降膽固醇藥物竟能防癌？研究揭示他汀類藥物可大幅降低肝癌風險！

本翻譯僅作學術交流用，無商業意圖，請勿轉載，如有疑議問請來信

最新統合分析指出，他汀類藥物除降低膽固醇外，對肝癌也具保護力！與未使用者相比，服用者肝癌風險降低達46%，特別是在糖尿病與肝硬化患者中效果更顯著，未來有望成為預防肝癌的新利器。

他汀類藥物使用與肝細胞癌風險：觀察性研究的綜合分析

Statin Use and the Risk of Hepatocellular Carcinoma: A Meta-Analysis of Observational Studies

Islam MM, Poly TN, Walther BA, Yang HC, Jack Li YC. Statin Use and the Risk of Hepatocellular Carcinoma: A Meta-Analysis of Observational Studies. Cancers (Basel). 2020;12(3):671. Published 2020 Mar 13. doi:10.3390/cancers12030671

https://pmc.ncbi.nlm.nih.gov/articles/PMC7139959/

摘要 Abstract

背景與目的：他汀類藥物是治療高膽固醇血症的一線藥物。幾項研究已經調查了他汀類藥物對肝細胞癌（HCC）風險的影響。然而，他汀類藥物在多大程度上可以預防 HCC 仍然不確定。因此，我們對相關研究進行了元分析，以量化他汀類藥物使用與 HCC 風險之間的關聯程度。方法：對 1990 年 1 月 1 日至 2019 年 9 月 1 日之間發表的研究進行了 PubMed、EMBASE、Google Scholar、Web of Science 和 Scopus 的系統文獻搜索，語言不受限制。兩位評審獨立評估文獻，並納入報告他汀類藥物使用與 HCC 風險之間關聯的觀察性和實驗性研究。使用隨機效應模型計算整體風險比（RR）及 95%置信區間（CI），並使用 Q 統計量和 I ² 統計量評估研究之間的異質性。還使用紐卡斯爾-渥太華量表（NOS）評估納入研究的質量。結果：共識別出 24 項研究，涉及 59,073 名 HCC 患者。 使用他汀類藥物與肝細胞癌（HCC）發展風險降低相關（相對風險：0.54，95% 置信區間：0.47–0.61，I ² = 84.39%），與非使用者相比。此外，糖尿病患者（相對風險：0.44，95% 置信區間：0.28–0.70）、肝硬化患者（相對風險：0.36，95% 置信區間：0.30–0.42）和接受抗病毒治療的患者（相對風險：0.21，95% 置信區間：0.08–0.59）中，HCC 風險降低的比率也顯著。結論：本研究提供了進一步的證據，支持他汀類藥物對 HCC 發生率的有益抑制作用。本研究的亞組分析也強調他汀類藥物與 HCC 風險降低顯著相關，並可能有助於指導未來的預防工作。需要進一步的大型臨床研究來確定他汀類藥物是否與 HCC 風險降低相關。

Background and Aims: Statins are the first-line medication to treating hypercholesterolemia. Several studies have investigated the impact of statins on the risk of hepatocellular carcinoma (HCC). However, the extent to which statins may prevent HCC remains uncertain. Therefore, we performed a meta-analysis of relevant studies to quantify the magnitude of the association between statins use and the risk of HCC. Methods: A systematic literature search of PubMed, EMBASE, Google Scholar, Web of Science, and Scopus was performed for studies published between January 1, 1990, and September 1, 2019, with no restriction of language. Two reviewers independently evaluated the literature and included observational and experimental studies that reported the association between statin use and HCC risk. The random-effect model was used to calculate the overall risk ratio (RR) with a 95% confidence interval (CI), and the heterogeneity among the studies was assessed using the Q statistic and I² statistic. The Newcastle Ottawa Scale (NOS) was also used to evaluate the quality of the included studies. Results: A total of 24 studies with 59,073 HCC patients was identified. Statin use was associated with a reduced risk of HCC development (RR: 0.54, 95% CI: 0.47–0.61, I² = 84.39%) compared with nonusers. Moreover, the rate of HCC reduction was also significant among patients with diabetes (RR: 0.44, 95% CI: 0.28–0.70), liver cirrhosis (RR: 0.36, 95% CI: 0.30–0.42), and antiviral therapy (RR: 0.21, 95% CI: 0.08–0.59) compared with nonusers. Conclusion: This study serves as additional evidence supporting the beneficial inhibitory effect of statins on HCC incidence. The subgroup analyses of this study also highlight that statins are significantly associated with a reduced risk of HCC and may help to direct future prevention efforts. Additional large clinical studies are needed to determine whether statins are associated with a lower risk of HCC.

關鍵詞：肝細胞癌、肝癌、肝硬化、脂肪肝、肝纖維化、他汀類藥物
Keywords: Hepatocellular carcinoma, liver cancer, liver cirrhosis, fatty liver, liver fibrosis, statins

1. 引言 1. Introduction

肝細胞癌（HCC）是全球日益嚴重的公共健康問題，也是最常見的肝臟原發性惡性腫瘤[ 1 ]。HCC 因為是第六種最常見的癌症類型和全球癌症相關死亡的第二大原因而受到密切關注[ 2 ]。HCC 患者的發病率顯著增加，預計到 2032 年將上升至 2200 萬[ 3 ]。HCC 通常發生在慢性肝病患者中[ 4 ]。慢性肝病，如丙型肝炎病毒（HCV）、乙型肝炎病毒、非酒精性脂肪肝病、自身免疫性肝病和酒精性肝病，會導致肝硬化，最終發展為 HCC[ 5 , 6 , 7 ]。大約 98%的 HCC 患者存在肝硬化[ 8 ]。先前的研究還報告指出，糖尿病患者的 HCC 發病風險比非糖尿病患者高出兩倍[ 4 , 9 ]。幾項研究報告了他汀類藥物使用與慢性肝病之間的反向關聯[ 10 , 11 ]，包括 HCC 的發展[ 12 ]。

Hepatocellular carcinoma (HCC) is a growing public health issue worldwide and the most common primary malignancy of the liver [1]. HCC has received close attention for being the sixth most frequent type of cancer and the second leading cause of cancer-related mortality worldwide [2]. The incidence rate of HCC patients has increased significantly, predicted to rise to 22 million by 2032 [3]. HCC often develops in patients with chronic liver disease [4]. Chronic liver diseases, such as hepatitis C virus (HCV), hepatitis B virus, nonalcoholic fatty liver disease, autoimmune liver disease, and alcoholic liver disease lead to liver cirrhosis and eventually to HCC [5,6,7]. Liver cirrhosis is present in approximately 98% of HCC patients [8]. Previous studies also reported that patients with diabetes had a greater (two-fold) risk of HCC incidence than those without diabetes [4,9]. Several studies have reported an inverse association between statin use and chronic liver diseases [10,11], including HCC development [12].

他汀類藥物，3-羥基-3-甲基戊二酸輔酶 A (HMG-CoA) 還原酶抑制劑，通常用作心血管疾病和中風的標準治療，以降低血膽固醇水平 [ 13 ]。一項涉及 4298 名肝細胞癌（HCC）患者的十項流行病學研究的綜合分析顯示，使用他汀類藥物可降低 HCC 發病率（比值比（OR）：0.63，95%置信區間（CI）：0.52–0.76），與不使用者相比 [ 14 ]。除了在膽固醇降低方面的效率外，體外的前臨床研究顯示他汀類藥物還具有抗血管生成、免疫調節、抗增殖和抗纖維化的特性，這可能減少腫瘤生長或 HCC 發展 [ 15 , 16 ]。此外，體內研究顯示在抗腫瘤效果方面有希望的結果，例如在各種動物模型中抑制細胞增殖和促進腫瘤細胞分化 [ 17 , 18 ]。 他汀類藥物可能通過抑制包括 Rho 依賴性激酶[ 19 ]、腫瘤壞死因子（TNF）介導的白介素（IL6）產生[ 20 ]、Akt[ 21 ]、Myc 介導的細胞增殖等致癌途徑來幫助預防肝細胞癌（HCC）[ 22 ]（ Figure 1 ）。

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are commonly used as standard therapy for the management and prevention of cardiovascular disease and stroke by reducing blood cholesterol level [13]. A meta-analysis of ten epidemiological studies involving 4298 patients with HCC demonstrated that statin use reduced HCC incidence (Odd Ratio (OR): 0.63, 95% confidence interval (CI): 0.52–0.76) compared to nonusers [14]. Besides their efficiency in cholesterol reduction in vitro preclinical studies showed that statins also have antiangiogenic, immunomodulatory, antiproliferative, and antifibrotic properties that probably reduce tumor growth or HCC development [15,16]. Moreover, in vivo studies showed promising results in antitumor effects such as the inhibition of cell proliferation and the promotion of tumor cell differentiation in various animal models [17,18]. Statins perhaps help to prevent HCC by suppressing oncogenic pathways including Rho-dependent kinase [19], tumor necrosis factor (TNF)-mediated interleukin (IL6) production [20], Akt [21], Myc-medicated cell proliferation, and so on [22] (Figure 1).

肝細胞癌（HCC）的風險因素及他汀類藥物在肝臟疾病中的作用。 Risk factors of hepatocellular carcinoma (HCC) and the effect of statins in hepatic diseases.

他汀類藥物的有益效果在肝癌患者中已被廣泛報導。因此，評估它們在不同劑量、類型、地區和其他疾病條件下的效果是重要的。為了更好地評估他汀類藥物可能降低 HCC 風險的程度，我們調查了最近發表的相關研究，這些研究探討了他汀類藥物使用與 HCC 發展風險之間的關聯。我們的主要目標是解決不一致之處，並測量他汀類藥物與 HCC 發展風險之間的關聯性質和大小。

The beneficial effects of statin use have ubiquitously been reported for liver cancer patients. Therefore, it is important to evaluate their effects in various doses, types, regions, and other disease conditions. To better evaluate the extent to which statins may reduce the risk of HCC, we surveyed recently published relevant studies that investigated the association between statin use and the risk of HCC development. Our primary objective was to resolve discrepancies and to measure the nature and magnitude of the association between statins and the risk of HCC development.

2. 結果 2. Results

電子數據庫的初步出版物搜索共產生了 3245 篇出版物。在消除重複後，根據預定的排除標準，共排除了 3113 項研究，剩下 32 篇文章進行全文審查。此外，在篩選 32 篇相關文章的參考文獻列表後，又增加了兩篇文章。根據審查標準，又排除了 10 篇文章，最終留下 24 篇出版物供我們目前的元分析使用 [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] ( Figure 2 )。

The initial publications search of the electronic databases yielded 3245 publications. After eliminating duplication, a total of 3113 studies were excluded based on the predefined exclusion criteria which left 32 articles for full-text review. Furthermore, two articles were added after screening the reference lists of the 32 relevant articles. Based on the review criteria, another 10 articles were excluded, which left a total of 24 publications for our present meta-analysis [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46] (Figure 2).

PRISMA（系統評價與統合分析的首選報告項目）研究選擇流程圖。 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram for study selection.

