• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid-enhanced magnetic resonance imaging for evaluating fibrosis regression in chronic hepatitis C patients after direct-acting antiviral

    2022-06-10 07:59:00XiaoHeLiRuiHuangMingYangJianWangYingHuiGaoQianJinDanLiMaLaiWeiHuiYingRao
    World Journal of Gastroenterology 2022年20期

    Xiao-He Li, Rui Huang, Ming Yang, Jian Wang, Ying-Hui Gao, Qian Jin, Dan-Li Ma, Lai Wei, Hui-Ying Rao

    Abstract

    Key Words: Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid-enhanced magnetic resonance imaging; Contrast enhancement index; Hepatitis C virus; Direct acting antiviral; Sustained virological response; Fibrosis regression

    INTRODUCTION

    Chronic hepatitis C (CHC) remains one of the major etiologies of chronic liver disease, causing substantial morbidity and mortality globally[1 ,2 ]. Remarkably well-tolerated, effective, and short-time direct acting antiviral (DAA) regimens have revolutionized therapy for hepatitis C virus (HCV)infection, achieving a high rate of sustained virological response (SVR). However, it has also been reported that despite achieving SVR, patients may still experience disease progression[3 ,4 ]. It is critical to follow up pathological changes in the liver after DAA therapy. A growing number of studies have focused on the use of non-invasive tests to substitute liver biopsy[5 -7 ]. However, there are few validated thresholds for longitudinal assessment that correspond to histologic changes in fibrosis, and there is no definite non-invasive method for diagnosing the stage changes in fibrosis after SVR.

    Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA; Promovist?in Europe and Eovist?in the United States, Bayer Healthcare, Berlin, Germany) is a liver-specific magnetic resonance imaging (MRI) contrast agent[8 ]. The hepatocyte uptake and biliary excretion of Gd-EOBDTPA mainly take placeviaorganic anion transporting polypeptides OATP1 B1 /3 on the sinusoidal membrane and multidrug resistance-associated proteins MRP2 on the canalicular membrane. Therefore,after intravenous injection, Gd-EOB-DTPA shows extracellular distribution in the dynamic phase and hepatocyte-specific transportation in the hepatobiliary phase (HBP). Decrease in the number of normal hepatocytes and impaired hepatocyte function may reduce the hepatic enhancement of the HBP[9 ]. It has been reported using Gd-EOB-DTPA-enhanced MRI to identify hepatocellular carcinoma[10 ],evaluate liver function[11 ,12 ], stage liver fibrosis[13 ,14 ], and predict liver failure after hepatectomy[15 ].

    To the best of our knowledge, no studies have used Gd-EOB-DTPA-enhanced MRI to evaluate changes in fibrosis after SVR with paired liver biopsy. The primary aim of our study was to evaluate the diagnostic performance of Gd-EOB-DTPA-enhanced MRI in staging liver fibrosis. The secondary aim was to confirm whether this diagnostic test can be used for longitudinal assessment of liver fibrosis in patients with CHC after achieving SVR treated by DAA regimens.

    MATERIALS AND METHODS

    Study design

    Patients with chronic HCV infection treated with DAAs in our hepatology center between January 2014 and December 2016 were prospectively invited to undergo Gd-EOB-DTPA-enhanced MRI and liver biopsy. Patients with qualified Gd-EOB-DTPA-enhanced MRI data and liver biopsy samples were enrolled. The selection of DAA regimens was based on the genotype and state of liver disease. The patients who achieved SVR after DAA therapy underwent the examinations a second time. Exclusion criterias were: (1 ) Non-HCV etiology-related chronic liver disease (such as chronic hepatitis B, drug-or alcohol-related liver disease, non-alcoholic steatohepatitis,etc.); (2 ) Clinical hepatic decompensation; (3 )Solid organ transplantation; (4 ) Malignancy; (5 ) Combined with other systemic disease (immune system disease, blood system disease,etc.) and (6 ) Contraindications for MRI and liver biopsy. SVR was defined as undetectable HCV RNA 24 wk after the end of treatment.

