丁玉平, 李 海, 張 文, 夏時海, 畢 珣
(中國人民武裝警察部隊后勤學院附屬醫(yī)院 a.消化二科; b.體檢管理中心, 天津 300162)
論著/其他
ALT升高的非酒精性脂肪性肝病的流行病學特征及其危險因素分析
丁玉平a, 李 海a, 張 文a, 夏時海a, 畢 珣b
(中國人民武裝警察部隊后勤學院附屬醫(yī)院 a.消化二科; b.體檢管理中心, 天津 300162)
目的探討非酒精性脂肪性肝病(NAFLD)中ALT升高患者的流行病學特征和相關危險因素。方法收集2016年4月4日-2016年9月13日中國人民武裝警察部隊后勤學院附屬醫(yī)院收治的NAFLD患者1007例,其中ALT升高(大于正常值上限50 U/L)123例(ALT升高組),ALT正常884例(ALT正常組)。對患者一般資料及實驗室指標血常規(guī)外周血單核細胞數(shù)、空腹血糖、TG、TC、HDL、LDL、LDL/HDL、ALT、AST、GGT、ALP、尿酸(UA)、肌酐、尿素氮、尿蛋白、尿微量蛋白、血壓、BMI、膽系伴發(fā)疾病情況及甲狀腺結節(jié)情況等進行統(tǒng)計分析。符合正態(tài)分布的計量資料2組間比較采用t檢驗,不符合正態(tài)分布的計量資料2組間比較采用Mann-WhitneyU檢驗;計數(shù)資料組間比較采χ2檢驗。多因素分析采用logistic回歸分析。結果1007例NAFLD患者中男752例,女255例。ALT升高組中男性占13.7%(103/752),女性占7.8%(20/255),男女患病率比較差異有統(tǒng)計學意義(χ2=5.552,P=0.018)。1007例患者按照年齡分為20~39歲組(n=242)、40~59歲組(n=555)及60~90歲組(n=210),3組間ALT升高比例比較差異有統(tǒng)計學意義(26.03% vs 8.83% vs 5.24%,χ2=52.327,P<0.001),進一步兩兩比較,20~39歲ALT升高患者所占比例高于40~59歲組和60~90歲組(χ2值分別為39.886、34.009,P值均<0.001)。 ALT升高組年齡相對年輕(以中青年為主)、BMI相對較高,差異顯著(t值分別為7.419、-4.595,P值均<0.001);2組的UA、外周血單核細胞數(shù)、LDL/HDL、HDL、AST、GGT水平比較差異均有統(tǒng)計學意義(U值分別為42 942、47 697、48 106、49 086、31 938、36 283,P值均<0.05)。ALT升高組NAFLD患者合并甲狀腺結節(jié)罹患率(392/1007)比ALT正常組低,差異有統(tǒng)計學意義(40.2% vs 30.1% ,P<0.05)。單因素分析顯示,男性、年齡(中青年)、高外周血單核細胞數(shù)量、LDL/HDL增高、低水平的HDL、高水平GGT、較高的BMI、無甲狀腺結節(jié)與NAFLD患者ALT升高有一定相關度(P值均<0.05);多因素logistic回歸分析發(fā)現(xiàn)中青年(20~39歲)、高水平外周血單核細胞、高水平GGT是NAFLD患者ALT升高的獨立危險因素(P值均<0.001)。結論中青年(20~39歲)、高外周血單核細胞水平、高GGT水平是NAFLD患者中ALT升高的預警因素,對非酒精性脂肪性肝炎的早期診斷可能具有提示意義。
非酒精性脂肪性肝?。?丙氨酸轉氨酶; 流行病學; 危險因素
非酒精性脂肪性肝病(NAFLD)是與胰島素抵抗和遺傳易感性密切相關的代謝應激性肝損傷,其組織病理學包括單純性脂肪肝、非酒精性脂肪性肝炎(NASH)、肝硬化、甚至原發(fā)性肝癌等過程[1]。在西方國家25%~30%的人患有NAFLD,其中約20%的患者加重進展為NASH[2]。NASH除肝細胞脂肪變外,肝小葉內出現(xiàn)炎癥伴點灶狀壞死,并可出現(xiàn)由于細胞骨架破壞形成肝纖維化、肝硬化[3],最新研究[4]提示NAFLD患者隨著纖維化進展,總體病死率增加,與肝病相關的病死率也增加。