劉菲菲,張海月,張倩,王魯文,龔作炯
慢性丙型肝炎合并2型糖尿病患者臨床特征及胰島素抵抗對(duì)抗病毒療效影響的Meta分析
劉菲菲,張海月,張倩,王魯文,龔作炯
目的分析慢性丙型肝炎(CHC)合并2型糖尿病患者的臨床特征及胰島素抵抗(IR)對(duì)干擾素治療CHC患者臨床療效的影響。方法應(yīng)用計(jì)算機(jī)檢索PubMed、Ovid、ScienceDirect、Embase、萬(wàn)方、維普數(shù)據(jù)庫(kù)1970年至2015年1月發(fā)表的關(guān)于CHC合并2型糖尿病的臨床特征及IR與CHC抗病毒治療效果關(guān)系的文獻(xiàn)。應(yīng)用RevMan 5.2軟件進(jìn)行Meta分析。結(jié)果本研究納入22篇合格文獻(xiàn),全部為英文文獻(xiàn)。關(guān)于CHC合并2型糖尿病臨床特征文獻(xiàn)11篇,IR對(duì)干擾素治療CHC病毒學(xué)應(yīng)答產(chǎn)生影響文獻(xiàn)11篇;CHC合并2型糖尿病患者的年齡、體質(zhì)指數(shù)(BMI)顯著高于單純CHC或單純糖尿病患者[P=0.0001,SMD=0.30,95%CI(0.15,0.45),P=0.04,SMD= 0.17,95%CI(0.01,0.34)],CHC合并2型糖尿病患者糖尿病家族史顯著多于單純CHC或單純糖尿病患者[P=0.01,RR=1.07,95%CI(1.02,1.13)];CHC合并2型糖尿病患者感染HCV基因1型的比例顯著低于單純CHC患者[P=0.01,RR=0.82,95%CI(0.71,0.95)],但兩組感染2型或3型比例無(wú)顯著性差異[P=0.25,RR=1.16,95%CI (0.90,1.50),P=0.92,RR=1.06,95%CI(0.30,3.78)]);干擾素治療CHC患者獲得非持續(xù)病毒學(xué)應(yīng)答(NSVR)組HOMA-IR水平和IR發(fā)生率顯著高于獲得持續(xù)病毒學(xué)應(yīng)答(SVR)組[P<0.0001,SMD=0.80,95%CI(0.63,0.97),P<0.0001,OR=2.0,95%CI(1.59,2.52)]。結(jié)論CHC合并2型糖尿病患者臨床特征為高齡、高BMI水平和多伴有糖尿病家族史。感染基因1型CHC患者合并2型糖尿病機(jī)會(huì)小,而合并IR會(huì)降低干擾素抗病毒治療后SVR發(fā)生率,是影響干擾素治療CHC療效的重要不利因素之一。
慢性丙型肝炎;2型糖尿病;胰島素抵抗;基因型;干擾素-α
慢性丙型肝炎(Chronic hepatitis C,CHC)是由丙型肝炎病毒(Hepatitis C virus,HCV)引起的傳染性肝臟疾病。CHC的臨床表現(xiàn)多樣,除了有典型的肝臟損害表現(xiàn)外,還往往合并許多肝外表現(xiàn),如混合性冷凝球蛋白血癥、甲狀腺炎、遲發(fā)性皮膚卟啉癥等[1]。近年來(lái),有些研究表明,CHC與2型糖尿病的發(fā)生關(guān)系密切[2,3]。2型糖尿病患者存在胰島素抵抗(Insulin resistance,IR)。研究表明IR會(huì)影響α-干擾素治療CHC患者的病毒學(xué)應(yīng)答。本研究從循證醫(yī)學(xué)的角度對(duì)CHC合并2型糖尿病患者的臨床特征及IR對(duì)α-干擾素抗病毒治療后發(fā)生持續(xù)病毒學(xué)應(yīng)答(Sustained virologic response,SVR)的影響進(jìn)行了Meta分析,以期為臨床提供更多的指導(dǎo)。
1.1文獻(xiàn)檢索計(jì)算機(jī)檢索PubMed、Ovid、ScienceDirect、Embase、萬(wàn)方、維普數(shù)據(jù)庫(kù),涵蓋1970年至2015年1月1日所有相關(guān)文獻(xiàn)。同時(shí)手工檢索納入文獻(xiàn)的參考文獻(xiàn)。中文檢索詞為“慢性丙型肝炎”、“2型糖尿病”、“胰島素抵抗”、“α-干擾素”、“治療”。英文檢索詞為“Chronic hepatitis C”、“Diabetes type 2”、“Diabetes”、“Insulin resistance”、“Interferon-α”、“Therapy”。納入標(biāo)準(zhǔn):(1)隨機(jī)對(duì)照試驗(yàn);(2)經(jīng)臨床診斷為CHC合并2型糖尿病患者;(3)α-干擾素治療;(4)包括年齡、性別、體質(zhì)指數(shù)(Body mass index,BMI)、有無(wú)糖尿病家族史、HOMA-IR、基因型、IR、SVR、非持續(xù)病毒學(xué)應(yīng)答(Non sustained viral response,NSVR)等資料。排除標(biāo)準(zhǔn):(1)僅有摘要;(2)非隨機(jī)化試驗(yàn)。
