 level in patients with mitochondrial disease severity (NMDAS score) was positively related to.6.ROC under the curve Area (AUC): GDF15:AUC 0.998 [95% CI 0.993-1], p0.001 FGF21:AUC 0.925 ([95%CI), 0.860-0.966], p0.001, AUC (0.870): lactic acid 95% CI [0.794-0.926], P < 0.001), creatine kinase ([0.452-0.650]: AUC 0.553 CI 95%, p= 0.3774). Conclusion: serum GDF15 is a sensitive marker of mitochondrial diseases, can as the primary examination method to diagnosis of mitochondrial diseases.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R746

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