TWI597051B - 高半胱胺酸用於偵測及診斷人類眼部之息肉狀脈絡膜血管病變的用途及方法 - Google Patents
高半胱胺酸用於偵測及診斷人類眼部之息肉狀脈絡膜血管病變的用途及方法 Download PDFInfo
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Description
本發明涉及關於息肉狀脈絡膜血管病變(polypoidal choroidal vasculopathy，PCV)的偵測、預測及診斷，尤指基於高同型半胱氨酸血症(Hyperhomocysteinemia)的作用程度偵測人類眼部之息肉狀脈絡膜血管病變。
眼部息肉狀脈絡膜血管病變(polypoidal choroidal vasculopathy，PCV)是造成失明常見的病因，由於這類的新生血管較為脆弱，較容易破裂出血以及營養供應不良，且容易造成感光細胞的萎縮及死亡。
現今，醫生診斷該病變最有效的方式是利用眼底循血綠血管攝影(indocyanine green angiography，ICGA)，藉由影像之高螢光的區域，且根據其他伴隨的病症或在低螢光光暈及前五分鐘急遽從暗變亮上的亮度變化，來診斷息肉狀脈絡膜血管病變的位置。
再者，老年性黃斑部病變(age-related macular degeneration，AMD)在亞洲是造成老年失明的常見病症，其中老年性黃斑部病變可分為乾性(dry，early)及濕性(wet，late)，乾性老年性黃斑部病變在視網膜色素上皮層(retinal pigment epithelium，RPE)上長出脈絡膜玻璃膜疣(drusen)或地圖狀萎縮(geographic atrophy)，進而慢性地導致視力衰退，濕性老年性黃斑部病變則由於脈絡膜新生血管(choroidal neovascularization，CNV)，容易造成血管破裂出血及養分供應不夠，進而造成視網膜破壞，所以會損害視網膜視覺中心而失明，以及形成視網膜破洞。因此，老年性黃斑部病變的罹病原因一般與年齡老化、抽菸、喝酒、糖尿病、高血壓、基因及曝露於藍光有關。
高半胱氨酸(homocysteine)是蛋氨酸的代謝過程中產生的天然存在的含硫氨基酸。高半胱氨酸的高血漿程度已被確定為血管疾病的危險因子，如心血管疾病及中風、老年癡呆症及阿爾茨海默氏病症。在患者具有視網膜血管閉塞性疾病、假性青光眼及糖尿病性視網膜疾病中亦可觀察到升高的血漿高半胱氨酸之程度。同樣地，在具有老年性黃斑部病變的患者中也可觀察到升高的血漿高半胱氨酸之程度。
C-反應蛋白(C-reactive protein，CRP)是一種全身性炎症的生物標記以及心血管疾病的一個危險因素。日本研究人員研究發現升高的高靈敏度C反應蛋白(high sensitivity C-reactive protein，hsCRP)的程度與息肉狀脈絡膜血管病變有顯著的關聯，且得出炎症過程參與息肉狀脈絡膜血管病變的發病機制之結論。
因此，如何進一步闡明及證實息肉狀脈絡膜血管病變與血管疾病的危險因素有關，實為目前各界亟欲解決之技術問題。
鑒於上述習知技術之缺點，本發明提供一種偵測或診斷人類眼部之息肉狀脈絡膜血管病變(polypoidal choroidal vasculopathy，PCV)的生物標記，係包括：確定高同型半胱氨酸血症(Hyperhomocysteinemia)的作用程度，其中，該高同型半胱氨酸血症的作用程度與該人類眼部之該息肉狀脈絡膜血管病變高度相關聯。
再者，本發明進一步提供一種偵測或診斷人類眼部之息肉狀脈絡膜血管病變的方法，係包括以下步驟：確定從該人類眼部取得之複數個生物樣品之高同型半胱氨酸血症的作用程度；以及將該高同型半胱氨酸血症的作用程度與高同型半胱氨酸血症的作用對照程度比較，其中，該高同型半胱氨酸血症的作用程度與該人類眼部之該息肉狀脈絡膜血管病變高度相關聯。
較佳地，該複數個生物樣品的資料可包括年齡、性別、生活方式因素、吸菸、飲酒量、用藥史、高血壓病史、糖尿病病史、冠狀動脈疾病病史、腦血管疾病病史，但本發明不限於此。
較佳地，該高同型半胱氨酸血症的作用程度可藉由以下分析方法確定：總血漿高半胱氨酸分析(total plasma homocysteine analysis)、高敏感度C反應蛋白分析(high sensitivity C-reactive protein (hsCRP) analysis)及統計分析，但本發明不限於此。
較佳地，該統計分析使用多變量邏輯迴歸模型(multivariable logistic regression model)判斷血漿高半胱氨酸及高敏感度C反應蛋白的作用程度與該息肉狀脈絡膜血管病變的關聯性。
