臺灣博碩士論文加值系統

阻塞型睡眠呼吸中止症（obstructive sleep apnea, OSA）是由於患者上呼吸道肌肉部分或完全塌陷，導致睡眠期間呼吸氣流中斷，產生慢性間歇性缺氧（chronic intermittent hypoxia, CIH）。在流行病學研究證明OSA對於高血壓、冠狀動脈疾病、中風等為獨立的危險因子，在職業駕駛族群中，也發現到有較高的發生率。近年來，許多研究表示OSA產生的慢性間歇性缺氧可能導致慢性肝損傷，其組織學特徵與非酒精型脂肪肝（non-alcoholic fatty liver disease, NAFLD）相似，但OSA與B型肝炎、C型肝炎及肝硬化的相關研究並不多。而NAFLD會逐漸發展為脂肪肝炎，甚至轉變為更嚴重的肝硬化，在肝臟疾病的進程中，氧化壓力也扮演了十分重要的角色，且我們能藉由肝臟生化指標血清天冬氨酸氨基轉移酶（aspartate aminotransferase, AST）、丙酮酸轉胺脢（alanine aminotransferase, ALT）的升高，判斷肝臟發炎初期與異常。
本研究（a）以健保資料庫探討OSA患者中肝病後續發展的風險。另外，（b）以台灣職業駕駛為對象，討論OSA嚴重程度與血液生化指標之間的相關性，以及氧化壓力是否與肝臟生化指標相關，參與肝臟疾病的進程。
研究方法為（a）利用台灣全民健保申報資料，研究收集了2000-2008年17,374 OSA確診病例，對照組是從同一資料庫中選擇年齡、性別、都市化、收入與最初加入的日期配對，而選出69,496人。所有受試者追蹤至2010年，隨後進行評估肝臟疾病的盛行率與累積發生率；以及（b）在職業駕駛資料庫之受試者進行問卷及多頻道睡眠生理檢查（polysomnography, PSG），測量呼吸中止及過淺指數（apnea hypopnea index, AHI）及氧減指數（oxygen desaturation index, ODI），並依嚴重程度分為輕、中、重三組。另外採集血液樣本分析ALT、AST、三酸甘油脂、總膽固醇、低密度脂蛋白等生化指標，以及氧化壓力指標丙二醛（malonaldehyde, MDA）、DNA損傷標記8-OHdG（8-hydroxy-2-deoxyguanosine, 8OHdG），比較各組間差異。
研究結果顯示在健保資料庫中OSA患者發生肝臟疾病的風險（aHR = 5.52，p < 0.001）顯著較對照組高。在非酒精性脂肪性肝病、肝硬化和C型肝炎aHR分別為5.29、7.50和7.19且皆達顯著（p < 0.001）。與此相反，B型肝炎有最小的aHR（3.71，p < 0.001）。而在職業駕駛資料庫中OSA患者AST、ALT顯著高於正常組，且在OSA嚴重度分組中BMI、ALT有顯著的差異（p < 0.03）。氧化壓力MDA在OSA及肝臟異常組中則有最高值（49.8 ± 18.4），且在多變量迴歸模式中，重度OSA組之MDA與AST（p = 0.02）及ALT（p = 0.01）皆達統計顯著。
結論為在一般族群中OSA患者與對照組肝臟疾病的風險相比，OSA患者高出五倍以上;尤其是NAFLD。而在職業駕駛中，推測OSA可能為影響肝生化指標的因素，重度患者可能發展為肝病，且氧化壓力可能參與肝臟疾病的進程，加速肝臟惡化，顯示OSA患者中肝病為非常重要的健康問題。

Obstructive sleep apnea (OSA) is a disorder that is characterized by repeated episodes of sleep disruption due to upper airway obstruction. Previous studies has been suggested that chronic intermittent hypoxia (CIH) resulting from OSA could be an independent factor for early stage of nonalcoholic fatty liver disease (NAFLD) in addition to other well-recognized factors. NAFLD is a disorder that often presents with elevated serum aminotransferase levels (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)). However, limited studies have been postulated the relations between OSA and serum aminotransferase levels among occupational groups. Oxidative stress also plays an important role in the pathogenesis of viral hepatitis for the increasing severity of fibrosis progress in patients. However, studies of NAFLD, Cirrhosis, hepatitis B, and hepatitis C infection among OSA patients are limited.
The objective of this study (a) to investigate the risk of the subsequent development of liver diseases among OSA patients and (b) is to evaluate the association between serum aminotransferase levels and severity of OSA and estimate the association between serum aminotransferase levels and oxidative stress.
We (a) use Taiwan National Health Insurance claims data, collected subjects on a cohort of 17,374 patients with OSA diagnosed between 2000 and 2008. A comparison group of 69496 persons was selected from the same database and matched by age, gender, urbanization, income, and date of initial admission and (b) recruited 185 workers who examined by polysomnography (PSG) to gain the the apnea-hypopnea index (AHI) and divided into four groups, normal (AHI<5), mild (5≦AHI<15), morderate (15≦AHI<30) and severe (AHI≧30). Meanwhile, blood and urine samples were collected to analyses the biomarkers of interesting, especially AST, ALT, malonaldehyde (MDA) and 8-hydroxy-2-deoxyguanosine (8OHdG).
The overall risk of liver diseases among OSA patients was significantly higher than in the comparison group (aHR = 5.52, p<0.001). Non-alcoholic fatty liver disease, cirrhosis, and hepatitis C had significant aHRs of 5.29, 7.50, and 7.19 (all at p<0.001), respectively. In contrast, hepatitis B had the smallest aHR of 3.71. Another results shows that OSA group in AST and ALT are higher than normal group, and the ALT of the mild group was significantly higher than that of the normal group (all p=0.03). And in multiple regression, the MDA has correlation between AST and ALT in severe OSA group (p = 0.02, p = 0.01, respectively.
In conclusion, (a) the risk of liver diseases was more than five times higher among OSA patients compared with the comparison group in this large population-based study; particularly for NAFLD. (b) occupational workers with OSA could lead the raising serum ALT levels and may induce the more severe damage of liver. The oxidative stress may join the liver disease progress. The potential health effects of workers with OSA should be pay more attention in the future.

