The Risk and Protective Factors on Dementia in Patients with Hepatitis C, Hypertension and Diabetes

研究背景： 影響失智症的病因很多，不同失智症的致病因子可能不同，除了遺傳、年齡、性別以外，許多研究指出，感染因子如HIV、與血管相關疾病如糖尿病、高血壓、代謝症候群、吸菸等因素，也是影響失智症發病的影響因子。但失智症確切的致病機轉仍未確定，因此目前失智症的診斷與治療仍有許多面向需要更進一步研究。 C型肝炎為台灣常見的傳染性肝病， C型肝炎病毒(HCV) 感染會增加肝炎、肝硬化與肝癌的機會。因HCV可以穿過血腦屏障，HCV除了對肝臟的影響外，近年來許多研究也發現HCV對腦部有許多影響，如HCV患者的腦中風機率較高、HCV的患者認知功能較一般正常人差等。 高血壓也常被認為是失智症危險因子。高血壓有許多機轉會造成失智症，但治療高血壓與相關治療的藥物是否可以減低失智症發生的機率目前並不清楚。血管張力素受器阻斷劑(Angiotensin receptor blockers, ARBs)是一種降血壓藥物，近期研究發現不只有降血壓的療效，也有降低認知功能退化等效果。 失智症常見的危險因子還有糖尿病，但糖尿病與失智症的因果機轉與關係尚不清楚。血糖控制、治療糖尿病藥物、糖尿病造成神經血管病變，都被懷疑與失智症相關，但是確實的致病機轉尚無定論。 目前失智症尚無有效的治療，找出危險與保護因子是預防失智症的有效方式。因為失智症的影響因子影響的時間長久，又致病因子之間相互影響複雜，雖然有許多相關研究，但是仍然有許多有待證實的問題。本研究將利用台灣健保資料庫來分析C型肝炎、血管張力素受器阻斷劑與糖尿病疾病嚴重度等相關因子對於失智症的影響。 研究方法： 藉由台灣健保資料庫資料，針對五十歲以上的患者，以世代研究設計方式，來探討 (一) C型肝炎；(二) 血管張力素受器阻斷劑；(三) 糖尿病嚴重度與失智症的關聯。 研究族群如下： (一) C型肝炎研究：根據年齡、性別、地域、投保薪資與共病，以一比一方式配對出58570組C型肝炎患者與健康族群。 (二) ARB研究：根據年齡、性別、地域、投保薪資與共病，以一比一方式配對出24531組血管張力素受器阻斷劑患者與非暴露族群。 (三) 糖尿病研究針對新發糖尿病患者為目標族群，共431178位患者納入追蹤。以aDCSI作為糖尿病疾病嚴重度之評估指標研究失智症的風險比值。 上述研究分別控制其年齡、性別、收入(投保金額)、地區與其他影響失智症的共病，追蹤自1997年至2009年，研究發生失智症的機會。Kaplan-Meier method來評估探討因子對於失智症的累積風險，以Cox 比例風險回歸 (Cox Proportional Hazards Model)來分析其風險比值(Hazard Ratios)。 結果： (一) 配對後C型肝炎組有2989位患者罹患失智症，發生率為56.0/每萬人年；相較於健康族群的47.7/每萬人年，有明顯差異。經校正肝臟相關疾病、肝硬化、肝昏迷、肝癌等因子後，C型肝炎對於失智症風險比值為1.36。 (二) 配對後ARB劑組有1322位患者罹患失智症，發生率為51.1/每萬人年；相較於血管疾患高風險族群的87.1/每萬人年，有明顯差異。ARB的累積劑量上，大於1460 DDD (藥物耗用標準化之定義每日劑量, defined daily dose) 的病患風險明顯低於小於1460 DDD病患 (HR 0.37 vs. 0.61; p < 0.05)。 (三) 納入研究新發糖尿病病患，6.2%診斷為失智症。不同嚴重度病患aDCSI 分數為1、2、3與大於3的各組其失智症風險比值(與DCSI=0)分別為1.04 (0.99-1.09), 1.40 (1.34-1.46), 1.54 (1.47-1.61) 與1.70 (1.63-1.78)。糖尿病惡化速度越快族群，失智症的風險比值也越高 (風險比值 2.38, 6.95, 24.0；aDCSI值增加 0.51-1.00, 1.01-2.00 與>2.00/每年，對比於 aDCSI值增加 <0.50/每年，P < 0.001 for trend)。 結論：由我們的研究結果發現：C型肝炎會增加36% 的失智症風險；在血管相關疾患高風險病患，血管張力素受器阻斷劑可能降低失智症風險；糖尿病病患惡化速率越快，失智症的風險越高。因為失智症影響健康層面廣泛，目前並無良好的治療，僅能以減少危險因子，來降低失罹患失智症風險。惟機轉仍須進一步研究確認。Background: Dementia is a syndrome of chronic, progressive cognitive impairment involving multiple domains of cognition, significant enough to cause functional impairment and not due to a medically reversible cause. The clinical hallmark of dementia is a gradual decline in cognitive function, and patients with assessments that indicate cognitive impairment should be further evaluated to determine an appropriate diagnosis or identify other causes. Although not all subjects with cognitive impairment develop dementia, cognitive deficits have been proposed to be able to identify patients at risk of developing dementia in the pre-clinical stage. The early detection of cognition decline and risk factors are important to prevent the progression of dementia. The reimbursement database of the National Health Insurance program in Taiwan provides an opportunity for research. There were three objectives to this research; (1) to investigate the potential increased risk for dementia in patients infected with hepatitis C virus (HCV) in Taiwan; (2) to investigate the effects of antihypertensive drugs, especially angiotensin receptor blockers (ARBs) on dementia and its subtypes; (3) to determine if there is a