較佳地，本發明之偵測或診斷人類眼部之息肉狀脈絡膜血管病變的方法復包括以下步驟：對該人類眼部進行最佳矯正視力檢查(best-corrected visual acuity examination)、裂隙燈生物顯微鏡檢查(slit lamp biomicroscopy examination)及眼底鏡檢查(fundoscopy examination)。
以下係藉由特定的具體實施例說明本發明之實施方式，熟悉此技藝之人士可由本說明書所揭示之內容輕易地瞭解本發明之其他優點及功效。本發明亦可藉由其他不同的具體實例加以施行或應用，本發明說明書中的各項細節亦可基於不同觀點與應用在不悖離本發明之精神下進行各種修飾與變更。
以下依據本發明的實施例，描述本發明之偵測及診斷人類眼部之息肉狀脈絡膜血管病變(polypoidal choroidal vasculopathy，PCV)的生物標記。
在本發明的實施例中，確診為PCV的患者將進行研究。除了老年性黃斑部病變(age-related macular degeneration，AMD)、視網膜血管病變、糖尿病性視網膜病變或青光眼，對照組(control group)可包括接受常規身體檢查或後續的疾病，然後每一情況的年齡和性別與對照組相匹配。
其中所有研究對象為中華民族患者。
在本發明的實施例中，所有參與者均接受完整的眼科檢查，其中包括最佳矯正視力檢查(best-corrected acuity examination)、裂隙燈生物顯微鏡檢查(slit lamp biomicroscopy examination)及眼底鏡檢查(fundoscopy examination)。再者，在本發明的實施例中，本發明通過瞳孔放大，使用眼底照相機(CF-60 UD，佳能公司，日本，東京)及ICGA(海德堡視網膜血管造影II，海德堡工程，德國，海德堡)進行眼底照相及螢光血管造影(fluorescein angiography，FA)。視網膜圖像均由兩個視網膜專家(P.K.L.和J.H.L.)以隱密的方式進行。只有具有特徵性息肉狀脈絡膜血管擴張(息肉樣病變或息肉)的ICGA受試者被診斷為PCV，PCV的位置被分成凹外(extrafoveal)，近中心凹(juxtafoveal，在200微米內凹)、凹下(subfoveal)和乳頭周圍區域(peripapillary area，在內視盤之盤直徑內)。
在本發明的實施例中，所有受試者的資料包括年齡、性別、吸煙、飲酒、服藥史的生活方式因素、高血壓病史、糖尿病(diabetes mellitus，DM)疾病、冠狀動脈疾病、腦血管疾病及腎功能不全等等，但不限於本發明。
在本發明的實施例中，以坐姿方式獲得空腹靜脈血液樣本，且收集在含有肝素的試管，接著立即將樣本於4℃使用實驗室離心機進行離心，以及藉由具有0.5μmol/L的靈敏度及6.8%於4.9μmol/L及3.9%於61.6μmol/L的總變異係數(coeficient of variation，CV)之自動化化學發光免疫(ADVIA Centaur system，Siemens，East Walpole，MA，USA)測量血漿高半胱氨酸程度。此外，上述之測定方法亦包括螢光偏振免疫測定法(fluorescent polarization immunoassay)及高效液相色譜法(high-performance liquid chromatography，HPLC)。
在本發明的實施例中，本發明獲得靜脈血液樣本，且收集在血清分離管中。藉由比率濁度測定法(rate nephelometry)，利用自動化濁度計
(Immage 800，Beckman Coulter，Fullerton，CA，USA)測量血清hsCRP。在此hsCRP的測定法中，藉由具有0.2mg/L的分析靈敏度及5.17%於0.79mg/L及3.8%於13.4mg/L的總變異係數，已經顯示出本發明的測定方法與其他常用的測定方法具有極佳的相關性。
在本發明的實施例中，高半胱氨酸血症與升高hsCRP的程度分別被定義為高於對照組的九十五百分位之百分位數(95th percentile)程度。
在本發明之統計分析方法中，在人口和醫療方面，使用學生t檢驗(Student’s t-test)及皮爾森卡方檢驗(Pearsons’s chi-square test)分別對PCV病例和對照組之間的連續和分類變量進行比較。血漿高半胱氨酸及血清hsCRP為中位數(四分位距(interquartile range))，以及由於高半胱氨酸及hsCRP並非為常態分佈(normal distribution)，所以藉由Mann-Whitney U檢驗與對照組相比較。
在本發明之統計分析方法中，多變量邏輯回歸模型(multivariable logistic regression model)被用來評估PCV是否與血漿高半胱氨酸或血清hsCRP有關。所有的勝算比(odds ratios，ORs)均依據年齡、性別、生活方式因素(吸煙和飲酒)及疾病史(高血壓、糖尿病、冠狀動脈疾病及腦血管疾病)進行調整。