Table 1 顯示了包含的 24 篇出版物的摘要。這些出版物包含 2,674,298 名參與者，其中 59,073 名為肝細胞癌（HCC）參與者。十二篇出版物為病例對照研究 [ 23 , 24 , 26 , 27 , 30 , 32 , 33 , 34 , 35 , 39 , 40 , 43 ]，十篇出版物為隊列研究 [ 23 , 25 , 28 , 29 , 31 , 36 , 37 , 38 , 41 , 42 ]，三篇出版物為隨機對照試驗研究 [ 44 , 45 , 46 ]。其中，十二篇出版物來自西方 [ 23 , 24 , 28 , 30 , 32 , 33 , 38 , 40 , 41 , 42 , 43 , 44 , 46 ] 國家，十二篇出版物來自亞洲 [ 25 , 26 , 27 , 29 , 31 , 34 , 35 , 36 , 37 , 39 , 44 , 45 ] 國家。所有研究均使用國際疾病分類（ICD）代碼來識別 HCC 患者，並使用 ATC（解剖療法化學分類系統）代碼來識別他汀類藥物使用者。

Table 1 shows a summary of the included 24 publications. The publications comprised 2,674,298 participants, with 59,073 HCC participants. Twelve publications were case-control studies [23,24,26,27,30,32,33,34,35,39,40,43], ten publications were cohort studies [23,25,28,29,31,36,37,38,41,42], and three publications were randomized control trial studies [44,45,46]. Of these, twelve publications were from Western [23,24,28,30,32,33,38,40,41,42,43,44,46] countries and twelve publications were from Asian [25,26,27,29,31,34,35,36,37,39,44,45] countries. All the studies used the International Classification of Diseases (ICD) code to identify HCC patients and the ATC (Anatomical Therapeutic Chemical Classification System) code to identify statin users.

納入研究的特徵。 Characteristics of included studies.

注意：NR = 未報告，CC = 病例對照，RCT = 隨機對照試驗，ICD = 國際疾病分類，Pts = 參與者，OR = 比值比，HR = 危險比，CI = 信賴區間，HCC = 肝細胞癌，DM = 糖尿病，IBDC：鶴的包涵體病，NAFLD：非酒精性脂肪肝病，HCV：丙型肝炎病毒，HBV：乙型肝炎病毒。

Note: NR = Not reported, CC = Case-Control, RCT = Randomized Control Trial, ICD = International Classification of Diseases, Pts = Participants, OR = Odd Ratio, HR = Hazard Ratio, CI = confidence interval, HCC = Hepatocellular Carcinoma, DM = Diabetic Mellitus, IBDC: Inclusion Body Disease of Cranes, NAFLD: Non-alcoholic fatty liver disease, HCV: Hepatitis C virus, HBV: Hepatitis B virus.

我們利用紐卡斯爾-渥太華量表來評估每項研究的質量，該量表通常用於非隨機研究，並已被科克倫合作組織推薦 [ 47 ]。我們還使用科克倫工具（科克倫社區，倫敦，英國）來評估隨機研究的質量 [ 48 ]。NOS（紐卡斯爾-渥太華量表）分數範圍為 7–9，因此，證據水平為高。 

We utilized the Newcastle Ottawa scale to assess the quality of each study, which is usually applied for non-randomized studies and has been recommended by the Cochrane collaboration [47]. We also assessed randomized study quality with the Cochrane tools (Cochrane Community, London, UK) [48]. The range of the NOS (The Newcastle-Ottawa Scale) score was 7–9, and therefore, the level of evidence was high.

2.4.1. 主要分析  2.4.1. Primary Analysis

我們的統合分析包含了 24 項研究，共有 59,073 名肝細胞癌（HCC）個體。在合併分析中，整體使用他汀類藥物與 HCC 發展風險顯著降低相關（RR：0.54，95% CI：0.47–0.61），與不使用者相比（ Figure 3 ）。
Our meta-analysis comprised 24 studies with 59,073 HCC individuals. In the pooled analysis, overall statin use was significantly associated with a reduced risk of HCC development (RR: 0.54, 95% CI: 0.47–0.61), compared to nonusers (Figure 3).

他汀類藥物使用與肝細胞癌（HCC）風險。 Statin use and hepatocellular carcinoma (HCC) risk.

2.4.2. 次要分析
2.4.2. Secondary Analysis

在次要分析中，考慮了使用他汀類藥物與糖尿病（DM）、肝病或抗病毒治療患者中肝細胞癌（HCC）發展之間的關係。在糖尿病患者中，使用他汀類藥物與 HCC 風險顯著降低相關（相對風險：0.44，95% 置信區間：0.28–0.70），與不使用者相比。在沒有糖尿病的患者中，使用他汀類藥物也顯示出 HCC 風險顯著降低（相對風險：0.58，95% 置信區間：0.48–0.69）。在肝硬化患者中，他汀類藥物與 HCC 呈負相關（相對風險：0.36，95% 置信區間：0.30–0.42）。在沒有肝硬化的患者中，使用他汀類藥物也顯示出 HCC 發生率顯著降低（相對風險：0.50，95% 置信區間：0.35–0.71）。

In the secondary analysis, the relationship between statin use and HCC development in patients with DM (Diabetes Mellitus), liver diseases, or antiviral therapy was considered. In patients with DM, statin use was significantly associated with a reduced risk of HCC (RR: 0.44, 95% CI: 0.28–0.70) compared to that of nonusers. In patients without DM, statin use also showed a significant risk reduction of HCC (RR: 0.58, 95% CI: 0.48–0.69) (Figure 4). In patients with liver cirrhosis, statins had an inverse association with HCC (RR: 0.36, 95% CI: 0.30–0.42). In patients without liver cirrhosis, statin use also showed a significant reduction of HCC incidence (RR: 0.50, 95% CI: 0.35–0.71) (Figure 5).

他汀類藥物的使用與患有 (A) 糖尿病 (DM) 和 (B) 無糖尿病 (DM) 的患者肝細胞癌 (HCC) 風險的關係。 Statin use and the risk of hepatocellular carcinoma (HCC) in patients with (A) DM and (B) without diabetes mellitus (DM). 他汀類藥物的使用與 (A) 肝硬化患者和 (B) 非肝硬化患者的肝細胞癌 (HCC) 風險。 Statin use and the risk of hepatocellular carcinoma (HCC) in patients with (A) liver cirrhosis and (B) without liver cirrhosis. 他汀類藥物的使用與 (A) 肝硬化患者和 (B) 非肝硬化患者的肝細胞癌 (HCC) 風險。 Statin use and the risk of hepatocellular carcinoma (HCC) in patients with (A) liver cirrhosis and (B) without liver cirrhosis.

在子群分析中考慮了研究設計、地區、劑量和不同類型的他汀類藥物（ Table 2 ）。觀察性研究設計的整體合併風險比（RR）為 0.52（95% CI：0.46–0.60），而隨機對照試驗（RCT）研究設計的整體合併 RR 為 0.95（95% CI：0.61–1.47）。此外，我們還調查了他汀類藥物使用與肝細胞癌（HCC）發展之間的關聯，針對來自不同地區的患者。亞洲和西方人群的合併 RR 分別為 0.49（95% CI：0.42–0.57）和 0.59（95% CI：0.49–0.70）。

The study design, region, dose, and different types of statins were considered in the subgroup analysis (Table 2). The overall pooled Risk Ratio (RR) for the observational study design was 0.52 (95% CI: 0.46–0.60), and the overall pooled RR for the RCT study design was 0.95 (95% CI: 0.61–1.47). Furthermore, we investigated the association between statin use and HCC development among patients from different regions. The pooled RR for Asian and Western populations were 0.49 (95% CI: 0.42–0.57), and 0.59 (95% CI: 0.49–0.70), respectively.

表 2。 Table 2. 子群分析。 Subgroup analysis.

在劑量依賴性分析中，隨著累積定義每日劑量（cDDD）的增加，風險降低的效果在與非使用者相比時更加明顯（RR 0.55（95% CI：0.46–0.65）和 RR 0.47（95% CI：0.36–0.61），對於≤365 cDDD 和>365 cDDD，分別；趨勢 p < 0.0001）。對不同類型的他汀類藥物的分析顯示出保護作用，特別是對於氟伐他汀（RR 0.41，95% CI：0.25–0.66，p < 0.001）、洛伐他汀（RR 0.43，95% CI：0.21–0.86，p = 0.01）、羅蘇伐他汀（RR 0.47，95% CI：0.26–0.84，p = 0.01）、辛伐他汀（RR 0.54，95% CI：0.46–0.63，p < 0.001）和阿托伐他汀（RR 0.55，95% CI：0.43–0.69，p < 0.001）。然而，塞伐他汀和普伐他汀顯示出保護作用（RR 0.61，95% CI：0.26–1.42，p = 0.25 和 RR 0.76，95% CI：0.56–1.03，p = 0.08），但統計上不顯著（ Supplementary Figure S1–12 ）。

In the dose-dependent analysis, risk reduction was accentuated with an increase of the cumulative defined daily doses (cDDD) compared with nonusers (RR 0.55 (95% CI: 0.46–0.65) and RR 0.47 (95% CI: 0.36–0.61) for ≤365 cDDD and >365 cDDD, respectively; p for trend <0.0001). An analysis of different types of statins showed protective effects, particularly for fluvastatin (RR 0.41, 95% CI: 0.25–0.66, p < 0.001), lovastatin (RR 0.43, 95% CI: 0.21–0.86, p = 0.01), rosuvastatin (RR 0.47, 95% CI: 0.26–0.84, p = 0.01), simvastatin (RR 0.54, 95% CI:0.46–0.63, p < 0.001), and atorvastatin (RR 0.55, 95% CI: 0.43–0.69, p < 0.001). However, cerivastatin and pravastatin showed protective effects (RR 0.61, 95% CI: 0.26–1.42, p = 0.25 and RR 0.76, 95% CI: 0.56–1.03, p = 0.08) but were statistically insignificant (Supplementary Figure S1–12).

為了檢測出版偏倚，合併分析或子組分析並不足夠。因此，我們使用了埃格爾檢驗和貝格檢驗來識別出版偏倚。然而，漏斗圖的視覺檢查顯示沒有出版偏倚，後來通過貝格調整的秩相關檢驗確認了這一點（ Supplementary Figure S13 ）。

To detect publication bias, the pooled analysis or subgroup analyses were not sufficient. Therefore, we used the Egger test and the Begg test to identify publication bias. However, visual inspection of the funnel plot revealed no publication bias, later confirmed by the Begg adjusted rank correlation test (Supplementary Figure S13).