    Liver biopsy was performed within 1 mo before treatment and 3 mo after SVR. MRI was performed prior to liver biopsy within 1 mo. MRI with marked motion artifacts and specimens of liver tissue with lengths < 10 mm or < six portal areas under the microscope were regarded as inappropriate[16 ].Demographic information, virologic data, and laboratory findings were collected.

    MRI protocol

    All liver MRI examinations were performed with a Discover 7503 .0 T MR scanner (GE Healthcare,Milwaukee, WI, United States) using a 32 -channel torso array coil. Patients were in the supine position during horizontal axis scanning and had received prior training on how to breathe. Gd-EOB-DTPA(Promovist?, Bayer Healthcare) was injected intravenously as a contrast agent at a dose of 0 .1 mL/kg body weight with a flow rate of 2 mL/s, followed by a 20 -mL 0 .09 % NaCl flush. Three-dimensional T1 -weighted contrast-enhanced MRI was conducted in the unenhanced phase (UEP), arterial phase (AP, 25 s), portal phase (60 s), and HBP (20 min).

    Image analysis

    The signal intensities (SIs) of the liver parenchyma and paraspinal muscle in the UEP (SIUEP-liverand SIUEP-muscle) and HBP (SIHBP-liverand SIHBP-muscle) were independently measured by two professional radiologists with nearly 4 and 6 years of experience in interpreting abdominal MRIs, using regions of interests (ROIs). The radiologists were blinded to the patients’ clinical data and pathological changes.

    Four ROIs were manually circled (size: 100 -150 mm2 ) in the posterior and anterior segments of the right hepatic lobe and inner and lateral segments of the left hepatic lobe at the hepatic hilar level. The location of the ROIs had to be at the center of each segment, far from the abdominal wall, and avoiding visible blood vessels, bile ducts, and lesions. The ROI of the paraspinal muscle was mainly circled on the left side.

    The contrast enhancement index (CEI) was calculated using the following formula[17 ]:

    CEI = (SIHBP-liver/SIHBP-muscle)/( SIUEP-liver/SIUEP-muscle)

    The change rate in the CEI (ΔCEI%) between pre-treatment (CEIpre) and post-SVR (CEIpost) was calculated as (CEIpost/CEIpre× 100 %).

    Histopathological analysis

    Specimens were fixed in formalin immediately after liver biopsy and embedded in paraffin; 4 -μm-thick sections were cut and stained with hematoxylin and eosin and Masson’s trichrome. Two professional hepato-pathologists, both with nearly 30 years of working experience, assessed the degree and stage of necroinflammation and fibrosis of the specimens using the Ishak scoring system [modified histological activity index (mHAI) and Ishak score][18 ]. The pathologists were blinded to the imaging results and patient clinical data. The stages of liver fibrosis were divided into three groups according to the Ishak score, 0 -2 , 3 -4 , and 5 -6 , respectively. Necro-inflammatory severity was graded according to the mHAI score as 0 -4 , 5 -8 , 9 -12 , and 13 -18 [19 ]. Fibrosis regression was defined as a decrease of at least one point in the Ishak score after SVR[20 ].

    Non-invasive fibrosis measurements

    Experienced technicians conducted liver stiffness measurements (LSMs) with FibroScan (Echosens,Paris, France). An effective result should have a successful rate > 60 % and interquartile range/median ratio ≤ 30 %.

    With respect to serologic biomarkers of fibrosis, the aspartate aminotransferase (AST)-to-platelet ratio(APRI) and Fibrosis-4 (FIB-4 ) were calculated as following:

    APRI = [(AST/ULN)/platelet count (× 109 /L)] × 100 [21 ]; FIB-4 = (age × AST)/[(platelet count) (× 109 /L) × ALT1 /2 ][22 ]

    The change rates in APRI, FIB-4 , and LSM between pre-SVR (valuepre) and post-SVR (valuepost) were calculated similarly with the CEI calculation.