單純肝脂肪變較少進展為肝纖維化,但進展到NASH的患者很可能繼續(xù)發(fā)展為肝纖維化、肝硬化甚至是肝癌等難以治愈的終末肝病[5]。過去10年來的研究[6]表明,NASH與肝硬化、肝癌的相關性證據(jù)不斷增加。ALT升高是在一個時間截點反映NAFLD肝臟酶學改變的標志,可能存在肝脂肪變基礎上的肝臟炎癥發(fā)作,對于ALT正常的NAFLD也可能存在NAFLD合并纖維化的情況,ALT升高的NAFLD人群雖然不能確診為NASH,但與NASH有一定關聯(lián)[7],鑒于該類人群易于檢測發(fā)現(xiàn),故對NAFLD疾病的進展有一定的提示意義。目前在國內對ALT升高的NAFLD仍缺少較大樣本的研究。本研究緊密結合臨床生化檢測及體征,以影響NAFLD人群ALT升高發(fā)生的危險因素為切入點,探討ALT升高NAFLD與ALT正常NAFLD的臨床差異,為早期NASH的預警提供依據(jù)[8]。
1.1 研究對象 收集2016年4月4日-2016年9月13日本院收治的NAFLD患者。所有患者均經腹部B超檢查初步診斷為脂肪肝[8],NAFLD彩超診斷標準:(1)肝臟近場回聲彌漫性增強(“明亮肝”),回聲強于腎臟;(2)肝內管道結構顯示不清;(3)肝臟遠場回聲逐漸衰減。表現(xiàn)其中兩項者即為彌漫性脂肪肝。NAFLD排除標準:(1)排除酒精性肝病,每周攝入酒精量男性≥140 g,女性每周≥70 g或每天攝入酒精量≥40 g;(2)排除可以引起脂肪肝的其他疾病(通過詢問病史),如慢性丙型肝炎、自身免疫性肝病、肝豆狀核變性等,藥物性肝損傷(他莫昔芬、乙胺碘呋酮、丙戊酸鈉、甲氨蝶呤、糖皮質激素等);(3)排除可發(fā)生脂肪肝的全身性疾病(通過詢問病史),如全胃腸外營養(yǎng)、炎癥性腸病、甲狀腺功能減退癥、庫欣綜合征、β脂蛋白缺乏血癥以及一些與胰島素抵抗相關的綜合征;(4)排除合并嗜肝病毒(HAV、HBV、HCV、HDV、HEV)感染以及非嗜肝病毒(CMV、EBV)感染的NAFLD(通過詢問發(fā)熱及消化道癥狀病史及病毒學的體檢檢測)。
1.2 基本信息及實驗室指標 收集所有患者的基本信息,包括性別、年齡、身高、體質量。主要檢測指標包括血常規(guī)外周血單核細胞數(shù)、空腹血糖、TG、TC、HDL、LDL、LDL/HDL、ALT、AST、GGT、ALP、尿酸(UA)、肌酐、尿素氮、尿蛋白、尿微量蛋白、血壓、BMI、膽系伴發(fā)疾病情況(膽囊息肉、膽囊結石、膽管結石、膽囊切除)及甲狀腺結節(jié)情況。
2.1 一般資料 共納入1007例NAFLD患者,其中男752例,女255例。1007例中ALT升高123例(ALT升高組),ALT正常884例(ALT正常組)。ALT正常組中男性占86.3%(649/752),女性占92.2%(235/255)。
ALT升高組中男性占13.7%(103/752),女性占7.8%(20/255),男女患病率比較差異有統(tǒng)計學意義(χ2=5.552,P=0.018)。
1007例患者按照年齡分為20~39歲組(n=242)、40~59歲組(n=555)及60~90歲組(n=210),3組間ALT升高比例比較差異有統(tǒng)計學意義(P<0.001);進一步兩兩比較,20~39歲ALT升高患者所占比例高于40~59歲組和60~90歲組(χ2值分別為39.886、34.009,P值均<0.001)(表1)。
表1 不同年齡段的NAFLD患者ALT情況比較[例(%)]
注:與20~39歲組比較,1)P<0.001
2.2 ALT正常組與ALT升高組患者各項指標比較 2組比較,ALT升高組年齡相對年輕(以中青年為主)、BMI相對較高,差異有統(tǒng)計學意義(P值均<0.001);2組的UA、外周血單核細胞數(shù)、LDL/HDL、HDL、AST、GGT水平比較差異均有統(tǒng)計學意義(P值均<0.05)(表2)。