3. 討論 3. Discussion

在這項涵蓋 24 項研究、共計 59,073 名肝細胞癌（HCC）患者的綜合分析中，使用他汀類藥物與 HCC 風險顯著降低相關（相對風險：0.54，95%置信區間：0.47–0.61，I ² = 84.39%）。我們還分析了他汀類藥物對於具有高風險因素（ Supplementary Figure S14 ）的患者在 HCC 風險降低方面的有益效果，包括糖尿病和肝硬化。先前的研究報告指出，糖尿病和肝硬化患者與 HCC 風險增加顯著相關。然而，我們的研究結果顯示，他汀類藥物顯著降低了糖尿病和肝硬化患者的 HCC 風險。此外，使用他汀類藥物的 HCC 風險降低率在糖尿病或肝硬化患者中高於在沒有糖尿病或肝硬化的患者中。使用更高累積劑量的他汀類藥物與較低累積劑量相比，風險降低的效果更顯著。使用氟伐他汀、洛伐他汀和羅蘇伐他汀對降低 HCC 風險的效果優於其他他汀類藥物。

In this meta-analysis of 24 studies with a total of 59,073 HCC individuals, statins were significantly associated with reductions in the risk of HCC (RR: 0.54, 95% CI: 0.47–0.61, I² = 84.39%). We also analyzed the beneficial effect of statins on HCC risk reduction in patients with high-risk factors (Supplementary Figure S14), including diabetes and liver cirrhosis. Previous studies reported that patients with diabetes and liver cirrhosis were significantly associated with an increased risk of HCC. However, findings of our study showed that statins significantly reduced the risk of HCC in patients with diabetes and liver cirrhosis. Moreover, the rate of HCC reduction with statins use was greater in patients with diabetes or liver cirrhosis than in patients without diabetes or liver cirrhosis. Higher cumulative doses of statins use were associated with greater risk reductions than lower cumulative doses of statins. The use of fluvastatin, lovastatin, and rosuvastatin showed greater effects for reducing the risk of HCC than the use of other statins.

本研究對 HCC 風險的發現與三項先前的系統性回顧和統合分析相似。2013 年的一項研究發現，統計藥物在 10 項研究的分析中減少了 HCC，參與者總數為 1,459,417 名，其中 4298 名為 HCC 患者（OR：0.63，95％ CI：0.52–0.76）[ 14 ]。在接下來的一年中，一項包含 12 項研究的統合分析，參與者總數為 5,640,313 名，也建議 HCC 的減少（RR：0.58，95％ CI：0.51–0.67）[ 49 ]。另一項對 87,127 名參與者的五項觀察性研究的統合分析也評估了不同類型的統計藥物使用與 HCC 風險的減少[ 50 ]，並發現與其他類型的統計藥物相比，氟伐他汀對減少 HCC 風險最為有效（RR：0.55，95％ CI：0.26–1.11）。我們的研究在三個方面更新和擴展了這些先前系統性回顧和統合分析的證據。首先，我們納入了來自不同大陸的更多觀察性研究。其次，我們納入了比先前研究更多的亞組分析。 最後，我們評估了與他汀類藥物使用和肝細胞癌風險相關的幾個額外因素，例如糖尿病和肝硬化，以檢查這些額外因素可能造成的任何偏見或影響。

The findings of this study on HCC risk are similar to three previous systematic reviews and meta-analyses. A study in 2013 found that statins decreased HCC in analyses of 10 studies with a total of 1,459,417 participants with 4298 HCC patients (OR: 0.63, 95% CI: 0.52–0.76) [14]. In the next year, a meta-analysis that included 12 studies with a total of 5,640,313 participants also suggested a reduction of HCC (RR: 0.58, 95% CI: 0.51–0.67) [49]. Another meta-analysis of five observational studies with 87,127 participants also evaluated different types of statin use and reduction of HCC risk [50] and found that fluvastatin is the most effective for reducing HCC risk (RR: 0.55, 95% CI: 0.26–1.11) compared with the reductions associated with other types of statins. Our study has updated and extended the evidence of these prior systematic reviews and meta-analyses in three ways. First, we included more observational studies from different continents. Second, we included more subgroup analyses than previous studies. Finally, we evaluated several additional factors associated with statins use and HCC risk, e.g., diabetes and liver cirrhosis, to examine any possible bias or influence of these additional factors.

有幾個令人信服的生物學解釋表明，使用他汀類藥物可以降低肝細胞癌（HCC）的風險。他汀類藥物確實具有多重效應來降低 HCC 的風險，包括抗氧化、抗炎、內皮功能和抗纖維化特性（ Figure 6 ）。目前，他汀類藥物是治療高膽固醇血症的最佳選擇，因為它們抑制主要負責刺激膽固醇合成的美伐酸途徑（ 51 ）。然而，使用他汀類藥物實際上會降低膽固醇合成途徑下游代謝物的表達，包括法尼基焦磷酸鹽和香葉基焦磷酸鹽，從而減緩 GTP 酶的前烯基化，這降低了 Ras 和 Rho 的轉位及其功能，減少細胞增殖和遷移（ 52 ）。他汀類藥物通過肝細胞的旁分泌效應抑制脂肪變性引起的肝星狀細胞（HSC）活化。他汀類藥物還可以下調促纖維化基因表達（TGF-β1、α-SMA 和基質金屬蛋白酶抑制劑-1）和 HSC 中α-SMA 的蛋白表達；因此，它減少肝纖維化（ 53 ）。 此外，慢性肝損傷也是肝細胞癌（HCC）發展的重要因素[ 54 ]。他汀類藥物的使用進一步通過分泌炎症介導的損傷發生分子模式，包括 IL-6、IL-1β、TNF 和活性氧（ROS），誘導肝細胞凋亡[ 55 ]。然而，他汀類藥物能夠通過去活化 IL-6 和 TNF-α的表達，以及顯著減弱金屬蛋白酶的活性和 ROS 的產生來減輕肝臟炎症[ 53 , 56 ]。腫瘤內異質性為腫瘤演變和藥物抗性提供能量[ 57 , 58 ]。適當處理目前他汀類藥物的使用並展望未來的使用是既及時又重要的，未來他汀類藥物可能應用於更廣泛的 HCC 減少[ 59 , 60 ]。最後，他汀類藥物激活原癌基因轉錄因子 Myc[ 61 ]，並加速抑制性 miRNA-145 的表達[ 62 ]，最終控制腫瘤細胞的遷移和侵襲。

There are several convincing biological explanations that statin use can reduce the risk of HCC. Statins indeed have several pleiotropic effects to reduce the risk of HCC, including antioxidative, anti-inflammatory, endothelial function, and anti-fibrotic properties (Figure 6). Statins are currently the ultimate choice to treat hypercholesterolemia because they inhibit the mevalonate pathway which is mainly responsible for stimulating cholesterol synthesis [51]. However, the use of statins actually reduces the expression of downstream metabolites of the cholesterol synthesis pathway, including farnesyl pyrophosphate, and geranyl pyrophosphate, thereby slowing the prenylation of GTPase down, which decreases the translocation of Ras and Rho and their functions, decreasing cell proliferation and migration [52]. Steatosis-induced HSC activation is suppressed by statins, through the paracrine effect of hepatocytes. Statins can also downregulate profibrogenic gene expressions (TGF-β1, α-SMA, and tissue inhibitor of metalloproteinases-1) and protein expression of αSMA in HSCs; thus, it reduces liver fibrosis [53]. Furthermore, chronic hepatic injury is also an important factor in HCC development [54]. Statin use further induces hepatocyte apoptosis by secreting inflammation-mediated damage occurring molecular patterns including IL-6, IL-1β, TNF, and reactive oxygen species (ROS) [55]. However, statins have the ability to mitigate hepatic inflammation by deactivating IL-6 and TNF-α expression and by significantly attenuating metalloproteinases activity and production of ROS [53,56]. Intratumor heterogeneity supplies energy for tumor evolution and drug resistance [57,58]. It is both intrinsically timely and important to properly address the current use of statins and to provide an outlook for future use, where statins may be applied to a wider range of HCC reduction [59,60]. Finally, statins activate the protooncogenic transcription factor Myc [61] and accelerate the expression of the suppressor miRNA-145 [62], which ultimately controls tumor cell migration and invasion.

他汀類藥物預防肝細胞癌（HCC）的機制。 Mechanism of statins to prevent hepatocellular carcinoma (HCC).

本研究是一項關於此主題的大型更新的綜合分析，包括隨機對照試驗和觀察性研究（病例對照研究和隊列研究）。所有納入的研究質量較高，其各自的 NOS 分數範圍在 7 到 9 之間。所有的效應大小都已調整了潛在的混雜因素（ Supplementary Figure S15 ），而且在主要和子組分析中異質性相對較低。

This study is a large updated meta-analysis on this topic, including both randomized controlled trials and observational studies (case-control and cohort studies). All the included studies were of higher quality with their respective NOS scores ranging between 7 and 9. All the effect sizes ware adjusted with potential confounding factors (Supplementary Figure S15), and the heterogeneity was relatively low in both primary and subgroup analyses.

這項綜合分析有幾個需要解決的限制。首先，所有納入的研究都調整了潛在的混雜因素，但這些混雜因素並不相同。例如，有些研究未能調整肝病的嚴重程度（以 Child–Pugh 分數分類）、酒精消耗、糖尿病或不同的病毒性疾病。其次，大多數納入的研究都是觀察性研究（隊列研究和病例對照研究），而 HCC 患者是通過 ICD 代碼識別的。因此，尚不清楚使用他汀類藥物的 HCC 患者是否得到了適當的隨訪，以及這些人群的用藥依從性如何。第三，一些研究使用相同的數據庫來評估他汀類藥物使用與 HCC 風險之間的關聯。儘管納入的研究的研究期間並不相同，但某些患者可能在納入的研究中重疊。

This meta-analysis has several limitations that need to be addressed. First, all the included studies were adjusted with potential confounding factors, but these confounding factors were not the same. For example, some failed to adjust their study for factors such as the severity of liver disease (classified with the Child–Pugh score), alcohol consumption, diabetes, or different viral diseases. Second, most included studies were observational (cohort and case-control study) and the HCC patients were identified by the ICD code. Therefore, it is not clear that the HCC patients who used statins were followed properly and what was the medication compliance of these populations. Third, some studies used the same databases to assess the association between statin use and HCC risk. Even though the study duration was not the same for any of the included studies, some patients might overlap in the included studies.