    Statistical analyses

    Descriptive analyses were performed for sociodemographic characteristics (age, sex), clinical data[alanine aminotransferase (ALT), AST, total bilirubin (TB), albumin (Alb), platelet (PLT) count, HCV RNA, genotype, FIB-4 , APRI, LSM, and CEI], histological grading, and staging.

    Descriptive analyses were performed for sociodemographic characteristics, clinical data, histological characteristics, and the CEI. The value of HCV RNA was logarithmically transformed with 10 as the base. Continuous variables are expressed as median (interquartile range) (ALT, AST, TB, PLT, APRI,FIB-4 , and LSM) or mean ± SD [age, Alb, international normalized ratio (INR), HCV RNA, mHAI, and CEI]. Categorical variables (sex, numbers of patients in the different mHAI and Ishak score groups) are presented as counts and percentages. The absolute values of the interclass correlation coefficients (ICC)were measured for SIs to confirm the interobserver reliability between reviewers. Student’s t-test (age,Alb, INR, HCV RNA, mHAI, and CEI) and Mann-Whitney U test (ALT, AST, TB, and PLT) were used to compare continuous variables, and the chi-square test was used for classified variables (sex, HCV genotype). The comparison between pre-and post-SVR was performed with the Wilcoxon sign rank test(ALT, AST, TB, PLT, FIB-4 , APRI, and LSM) and paired sample t-test (Alb, INR, and CEI). Spearman’s correlation coefficient was calculated for the CEI, mHAI, and Ishak score. The predictive value of the CEI, APRI, FIB-4 , and LSM for liver fibrosis was assessed using the area under the receiver operating characteristic curve (AUROC). Sensitivity, specificity, positive predictive value, and negative predictive value were also calculated. An optimal cut-off value was chosen to maximize the Youden index, which is defined as (sensitivity + specificity-1 ). P values < 0 .05 were considered statistically significant.Statistical analyses were performed using IBM SPSS version 26 .0 (IBM Corp., Armonk, NY, United States).

    RESULTS

    Forty-five patients underwent Gd-EOB-DTPA-enhanced MRI and liver biopsy at baseline and six with unqualified samples were excluded. Among the enrolled patients (n= 39 ), six were recommended to receive treatment with DAA plus Peg-IFN, and three had virological breakthrough. Twenty-five patients underwent MRI and liver biopsy again after achieving SVR, and 21 pairs of data were eligible.Therefore, there were 60 qualified and pairable MRI images and liver tissue samples available for analyzing correlation between CEI and liver pathology. The study flow chart is shown in Figure 1 .

    Intraclass correlation coefficients

    Two radiologists interpreted the Gd-EOB-DTPA-enhanced MRI images. The ICC for the measured SI values were excellent (greater than 0 .9 ) for before and after achieving SVR. The ICC of the CEI was 0 .729 (0 .481 , 0 .858 ) and 0 .886 (0 .744 , 0 .952 ) pre and post SVR, respectively. Details of the inter-observer agreements of the ROI measurements and CEI are presented in Supplementary Table 1 .

    Figure 1 The study flow chart. HCV: Hepatitis C virus; Gd-EOD-DTPA: Gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid; MRI: Magnetic resonance imaging; IFN: Interferon; SVR: Sustained virological response.

    Patient characteristics

    The 39 patients enrolled had a mean age of (42 .3 ± 14 .4 ) years, mean HCV RNA of (6 .4 ± 0 .7 ) log10 IU/mL, and 20 (51 .3 %) were male. The distribution of HCV genotypes (GT) was 1 , 2 , 3 , and 6 in 19 (48 .7 %), 4 (10 .3 %), 13 (33 .3 %), and 3 (7 .7 %) patients, respectively. Patients with Ishak score of 5 -6 were elder, had higher ALT and lower PLT levels than those with Ishak scores of 0 -2 (P < 0 .05 ) (Table 1 ).

