非酒精性脂肪性肝病患者早期腎損傷的潛在因素分析

三峽大學人民醫(yī)院消化內(nèi)科，湖北 宜昌 443000

【Abstract】ObjectiveTo investigate the potential factors of early renal injury in adult non-alcoholic fatty liver disease (NAFLD) patients and improve the diagnosis rate of early renal injury.MethodsA total of 125 patients with NAFLD were collected in outpatient and inpatient, 78 cases of simple obesity (SO) group, routine liver biochemicaly, renal biochemical and early renal injury indicators were tested. The glomerular filtration rate (eGFR) and insulin resistance index (HOMA-IR) were calculated.ResultsNAFLD group was compared with SO group, the ALT, AST, FINS, Scr, urine trace albumin/creatinine (ACR), β2-microglobulin (β2-MG), eGFR and insulin resistance index (HOMA-IR) were statistically difference.Spearmancorrelation analysis showed that ACR was positively correlated with body mass index (BMI), waist circumference, fasting glucose (FBG), FINS, cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), HOMA-IR. HOMA-IR had the greatest influence of ACR.ConclusionACR and HOMA-IR are more sensitive than Scr, eGFR and β2-MG to detect early renal injury, and the combined analysis can improve the diagnostic rate of early renal injury.

【Keywords】 Non-alcoholic fatty liver disease; Simple obesity; Urine trace albumin/creatinine; Insulin resistance index

隨著人們生活方式改變，非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)的患病率在逐漸升高。近年來，國外研究發(fā)現(xiàn)，NAFLD可增加患慢性腎病(chronic kidney disease，CKD)的發(fā)病風險[1-2]。CKD是一個全球健康問題，具有高發(fā)病率和高死亡率特點，該病的潛在危險因素包括高齡、肥胖、高血壓、糖尿病，及時發(fā)現(xiàn)并治療早期腎損傷至關重要，CKD被預防或被延遲將成為可能[3-4]。本研究主要分析NAFLD患者早期腎臟損傷狀況及其影響因素，提高腎損傷的診斷率，為臨床上更好地管理NAFLD患者，早期防治CKD的發(fā)生、發(fā)展提供理論依據(jù)。

1 資料與方法

1.1一般資料選取2016年1月至2017年6月三峽大學人民醫(yī)院門診就診及住院的NAFLD患者125例，男103例，女22例，平均年齡55.4歲。選擇同期體檢的單純性肥胖者(simple obesity，SO)78例為對照組(SO組)，男62例，女16例，平均年齡48.6歲。兩組在年齡、性別方面相比，差異無統(tǒng)計學意義(P>0.05),具有可比性。本次研究相關檢查均得到研究對象的知情同意,并簽署同意書；且經(jīng)醫(yī)院倫理委員會批準。

1.2納入及排除標準NAFLD入選對象均符合2010年中華醫(yī)學會肝臟病學分會脂肪肝和酒精性肝病學組修訂的《非酒精性脂肪性肝病診斷標準》，排除標準：過量飲酒史，飲酒折合乙醇量男性>20 g/d，女性>10 g/d，無高血壓病、糖尿病，慢性腎炎或慢性腎病史，惡性腫瘤史，血清HBsAg和/或抗-HCV陽性。影像學診斷具備以下3項腹部超聲表現(xiàn)中的兩項者為彌漫性脂肪肝：(1)肝臟近場回聲彌漫性增強(“明亮肝”)，回聲強于腎臟；(2)肝內(nèi)管道結構顯示不清；(3)肝臟遠場回聲逐漸衰減。所有患者均為初次來我院就診，未接受過任何治療措施。

1.3 研究方法

1.3.1 標本采集：所有入選者清晨空腹抽取外周靜脈血5 ml，分離血清待檢。

1.3.2 觀察指標：均記錄人體學資料：性別、年齡、身高等。收集血清和晨尿檢測：(1)肝臟生化指標：天冬氨酸氨基轉(zhuǎn)移酶(AST)、丙氨酸氨基轉(zhuǎn)移酶(ALT)；(2)代謝指標：膽固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、空腹血糖(FBG)；(3)腎臟生化及早期腎損指標：尿酸(UA)、血清肌酐(Scr)、尿微量白蛋白/肌酐(ACR)、β2-微球蛋白(β2-MG)、空腹胰島素(FINS)。

1.3.3 工作定義：計算體質(zhì)量指數(shù)(body mass index，BMI)；采用腎臟病飲食改良(modification of diet in renal disease，MDRD)公式：男性GFR(ml/min per 1.73 m2)=186×(Scr)-1.154×(年齡)-0.203；女性GFR(ml/min per 1.73 m2)=186×(Scr)-1.154×(年齡)-0.203×0.742。其中GFR為腎小球濾過率，Scr為血清肌酐(mg/dl)，年齡以歲為單位。腎損傷被定義為eGFR<90 ml/min per 1.73 m2。超重或肥胖診斷依據(jù)2005年國際糖尿病聯(lián)盟標準[6]，即：腰圍>90 cm(男性)、>80 cm(女性)，和(或)BMI>25 kg/m2。采用穩(wěn)態(tài)模型評估計算法計算胰島素抵抗指數(shù)(insulin resistance index，HOMA-IR)，HOMA-IR=FBG(mmol/L)×FINS(μU/ml)/22.5。