1.2納入文獻(xiàn)質(zhì)量評(píng)價(jià)根據(jù)Cochrane協(xié)作網(wǎng)推薦的偏倚風(fēng)險(xiǎn)評(píng)估方法對(duì)納入的RCT文獻(xiàn)進(jìn)行評(píng)估,①隨機(jī)分配方案的產(chǎn)生;②隱蔽分組;③對(duì)患者或醫(yī)生實(shí)施盲法;④對(duì)資料收集和分析人員實(shí)施盲法;⑤結(jié)果數(shù)據(jù)是否完整;⑥選擇性的結(jié)果報(bào)告;⑦影響真實(shí)性的其他潛在風(fēng)險(xiǎn)。
1.3Meta分析應(yīng)用Cochrane協(xié)作網(wǎng)提供的RevMan 5.2軟件。首先采用x2檢驗(yàn)和I2檢驗(yàn)對(duì)同類(lèi)研究間的異質(zhì)性進(jìn)行評(píng)價(jià)。當(dāng)P≥0.10,I2<50%時(shí),說(shuō)明研究間存在異質(zhì)性的可能性小,使用固定效應(yīng)模型分析;當(dāng)P<0.10,I2>50%時(shí),說(shuō)明研究間具有異質(zhì)性,則對(duì)其異質(zhì)性的來(lái)源進(jìn)行分析。根據(jù)可能出現(xiàn)的異質(zhì)性因素進(jìn)行亞組分析(對(duì)只有一項(xiàng)亞組的研究仍采用與Meta分析相同的統(tǒng)計(jì)量),必要時(shí)采用敏感性分析來(lái)分析檢驗(yàn)結(jié)果的穩(wěn)定性。當(dāng)異質(zhì)性過(guò)大并不能判斷其來(lái)源時(shí)則放棄Meta分析,改為描述性報(bào)告結(jié)果。計(jì)數(shù)資料采用相對(duì)危險(xiǎn)度(Relative risk,RR)作為分析統(tǒng)計(jì)量,對(duì)連續(xù)性資料,當(dāng)使用測(cè)量工具相同,則采用加權(quán)均數(shù)差(Weighted mean difference,WMD)進(jìn)行分析;當(dāng)相同變量使用不同的測(cè)量工具,則采用標(biāo)準(zhǔn)化均數(shù)差(Standardized mean difference,SMD)進(jìn)行分析。所有分析均計(jì)算95%可信區(qū)間(Credibility interval,CI)。
2.1文獻(xiàn)檢索情況初步檢出相關(guān)文獻(xiàn)241篇,其中英文211篇,中文30篇。經(jīng)閱讀文題和摘要后剔除明顯不符合納入標(biāo)準(zhǔn)的文獻(xiàn)176篇。然后,閱讀全文和進(jìn)行質(zhì)量評(píng)價(jià)后,進(jìn)一步剔除重復(fù)發(fā)表、交叉發(fā)表和不符合納入標(biāo)準(zhǔn)的文獻(xiàn)42篇,最終納入22篇合格文獻(xiàn)[4~25],全部為英文文獻(xiàn)。關(guān)于CHC合并2型糖尿病臨床特征文獻(xiàn)11篇[4~14],IR對(duì)干擾素治療CHC病毒學(xué)應(yīng)答產(chǎn)生影響文獻(xiàn)11篇[15~25]。文獻(xiàn)主要特征見(jiàn)表1。
2.2納入研究的偏倚風(fēng)險(xiǎn)評(píng)價(jià)對(duì)22篇文獻(xiàn)的基線資料進(jìn)行分析,發(fā)現(xiàn)它們具有可比性,但存在不同水平的偏倚。可能存在的偏倚主要表現(xiàn)在:(1)發(fā)表偏倚:分析CHC合并糖尿病患者的家族史、性別、基因1型、基因2型的漏斗圖發(fā)現(xiàn),圖形不對(duì)稱,有一定的差異。比較SVR與NSVR人群HOMA-IR和IR的漏斗圖發(fā)現(xiàn),圖形不對(duì)稱,有一定的差異;(2)語(yǔ)種偏倚:本次研究使用中英文檢索,但由于中文檢索結(jié)果未見(jiàn)符合條件的文獻(xiàn),故予以排除,納入的文獻(xiàn)全為英文文獻(xiàn)。文獻(xiàn)本身的偏倚主要表現(xiàn)在每篇文獻(xiàn)的HOMA-IR水平的分界值不同,導(dǎo)致測(cè)量偏倚的可能性大。