2.3 2組患者其他系統(tǒng)性疾病發(fā)生率的比較 1007例NAFLD患者中,肌酐(19/1007)、尿素氮(12/1007)、尿蛋白(14/1007)異常比例均較低,而NAFLD患者中尿微量白蛋白陽性率(61/1007)、罹患心肌缺血(130/1007)、合并膽系疾病(162/1007)、合并高血壓(332/1007)比率較高,但2組間比較差異均無統(tǒng)計學意義(P值均>0.05);ALT升高組NAFLD患者合并甲狀腺結節(jié)罹患率(392/1007)比ALT正常組低,差異有統(tǒng)計學意義(P<0.05)(表3)。
表2 2組患者年齡及生化指標比較
注:本表中的部分指標檢測結果在正常值范圍以內的,統(tǒng)計錄入時只顯示正常(無具體測量值),故本文分析數(shù)據(jù)時取相應指標正常值的上限與下限的平均值
2.4 ALT升高組患者的單因素與多因素logistic回歸分析 單因素分析顯示,男性、年齡(中青年)、高外周血單核細胞數(shù)量、LDL/HDL增高、低水平的HDL、高水平GGT、較高的BMI、無甲狀腺結節(jié)與NAFLD患者ALT升高有一定相關度(P值均<0.05);多因素logistic回歸分析發(fā)現(xiàn)中青年(20~39歲)、高水平外周血單核細胞、高水平GGT是NAFLD患者ALT升高的獨立危險因素(P值均<0.05)(表4)。
我國大陸90年代,應用彩超的體檢提示脂肪肝發(fā)病率為1%~30%,主要限于標準不同、調查方法多樣、調查對象城鄉(xiāng)差距較大,發(fā)病率不統(tǒng)一[9]。2014一項中國人群脂肪肝的Meta分析[10]顯示脂肪肝的發(fā)病率為16.73%,男性(19.28%)高于女性(14.1%)(P=0.007 1),在沿海地區(qū)男性比率達到21.82%,亦高于女性17.01%(P=0.015 7),但該研究的不足之處是脂肪肝人群未能有效排除酒精性脂肪性肝病患者。在美國,NASH所致的肝硬化與NAFLD所致的纖維化,2009年-2012年比1999年-2002年分別增加了2.5倍和2倍。2010年來自美國“全國健康和營養(yǎng)檢查調查”數(shù)據(jù)[11]顯示,NASH導致的肝硬化達到417 524 例,而NAFLD所致的肝纖維化達到4 104 871例。NASH在全球人口的發(fā)病率將達到10%~24%,而在肥胖糖尿病患者中這一數(shù)據(jù)可達25%~75%[12]。但截至目前,NAFLD的發(fā)病率以及NASH在中國NAFLD的發(fā)病率,國內仍缺少大樣本的研究數(shù)據(jù),本研究結果提示NAFLD患者中ALT升高的發(fā)病率為12.2%,男性高于女性。
目前對NASH的診斷主要基于:(1)存在肝脂肪變的影像學或組織學依據(jù);(2)無飲酒史或飲酒折合乙醇量<140 g/周(女性<70 g/周);(3)除外病毒性肝炎、藥物性肝病、全胃腸外營養(yǎng)、肝豆狀核變性、自身免疫性肝病等可導致脂肪肝的特定疾病。雖然肝穿刺活組織病理學檢查是診斷NASH的重要依據(jù),但我國缺少大宗數(shù)據(jù)研究,NASH的臨床確診具有一定困難。有研究[13]提示ALT水平在無脂肪肝[(19.36±9.52) U/L]、單純脂肪變[(23.97±11.00) U/L]、邊界NASH[(26.59±11.63) U/L]、NASH[(48.75±42.64) U/L]患者中的表達有統(tǒng)計學差異,通過肝穿刺活組織檢查證實ALT水平>45 U/L可以很好預測NAFLD中的NASH。Losekann等[14]通過肝組織病理證實ALT≥1.5倍正常值上限的患者均患有NASH,ALT>1.5倍正常值上限、血糖≥ 126 mg/dl、 甘油三
脂≥150 mg/dl是NASH的獨立預測因素。在NAFLD肝穿刺病例中,ALT預測NASH的受試者工作特征曲線下面積可以達到0.829[15]。以上研究均提示ALT水平對NAFLD患者中NASH的預測具有一定提示價值。
