糖尿病截肢中腓腸神經之血管病變

Vascular abnormalities in sural nerve of diabetic amputee

甘弘偉(Hung-Wei Kan)

指導教授 ： 謝松蒼

國立臺灣大學/醫學院/解剖學暨生物細胞學研究所/碩士(2010年)

https://doi.org/10.6342/NTU.2010.03560

摘要

糖尿病是常見造成周邊神經病變的原因之一，糖尿病神經病變(diabetic neuropathy)會出現神經生理學上神經傳導速度降低與感覺神經功能減退，以及病理學上神經軸索退化(axonal degeneration)等特徵。目前的假說認為，糖尿病所引起的微血管病變(vascular abnormalities)可能引起周邊神經組織缺血、缺氧，是導致神經軸索退化(axonal degeneration)的原因之一。然而，至今鮮少研究探討糖尿病患者中微血管病變和神經退化嚴重程度之間的關係。本研究利用型態學的方法分析糖尿病截肢患者(n = 23)與正常人(n = 3)之腓腸神經(sural nerve)，發現糖尿病截肢患者的微血管管壁厚度(capillary wall thickness)與正常人相比會顯著增厚(p < 0.05)；微血管的管腔面積與正常人相比會顯著變窄(p < 0.005)。並且發現微血管管壁厚度與糖尿病截肢患者的神經病變的嚴重程度有關，會與有髓鞘神經纖維密度(myelinated fiber density)呈現顯著的負相關(p < 0.005)。我們更進一步發現，除了微血管管壁厚度，神經內膜微血管密度(endoneurial capillary density)與堵塞的微血管所佔比例也與糖尿病神經病變的嚴重程度有關，分別與有髓鞘神經纖維密度呈現顯著的正相關(p < 0.005)與負相關(p < 0.05)。此外，有髓鞘神經纖維直徑小於5 μm所佔比例也與有髓鞘神經纖維密度和神經內膜微血管密度都呈現顯著的負相關(p < 0.05)。我們利用免疫組織化學染色的方法，希望了解造成微血管病變以及神經病變的分子機制。結果發現糖尿病截肢患者表現纖維蛋白(fibrin)的血管所佔比例和有髓鞘神經纖維密度呈現顯著的負相關(p = 0.01)；59%的糖尿病截肢患者的微血管內皮細胞有糖化終產物受器(receptor for advanced glycation end-products)的表現。最後，我們比較了在臨床上得到的的血管流速資料，發現股總動脈(common femoral artery)及股淺動脈(superficial femoral artery)之血管流速和微血管管腔面積所佔比例呈現顯著的正相關(p < 0.05)。
綜合以上的結果，我們提供了糖尿病截肢患者中，微血管病變與神經病變嚴重程度之間相關聯的型態學證據。並且了解纖維蛋白分解過程(fibrinolysis)異常，造成纖維蛋白不正常堆積於微血管管腔，可能也與糖尿病神經病變的嚴重程度有關。然而，雖然糖尿病截肢患者的體內血糖過高，但糖化終產物受器的表現是否會影響微血管細胞造成型態上的變化，則需要進一步的研究來釐清。

關鍵字

糖尿病神經病變 ； 截肢 ； 軸索退化 ； 微血管病變 ； 神經切片

並列摘要

Diabetic neuropathy is the most common form of neuropathies. In the neurophysiology and pathology studies, diabetic neuropathy is characterized by a loss of sensation and axonal degeneration in peripheral nerves. The hypothesis that diabetes mellitus induced vascular abnormalities and consequent ischemia or hypoxia cause axonal degeneration, however, has rarely been documented. This study aimed to investigate the relationship between the severity of diabetic neuropathy and vascular abnormalities.
We performed morphological analysis of sural nerve biopsies from 23 diabetic amputee and 3 control subjects. For diabetic amputee compared with control subjects, there were significant differences in capillary wall thickness (p < 0.05) and the proportion of the vessels with reduced lumen area (p < 0.005). Among diabetic amputee, our results indicated that the severity of neuropathy was correlated with capillary wall thickness (p < 0.005), endoneurial capillary density (p < 0.005) and the proportion of closed capillary (p < 0.05). Moreover, the proportion of thinly mylinated nerve fiber was negatively correlated with both mylinated fiber density (p < 0.05) and endoneurial capillary density (p < 0.05).
To identify the molecular mechanism contributing to the development and progression of vascular abnormalities or diabetic neuropathy, immunohistochemistry was performed. The proportion of fibrin (+) vessels was negatively correlated with myelinated fiber density (p < 0.05) and the receptor for advanced glycation end-products (RAGE) was expressed in the vascular endothelial cells of 59% diabetic amputee.
According to the clinical data, the blood flow as assessed by common femoral artery and superficial femoral artery was positively correlated with the proportion of lumen area (P<0.05).
In conclusion, the above observations provided a structural and pathological evidence that vascular abnormalities related to ischemia or hypoxia in peripheral nerves leading to the development and progression of diabetic neuropathy. The dysfunction of fibrinolysis was increased in diabetic neuropathy. Although diabetic amputee suffered from hyperglycemia, it still requires further investigations to test whether the expression of RAGE influences the morphology of capillary cells.

並列關鍵字

diabetic neuropathy ； amputation ； axonal degeneration ； microangiopathy ； nerve biopsy

參考文獻

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