肝脏质子密度脂肪分数直方图参数评估肝纤维化对肝脂肪变性影响的实验研究

Effect of hepatic fibrosis on proton density fat fraction based on histogram analysis in evaluating hepatic steatosis: an experimental study

目的探讨肝脏质子密度脂肪分数(PDFF)直方图参数评估实验兔肝脂肪变性和纤维化程度的价值,以及肝纤维化对PDFF直方图参数评价肝脂肪变性效能的影响。方法2020年3月至12月,选取135只新西兰大白兔,采用随机数表法将实验兔分为对照组(30只)、实验组(105只)。将CCl4和橄榄油按体积比1∶1配成50%CCl4油溶液,实验组连续皮下注射;对照组皮下注射等剂量生理盐水。实验组及对照组在第4、8、12周末采用随机数表法分别随机选取35只、10只进行三维多回波mDixon-Quant扫描。选择全肝组织为感兴趣区进行PDFF直方图分析,提取直方图参数,包括体积、平均值、中位值、标准差、第25、50、75、90百分位数(20^(th)、50^(th)、75^(th)、90^(th))、峰值、偏度、熵值、异质性。扫描后即刻处死实验兔,获得肝组织病理学脂肪分数(PSH)和纤维沉积分数(POF),并以中位数为界分为轻度肝脂肪变性组(61只)、中重度肝脂肪变性组(64只)和轻度肝纤维化组(63只)、中重度肝纤维化组(62只)。采用Spearman相关性分析用于评价PDFF直方图参数与PSH、与POF相关性;多重线性回归分析筛选评估PSH及POF的独立PDFF直方图参数。以受试者操作特征(ROC)曲线分析PDFF直方图参数评估轻度与中重度肝脂肪变性和肝纤维化的效能。在存在肝纤维化的实验兔中(POF>0,96只),对肝纤维化进行校正,比较校正前后最优参数评估轻度与中重度肝脂肪变性的曲线下面积(AUC),AUC的比较采用DeLong检验。结果125只实验兔纳入本研究。PDFF平均值、中位值、标准差、75^(th)、90^(th)、PSH、熵值与PSH有相关性(r=0.558、0.522、0.319、0.723、0.646、-0.589,P均<0.05)。PDFF 75^(th)及熵值为评估PSH的独立参数(β=2.347、-5.960,P=0.018、0.001)。PDFF 75^(th)评价肝脂肪变性的AUC最大,为0.915(P=0.001)。PDFF体积、平均值、中位值、标准差、75^(th)、90^(th)、熵值与POF有相关性(r=0.355、0.393、0.376、0.298、0.485、0.426、-0.681,P均<0.05)。熵值、标准差及肝体积为评估POF的独立参数(β=-11.041、1.356、0.190,P=0.001、0.026、0.016)。PDFF熵值鉴别肝纤维化AUC最大,为0.771(P=0.001)。肝纤维化组与非肝纤维化组中,PDFF 75^(th)与PSH相关系数分别为0.512(P=0.001)和0.751(P=0.002);在肝纤维化实验兔中,评估肝脂肪变性的AUC分别为0.895、0.950,差异有统计学意义(Z=2.970,P=0.025)。结论肝脏PDFF直方图分析可用于实验兔肝脂肪变性及肝纤维化评估,肝纤维化的存在降低了PDFF 75^(th)评价肝脂肪变性的效能。

Objective To explore the value of proton density fat fraction(PDFF)based on histogram analysis for quantification hepatic steatosis and fibrosis in rabbit model and the interference of hepatic fibrosis to the evaluation of hepatic steatosis with PDFF.Methods From March to November 2020,135 New Zealand white rabbits were randomly divided into control group(n=30)and experimental group(n=105)using a random number table.The volume ratio of CCl4 and olive oil was 1∶1 to prepare 50%CCl4 oil solution,and experimental rabbits were subcutaneously injected with the oil solution.An equal dose of normal saline was subcutaneously injected for control group rabbits.At the end of the 4th,8th,and 12th week,35 in the experimental group and 10 rabbits in the control group were randomly selected to conduct the mDixon-Quant scanning,and histogram analysis of PDFF was analyzed including volume,mean,median,standard deviation,25^(th),50^(th),75^(th),90^(th) quantile,skewness,kurtosis,entropy and inhomogeneity.After the examination,the rabbits were sacrificed and the liver percentage of steatosis(PSH)and fibrosis(POF)were recorded by semi-quantitative analysis.Spearman correlation analysis was used to correlate PDFF with PSH and POF.Multiple linear regression analysis was used to determine independent PDFF histogram parameters for evaluating PSH and POF.A receiver operator characteristic(ROC)curve was used to assess the diagnostic accuracy of PDFF for discriminating mild from moderate-severe hepatic steatosis and mild from moderate-severe hepatic fibrosis with median of PSH or POF for dichotomy,and DeLong test was used to compare the area under the curve(AUC).With the correction of hepatic fibrosis,correlation coefficient and AUC were compared of PDFF for discrimination mild from moderate-severe hepatic steatosis.Results The PDFF mean,median,standard deviation,75^(th),90^(th) showed correlation with PSH(r=0.558,0.522,0.319,0.723,0.646,-0.589,all P<0.05).The entropy and 75^(th) were independent parameters for evaluating PSH(β=2.347,-5.960,P=0.018,0.001).The PDFF 75^(th) was the optimal parameter for discriminating mild from moderate-severe hepatic steatosis with AUC=0.915(P=0.001).The PDFF volume,mean,median,standard deviation,75^(th),90^(th),entropy showed correlation with POF(r=0.355,0.393,0.376,0.298,0.485,0.426,-0.681,all P<0.05).The entropy,standard deviation and volume(β=-11.041,1.356,0.190,P=0.001,0.026,0.016)were independent parameters for evaluation of hepatic fibrosis,and the entropy was the optimal parameter for hepatic fibrosis(AUC=0.771,P=0.001).The correlation between PSH and PDFF 75^(th) was less pronounced when fibrosis was present(r=0.512,P=0.001)than when fibrosis was absent(r=0.751,P=0.002).The PDFF 75^(th) showed a significant difference in discriminating mild hepatic steatosis from moderate-severe hepatic steatosis after correction of POF(AUC=0.895,0.950,Z=2.970,P=0.025).Conclusions PDFF based on histogram analysis provided a noninvasive,accurate estimation of quantification for hepatic steatosis and fibrosis.Hepatic fibrosis reduced the correlation between hepatic steatosis and PDFF and the presence of hepatic fibrosis can confound the quantification of hepatic steatosis with PDFF.