我們更新的綜合分析包含了來自不同族群（四大洲）的 59,073 名肝細胞癌（HCC）患者的大量研究，合併風險比小於 0.5，且信賴區間狹窄。因此，我們的發現強烈表明，使用他汀類藥物對於降低 HCC 具有顯著且臨床相關的效果，包括在糖尿病和其他類型肝病等各種情況下。最近，對他汀類藥物潛在肝毒性的擔憂有所增加，幾項關於他汀類藥物使用的指導方針也持續警告這些風險。然而，許多研究也報告他汀類藥物引起的肝毒性極低（少於 3%的所有服用他汀類藥物的患者）。大量回顧性研究提到，即使他汀類藥物在減少肝臟失代償和肝細胞癌方面更有效，但對於肝硬化患者使用他汀類藥物是安全的。然而，並不建議在所有類型的肝硬化患者中普遍開立他汀類藥物。Kaplan 等人的一項研究 [ 62 ] 建議患有嚴重肝硬化/晚期失代償性肝硬化 (CTP C) 的患者在開始或持續使用他汀類藥物時，可能會經歷更多的不良後果而非好處。如果患者被診斷為失代償性肝硬化，則應謹慎以低劑量開立他汀類藥物，並應及時監測肌酸激酶水平 [ 63 ]。此外，Abraldes 等人 [ 64 ] 報告指出，在總膽紅素水平相當高的 Child–Pugh B 或 Child–Pugh C 患者中使用他汀類藥物可能存在風險。Child–Pugh A 肝硬化的患者可以從他汀類藥物的使用中獲得更多好處，但對於劑量和持續時間並沒有具體證據。然而，建議延長他汀類藥物的使用時間以獲得更好的益處效果。

Our updated meta-analysis included a large number of studies with 59,073 HCC patients from diverse populations (four continents), and the pooled risk ratio was less than 0.5 with a narrow confidence interval. Our findings therefore strongly suggest that statin use has a significant and clinically relevant effect on HCC reduction, including with various conditions such as diabetes and other types of liver diseases. Recently, concern has been raised about the potential hepatotoxicity of statins, and several guidelines regarding statin use also persistently warn of these risks. However, many studies have also reported that statin-induced hepatotoxicity is extremely low (less than 3% of all patients taking statins). A significant amount of retrospective studies mentioned that statins are safe for use in patients with cirrhosis, even if statins are more effective in reducing liver decompensation and hepatocellular carcinoma. However, prescribing statins ubiquitously is not recommended in patients with all types of cirrhosis. A study by Kaplan et al. [62] suggested that patients with serious cirrhosis/advanced decompensated cirrhosis (CTP C) may experience more unwanted consequences than benefits associated with initiating or continuing statin therapy. If the patients are diagnosed with decompensated cirrhosis, then statins should be prescribed with caution at low doses and should be accompanied with timely monitoring of creatinine phosphokinase levels [63]. Furthermore, Abraldes et al. [64] reported that the use of statins may be risky in Child–Pugh B or Child–Pugh C patients whose total bilirubin levels are quite high. Patients with Child–Pugh A cirrhosis can get more benefits from statin use but there is no specific evidence for dose and duration. However, longer duration of statin use is recommended to get better beneficial effects.

我們的結果支持他汀類藥物可以作為針對美伐酸途徑的抗癌療法的假設。本研究發現，脂溶性他汀類藥物，如洛伐他汀或辛伐他汀，對肝細胞癌的有益效果高於親水性他汀類藥物，如普伐他汀。我們的亞組分析的另一個發現表明，他汀類藥物在西方人群中的有益效果高於亞洲人群。亞洲和西方人之間的基因結構或多態性的變異可能會影響他汀類藥物的藥代動力學和藥效學特性[ 64 ]。更重要的是，它在不同類型的人群中顯示了化學預防的作用。根據這些發現，應進行前瞻性評估，以確定他汀類藥物是否可以用作抗癌藥物。他汀類藥物的化學預防效果僅在觀察性研究中顯示，但三項隨機對照試驗的合併估計並未顯示出顯著的化學預防效果。然而，這些研究僅包括少數個體（81 名參與者）和較短的隨訪時間。 同樣重要的是要指出，這些隨機對照試驗的主要結果集中在他汀類藥物對心血管死亡率的影響。此外，這些隨機對照試驗中納入的患者在發展肝細胞癌的風險較低。因此，這些研究的設計並不充分，以區分兩組（安慰劑與他汀類藥物）在肝細胞癌發展方面的顯著差異。他們並未篩查肝細胞癌患者，因為肝細胞癌的發生率是次要結果。因此，這些試驗的事後分析並不是為了評估他汀類藥物對肝細胞癌的保護作用。為了澄清這一問題，還需要進一步的前瞻性隨機對照試驗來證實我們的主要和亞組分析的結果。

Our results support the hypothesis that statins could be used as an anticancer therapy targeting the mevalonate pathway. The current study found that lipophilic statins, such as lovastatin or simvastatin, have a higher beneficial effect on HCC than hydrophilic statins such as pravastatin. Another finding from our subgroup analyses suggested that statins showed a higher beneficial effect in the Western population compared with the Asian population. Variation in genetic structure or polymorphism between Asian and Western people can influence statins’ pharmacokinetics and pharmacodynamics properties [64]. More importantly, it showed a chemopreventive role in different kinds of populations. According to these findings, a prospective evaluation should be carried out on whether statins can be used as anticancer drugs. The chemopreventive effects of statins have only been shown in observational studies, but the pooled estimate of three RCTs did not show a significant chemopreventive effect. However, these studies included only a small number of individuals (81 participants) and shorter duration of follow-up. It is also important to address that the primary outcome of these RCTs focused on the effect of statins on cardiovascular mortality. Moreover, the patients included in these RCTs had at low risk for development of HCC. Therefore, these studies were not well designed to distinguish significant differences in the two groups (placebo vs statin) with regard to HCC development. They did not screen the HCC patients because the incidence of HCC was the secondary outcome. Thus, post hoc analysis of these trials was not to judge the protective effect of statins against HCC. To make this issue clear, additional prospective randomized controlled trials are warranted to justify the findings from our primary and subgroup analyses.

然而，兩項大型臨床試驗正在美國和台灣進行，這些試驗具有巨大的潛力來證實或推翻我們在更新的綜合分析中的發現。在美國研究的前瞻性隨機對照試驗第二期（ NCT02968810 ）中，研究人員正在評估他汀類藥物對肝硬化患者肝癌的預防效果。同樣，在台灣，另一項前瞻性隨機臨床試驗第四期（ NCT03024684 ）正在評估治療後 HCC 復發的預防。由於開發新藥需要很長時間且成本高昂，藥物重定位正引起研究人員的關注，以尋找新的適應症。因此，這些臨床試驗的結果和我們的更新綜合分析為 HCC 患者帶來了新的希望。

However, two large clinical trials are ongoing in the United States and Taiwan which have immense potential to justify or nullify our findings in our updated meta-analysis. In the prospective randomized control trial Phase-II (NCT02968810) of the United States study, researchers are evaluating the preventive effect of statin on liver cancer in patients with liver cirrhosis. Similarly, in Taiwan, another prospective randomized clinical trial phase IV (NCT03024684) is evaluating preventive HCC recurrence after curative treatment. Since it takes a long time and is expensive to develop a new drug, drug repurposing is getting researchers’ attention in order to find new indications. Therefore, the results of these clinical trials and our updated meta-analysis bring new hope to patients with HCC.

4. 方法 4. Methods

在本研究中，我們遵循系統評價和元分析的首選報告項目（PRISMA）流程圖進行研究的納入和排除。此外，我們還考慮了流行病學觀察性研究的元分析（MOOSE）指導方針 [ 65 ]。

 Meta-Analyses (PRISMA) flow diagram for study inclusion and exclusion. Moreover, we also considered the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for observational studies [65].

我們系統性地在 PubMed、EMBASE、Web of Science、Google Scholar 和 Scopus 中搜尋相關研究，範圍涵蓋 1990 年 1 月 1 日至 2019 年 9 月 1 日之間發表的研究，且不限制語言。使用以下搜尋詞來尋找潛在研究：“肝細胞癌”或“肝癌”，以及“他汀類藥物”或“辛伐他汀”或“阿莫他汀”或“洛伐他汀”或“HMG-CoA 還原酶抑制劑”或“普伐他汀”或“羅蘇伐他汀”或“西伐他汀”或“匹伐他汀”（ Supplementary Table S1 ）。我們的初步評估由兩位作者（M.M.I.和 T.N.P.）分別進行。他們交叉檢查所有檢索到的文章的參考文獻列表，以尋找其他相關文章。

We systematically searched for relevant studies in PubMed, EMBASE, Web of Science, Google Scholar, and Scopus for studies published between January 1, 1990, and September 1, 2019, with no restriction of language. The following search terms were used to finds potential studies: “hepatocellular carcinoma”, OR “liver cancer”, and “statins” OR “simvastatin”, OR “atorvastatin”, OR “lovastatin”, OR “HMG-CoA reductase inhibitor(s)”, OR “pravastatin”, OR “rosuvastatin” OR “cerivastatin” OR “pitavastatin” (Supplementary Table S1). Our initial evaluation was separately conducted by two authors (M.M.I. and T.N.P.). They cross-checked all the reference lists from retrieved articles to find additional relevant articles.

參選資格僅限於大型觀察性研究（≥200 名參與者）和臨床試驗，這些研究僅調查他汀類藥物使用與肝細胞癌（HCC）風險之間的關聯，並將其作為主要結果。符合以下納入標準的研究將被納入：a）至少有 6 個月隨訪時間的大型觀察性研究；b）研究報告了使用他汀類藥物的成人（≥18 歲）與不使用他汀類藥物的 HCC 發展情況；c）研究明確定義了他汀類藥物的暴露及患者 HCC 的識別；d）研究明確估計了 HCC 的風險，並以危險比（HR）、比值比（OR）和風險比（RR）及 95%置信區間（CIs）表示。然而，僅為綜述文章、編輯信或個案報告的研究將被排除。參與者少於 200 名的研究也將被排除。

Eligibility was restricted to large observational (≥200 participants) and clinical trials only which investigated the association between statin use and the risk of HCC as the primary outcome. Studies were included if they met the following inclusion criteria: a) a large observational study with at least a 6-month follow-up time; b) the study reported the development of HCC in adult individuals (≥18 years old) with statin use versus non-statin use; c) the study clearly defined statin exposure and the identification of HCC in patients; and d) the study clearly estimated the risk of HCC as a hazard ratio (HR), odds ratio (OR), and risk ratio (RR) with 95% CIs. However, studies were excluded if they are only review articles, letters to the editors, or case reports. Studies including fewer participants (<200 participants) were also excluded.

同樣的兩位作者（M.M.I. 和 T.N.P.）獨立篩選了先前選定文獻的標題和摘要。他們遵循了通過與所有作者討論制定的預先指定的納入和排除標準，以識別相關研究。在審查過程中出現的任何分歧都通過考慮先前的指導方針來解決；任何剩餘的衝突則通過與主要研究者（Y.C.L.）的討論來解決。同樣的兩位作者（M.M.I. 和 T.N.P.）獨立進行了數據收集過程，並檢查了研究重複、人口規模和出版日期。
The same tw

M.I. and T.N.P.) independently screened the titles and abstracts of the previously selected literature. They followed prespecified inclusion and exclusion criteria developed through the discussion with all authors to identify relevant studies. Any disagreements during that reviewing process were resolved by the consideration of the prior guidelines; any remaining conflict was then resolved by discussion with the main investigator (Y.C.L.). The same two authors (M.M.I. and T.N.P.) independently conducted the data collection process and checked for study duplication, population sizes, and date of publications.

主要結果指標是使用他汀類藥物與肝細胞癌風險之間關聯的比值比（ORs）和風險比（HRs），以及 95%置信區間（CIs）。兩位作者（M.M.I.和 T.N.P.）識別並記錄了反映更高調整變數的效應大小，以考慮可能的混雜因素。還提取了未調整的結果以及他汀類藥物對肝細胞癌及其他潛在疾病的影響。從納入的研究中提取的其他信息包括作者姓名、出版年份、研究設計、參與者數量、肝細胞癌患者數量、肝細胞癌患者識別過程、他汀類藥物使用者的定義、劑量信息、不同類型他汀類藥物對肝細胞癌的影響、隨訪時間、設置和地區。

The primary outcome measures were ORs and HRs with 95% CIs for the association between statin use and the risk of HCC. Two authors (M.M.I. and T.N.P.) identified and recorded the effect sizes reflecting the higher degree of adjustment variables for possible confounding factors. Unadjusted findings and the effect of statins on HCC with other potential diseases were also extracted. Other information extracted from the included studies were author names, publication years, study designs, number of participants, number of HCC patients, process of HCC patient’s identifications, statins user’s definitions, doses information, effects of different types of statins on HCC, follow-up times, settings, and regions.