表1 納入文獻(xiàn)的基本特征
2.3CHC合并2型糖尿病患者的年齡特征納入5篇文獻(xiàn)[4~6,8,14]比較了199例CHC合并2型糖尿病患者與1536例CHC或者糖尿病患者的年齡。研究間存在異質(zhì)性(P=0.008,I2=71%),Meta分析結(jié)果顯示:兩組差異有統(tǒng)計(jì)學(xué)意義[Z=3.86,P= 0.0001,SMD=0.30,95%CI(0.15,0.45)],表明CHC合并糖尿病患者的年齡比單純CHC或糖尿病患者大(圖1)。
圖1 CHC合并糖尿病與CHC或糖尿病患者年齡比較
2.4 CHC合并2型糖尿病的性別特征納入7篇文獻(xiàn)[4~9,12,14]比較了684例CHC合并2型糖尿病患者與4808例CHC或者糖尿病患者的性別。各項(xiàng)研究間不存在異質(zhì)性(P=0.65,I2=0%),Meta分析結(jié)果顯示:兩組性別差異無(wú)統(tǒng)計(jì)學(xué)意義[Z=1.50,P=0.13,RR=1.07,95%CI(0.98,1.16)],說(shuō)明性別對(duì)CHC合并糖尿病的發(fā)病無(wú)顯著性影響。
2.5CHC合并2型糖尿病患者BMI水平情況共4篇文獻(xiàn)[4,6,8,14]比較了174例CHC合并2型糖尿病患者與967例CHC或者糖尿病患者BMI水平。研究間存在異質(zhì)性(P=0.001,I2=81%)。Meta分析顯示:兩組差異有統(tǒng)計(jì)學(xué)意義[Z=2.09,P=0.04,SMD= 0.17,95%CI(0.01,0.34)],表明CHC合并2型糖尿病患者BMI較單純CHC或糖尿病患者高。
2.6CHC合并2型糖尿病患者糖尿病家族史特征共4篇文獻(xiàn)[4,7,12,13]比較了601例CHC合并2型糖尿病患者與2943例CHC或者糖尿病患者糖尿病家族史情況,各項(xiàng)研究間存在異質(zhì)性(P<0.00001,I2=94%)。Meta分析顯示:兩組差異有統(tǒng)計(jì)學(xué)意義[Z=2.54,P= 0.01,RR=1.07,95%CI(1.02,1.13)],表明較多的CHC合并2型糖尿病患者有糖尿病家族史。
2.7CHC合并2型糖尿病患者感染HCV基因型比較共4篇文獻(xiàn)[4,5,10,11]比較了150例感染HCV基因1型CHC合并2型糖尿病患者與748例CHC患者感染HCV基因1型情況。各項(xiàng)研究間不存在異質(zhì)性(P=0.20,I2=35%)。Meta分析顯示:兩組差異有統(tǒng)計(jì)學(xué)意義[Z=2.59,P=0.01,RR=0.82,95%CI(0.71,0.95)],說(shuō)明感染基因1型CHC患者患糖尿病機(jī)會(huì)小;共4篇文獻(xiàn)[4,5,10,11]比較了150例感染基因型2型CHC合并2型糖尿病患者與748例CHC患者感染HCV基因2型的比例。各項(xiàng)研究間存在異質(zhì)性(P=0.02,I2=69%)。Meta分析結(jié)果顯示:兩組差異無(wú)統(tǒng)計(jì)學(xué)意義[Z=1.15,P=0.25,RR=1.16,95%CI=(0.90,1.50)],說(shuō)明感染基因2型不是易患2型糖尿病的因素;同樣,感染基因3型也不是易患2型糖尿病的因素。
2.8IR對(duì)干擾素治療CHC的影響共有6篇文獻(xiàn)[15~18,23,25]比較了干擾素治療CHC發(fā)生SVR 559例和NSVR 286例。各項(xiàng)研究間存在異質(zhì)性(P<0.00001,I2=98%)。Meta分析結(jié)果顯示:兩組差異有統(tǒng)計(jì)學(xué)意義[Z=9.36,P<0.0001,SMD=0.80,95%CI (0.63,0.97)],抗病毒治療后NSVR組HOMR-IR值顯著高于SVR組;共11篇文獻(xiàn)[15~25]比較了干擾素治療CHC發(fā)生NSVR 708例和SVR 688例伴隨IR情況。各項(xiàng)研究間存在異質(zhì)性(P=0.0005,I2=68%)。Meta分析結(jié)果顯示:兩組差異有統(tǒng)計(jì)學(xué)意義[Z=5.87,P<0.0001,OR=2.0,95%CI=(1.59,2.52)],提示NSVR組的IR發(fā)生率顯著高于SVR組。