    Of the 21 patients who achieved SVR and had paired MRI and liver tissue samples, 13 (62 %) received sofosbuvir/ribavirin therapy, and the other eight (38 %) received daclatasvir/asunaprevir regimens. As expected, the values of ALT, AST (P <0 .001 ), and necroinflammation grade (P = 0 .023 ) significantly decreased post SVR (Table 2 ). No significant change in fibrosis stage was observed. Among the noninvasive measurements, the median of LSM, FIB-4 , and APRI decreased significantly, the mean of the CEI increased slightly without statistically significant (P= 0 .29 ) (Table 2 ). After achieving SVR, 7 (33 %) patients achieved fibrosis regression. No patient with Ishak 5 -6 (n = 7 ) achieved fibrosis regression.

    The CEI decreased with the progression of liver fibrosis

    In patients with CHC, the CEI was negatively correlated with the grade of inflammation (r= -0 .56 ,P<0 .001 ) and stage of fibrosis (r = -0 .69 , P < 0 .001 ). The CEI decreased significantly among patients with Ishak scores 0 -2 , 3 -4 , and 5 -6 (1 .78 ± 0 .11 , 1 .64 ± 0 .11 , and 1 .50 ± 0 .09 , respectively, P < 0 .001 )(Figure 2 A). To further analyze the relationship between the CEI and liver pathology, we stratified the patients according to the mHAI (0 -4 , 5 -8 , 9 -12 , and 13 -18 ) and Ishak score (0 -2 , 3 -4 , and 5 -6 ; the numbers of patients in each subgroup are shown in Table 3 ).

    In patients with a mHAI of 0 -4 , the CEI in Group 2 (n = 11 ) was significantly lower than that in Group 1 (n = 14 ) [(1 .67 ± 0 .11 ) vs (1 .79 ± 0 .11 ), P = 0 .021 ] and the CEI of the only patient in Group 3 was 1 .52 (Figure 2 B). When the mHAI was 5 -8 , the CEI decreased in the order of fibrosis Group 1 (n = 3 ), 2 (n= 13 ), and 3 (n = 9 ) at 1 .75 ± 0 .06 , 1 .62 ± 0 .11 , and 1 .49 ± 0 .12 , respectively (P = 0 .032 ) (Figure 2 C). All patients with an mHAI of 13 -18 had liver cirrhosis (n = 9 ), and they were not grouped. In contrast, after subgrouping the patients based on the fibrosis grade, there were no significant differences in the CEI among the inflammation groups (allP> 0 .05 ) (Figure 2 D-F). Therefore, we believe that decrease in the CEI is mainly associated with the progression of fibrosis.

    The CEI is more useful for liver fibrosis diagnosis than the LSM, APRI, and FIB-4

    Table 4 shows a comparison of the predictive values between the CEI and other non-invasive methods.According to the AUROCs and cut-off values, we found that the diagnostic efficacy of the CEI, LSM,APRI, and FIB-4 before and after DAA treatment was similar for liver cirrhosis (Ishak score ≥ 5 ), whilethe cut-off values of serological markers such as the APRI and FIB-4 significantly decreased post SVR.The cut-off value of the LSM also showed a similar trend. For significant fibrosis (Ishak score ≥ 3 ), post SVR, the diagnostic efficacy of the LSM decreased, and the APRI and FIB-4 showed no diagnostic value.