使用紐卡斯爾-渥太華量表 (NOS) 來評估每項研究的個別質量 ( Supplementary Table S2 )。研究之間的異質性是通過 Q 統計量和 I ² 統計量計算的。此外，通過漏斗圖（埃格爾檢驗和貝格檢驗）評估出版偏倚。

The Newcastle Ottawa Scale (NOS) was applied for evaluating the individual quality of each study (Supplementary Table S2). The heterogeneity among the studies was calculated using the Q statistic and the I² statistic. Moreover, publication bias was assessed by the funnel plot-based (Egger test and the Begg test).

我們使用綜合分析（CMA）軟件（版本：3，Biostat，Englewood，NJ，美國）進行統計分析。計算了 95%置信區間（CIs）的風險比，以評估結果，p 值小於 0.05 被視為顯著。此外，使用隨機效應模型來匯總效應大小，並繪製漏斗圖以視覺化呈現效應大小。我們僅考慮在研究中報告的調整後效應大小進行分析，以考慮混雜變量。

We performed statistical analyses with the Comprehensive Meta-analysis (CMA) software (version: 3, Biostat, Englewood, NJ, USA). The risk ratio with 95% confidence intervals (CIs) was calculated to assess outcomes, and a p-value of less than 0.05 was considered significant. Furthermore, the random effect model was used to pool the effect size and funnel plots were drawn to present the effect sizes visually. We only considered adjusted effect sizes reported in studies for analysis to account for confounding variables.

5. 結論 5. Conclusions

據我們所知，這是迄今為止對他汀類藥物對肝細胞癌（HCC）益處進行評估的最全面的綜合分析。這項綜合分析的結果提供了額外的證據，因為它顯示他汀類藥物的使用可以降低 46%的 HCC 發展風險。此外，還需要進行更大規模的機制研究來確認或駁斥我們的發現。

To our knowledge, this is the most extensive meta-analysis so far that evaluated the beneficial effects of statins on HCC. The findings of this meta-analysis provided additional evidence because they showed that statin use can provide a 46% risk reduction in HCC development. Furthermore, a larger mechanistic study is warranted to confirm or refute our findings.