HCV感染呈全球性分布,威脅到全世界約3%的人口,每年新增300萬(wàn)~400萬(wàn)患者[26]。CHC與其他人群及肝病患者相比更易合并2型糖尿病。肝臟是參與體內(nèi)糖代謝的重要器官,肝臟通過(guò)糖原的合成、降解及通過(guò)影響血糖調(diào)節(jié)激素的水平而影響血糖。因此,肝臟嚴(yán)重受損時(shí)易出現(xiàn)血糖異常。本研究綜合分析CHC合并2型糖尿病患者的臨床特征,發(fā)現(xiàn)年齡、BMI值和糖尿病家族史是2型糖尿病發(fā)生的危險(xiǎn)因素,與其他研究報(bào)道一致[27],但性別對(duì)CHB合并2型糖尿病發(fā)病未表現(xiàn)出明顯的關(guān)系。因此,在臨床上針對(duì)高齡、高BMI、有糖尿病家族史的CHC患者應(yīng)注意監(jiān)測(cè)其血糖水平,必要時(shí)及早干預(yù),以降低CHC合并2型糖尿病的發(fā)生率。
HCV RNA聚合酶缺乏校對(duì)功能,使得病毒復(fù)制容易產(chǎn)生錯(cuò)誤,導(dǎo)致病毒基因組出現(xiàn)異源性群體。根據(jù)病毒分離株核苷酸變異情況可以分成不同的基因型和基因亞型。本文經(jīng)系統(tǒng)評(píng)價(jià)得出1型CHC患者合并2型糖尿病機(jī)會(huì)較小,而2、3型CHC對(duì)是否合并2型糖尿病并無(wú)明顯的影響。
干擾素是CHC患者抗病毒治療的首選藥物,在抗病毒后患者SVR受諸多因素的影響,如感染病毒基因型、治療前病毒載量、早期病毒學(xué)應(yīng)答、抗干擾素抗體、干擾素敏感決定區(qū)、宿主免疫狀況、是否有肝硬化等。本研究分析了IR對(duì)干擾素治療CHC患者臨床應(yīng)答率的影響。2型糖尿病存在IR,CHC本身也可以導(dǎo)致IR[28,29]。通過(guò)HOMA-IR計(jì)算來(lái)界定患者是否存在IR,結(jié)果在治療結(jié)束時(shí)NSVR組與SVR組患者相比有更高的HOMA-IR水平,說(shuō)明他們存在IR,故對(duì)干擾素治療的病毒學(xué)應(yīng)答較差,說(shuō)明IR是影響干擾素治療CHC療效的重要因素之一。因此,在臨床上決定對(duì)CHC患者行抗病毒治療時(shí),是否可通過(guò)改善其存在的IR,以期獲得更好的臨床療效,值得研究。由于所納入文獻(xiàn)并未全面地描述隨機(jī)方法、盲法實(shí)施、隱蔽分組等情況,可能使得文獻(xiàn)質(zhì)量偏低,上述結(jié)論仍需納入更多高質(zhì)量、大樣本、多中心的隨機(jī)對(duì)照試驗(yàn)來(lái)驗(yàn)證。
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(收稿:2015-11-05)
(本文編輯:陳從新)
·藥物性肝損傷·
ObjectiveTo investigate the clinical characteristics of patients with chronic hepatitis C(CHC)with concomitant type 2 diabetes and to assess the impact of insulin resistance(IR)on sustained virological response(SVR)in patients with hepatitis C to treatment of interferon-α(IFN-α).MethodsA systematic search of electronic databases for randomized clinical trials in Pubmed,Ovid,Science Direct,Embase,Wanfang database and VIP database from 1970 to January,2015 was done as