另外，在本發明之統計分析方法中，使用SPSS的Windows版本18(SPSS公司，芝加哥，伊利諾州，美國)進行本發明之計算。所有的P值均基於雙尾檢驗(two-tailed test)，以及小於0.05的P值被認為是顯著性差異(statistical significance)。
在一百二十四名患者中，三名患者被排除由於其腎功能不全，兩名患者亦被排除由於其具有AMD的CNV被診斷出。因此，最後共有一百十九名具有PCV患者與對照組相比較。
表1顯示息肉狀脈絡膜血管病變、對照組及P值的比較。
如表1所示，在PCV組及對照組中，平均年齡分別為72.1±13.0
年及69.3±10.9年，在這兩個群體中，男性佔優勢(74.8%)。在年齡、性別、高血壓、糖尿病、冠狀動脈疾病、腦血管疾病及生活方式因素(包括吸煙及飲酒情況下)方面，本發明顯示並無顯著性差異。
表2顯示全體及不同性別之息肉狀脈絡膜血管病變、對照組及P值的比較。
如表2所示，在中位數血漿高半胱氨酸程度方面，PCV組(中位數，12.20μmol/L，四分位距，9.67-16.66μmol/L)顯著地高於對照組(中位數，9.80μmol/L，四分位距，8.13-11.26μmol/L，P<0.001)。高半胱氨酸的評估可以進一步分為有糖尿病子組及無糖尿病子組。有糖尿病之PCV患者的血漿高半胱氨酸程度顯著地高於有糖尿病對照組(p值=0.001)。此外，無糖尿病之PCV患者的血漿高半胱氨酸程度亦顯著地高於無糖尿病對照組(P<0.001)。在中位數血清hsCRP方面，PCV組(中位數，0.16mg/dl，四分位距，0.06-0.30mg/dl)略高於對照組(中位數，0.11mg/dl，四分位距，0.06-0.25mg/dl，p值=0.07)。
此外，在對照組中，高半胱氨酸的九十五百分位之百分位數(95th percentile)為13.26μmol/L。與對照組(P<0.001)的一百十九名患者中之五名患者(4.2%)相比較，在一百十九名PCV患者中之四十七名患者(39.5%)超過上述臨界值。再者，在對照組中的hsCRP的九十五百分位之百分位數為0.70mg/dl。與對照組(p=0.12)的一百十三名患者中之六名患者(5.4%)相比較，在一百十八名患者中之十三名患者(11.1%)超過上述臨界值。
表3顯示高半胱氨酸及高靈敏度C反應蛋白之息肉狀脈絡膜血管病變、對照組及P值的比較。
如表3所示，在性別方面，與對照組相比較，PCV組的男性及女性具有顯著地較高的血漿高半胱氨酸程度(男性，P<0.001及女姓，P=0.02)以及高同型半胱氨酸血症的比例(男性，P<0.001及女性P=0.02)。hsCRP的結果一般而言為非顯著，除了升高的hsCRP在女性部分為較高比例(26.7%對比於對照組中的3.4%，P=0.01)(如表2所示)。若將高半胱氨酸程度分為三分位數(tertile)，與對照組相比較(67.2%對比於對照組中的32.8%，P<0.001)，PCV患者的顯著較高比例在最高的前三分之一具有高半胱氨酸程度。
關於多變量邏輯回歸分析方面，在調整年齡、性別、高血壓、糖尿病，冠狀動脈疾病、腦血管疾病、吸煙和飲酒後，本發明指出，升高的血漿高半胱氨酸程度與PCV的增加具有顯著性相關(OR，1.54；95%信賴區間(confidence interval，CI)，1.33-1.79，P<0.001)。具體而言，如表3所示，在回歸模型中，患者在高半胱氨酸的最高之前三分之一具有9倍增加風險的PCV(OR，8.8495%CI，3.68-21.21，P<0.001)。
因此，根據本發明之實施例，本發明之偵測或診斷人類眼部之息肉狀脈絡膜血管病變的生物標記可包括：確定高同型半胱氨酸血症(Hyperhomocysteinemia)的作用程度，其中，該高同型半胱氨酸血症的作用程度與該人類眼部之該息肉狀脈絡膜血管病變高度相關聯。
再者，本發明進一步提供一種偵測或診斷人類眼部之息肉狀脈絡膜血管病變的方法，本發明之偵測或診斷人類眼部之息肉狀脈絡膜血管病變的方法包括以下步驟：確定從該人類眼部取得之複數個生物樣品之高同型半胱氨酸血症的作用程度；以及將該高同型半胱氨酸血症的作用程度與高同型半胱氨酸血症的作用對照程度比較，其中，該高同型半胱氨酸血症的作用程度與該人類眼部之該息肉狀脈絡膜血管病變高度相關聯。
根據本發明之實施例，該複數個生物樣品的資料可包括年齡、性別、生活方式因素、吸菸、飲酒量、用藥史、高血壓病史、糖尿病病史、冠狀動脈疾病病史、腦血管疾病病史，但本發明不限於此。