參考文獻 References

• 1.Rawla P.、Sunkara T.、Muralidharan P.、Raj J.P. 全球肝細胞癌的趨勢和病因更新。當代腫瘤學。2018;22:141。doi: 10.5114/wo.2018.78941。
  1.Rawla P., Sunkara T., Muralidharan P., Raj J.P. Update in global trends and aetiology of hepatocellular carcinoma. Contemp. Oncol. 2018;22:141. doi: 10.5114/wo.2018.78941. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 2. Chan A.W., Zhong J., Berhane S., Toyoda H., Cucchetti A., Shi K., Tada T., Chong C.C., Xiang B.D., Li L.Q. 發展術前和術後模型以預測肝細胞癌在外科切除後的早期復發。肝臟學雜誌。2018;69:1284–1293。doi: 10.1016/j.jhep.2018.08.027. [ DOI ] [ PubMed ] [ Google Scholar ]
  2.Chan A.W., Zhong J., Berhane S., Toyoda H., Cucchetti A., Shi K., Tada T., Chong C.C., Xiang B.D., Li L.Q. Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection. J. Hepatol. 2018;69:1284–1293. doi: 10.1016/j.jhep.2018.08.027. [DOI] [PubMed] [Google Scholar]
• 3. Ghouri Y.A., Mian I., Rowe J.H. 肝細胞癌的回顧：流行病學、病因學和致癌過程。癌變學雜誌。2017;16:1。doi: 10.4103/jcar.JCar_9_16. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  3.Ghouri Y.A., Mian I., Rowe J.H. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J. Carcinog. 2017;16:1. doi: 10.4103/jcar.JCar_9_16. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 4. El-serag H.B., Tran T., Everhart J.E. 糖尿病增加慢性肝病和肝細胞癌的風險。胃腸病學。2004;126:460–468。doi: 10.1053/j.gastro.2003.10.065. [ DOI ] [ PubMed ] [ Google Scholar ]
  4.El-serag H.B., Tran T., Everhart J.E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126:460–468. doi: 10.1053/j.gastro.2003.10.065. [DOI] [PubMed] [Google Scholar]
• 5. Perz J.F., Armstrong G.L., Farrington L.A., Hutin Y.J., Bell B.P. 乙型肝炎病毒和丙型肝炎病毒感染對全球肝硬化和原發性肝癌的貢獻。肝臟學雜誌。2006;45:529–538。doi: 10.1016/j.jhep.2006.05.013. [ DOI ] [ PubMed ] [ Google Scholar ]
  5.Perz J.F., Armstrong G.L., Farrington L.A., Hutin Y.J., Bell B.P. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J. Hepatol. 2006;45:529–538. doi: 10.1016/j.jhep.2006.05.013. [DOI] [PubMed] [Google Scholar]
• 6.Preda C., Popescu C., Baicus C., Constantinescu I., Oproiu A., Voiosu T., Diculescu M., Negreanu L., Gheorghe L., Sporea I. 乙型肝炎病毒再激活的風險在接受 ombitasvir、paritaprevir/r + dasabuvir + ribavirin 治療的乙型肝炎病毒+ 乙型肝炎病毒共感染的代償性肝硬化患者中。J. Viral. Hepat. 2018;25:834–841. doi: 10.1111/jvh.12872. [ DOI ] [ PubMed ] [ Google Scholar ]
  6.Preda C., Popescu C., Baicus C., Constantinescu I., Oproiu A., Voiosu T., Diculescu M., Negreanu L., Gheorghe L., Sporea I. Risk of hepatitis B virus reactivation in hepatitis B virus+ hepatitis C virus-co-infected patients with compensated liver cirrhosis treated with ombitasvir, paritaprevir/r+ dasabuvir+ ribavirin. J. Viral. Hepat. 2018;25:834–841. doi: 10.1111/jvh.12872. [DOI] [PubMed] [Google Scholar]
• 7.Lee M.H., Yang H.I., Liu J., Batrla-Utermann R., Jen C.L., Iloeje U.H., Lu S.N., You S.L., Wang L.Y., Chen C.J. 在慢性乙型肝炎患者中，整合宿主和病毒特徵的長期肝硬化和肝細胞癌風險預測模型：風險評分。Hepatology. 2013;58:546–554. doi: 10.1002/hep.26385. [ DOI ] [ PubMed ] [ Google Scholar ]
  7.Lee M.H., Yang H.I., Liu J., Batrla-Utermann R., Jen C.L., Iloeje U.H., Lu S.N., You S.L., Wang L.Y., Chen C.J. Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: Risk scores integrating host and virus profiles. Hepatology. 2013;58:546–554. doi: 10.1002/hep.26385. [DOI] [PubMed] [Google Scholar]
• 8.Fattovich G., Stroffolini T., Zagni I., Donato F. 肝硬化中的肝細胞癌：發生率和風險因素。Gastroenterology. 2004;127:35–50. doi: 10.1053/j.gastro.2004.09.014. [ DOI ] [ PubMed ] [ Google Scholar ]
  8.Fattovich G., Stroffolini T., Zagni I., Donato F. Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology. 2004;127:35–50. doi: 10.1053/j.gastro.2004.09.014. [DOI] [PubMed] [Google Scholar]
• 9. Davila J., Morgan R., Shaib Y., McGlynn K., El-Serag H. 糖尿病增加美國肝細胞癌的風險：一項基於人群的病例對照研究。Gut. 2005;54:533–539. doi: 10.1136/gut.2004.052167. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  9.Davila J., Morgan R., Shaib Y., McGlynn K., El-Serag H. Diabetes increases the risk of hepatocellular carcinoma in the United States: A population based case control study. Gut. 2005;54:533–539. doi: 10.1136/gut.2004.052167. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 10. Simon T.G., King L.Y., Zheng H., Chung R.T. 使用他汀類藥物與慢性丙型肝炎纖維化進展風險降低相關。J. Hepatol. 2015;62:18–23. doi: 10.1016/j.jhep.2014.08.013. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  10.Simon T.G., King L.Y., Zheng H., Chung R.T. Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C. J. Hepatol. 2015;62:18–23. doi: 10.1016/j.jhep.2014.08.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 11. Yang Y.H., Chen W.C., Tsan Y.T., Chen M.J., Shih W.T., Tsai Y.H., Chen P.C. 他汀類藥物使用與丙型肝炎病毒感染患者發展肝硬化風險的關聯。J. Hepatol. 2015;63:1111–1117. doi: 10.1016/j.jhep.2015.07.006. [ DOI ] [ PubMed ] [ Google Scholar ]
  11.Yang Y.H., Chen W.C., Tsan Y.T., Chen M.J., Shih W.T., Tsai Y.H., Chen P.C. Statin use and the risk of cirrhosis development in patients with hepatitis C virus infection. J. Hepatol. 2015;63:1111–1117. doi: 10.1016/j.jhep.2015.07.006. [DOI] [PubMed] [Google Scholar]
• 12. Undela K., Shah C.S., Mothe R.K. 他汀類藥物使用與癌症風險：一項綜述性元分析。World J. Meta-Anal. 2017;26:41–53. doi: 10.13105/wjma.v5.i2.41. [ DOI ] [ Google Scholar ]
  12.Undela K., Shah C.S., Mothe R.K. Statin use and risk of cancer: An overview of meta-analyses. World J. Meta-Anal. 2017;26:41–53. doi: 10.13105/wjma.v5.i2.41. [DOI] [Google Scholar]
• 13. Baigent C., Blackwell L., Emberson J., Holland L., Reith C., Bhala N., Peto R., Barnes E., Keech A., Simes J. 更加積極降低 LDL 膽固醇的療效和安全性：來自 170,000 名參與者的 26 項隨機試驗數據的綜合分析。柳葉刀。2010;376:1670–1681。doi: 10.1016/S0140-6736(10)61350-5。 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  13.Baigent C., Blackwell L., Emberson J., Holland L., Reith C., Bhala N., Peto R., Barnes E., Keech A., Simes J. Efficacy and Safety of More Intensive Lowering of LDL Cholesterol: A Meta-Analysis of Data from 170,000 Participants in 26 Randomised Trials. Lancet. 2010;376:1670–1681. doi: 10.1016/S0140-6736(10)61350-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 14. Singh S., Singh P.P., Singh A.G., Murad M.H., Sanchez W. 他汀類藥物與肝細胞癌風險降低相關：系統評價和綜合分析。胃腸病學。2013;144:323–332。doi: 10.1053/j.gastro.2012.10.005。 [ DOI ] [ PubMed ] [ Google Scholar ]
  14.Singh S., Singh P.P., Singh A.G., Murad M.H., Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: A systematic review and meta-analysis. Gastroenterology. 2013;144:323–332. doi: 10.1053/j.gastro.2012.10.005. [DOI] [PubMed] [Google Scholar]
• 15. Souk K., Al-Badri M., Azar S. 他汀類藥物在肝硬化中的安全性和益處：一項綜述。實驗與臨床內分泌學與糖尿病。2015;123:577–580。doi: 10.1055/s-0035-1564093。 [ DOI ] [ PubMed ] [ Google Scholar ]
  15.Souk K., Al-Badri M., Azar S. The safety and benefit of statins in liver cirrhosis: A review. Exp. Clin. Endocrinol. Diabetes. 2015;123:577–580. doi: 10.1055/s-0035-1564093. [DOI] [PubMed] [Google Scholar]
• 16. Kubatka P., Kruzliak P., Rotrekl V., Jelinkova S., Mladosievicova B. 他汀類藥物在腫瘤研究中的應用：從實驗研究到臨床實踐。臨床腫瘤學與血液學評論。2014;92:296–311。doi: 10.1016/j.critrevonc.2014.08.002。 [ DOI ] [ PubMed ] [ Google Scholar ]
  16.Kubatka P., Kruzliak P., Rotrekl V., Jelinkova S., Mladosievicova B. Statins in oncological research: From experimental studies to clinical practice. Crit. Rev. Oncol. Hematol. 2014;92:296–311. doi: 10.1016/j.critrevonc.2014.08.002. [DOI] [PubMed] [Google Scholar]
• 17.Inano H., Suzuki K., Onoda M., Wakabayashi K. 西莫伐他汀在輻射誘導大鼠乳腺腫瘤發生促進階段的抗癌活性。 癌變。 1997;18:1723–1727. doi: 10.1093/carcin/18.9.1723. [ DOI ] [ PubMed ] [ Google Scholar ]
  17.Inano H., Suzuki K., Onoda M., Wakabayashi K. Anti-carcinogenic activity of simvastatin during the promotion phase of radiation-induced mammary tumorigenesis of rats. Carcinogenesis. 1997;18:1723–1727. doi: 10.1093/carcin/18.9.1723. [DOI] [PubMed] [Google Scholar]
• 18.Björkhem-Bergman L., Acimovic J., Torndal U.B., Parini P., Eriksson L.C. 洛伐他汀在肝癌大鼠模型中預防癌變。輔酶 Q10 補充的效果。抗癌研究。2010;30:1105–1112. [ PubMed ] [ Google Scholar ]
  18.Björkhem-Bergman L., Acimovic J., Torndal U.B., Parini P., Eriksson L.C. Lovastatin prevents carcinogenesis in a rat model for liver cancer. Effects of ubiquinone supplementation. Anticancer Res. 2010;30:1105–1112. [PubMed] [Google Scholar]
• 19. Relja B., Meder F., Wang M., Blaheta R., Henrich D., Marzi I., Lehnert M. 辛伐他汀通過降低整合素表達和 ROCK 來調節肝細胞癌細胞的黏附和增長。國際腫瘤學雜誌 2011;38:879–885. doi: 10.3892/ijo.2010.892. [ DOI ] [ PubMed ] [ Google Scholar ]
  19.Relja B., Meder F., Wang M., Blaheta R., Henrich D., Marzi I., Lehnert M. Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK. Int. J. Oncol. 2011;38:879–885. doi: 10.3892/ijo.2010.892. [DOI] [PubMed] [Google Scholar]
• 20.王杰、常藤、比嘉、北嶋一。皮他伐他汀對肝細胞癌細胞中由 TNF-α激活的 NF-κB 的抗炎作用。生物藥學通報。2006;29:634–639。doi: 10.1248/bpb.29.634。 [ DOI ] [ PubMed ] [ Google Scholar ]
  20.Wang J., Tokoro T., Higa S., Kitajima I. Anti-inflammatory effect of pitavastatin on NF-κB activated by TNF-α in hepatocellular carcinoma cells. Biol. Pharm. Bull. 2006;29:634–639. doi: 10.1248/bpb.29.634. [DOI] [PubMed] [Google Scholar]
• 21.加哈利、馬丁-雷內多、霍格伯格、斯特尼烏斯。阿托伐他汀通過 P2X 受體降低肝細胞中 HBx 誘導的磷酸化 Akt。分子癌症研究。2017;15:714–722。doi: 10.1158/1541-7786.MCR-16-0373。 [ DOI ] [ PubMed ] [ Google Scholar ]
  21.Ghalali A., Martin-Renedo J., Högberg J., Stenius U. Atorvastatin decreases HBx-induced phospho-Akt in hepatocytes via P2X receptors. Mol. Cancer Res. 2017;15:714–722. doi: 10.1158/1541-7786.MCR-16-0373. [DOI] [PubMed] [Google Scholar]
• 22.曹志、范-米諾格、貝洛文、葉托迪延科、阿爾澤諾、楊琦、甘比爾、費爾舍。MYC 磷酸化、激活及其在肝細胞癌中的腫瘤形成潛力受到 HMG-CoA 還原酶的調控。癌症研究。2011;71:2286–2297。doi: 10.1158/0008-5472.CAN-10-3367。 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  22.Cao Z., Fan-Minogue H., Bellovin D.I., Yevtodiyenko A., Arzeno J., Yang Q., Gambhir S.S., Felsher D.W. MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase. Cancer Res. 2011;71:2286–2297. doi: 10.1158/0008-5472.CAN-10-3367. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 23.陳凱婷、麥克梅納明、科爾曼、卡德威爾、穆爾奇、艾弗森、李阿杰、斯瑞夫特。他汀類藥物使用與肝癌風險：來自兩項基於人群的研究的證據。國際癌症期刊。2019;146:1250–1260。doi: 10.1002/ijc.32426。 [ DOI ] [ PubMed ] [ Google Scholar ]