本研究發(fā)現(xiàn)在NAFLD患者ALT升高組以中青年男性的比例較高,并表現(xiàn)出較高的BMI、UA水平及AST水平,這與國內龔先瓊等[16]在94例經肝穿刺證實的NAFLD患者中50例NASH研究結果類似。Meta分析[17-18]顯示,UA增高者發(fā)生NAFLD的cut-off值為308 μmol/L,其敏感度是94.12%(95%可信區(qū)間:71.3%~99.9%),特異度是70.6%(95%可信區(qū)間:44.0%~89.7%),提示UA在NAFLD患者中表達水平上調,可能參與NAFLD的形成機制。另有國內一小樣本NAFLD(50例)的肝穿刺研究[7]提示在年齡方面,NASH組(14例)與單純性脂肪肝組(20例)相比并無顯著差異,但比NASH纖維化組(8例)年齡要低,而ALT水平NASH組高于單純脂變組或NASH合并纖維化組,NASH組其他肝酶水平(AST、GGT)也明顯增加,同時表現(xiàn)出糖脂代謝紊亂的特征,比如TG、LDL增加,而HDL顯著降低。本研究結果顯示,ALT升高的NAFLD患者在AST與GGT升高的同時出現(xiàn)了HDL滴度的降低,以及LDL/HDL的增高,這可能提示NASH的進展與糖脂代謝密切相關。
我國多個地區(qū)報道[19-20]正常人群甲狀腺結節(jié)的發(fā)病率集中于20.9%~31.00%,但來自北京的研究[21]結果提示甲狀腺結節(jié)的總體流行率為49.0%,隨年齡增加也有增加趨勢,女性的比率高于男性,多因素分析提示BMI、吸煙習慣是甲狀腺結節(jié)的獨立危險因素。來自河北21 916例健康人群的體檢研究[22]發(fā)現(xiàn),甲狀腺結節(jié)患病率為31.70%、脂肪肝患病率為29.03%、兩病共患的患病率為9.54%,脂肪肝組甲狀腺結節(jié)患病率(32.86%)明顯高于非脂肪肝組(31.23%),多因素logistic回歸分析顯示:女性、高齡、脂肪肝是患甲狀腺結節(jié)的獨立危險因素,脂肪肝可能與甲狀腺結節(jié)的患病有關系。本研究中ALT升高組甲狀腺結節(jié)的患病率低于ALT正常組,可能與ALT升高組人群中青年男性高比例有關。脂肪肝與甲狀腺結節(jié)具有一定相關性,但脂肪性肝炎與甲狀腺結節(jié)的關系目前尚無充分證據(jù)。
近幾年發(fā)現(xiàn)脂肪性肝病不僅是引起肝病終末事件的重要肝病之一,越來越多的證據(jù)還提示其是多數(shù)系統(tǒng)性疾病(比如糖尿病、心腦血管疾病、慢性腎炎等)的早期反應[23]。本研究發(fā)現(xiàn)高血糖、高血壓、膽系疾病在NAFLD患者中具有較高患病率,而肌酐和尿素氮在NAFLD中的患病率較低,但尿微量蛋白在NAFLD患者中有一定比例的升高。研究結果未發(fā)現(xiàn)膽系疾病、血糖水平、血壓、肌酐、尿素氮、尿蛋白、尿微量蛋白在兩組中存在明顯差異,這可能提示NAFLD作為一個系統(tǒng)性疾病,損傷不同的靶向器官,ALT升高是靶向損傷肝臟的標志,與其他膽系、胰腺、心血管、腎臟等損傷不一定具有明顯的關聯(lián)性。
本研究發(fā)現(xiàn)中青年、外周血高水平單核細胞、高水平GGT是NAFLD患者ALT升高的獨立危險因素。外周血單核細胞的活化增殖可能參與NAFLD患者中NASH的發(fā)生發(fā)展[24],具體的作用機制有待進一步深入研究。GGT作為肝臟膽管梗阻的標志性酶,其升高可能預示NAFLD患者肝細胞水腫變性,甚至NASH的發(fā)生[15]。心腦血管疾病與惡性腫瘤是NAFLD疾病的不良結局,而NASH是NAFLD疾病中的重要環(huán)節(jié),在NASH患者中肝病相關的病死率明顯增加,對NASH的早期預警及采取有效的干預措施顯得極為重要[25]。
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Epidemiologicalcharacteristicsofnonalcoholicfattyliverdiseasewithelevatedalanineaminotransferaseandrelatedriskfactors
DINGYuping,LIHai,ZHANGWen,etal.