根據本發明之實施例，該高同型半胱氨酸血症的作用程度可藉由以下分析方法確定：總血漿高半胱胺酸分析(total plasma homocysteine analysis)、高敏感度C反應蛋白分析(high sensitivity C-reactive protein (hsCRP) analysis)及統計分析，但本發明不限於此。
根據本發明之實施例，該統計分析使用多變量邏輯迴歸模型(multivariable logistic regression model)判斷血漿高半胱胺酸及高敏感度C反應蛋白的作用程度與該息肉狀脈絡膜血管病變的關聯性。
根據本發明之實施例，本發明之偵測或診斷人類眼部之息肉狀脈絡膜血管病變的方法復包括以下步驟：對該人類眼部進行最佳矯正視力
檢查(best-corrected visual acuity examination)、裂隙燈生物顯微鏡檢查(slit lamp biomicroscopy examination)及眼底鏡檢查(fundoscopy examination)。
因此根據本發明之結果，本發明指出，升高的血漿高半胱氨酸及血清hsCRP均與PCV高度地相關聯。
然而，上述實施例僅例示性說明本發明之功效，而非用於限制本發明，任何熟習此項技藝之人士均可在不違背本發明之精神及範疇下，對上述實施例進行修飾與改變。此外，在上述該些實施例中之元件的數量僅為例示性說明，亦非用於限制本發明。因此本發明之權利保護範圍，應如以下之申請專利範圍所列。
Claims (7)
- 一種高半胱胺酸用於偵測及診斷人類眼部之息肉狀脈絡膜血管病變(polypoidal choroidal vasculopathy，PCV)的用途，係包括：確定人類眼部分離之一生物樣品之高同型半胱氨酸血症(hyperhomocysteinemia)的作用程度，其中，該高同型半胱氨酸血症的作用程度與該人類眼部之該息肉狀脈絡膜血管病變高度相關聯。
- 如申請專利範圍第1項所述之用途，其中，該高同型半胱氨酸血症的作用程度藉由以下分析方法確定：總血漿高半胱胺酸分析(total plasma homocysteine analysis)、高敏感度C反應蛋白分析(high sensitivity C-reactive protein(hsCRP)analysis)及統計分析。
- 如申請專利範圍第2項所述之用途，該統計分析使用多變量邏輯迴歸模型(multivariable logistic regression model)判斷血漿高半胱胺酸及高敏感度C反應蛋白的作用程度與該息肉狀脈絡膜血管病變的關聯性。
- 一種偵測及診斷人類眼部之息肉狀脈絡膜血管病變(polypoidal choroidal vasculopathy，PCV)的方法，係包括以下步驟：確定從該人類眼部分離之複數個生物樣品之高同型半胱氨酸血症(hyperhomocysteinemia)的作用程度；以及將該高同型半胱氨酸血症的作用程度與高同型半胱氨酸血症的作用對照程度比較，其中，該高同型半胱氨酸血症的作用程度與該人類眼部之該息肉狀脈絡膜血管病變高度相關聯。
- 如申請專利範圍第4項所述之偵測或診斷人類眼部之息肉狀脈絡膜血管病變的方法，其中，該複數個生物樣品的資料包括年齡、性別、生活方式因素、吸菸、飲酒量、用藥史、高血壓病史、糖尿病病史、冠狀動脈疾病病史、腦血管疾病病史。
- 如申請專利範圍第4項所述之偵測或診斷人類眼部之息肉狀脈絡膜血管病變的方法，其中，該高同型半胱氨酸血症的作用程度藉由以下分析方法確定：總血漿高半胱胺酸分析(total plasma homocysteine analysis)、高敏感度C反應蛋白分析(high sensitivity C-reactive protein(hsCRP)analysis)及統計分析。
- 如申請專利範圍第6項所述之偵測或診斷人類眼部之息肉狀脈絡膜血管病變的方法，其中，該統計分析使用多變量邏輯迴歸模型(multivariable logistic regression model)判斷血漿高半胱胺酸及高敏感度C反應蛋白的作用程度與該息肉狀脈絡膜血管病變的關聯性。
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| Khouri et al. | Primary open-angle glaucoma | |
| Papageorgiou et al. | Nonarteritic anterior ischemic optic neuropathy and double thrombophilic defect: a new observation | |
| Li et al. | Estimated cerebrospina fluid pressure and the 5-year incidence of primary open-angle glaucoma in a Chinese population |