  23.Tran K.T., McMenamin Ú.C., Coleman H.G., Cardwell C.R., Murchie P., Iversen L., Lee A.J., Thrift A.P. Statin use and risk of liver cancer: Evidence from two population-based studies. Int. J. Cancer. 2019;146:1250–1260. doi: 10.1002/ijc.32426. [DOI] [PubMed] [Google Scholar]
• 24. German M.N., Lutz M.K., Pickhardt P.J., Bruce R.J., Said A. 他汀類藥物在非酒精性脂肪肝疾病患者中對肝細胞癌具有保護作用：一項病例對照研究。J. Clin. Gastroenterol. 2019 doi: 10.1097/MCG.0000000000001260. [ DOI ] [ PubMed ] [ Google Scholar ]
  24.German M.N., Lutz M.K., Pickhardt P.J., Bruce R.J., Said A. Statin use is protective against hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: A case-control study. J. Clin. Gastroenterol. 2019 doi: 10.1097/MCG.0000000000001260. [DOI] [PubMed] [Google Scholar]
• 25. Goh M.J., Sinn D.H., Kim S., Woo S.Y., Cho H., Kang W., Gwak G.Y., Paik Y.H., Choi M.S., Lee J., 等。使用他汀類藥物與慢性乙型肝炎患者肝細胞癌風險的關係。肝臟病學。2019 年，doi: 10.1002/hep.30973。 [ DOI ] [ PubMed ] [ Google Scholar ]
  25.Goh M.J., Sinn D.H., Kim S., Woo S.Y., Cho H., Kang W., Gwak G.Y., Paik Y.H., Choi M.S., Lee J., et al. Statin use and the risk of hepatocellular carcinoma in patients with chronic hepatitis B. Hepatology. 2019 doi: 10.1002/hep.30973. [DOI] [PubMed] [Google Scholar]
• 26. Kim G., Jang S.Y., Nam C.M., Kang E.S. 在高風險患者中使用他汀類藥物與肝細胞癌風險的關係：一項全國性嵌套病例對照研究。肝臟學報。2018 年；68:476–484。doi: 10.1016/j.jhep.2017.10.018。 [ DOI ] [ PubMed ] [ Google Scholar ]
  26.Kim G., Jang S.Y., Nam C.M., Kang E.S. Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study. J. Hepatol. 2018;68:476–484. doi: 10.1016/j.jhep.2017.10.018. [DOI] [PubMed] [Google Scholar]
• 27.金光，張世英，韓恩，李英浩，朴世英，南昌美，姜恩淑。 他汀類藥物對 2 型糖尿病患者肝細胞癌的影響：一項全國性嵌套病例對照研究。國際癌症期刊。2017；140：798–806。doi：10.1002/ijc.30506。[ DOI ] [ PubMed ] [ Google Scholar ]
  27.Kim G., Jang S.Y., Han E., Lee Y.h., Park S.y., Nam C.M., Kang E.S. Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case-control study. Int. J. Cancer. 2017;140:798–806. doi: 10.1002/ijc.30506. [DOI] [PubMed] [Google Scholar]
• 28.西蒙·T.G.，博尼拉·H.，顏平，鍾瑞婷，巴特·A.A.。阿托伐他汀和氟伐他汀與肝硬化和肝細胞癌的劑量依賴性降低相關，針對感染 C 型肝炎病毒的患者：來自 ERCHIVES 的結果。肝臟病學。2016；64：47–57。doi：10.1002/hep.28506。[ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  28.Simon T.G., Bonilla H., Yan P., Chung R.T., Butt A.A. Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES. Hepatology. 2016;64:47–57. doi: 10.1002/hep.28506. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 29.謝家俊，黃國良，謝耀基，黃偉信，葉志誠，陳漢良。 他汀類藥物與住院 B 型肝炎感染人群肝細胞癌和死亡風險的關係：一項傾向得分標誌分析。肝臟病學。2015；63：1190–1197。doi：10.1016/j.jhep.2015.07.009。[ DOI ] [ PubMed ] [ Google Scholar ]
  29.Hsiang J.C., Wong G.L.H., Tse Y.K., Wong V.W.S., Yip T.C.F., Chan H.L.Y. Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: A propensity score landmark analysis. J. Hepatol. 2015;63:1190–1197. doi: 10.1016/j.jhep.2015.07.009. [DOI] [PubMed] [Google Scholar]
• 30. Björkhem-Bergman L., Backheden M., Söderberg Löfdal K. 安全性：他汀治療降低肝細胞癌的風險，但不降低結腸癌的風險——來自瑞典的一項全國性病例對照研究的結果。藥物流行病學與藥物安全性。2014;23:1101–1106。doi: 10.1002/pds.3685。 [ DOI ] [ PubMed ] [ Google Scholar ]
  30.Björkhem-Bergman L., Backheden M., Söderberg Löfdal K. Safety d: Statin treatment reduces the risk of hepatocellular carcinoma but not colon cancer—results from a nationwide case-control study in Sweden. Pharmacoepidemiol. Drug Saf. 2014;23:1101–1106. doi: 10.1002/pds.3685. [DOI] [PubMed] [Google Scholar]
• 31.陳志毅、關志峰、方雅婷、劉世豪、劉家誠、吳麗麗、張家俊、楊宏志、黃俊、米澤傑等。使用他汀類藥物和二甲雙胍的 HBV 患者癌症風險：一項基於人群的隊列研究。醫學。2015；94：462。doi：10.1097/MD.0000000000000462。[ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  31.Chen C.I., Kuan C.F., Fang Y.A., Liu S.H., Liu J.C., Wu L.L., Chang C.J., Yang H.C., Hwang J., Miser J.S., et al. Cancer risk in HBV patients with statin and metformin use: A population-based cohort study. Medicine. 2015;94:462. doi: 10.1097/MD.0000000000000462. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 32.McGlynn K.A., Hagberg K., Chen J., Graubard B.I., London W.T., Jick S., Sahasrabuddhe V.V. 他汀類藥物使用與臨床實踐研究數據鏈中原發性肝癌風險的關係。J. Natl. Cancer Inst. 2015;107 doi: 10.1093/jnci/djv009. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  32.McGlynn K.A., Hagberg K., Chen J., Graubard B.I., London W.T., Jick S., Sahasrabuddhe V.V. Statin use and risk for primary liver cancer in the clinical practice research datalink. J. Natl. Cancer Inst. 2015;107 doi: 10.1093/jnci/djv009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 33.McGlynn K.A., Divine G.W., Sahasrabuddhe V.V., Engel L.S., VanSlooten A., Wells K., Yood M.U., Alford S.H. 在美國人群中，使用他汀類藥物與肝細胞癌風險的關係。癌症流行病學。2014;38:523–527. doi: 10.1016/j.canep.2014.06.009. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  33.McGlynn K.A., Divine G.W., Sahasrabuddhe V.V., Engel L.S., VanSlooten A., Wells K., Yood M.U., Alford S.H. Statin use and risk of hepatocellular carcinoma in a US population. Cancer Epidemiol. 2014;38:523–527. doi: 10.1016/j.canep.2014.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 34.Lai S.W., Liao K.F., Lai H.C., Muo C.H., Sung F.C., Chen P.-C. 他汀類藥物使用與肝細胞癌風險的關係。癌症流行病學。2013;28:485–492. doi: 10.1007/s10654-013-9806-y. [ DOI ] [ PubMed ] [ Google Scholar ]
  34.Lai S.W., Liao K.F., Lai H.C., Muo C.H., Sung F.C., Chen P.-C. Statin use and risk of hepatocellular carcinoma. Cancer Epidemiol. 2013;28:485–492. doi: 10.1007/s10654-013-9806-y. [DOI] [PubMed] [Google Scholar]
• 35.Leung H.W., Chan A.L., Lo D., Leung J.H., Chen H.L. 常見癌症風險與他汀類藥物：在中國人群中的基於人群的病例對照研究。專家意見。藥物安全性。2013;12:19–27. doi: 10.1517/14740338.2013.744392. [ DOI ] [ PubMed ] [ Google Scholar ]
  35.Leung H.W., Chan A.L., Lo D., Leung J.H., Chen H.L. Common cancer risk and statins: A population-based case–control study in a Chinese population. Expert Opin. Drug Saf. 2013;12:19–27. doi: 10.1517/14740338.2013.744392. [DOI] [PubMed] [Google Scholar]
• 36.Tsan Y.T., Lee C.H., Ho W.C., Lin M.H., Wang J.D., Chen P.C. 他汀類藥物與感染 C 型肝炎病毒患者肝細胞癌風險的關係。臨床腫瘤學雜誌。2013;31:1514–1521. doi: 10.1200/JCO.2012.44.6831. [ DOI ] [ PubMed ] [ Google Scholar ]
  36.Tsan Y.T., Lee C.H., Ho W.C., Lin M.H., Wang J.D., Chen P.C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J. Clin. Oncol. 2013;31:1514–1521. doi: 10.1200/JCO.2012.44.6831. [DOI] [PubMed] [Google Scholar]
• 37.Tsan Y.T., Lee C.H., Wang J.D., Chen P.C. 他汀類藥物與乙型肝炎病毒感染患者肝細胞癌風險的關係。臨床腫瘤學雜誌 2012;30:623–630. doi: 10.1200/JCO.2011.36.0917. [ DOI ] [ PubMed ] [ Google Scholar ]
  37.Tsan Y.T., Lee C.H., Wang J.D., Chen P.C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J. Clin. Oncol. 2012;30:623–630. doi: 10.1200/JCO.2011.36.0917. [DOI] [PubMed] [Google Scholar]
• 38.Marelli C., Gunnarsson C., Ross S., Haas S., Stroup D.F., Cload P., Clopton P., DeMaria A.N. 他汀類藥物與癌症風險：來自一個擁有 1100 萬成年美國人電子病歷數據庫的 45,857 對匹配組的回顧性隊列分析。美國心臟病學會雜誌 2011;58:530–537. doi: 10.1016/j.jacc.2011.04.015. [ DOI ] [ PubMed ] [ Google Scholar ]
  38.Marelli C., Gunnarsson C., Ross S., Haas S., Stroup D.F., Cload P., Clopton P., DeMaria A.N. Statins and risk of cancer: A retrospective cohort analysis of 45,857 matched pairs from an electronic medical records database of 11 million adult Americans. J. Am. Coll. Cardiol. 2011;58:530–537. doi: 10.1016/j.jacc.2011.04.015. [DOI] [PubMed] [Google Scholar]
• 39.Chiu H.F., Ho S.C., Chen C.C., Yang C.Y. 他汀類藥物使用與肝癌風險的關係：一項基於人群的病例對照研究。美國胃腸病學雜誌 2011;106:894. doi: 10.1038/ajg.2010.475. [ DOI ] [ PubMed ] [ Google Scholar ]
  39.Chiu H.F., Ho S.C., Chen C.C., Yang C.Y. Statin use and the risk of liver cancer: A population-based case–control study. Am. J. Gastroenterol. 2011;106:894. doi: 10.1038/ajg.2010.475. [DOI] [PubMed] [Google Scholar]
• 40.El–Serag H.B., Johnson M.L., Hachem C., Morgana R.O. 他汀類藥物與糖尿病患者肝細胞癌風險降低相關。美國胃腸病學雜誌 2009;136:1601–1608. doi: 10.1053/j.gastro.2009.01.053. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  40.El–Serag H.B., Johnson M.L., Hachem C., Morgana R.O. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Am. J. Gastroenterol. 2009;136:1601–1608. doi: 10.1053/j.gastro.2009.01.053. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 41. Friedman G.D., Flick E.D., Udaltsova N., Chan Pharm D.J., Quesenberry C.P., Jr., Habel L.A. 筛选他汀类药物以评估可能的致癌风险：对 361,859 名接受者进行长达 9 年的随访。药物流行病学与安全性。2008;17:27–36. doi: 10.1002/pds.1507. [ DOI ] [ PubMed ] [ Google Scholar ]
  41.Friedman G.D., Flick E.D., Udaltsova N., Chan Pharm D.J., Quesenberry C.P., Jr., Habel L.A. Screening statins for possible carcinogenic risk: Up to 9 years of follow-up of 361 859 recipients. Pharmacoepidemiol. Drug Saf. 2008;17:27–36. doi: 10.1002/pds.1507. [DOI] [PubMed] [Google Scholar]
• 42. Friis S., Poulsen A.H., Johnsen S.P., McLaughlin J.K., Fryzek J.P., Dalton S.O., Sørensen H.T., Olsen J.H. 他汀类药物使用者的癌症风险：一项基于人群的队列研究。癌症杂志。2005;114:643–647. doi: 10.1002/ijc.20758. [ DOI ] [ PubMed ] [ Google Scholar ]
  42.Friis S., Poulsen A.H., Johnsen S.P., McLaughlin J.K., Fryzek J.P., Dalton S.O., Sørensen H.T., Olsen J.H. Cancer risk among statin users: A population-based cohort study. J. Cancer. 2005;114:643–647. doi: 10.1002/ijc.20758. [DOI] [PubMed] [Google Scholar]
• 43. Khurana V., Saluja A., Caldito G., Fort C., Schiff E. 他汀类药物对感染丙型肝炎病毒患者的肝细胞癌具有保护作用：一项针对 50 万名美国退伍军人的研究。胃肠病学。2005;128:714. [ Google Scholar ]
  43.Khurana V., Saluja A., Caldito G., Fort C., Schiff E. Statins are protective against hepatocellular cancer in patients with hepatitis C virus infection: Half a million US veterans’ study. Gastroenterology. 2005;128:714. [Google Scholar]