2 結果

2.1NAFLD組和SO組患者的人體學資料比較兩組患者性別、年齡、BMI、腰圍相比，差異無統(tǒng)計學意義(P>0.05)(見表1)。

表1 NAFLD組和SO組人體學資料比較Tab 1 Comparison of human data between NAFLD group and SO group

2.2NAFLD組和SO組肝臟生化、代謝指標、腎臟指標比較兩組的腎臟生化和早期腎臟損傷指標比較，總體NAFLD組的ALT、AST、FINS、HOMA-IR均升高(P<0.01)，余指標差異無統(tǒng)計學意義(P>0.05)?？傮wNAFLD組的Scr、ACR、β2-MG均升高，eGFR則降低(P<0.05)。余指標差異無統(tǒng)計學意義(P>0.05)(見表2～3)。

表2 NAFLD組和SO組肝臟生化、代謝指標比較Tab 2 Comparison of liver biochemical and metabolic indexes between NAFLD group and SO group

表3 NAFLD組和SO組代謝指標、腎臟指標比較Tab 3 Comparison of metabolic indexes and renal indexes between NAFLD group and SO group

2.3NAFLD組中ACR與各指標相關分析ACR與BMI、腰圍、FBG、FINS、TC、TG、LDL、HOMA-IR呈正相關(P<0.05)，與HDL呈負相關(P<0.01)，HOMA-IR對ACR的影響最大(見表4)。

表4 ACR同NAFLD各項指標的Spearman相關分析Tab 4 Spearman correlation analysis of ACR and NAFLD indicators

3 討論

NAFLD與CKD經(jīng)常合并存在，NAFLD與CKD的相互關系引人注目。2006年TARGHER等[7]最先指出在2型糖尿并NAFLD患者可增加CKD的發(fā)病率。2014年TARGHER等[8]又提出在1型糖尿病患者中NAFLD是CKD發(fā)生、發(fā)展的獨立危險因素。前瞻性研究顯示，NAFLD是CKD高發(fā)的危險因素，TARGHER等[9]對1 760例糖尿病患者隨訪6.5年，經(jīng)過對大量的混雜因素進行校正分析后發(fā)現(xiàn)，脂肪肝與CKD發(fā)病率增加顯著相關。

目前針對NAFLD與CKD的研究主要基于1型和2型糖尿病患者。本研究主要針對性別、年齡基線相同，同時排除糖尿病、高血壓病及腎病史等，健康體檢成人脂肪肝發(fā)生CKD的危險因素。本研究結果顯示，NAFLD組和SO組在BMI、腰圍、TC、TG、HDL、LDL、FBG差異均無統(tǒng)計學意義，但NAFLD組的ACR、β2-MG仍高于SO組，eGFR低于SO組，差異有統(tǒng)計學意義，提示NAFLD與早期腎臟損傷或CKD密切相關，NAFLD可能是早期腎臟損傷或CKD的危險因素。

eGFR、β2-MG是臨床上常用的反映腎功能的良好指標，但當尿微量白蛋白出現(xiàn)異常時，患者eGFR還處于正常范圍，且eGFR的計算復雜，不同情況下使用不同標準。研究[10-13]認為，CKD患者晨尿ACR和24 h尿微量白蛋白定量具有相關性，ACR替代24 h尿微量白蛋白定量來評估腎病患者尿微量白蛋白的排泄情況，預測早期腎臟損傷。本研究ACR與NAFLD相關指標的Spearman相關分析得出，ACR與BMI、腰圍、FBG、FINS、TG、TC、LDL、HOMA-IR呈正相關，其中HOMA-IR對ACR的影響最大，提示伴有IR的NAFLD患者更易發(fā)生早期腎臟損傷或CKD。NAFLD慢性炎性反應可導致IR加重，考慮釋放促炎性因子的釋放，并發(fā)高胰島素血癥，脂聯(lián)素的減少可進一步介導炎性反應及動脈粥樣硬化[14-15]。同時胰島素受體分布于所有腎單位細胞上，故IR可直接作用于腎組織，如內(nèi)皮細胞、足細胞、系膜細胞等，導致蛋白尿、腎間質(zhì)小管損傷及水鈉代謝紊亂，最終誘導CKD的發(fā)生和發(fā)展[16-18]。由此可看出，ACR和HOMA-IR是較Scr、eGFR、β2-MG更敏感檢測早期腎臟損傷的指標，對兩者進行聯(lián)合分析可提高早期腎損傷的診斷率。

對NAFLD進行早期干預，早期發(fā)現(xiàn)腎損傷的潛在危險因素至關重要，可降低CKD患病率，減輕社會產(chǎn)生的經(jīng)濟負擔。 總之，CKD可能是NAFLD最重要的轉(zhuǎn)歸，未來可能需要更多的研究來闡述NAFLD與CKD的關系。

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