    Table 1 Comparison of demographic and clinical data of patients

    Table 2 Clinical characteristics of patients for pre and post sustained virological response

    Table 3 Distribution of patients in stratified analysis

    Table 4 The area under receiver operating curve and cut-off value for liver cirrhosis and significant liver fibrosis at pre-sustained virological response and post-sustained virological response with contrast enhancement index, aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 and liver stiffness measurement

    Only dynamic change in the CEI can be used to evaluate fibrosis regression after achieving SVR

    Figure 3 shows the change of the CEI and other non-invasive methods in patients with (red column) and without (black column) fibrosis regression. Among the patients with fibrosis regression (n= 7 ), the CEI increased significantly (from 1 .68 ± 0 .09 to 1 .83 ± 0 .18 , P = 0 .043 ) after DAA treatment; similarly, the LSM [from 6 .6 (2 .6 ) to 4 .8 (1 .2 ), P = 0 .018 ] and APRI [from 0 .37 (0 .22 ) to 0 .20 (0 .08 ), P = 0 .018 ] values decreased significantly. For patients who did not achieve fibrosis regression (n= 14 ), only the CEI remained stable (P> 0 .05 ), while the LSM, APRI, and FIB-4 decreased significantly (P < 0 .05 ). It is suggested that the decrease in the latter three noninvasive measurements after treatment may not be related to fibrosis regression. By comparing the change ratios of the four noninvasive indexes before and after treatment, only CEI% changed significantly, and CEI% was moderately positively correlated with fibrosis regression (r= 0 .50 , P = 0 .021 ) (Table 5 ).

    Figure 2 Contrast enhancement index decreased with the progression of liver fibrosis. A: Contrast enhancement index (CEI) decreased with the progression of fibrosis, and there was significant difference between patients with Ishak score 0 -2 , 3 -4 and 5 -6 ; B: In patients with modified histology activity index(mHAI) score of 0 -4 , CEI was lower in patients with Ishak score of 3 -4 compared with 0 -2 ; C: In patients with mHAI score of 5 -8 , CEI decreased with the progression of fibrosis stage; D-F: When the Ishak scores was fixed as 0 -2 , 3 -4 and 5 -6 respectively, the value of CEI was not related to the progression of inflammation. aP <0 .05 ; bP < 0 .001 . CEI: Contrast enhancement index; mHAI: Modified histology activity index.

    DISCUSSION

    In this study, paired liver biopsy and Gd-EOB-DTPA-enhanced MRI data of patients with CHC before and after SVR were reported for the first time. This study concluded that the CEI of Gd-EOB-DTPAenhanced MRI in the HBP decreased with the progression of liver fibrosis. For patients with CHC, the CEI can be used to distinguish among the different stages of liver fibrosis at baseline and after achieving SVR more effectively than the APRI, FIB-4 , and LSM. The change in the CEI between pre and post SVR was related to fibrosis regression. This result increased the options for dynamic assessment of liver fibrosis after achieving SVR.

    In our study, patients treated with DAA plus interferon were excluded. Although the combination therapy may have no effect on the evaluation of liver pathology, based on the current situation of CHC treatment, majority of patients can be cured by simple DAAs. So, we pay more attention on correlation between CEI and pathology changes in patients cured by simple DAAs. It is worth mentioning that,HCV RNA was both detected at 12 - and 24 -wk after the end of treatment. The value of HCV RNA at 12 -wk were also undetectable in patients achieving SVR24 . Since patients were enrolled between 2014 -2016 ,SVR12 and SVR24 both could be used at that time, while the 24 -wk SVR last longer, it was used in our article. We specially agree that the current definition of SVR as an undetectable HCV RNA at 12 wk after the end of treatment.

    In the correlation analysis, we found that the CEI was mild negative related to both grade of inflammation and stage of fibrosis. Further hierarchical analysis showed that the CEI mainly decreased with the progression of liver fibrosis, which was consistent with the results of a previous multiple regression analysis[23 ]. As mentioned above, after achieving SVR, the overall liver fibrosis status was not notably improved, and the CEI also did not change significantly. Therefore, we combined 60 pairs of CEI and liver pathology data before and after treatment for analysis. It should be mentioned that the overall mHAI decreased after treatment, which may have affected the results. However, in our pre-analysis, wefound that in the 21 paired MRI and liver biopsy samples after treatment, the correlation between the mHAI and Ishak score (r= 0 .74 , P < 0 .001 ) remained significant. This may be because the patients with a mHAI > 13 at baseline had liver cirrhosis. After achieving SVR, there was no significant improvement in fibrosis or in the inflammation status. It was also shown that the correlation between the CEI and fibrosis stage remained relatively stable and was not related to the treatment state.