• 44. Matsushita Y., Sugihara M., Kaburagi J., Ozawa M., Iwashita M., Yoshida S., Saito H., Hattori Y.J.P. 普伐他汀使用与癌症风险：来自日本长期前瞻性对照试验的个体患者数据的荟萃分析。药物流行病学与安全性。2010;19:196–202. doi: 10.1002/pds.1870. [ DOI ] [ PubMed ] [ Google Scholar ]
  44.Matsushita Y., Sugihara M., Kaburagi J., Ozawa M., Iwashita M., Yoshida S., Saito H., Hattori Y.J.P. Pravastatin use and cancer risk: A meta-analysis of individual patient data from long-term prospective controlled trials in Japan. Pharmacoepidemiol. Drug Saf. 2010;19:196–202. doi: 10.1002/pds.1870. [DOI] [PubMed] [Google Scholar]
• 45.佐藤 S.，安木 W.，小林 T.，淡田 N. 使用普伐他汀與冠心病患者五年癌症發生率的關係：來自冠狀動脈硬化預防研究。流行病學雜誌。2006；16：201–206。doi: 10.2188/jea.16.201. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  45.Sato S., Ajiki W., Kobayashi T., Awata N. Pravastatin use and the five-year incidence of cancer in coronary heart disease patients: From the prevention of coronary sclerosis study. J. Epidemiol. 2006;16:201–206. doi: 10.2188/jea.16.201. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 46.試驗者 C.T. 降低 LDL 膽固醇對癌症的影響缺乏：來自 27 項隨機試驗中 175,000 人的個體數據的 meta 分析。PLoS ONE。2012；7：e29849。doi: 10.1371/journal.pone.0029849. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  46.Trialists C.T. Lack of effect of lowering LDL cholesterol on cancer: Meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS ONE. 2012;7:e29849. doi: 10.1371/journal.pone.0029849. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 47.斯坦 A. 對於在 meta 分析中評估非隨機研究質量的紐卡斯爾-渥太華量表的批判性評估。歐洲流行病學雜誌。2010；25：603–605。doi: 10.1007/s10654-010-9491-z. [ DOI ] [ PubMed ] [ Google Scholar ]
  47.Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur. J. Epidemiol. 2010;25:603–605. doi: 10.1007/s10654-010-9491-z. [DOI] [PubMed] [Google Scholar]
• 48.希金斯 J.P.，阿特曼 D.G.，戈茨切 P.C.，尤尼 P.，莫赫 D.，奧克斯曼 A.D.，薩沃維奇 J.，舒爾茲 K.F.，維克斯 L.，斯特恩 J.A. 科克倫合作組織評估隨機試驗偏倚風險的工具。BMJ。2011；343：5928。doi: 10.1136/bmj.d5928. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  48.Higgins J.P., Altman D.G., Gøtzsche P.C., Jüni P., Moher D., Oxman A.D., Savović J., Schulz K.F., Weeks L., Sterne J.A. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:5928. doi: 10.1136/bmj.d5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 49.施明，鄭浩，聶彬，龔偉，崔曉。使用他汀類藥物與肝癌風險：更新的 Meta 分析。BMJ Open。2014；4：e005399。doi: 10.1136/bmjopen-2014-005399。[ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  49.Shi M., Zheng H., Nie B., Gong W., Cui X. Statin use and risk of liver cancer: An update meta-analysis. BMJ Open. 2014;4:e005399. doi: 10.1136/bmjopen-2014-005399. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 50.周宇陽，朱國強，王勇，鄭建南，阮麗燕，程志，胡斌，傅世偉，鄭明華。系統評價與網絡 Meta 分析：他汀類藥物與肝細胞癌風險。Oncotarget。2016；7：21753。doi: 10.18632/oncotarget.7832。[ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  50.Zhou Y.Y., Zhu G.Q., Wang Y., Zheng J.N., Ruan L.Y., Cheng Z., Hu B., Fu S.W., Zheng M.H. Systematic review with network meta-analysis: Statins and risk of hepatocellular carcinoma. Oncotarget. 2016;7:21753. doi: 10.18632/oncotarget.7832. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 51.伊安內利，隆巴爾迪，米隆，普奇，德里恩佐，布杜隆，布魯澤塞。針對美伐酸途徑的癌症治療：他汀類藥物的再利用。Recent Pat. AntiCancer Drug Discov. 2018；13：184–200。doi: 10.2174/1574892812666171129141211。[ DOI ] [ PubMed ] [ Google Scholar ]
  51.Iannelli F., Lombardi R., Milone M.R., Pucci B., De Rienzo S., Budillon A., Bruzzese F. Targeting mevalonate pathway in cancer treatment: Repurposing of statins. Recent Pat. AntiCancer Drug Discov. 2018;13:184–200. doi: 10.2174/1574892812666171129141211. [DOI] [PubMed] [Google Scholar]
• 52.加澤羅，普羅托，甘傑米，馬爾菲塔諾，奇亞利亞，皮薩提，聖托羅，拉埃扎，比富爾科。他汀類藥物的藥理作用：在癌症管理中的批判性評估。Pharmacol. Rev. 2012；64：102–146。doi: 10.1124/pr.111.004994。[ DOI ] [ PubMed ] [ Google Scholar ]
  52.Gazzerro P., Proto M.C., Gangemi G., Malfitano A.M., Ciaglia E., Pisanti S., Santoro A., Laezza C., Bifulco M. Pharmacological actions of statins: A critical appraisal in the management of cancer. Pharmacol. Rev. 2012;64:102–146. doi: 10.1124/pr.111.004994. [DOI] [PubMed] [Google Scholar]
• 53.莊麗文、許雅君、李庭芳、林怡、邱雅婷、楊克誠、吳俊杰、黃怡婷。氟伐他汀通過抑制肝細胞對肝星狀細胞的旁分泌效應減輕大鼠肝脂肪變性引起的纖維化。BMC 胃腸病學。2015;15:22。doi: 10.1186/s12876-015-0248-8。[ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  53.Chong L.W., Hsu Y.C., Lee T.F., Lin Y., Chiu Y.T., Yang K.C., Wu J.C., Huang Y.T. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. BMC Gastroenterol. 2015;15:22. doi: 10.1186/s12876-015-0248-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 54.保田義、福士博、田邊和。預防肝細胞癌：潛在目標、實驗模型和臨床挑戰。當前癌症藥物靶點。2012;12:1129–1159。[ PMC free article ] [ PubMed ] [ Google Scholar ]
  54.Hoshida Y., Fuchs B., Tanabe K. Prevention of hepatocellular carcinoma: Potential targets, experimental models, and clinical challenges. Curr. Cancer Drug Targets. 2012;12:1129–1159. [PMC free article] [PubMed] [Google Scholar]
• 55.東崎智、弗里德曼 S.L.、保田義。肝星狀細胞作為肝纖維化的關鍵靶點。藥物遞送評論進展。2017;121:27–42。doi: 10.1016/j.addr.2017.05.007。[ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
  55.Higashi T., Friedman S.L., Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv. Drug Deliv. Rev. 2017;121:27–42. doi: 10.1016/j.addr.2017.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 56.郭博、穆豪特 F.、米特 S.、馬赫 F. 他汀類藥物作為新型免疫調節劑的認識。自然醫學。2000;6:1399。doi: 10.1038/82219。[ DOI ] [ PubMed ] [ Google Scholar ]
  56.Kwak B., Mulhaupt F., Myit S., Mach F. Statins as a newly recognized type of immunomodulator. Nat. Med. 2000;6:1399. doi: 10.1038/82219. [DOI] [PubMed] [Google Scholar]
• 57.赫雷羅 J.I.、桑格羅 B.、基羅加 J.、帕爾多 F.、赫拉伊茲 M.、西恩富戈斯 J.A.、普里埃托 J. 腫瘤特徵對肝硬化和肝細胞癌患者肝臟移植結果的影響。肝臟移植。2001;7:631–636。doi: 10.1053/jlts.2001.25458. [ DOI ] [ PubMed ] [ Google Scholar ]
  57.Herrero J.I., Sangro B., Quiroga J., Pardo F., Herraiz M., Cienfuegos J.A., Prieto J. Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transplant. 2001;7:631–636. doi: 10.1053/jlts.2001.25458. [DOI] [PubMed] [Google Scholar]
• 58.賈馬爾-漢賈尼 M.、威爾遜 G.A.、麥格拉哈 N.、比爾克巴克 N.J.、沃特金斯 T.B.、維里亞 S.、沙菲 S.、約翰遜 D.H.、米特 R.、羅森塔爾 R. 追蹤非小細胞肺癌的演變。新英格蘭醫學雜誌。2017;376:2109–2121。doi: 10.1056/NEJMoa1616288. [ DOI ] [ PubMed ] [ Google Scholar ]
  58.Jamal-Hanjani M., Wilson G.A., McGranahan N., Birkbak N.J., Watkins T.B., Veeriah S., Shafi S., Johnson D.H., Mitter R., Rosenthal R. Tracking the evolution of non–small-cell lung cancer. N. Engl. J. Med. 2017;376:2109–2121. doi: 10.1056/NEJMoa1616288. [DOI] [PubMed] [Google Scholar]
• 59.格魯特維爾德 M.、珀西瓦爾 B.、吉布森 M.、奧斯曼 Y.、埃德加 M.、莫利納里 M.、馬瑟 M.L.、卡薩諾瓦 F.、威爾遜 P.B. 低場台式 NMR 光譜在化學和生化分析中的進展。分析化學。2019;1067:11–30。doi: 10.1016/j.aca.2019.02.026. [ DOI ] [ PubMed ] [ Google Scholar ]
  59.Grootveld M., Percival B., Gibson M., Osman Y., Edgar M., Molinari M., Mather M.L., Casanova F., Wilson P.B. Progress in low-field benchtop NMR spectroscopy in chemical and biochemical analysis. Anal. Chim. Acta. 2019;1067:11–30. doi: 10.1016/j.aca.2019.02.026. [DOI] [PubMed] [Google Scholar]
• 60.Dongiovanni P., Petta S., Mannisto V., Mancina R.M., Pipitone R., Karja V., Maggioni M., Kakela P., Wiklund O., Mozzi E. 他汀類藥物使用與高風險個體的非酒精性脂肪性肝炎。J. Hepatol. 2015;63:705–712. doi: 10.1016/j.jhep.2015.05.006. [ DOI ] [ PubMed ] [ Google Scholar ]
  60.Dongiovanni P., Petta S., Mannisto V., Mancina R.M., Pipitone R., Karja V., Maggioni M., Kakela P., Wiklund O., Mozzi E. Statin use and non-alcoholic steatohepatitis in at risk individuals. J. Hepatol. 2015;63:705–712. doi: 10.1016/j.jhep.2015.05.006. [DOI] [PubMed] [Google Scholar]
• 61. Montero J., Morales A., Llacuna L., Lluis J.M., Terrones O., Basanez G., Antonsson B., Prieto J., García-Ruiz C., Colell A. 線粒體膽固醇促進肝細胞癌的化療抗性。癌症研究。2008;68:5246–5256。doi: 10.1158/0008-5472.CAN-07-6161。 [ DOI ] [ PubMed ] [ Google Scholar ]
  61.Montero J., Morales A., Llacuna L., Lluis J.M., Terrones O., Basanez G., Antonsson B., Prieto J., García-Ruiz C., Colell A. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res. 2008;68:5246–5256. doi: 10.1158/0008-5472.CAN-07-6161. [DOI] [PubMed] [Google Scholar]
• 62.Docrat T.F., Nagiah S., Krishnan A., Naidoo D.B., Chuturgoon A.A. 阿托伐他汀通過調節 PI3K/AKT 信號通路在 HEPG2 細胞中誘導 MicroRNA-145 表達。化學與生物相互作用。2018;287:32–40。doi: 10.1016/j.cbi.2018.04.005。[ DOI ] [ PubMed ] [ Google Scholar ]
  62.Docrat T.F., Nagiah S., Krishnan A., Naidoo D.B., Chuturgoon A.A. Atorvastatin induces MicroRNA-145 expression in HEPG2 cells via regulation of the PI3K/AKT signalling pathway. Chem. Biol. Interact. 2018;287:32–40. doi: 10.1016/j.cbi.2018.04.005. [DOI] [PubMed] [Google Scholar]
• 63. Moctezuma-Velázquez C., Abraldes J.G., Montano-Loza A.J. 在慢性肝病和肝硬化患者中使用他汀類藥物。當前治療選擇胃腸病學。2018;16:226–240. doi: 10.1007/s11938-018-0180-4. [ DOI ] [ PubMed ] [ Google Scholar ]
  63.Moctezuma-Velázquez C., Abraldes J.G., Montano-Loza A.J. The use of statins in patients with chronic liver disease and cirrhosis. Curr. Treat. Options Gastroenterol. 2018;16:226–240. doi: 10.1007/s11938-018-0180-4. [DOI] [PubMed] [Google Scholar]
• 64. Abraldes J.G., Albillos A., Bañares R., Turnes J., González R., García–Pagán J.C., Bosch J. 西莫伐他汀降低肝硬化和門脈高壓患者的門脈壓：一項隨機對照試驗。胃腸病學。2009;136:1651–1658. doi: 10.1053/j.gastro.2009.01.043. [ DOI ] [ PubMed ] [ Google Scholar ]
  64.Abraldes J.G., Albillos A., Bañares R., Turnes J., González R., García–Pagán J.C., Bosch J. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: A randomized controlled trial. Gastroenterology. 2009;136:1651–1658. doi: 10.1053/j.gastro.2009.01.043. [DOI] [PubMed] [Google Scholar]
• 65. Moher D., Liberati A., Tetzlaff J., Altman D.G. 系統評價和 Meta 分析的首選報告項目：PRISMA 聲明。內科年鑑。2009;151:264–269. doi: 10.7326/0003-4819-151-4-200908180-00135. [ DOI ] [ PubMed ] [ Google Scholar ]
  65.Moher D., Liberati A., Tetzlaff J., Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann. Intern. Med. 2009;151:264–269. doi: 10.7326/0003-4819-151-4-200908180-00135. [DOI] [PubMed] [Google Scholar]