relationship between the severity of diabetes and the risk of dementia in Taiwanese patients. Methods: We conducted three population-based cohort studies based on the Taiwan National Health Insurance Research Database. (1) In the HCV cohort study, a total of 58,570 matched (1:1) pairs of HCV-infected patients and non-HCV-infected patients were included from all potential participants aged 50 years or more. (2) In the ARB study, a total of 24,531 matched pairs (1:1) of ARB-exposed and non-ARB-exposed subjects were included. (3) In the diabetes study, a total of 431,178 new-onset diabetic patients were included as the diabetes cohort. The severity of diabetes was evaluated using the adapted Diabetes Complications Severity Index (aDCSI). Each subject was individually tracked from 1997 to 2010 (2009 in the HCV cohort) to identify incident cases of dementia (onset in 1999 or later). Cox proportional hazard regression analysis was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between HCV infection and dementia, ARBs and dementia, and the severity of diabetes and dementia. Results: (1) There were 2,989 dementia cases in the HCV-infected cohort during the follow-up period of 533,861.1 person-years; the overall incidence rate of dementia was significantly different from the non-HCV cohort (56.0 vs. 47.7 cases per 10,000 person-years, p < 0.05). The adjusted HR for dementia was 1.36 (95% CI, 1.27-1.42) for the HCV-infected patients after adjusting for alcohol-related disease, liver cirrhosis, hepatic encephalopathy and hepatocellular carcinoma. (2) There were 1,322 cases (5.4%) of dementia in the ARB cohort and 2,181 cases (8.9%) in the non-ARB cohort during the eleven-year follow-up period. The multivariate-adjusted HRs for dementia, Alzheimer’s disease and vascular dementia were 0.54 (95% CI, 0.51-0.59), 0.53 (95% CI, 0.43-0.64) and 0.63 (95% CI, 0.54-0.73) for the subjects who received ARB treatment, respectively. In terms of cumulative dosage, the subjects with more than 1460 defined daily doses (DDD) of ARBs had a lower risk than those who received less than 1460 DDD (HR 0.37 vs. 0.61; p < 0.05). (3) A total of 431,178 new-onset diabetic patients were included, 6.2% of whom were diagnosed with dementia. At the end of the follow-up period, the HRs for dementia were 1.04 (95% CI, 0.99-1.09), 1.40 (95% CI, 1.34-1.46, p < 0.001), 1.54 (95% CI, 1.47-1.61, p < 0.001) and 1.70 (95% CI, 1.63-1.78, p < 0.001) with an aDCSI score of 1, 2, 3 and more than 3, respectively. Compared with the patients with mild progressive, the adjusted HRs increased with aDCSI change (two-year HRs: 1.30, 1.53, 1.97; final HRs 2.38, 6.95, 24.0 with an increase in aDCSI score per year of 0.51-1.00, 1.01-2.00 and more than 2.00, respectively, vs. less than 0.50; p < 0.001 for trend). Conclusions: These results suggest that HCV infection may increase the risk of dementia, and that the use of ARBs may be associated with a reduced risk of dementia in patients at high vascular risk. Diabetic patients with rapid progression and exacerbated severity had a higher risk of dementia. Further mechanistic research is needed to validate our findings