目錄
誌謝 i
中文摘要 iii
英文摘要 vi
表目錄 xii
圖目錄 xiii

第一章 緒論 - 1 -
第一節 研究背景與研究動機 - 1 -
第二節 研究的重要性 - 3 -
第三節 研究假設 - 4 -

第二章 文獻回顧 - 5 -
第一節 睡眠呼吸中止症（sleep apnea, SA) - 5 -
2.1.1 OSA發生原因及定義 - 5 -
2.1.2 OSA診斷及治療 - 7 -
2.1.3 OSA流行病學 - 9 -
2.1.4 職業族群之OSA - 10 -
2.1.5 OSA與氧化壓力產生之關係 - 11 -
第二節 肝臟疾病 （Liver disease, LD）- 13 -
2.3.1 非酒精性脂肪肝（Non-alcoholic fatty liver disease, NAFLD）- 13 -
2.3.2 B型肝炎 （Hepatitis B, HBV）- 17 -
2.3.3 C型肝炎 （Hepatitis C, HCV）- 19 -
2.3.4 肝硬化 - 22 -
2.3.5 肝臟生化指標 - 25 -
2.3.6 職業族群之LD - 26 -
第三節 肝臟疾病之進程 - 27 -
2.3.1 二次傷害假說（Two-hit theory）- 27 -
2.3.2 假說之相關研究 - 28 -
第四節 氧化壓力傷害指標 - 31 -
2.4.1 丙二醛（malondialdehyde, MDA）- 31 -
2.4.2 8-OHdG（8-hydroxy-2-deoxyguanosine, 8OHdG）- 32 -
第五節 睡眠呼吸中止症與肝臟疾病 - 33 -
2.4.3 OSA與NAFLD之關係 - 33 -
2.4.4 OSA 與B、C型肝炎之關係 - 35 -

第三章 研究目的與架構 - 36 -
第一節 研究目的 - 36 -
第二節 研究架構 - 37 -
4.2.1 健保資料庫 - 37 -
4.2.2 職業駕駛資料庫 - 38 -

第四章 研究方法 - 39 -
第一節 健保資料庫 - 39 -
4.1.1 研究對象 - 39 -
4.1.2 研究樣本收集 - 39 -
4.1.3 統計方法 - 42 -
第二節 職業駕駛資料庫 - 43 -
4.2.1 研究對象 - 43 -
4.2.2 研究樣本收集 - 43 -
4.2.3 統計方法 - 51 -

第五章 研究結果 - 53 -
第一節 健保資料庫研究結果 - 53 -
5.1.1 有無OSA之分組基本資料分布結果 - 53 -
5.1.2 OSA患者和對照組在不同肝臟疾病發生率之比較 - 54 -
5.1.3 利用存活分析估計肝臟疾病的累積發病率 - 55 -
5.1.4 利用Cox比例風險回歸估計不同的肝臟疾病HR值 - 57 -
第二節 職業駕駛資料庫研究結果 - 58 -
5.2.1 受試員工基本資料及睡眠資料分析結果 - 58 -
5.2.2 不同OSA嚴重程度中員工血液生化及肝臟生化指標分布 - 59 -
5.2.3 OSA與肝臟生化指標之相關性 - 61 -
第三節 睡眠狀態與肝臟生化指標異常之交互作用結果 - 64 -
5.3.1 肝臟指標異常與OSA嚴重程度分組分析結果 - 64 -
第四節 肝臟生化指標與氧化壓力相關性研究結果 - 66 -
5.4.1 氧化壓力及肝臟指標在有無OSA分析結果 - 66 -
5.4.2 氧化壓力與肝臟指標之相關性結果 - 68 -

第六章 討論 - 73 -
第一節 一般族群健保資料庫綜合討論 - 73 -
6.1.1 肝臟疾病與睡眠呼吸中止症之相關性 - 73 -
6.1.2 肝臟疾病與睡眠呼吸中止症之缺氧狀態 - 74 -
第二節 職業駕駛族群綜合討論 - 76 -
6.2.1 基本資料與睡眠呼吸中止症嚴重程度之相關探討 - 76 -
6.2.2 肝臟生化指標與睡眠呼吸中止症嚴重程度 - 76 -
6.2.3 肝臟疾病進程與睡眠呼吸中止症之相關性 - 78 -
第三節 職業駕駛族群氧化壓力及肝臟指標之綜合討論 - 80 -
6.3.1 氧化壓力與OSA之相關探討 - 80 -
6.3.2 氧化壓力與肝臟生化指標之相關探討 - 81 -

第七章 結論與建議 - 83 -
第一節 結論與建議 - 83 -
7.1.1 健保資料庫之結論與建議 - 83 -
7.1.2 職業駕駛資料庫之結論與建議 - 83 -
第二節 研究限制 - 84 -
7.2.1 健保資料庫之限制 - 84 -
7.2.2 職業駕駛資料庫之限制 - 85 -

第八章 參考文獻 - 86 -
附錄 - 101 -
附件一、人體試驗委員會同意函 - 101 -
附件二、睡眠問卷 - 103 -

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