respect to clinical features of CHC with type 2 diabetes,and the correlation between IR and SVR.The Meta analysis was performed by using the RevMan 5.2 software.ResultTwenty-two papers published in English were retrieved in this study,with eleven on CHC with type two diabetes,and eleven on IR impacting response to IFN-α therapy.Patients with CHC and type 2 diabetes had older age and higher BMI than in patients with CHC or diabetes alone[P=0.0001,SMD=0.30,95%CI (0.15,0.45),P=0.04,SMD=0.17,95%CI(0.01,0.34)];More patients with CHC and type 2 diabetes had family history of diabetis than in patients with CHC or diabetes alone[P=0.01,RR=1.07,95%CI(1.02,1.13)];The incidence of genotype 1 infection in CHC patients with type 2 diabetes was significantly lower than in that of CHC alone[P=0.01,RR=0.82,95%CI(0.71,0.95)],while there was no significant differences as respect of genotypes 2/3infectioninthetwogroups[P=0.25,RR= 1.16,95%CI(0.90,1.50),P=0.92,RR=1.06,95%CI (0.30,3.78)];TheincidenceofIRwashigherin CHC patients with non-sustained virological response (NSVR)to interferon-α therapy than in those who got SVR[P<0.0001,SMD=0.80,95%CI(0.63,0.97),P<0.0001,OR=2.0,95%CI(1.59,2.52)].ConclusionsPatients with CHC and type 2 diabetes tends to be elderly with higher BMI levels and much more family history of diabetes.IR is associated with a lower SVR in CHC patients receiving IFN-α therapy.
Hepatitis C;Type 2 diabetes;Interferon-α;Genotypes;Insulin resistance
10.3969/j.issn.1672-5069.2016.04.013
430060武漢市武漢大學(xué)人民醫(yī)院感染病科
劉菲菲,女,24歲,碩士研究生。主要從事病毒性肝炎防治研究。E-mail:349204481@qq.com
龔作炯,E-mail:zjgong@163.com
Clinical features of patients with chronic hepatitis C with concomitant diabetes type 2 and impact of insulin resistance on efficacy of antiviral therapy:a Meta analysisLiu Feifei,Zhang Haiyue,Zhang Qian,et al.Department of Infectious Diseases,People's Hospital,Wuhan University,Wuhan 430060,Hubei Province,China