    Table 5 Relationship between the changes of contrast enhancement index, aminotransferase-to-platelet ratio index, Fibrosis-4 , liver stiffness measurement and fibrosis regression

    Figure 3 Comparison of four noninvasive methods before and after sustained virological response between patients with fibrosis regression or not. A: Value of contrast enhancement index; B: Value of liver stiffness measurement; C: Value of aspartate aminotransferase-to-platelet ratio index; D: Value or Fibrosis-4 in patients with (Red column) and without (Black column) fibrosis regression at baseline and after achieving sustained virological response (SVR). Red column: Patients had fibrosis regression after achieving SVR (n = 7 ). Black column: Patients didn’t have fibrosis regression after achieving SVR(n = 14 ). aP < 0 .05 ; bP < 0 .001 . CEI: Contrast enhancement index; SVR: Sustained virological response; LSM: Liver stiffness measurement; APRI: Aspartate aminotransferase-to-platelet ratio index; FIB-4 : Fibrosis-4 .

    In patients with liver cirrhosis (Ishak score 5 -6 ), the diagnostic values of the CEI and of the other noninvasive methods were similar, which was also partly previously reported by a cross-sectional comparative analysis[23 ]. As the inflammatory status improved with antiviral treatment, the cut-off values of the APRI (from 1 .05 to 0 .24 ) and FIB-4 (from 1 .78 to 1 .28 ) both substantially decreased for the same fibrosis status. The serological biomarkers had no diagnostic value for significant fibrosis after HCV eradication, mainly because with the rapid regression of liver necroinflammation, the ALT and AST levels returned to normal, reducing the diagnostic accuracy of serological biomarkers. Although accessible and common, the APRI and FIB-4 may not be suitable for the surveillance of patients with CHC post SVR[21 ,24 ].

    Other than the serological biomarkers, the LSM obtained with TE is currently considered useful for fibrosis monitoring[25 -27 ]. However, several studies have reported a rapid decrease in the LSM mainly related to inflammation regression, and its cut-off values are influenced by liver morphometry. Hence,the decrease in the LSM may be misinterpreted as change in the liver fibrosis stage[6 ,28 ]. A longitudinal study of 2 years showed that following SVR attainment, the improvements in the LSM were overstated compared to histologic staging[28 ]. Therefore, the follow-up value of liver fibrosis regression in patients with HCV SVR needs to be further verified. Our findings strengthened this notion in a relative short follow-up time (median of 6 .2 mo). The cut-off value of the LSM decreased slightly in patients with liver cirrhosis (from 10 .8 kPa to 7 .1 kPa), wherein an LSM value of 7 .1 kPa obtained with TE was defined as the threshold for absence of or minimal fibrosis in patients with CHC[29 ]. The comparative analysis also showed significant decrease in the LSM value in patients without fibrosis regression.

    Apart from the CEI, several studies have reported multiple hepatobiliary liver enhancement indexes of Gd-EOB-DTPA-enhanced MRI, including RE (calculated as [SIHBP-SIUEP]/SIUEPof the liver parenchyma), liver-to-portal vein contrast ratio (calculated by dividing the liver parenchyma SI by the portal vein SI on HBP images), and liver-to-spleen contrast ratio (calculated by dividing the liver parenchyma SI by the spleen SI on HBP images)[30 -32 ]. In previous reports, the signals of the portal vein and spleen were integrated with plasma or extracellular extravascular space exposure to the contrast agent, thus showing that the liver-to-portal vein contrast ratio and liver-to-spleen contrast ratio were more strongly related to liver function than to liver fibrosis[12 ,33 ]. Adjustment of the signal of the paraspinal muscle for SIliveron the same slice was performed to normalize the shimming influences and correct for technical bias. Compared with other organs, SImusclewas more stable and less influenced by age and liver function. Janget al[23 ] also validated this view. A few articles have shown similar diagnostic accuracies for RE and the CEI. In our study, RE was mildly negatively associated with liver inflammation (r= -0 .57 , P = 0 .007 ) and fibrosis (r = -0 .44 , P = 0 .043 ) (unreported), possibly because the SI of the liver after injecting Gd-EOB-DTPA changes, as the window level and width differ in the images[34 ].