(SecondDepartmentofGastroenterology,TheAffiliatedHospitalofLogisticsUniversityofChinesePeople′sArmedPoliceForces,Tianjin300162,China)
ObjectiveTo investigate the epidemiological characteristics of nonalcoholic fatty liver disease (NAFLD) with elevated alanine aminotransferase (ALT) and related risk factors.MethodsA total of 1007 patients with NAFLD who were admitted to The Affiliated Hospital of Logistics University of Chinese People′s Armed Police Forces from April 4, 2016 to September 13, 2016 were enrolled, and among these patients, 123 had an elevated ALT level (higher than the upper limit of normal 50 U/L) (elevated ALT group) and 884 had normal ALT (normal ALT group). A statistical analysis was performed for their general data and laboratory markers [number of peripheral blood mononuclear cells, fasting blood glucose, triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), LDL/HDL ratio, ALT, aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), uric acid (UA), creatinine, blood urea nitrogen, urinary protein, urinary microproteins], blood pressure, body mass index (BMI), concomitant biliary disease, and thyroid nodules. Thet-test was used for comparison of normally distributed continuous data between groups, and the Mann-WhitneyUtest was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. A multivariate logistic regression analysis was used to identify the risk factors for elevated ALT in NAFLD patients.ResultsAmong the 1007 patients with NAFLD, there were 752 male and 255 female patients. Of all male patients, 13.7% (103/752) were in the elevated ALT group, and of all female patients, 7.8% (20/255) were in the elevated ALT group; there was a significant difference in the prevalence rate between male and female patients (χ2=5.552,P=0.018). According to the age, the 1007 patients were divided into 20-39 year group with 242 patients, 40-59 year group with 555 patients, and 60-90 year group with 210 patients, and there was a significant difference in the proportion of patients with an elevated ALT level between these three groups (26.03% vs 8.83% vs 5.24%,χ2=52.327,P<0.001); further comparison between any two groups showed that the 20-39 year group had a significantly higher proportion of patients with an elevated ALT level than the 40-59 year group and the 60-90 year group (χ2=39.886 and 34.009, bothP<0.001). Most patients in the elevated ALT group were young and middle-aged adults, and compared with the normal ALT group, the elevated ALT group had a significantly younger age and a significant higher BMI (t=7.419 and -4.595, bothP<0.001); there were also significant differences between the two groups in UA, number of peripheral blood mononuclear cells, LDL/HDL ratio, HDL, AST, and GGT (U=42 942, 47 697, 48 106, 49 086, 31 938, and 36 283, allP<0.05). Of all 1007 patients, 392 had NAFLD complicated by thyroid nodules, and the elevated ALT group had a significantly higher proportion of such patients than the normal ALT group (40.2% vs 30.1%,P<0.05). The univariate analysis showed that male sex, age (young and middle ages), a high number of peripheral blood mononuclear cells, increased LDL/HDL ratio, a low level of HDL, a high level of GGT, a high BMI, and absence of thyroid nodules were associated with elevated ALT in NAFLD patients (allP<0.05). The multivariate logistic regression analysis showed that young and middle ages (20-39 years), a high number of peripheral blood mononuclear cells, and a high level of GGT were independent risk factors for elevated ALT in NAFLD patients (allP<0.001).ConclusionYoung and middle ages (20-39 years), a high number of peripheral blood mononuclear cells, and a high level of GGT are predictive factors for elevated ALT in NAFLD patients and may have a certain value in guiding the early diagnosis of nonalcoholic steatohepatitis.
nonalcoholic fatty liver disease; alanine transaminase; epidemiology; risk factors
R575.5
A
1001-5256(2017)12-2355-06
10.3969/j.issn.1001-5256.2017.12.020
2017-10-16;修回日期:2017-11-09。 基金項目:武警后勤學院博士啟動基金(WHB201517) 作者簡介:丁玉平(1982-),男,主治醫(yī)師,博士,主要從事肝病診治及其發(fā)病機制的研究。 通信作者:畢珣,電子信箱:dingyuping117@163.com。
引證本文:DING YP, LI H, ZHANG W, et al. Epidemiological characteristics of nonalcoholic fatty liver disease with elevated alanine aminotransferase and related risk factors[J]. J Clin Hepatol, 2017, 33(12): 2355-2360. (in Chinese)
丁玉平, 李海, 張文, 等. ALT升高的非酒精性脂肪性肝病的流行病學特征及其危險因素分析[J]. 臨床肝膽病雜志, 2017, 33(12): 2355-2360.
(本文編輯:林 姣)