    There were several limitations in our study. First, limited by the inclusion criteria, the sample size was small, and the CEI% of patients with fibrosis regression was close to 1 . We will explore further by expanding the sample size. Second, we did not use MR elastography (MRE) or T1 -mapping to predict liver fibrosis, which have a superior diagnostic value in predicting liver fibrosis than Gd-EOB-DTPAenhanced MRI[35 ,36 ]. However, except for the influence of body mass index and ascites on TE, the sequencing method in MRE is not unified, and the threshold value changes across different methods[26 ]. In recent years, MR relaxometry in the form of T1 mapping has been considered promising as a non-invasive method for characterizing hepatic fibrosis using the look-locker technique for measurement. Our patients were enrolled between 2014 and 2016 , when T1 mapping was not in use.Third, although histology is a gold standard procedure, the tissues used in our study were all from liver biopsies rather than from hepatectomy, and there may have been misjudgment regarding the histological changes. Fourth, the mean follow-up duration after achieving SVR was only 6 .2 mo, and a longer follow-up period is warranted.

    CONCLUSION

    In conclusion, the CEI of Gd-EOB-DTPA-enhanced MRI can be used to diagnose liver fibrosis in patients with CHC. The change of the CEI can be used to monitor fibrosis regression post SVR by DAA therapy.

    ARTICLE HIGHLIGHTS

    Research objectives

    To investigated the diagnostic and follow-up values of Gd-EOB-DTPA-enhanced MRI for hepatic histology in patients with CHC. We further explore the value of Gd-EOB-DTPA enhanced MRI in evaluating fibrosis regression in patients with CHC after achieving sustained virological response (SVR)treated by DAAs.

    Research methods

    Chronic HCV infected patients with paired liver biopsy and Gd-EOB-DTPA enhanced MRI before and after DAA treated was included. Contrast enhancement index (CEI) was calculated according with signal intensityviaMRI, and the correlation between CEI and histology change was evaluated. Fibrosis regression was defined as a ≥ 1 -point decrease in the Ishak fibrosis score. The diagnostic and follow-up values of the CEI, liver stiffness measurements (LSM), aminotransferase (AST)-to-platelet ratio (APRI)and Fibrosis-4 (FIB-4 ) were compared.

    Research results

    Thirty-nine patients with CHC were enrolled, with average age of 42 .3 ± 14 .4 years and 20 /39 (51 .3 %)were male. Twenty-one enrolled patients had eligible paired Gd-EOB-DTPA-enhanced MRI and liver tissues after achieving SVR. According to correlation and the hierarchical analysis, the CEI mainly decreased with the progression of liver fibrosis. Compared with LSM, APRI and FIB-4 , the CEI is more useful for liver fibrosis diagnosis, the correlation between the CEI and fibrosis stage was relatively stable and was not related to the treatment state. In paired analysis using liver pathology and CEI before and after treatment, only the dynamic change in the CEI can be used to evaluate fibrosis regression after achieving SVR.

    Research conclusions

    The CEI of Gd-EOB-DTPA-enhanced MRI can be used as a non-invasive method to diagnose liver fibrosis in patients with CHC. The dynamic change of the CEI can be used to monitor fibrosis regression post SVR in patients with CHC after DAA therapy.

    Research perspectives

    Larger and longer-term prospective studies in patients with CHC should be performed in future studies.

    ACKNOWLEDGEMENTS

    We are sincerely grateful to the radiologists Dr. Xiao-Xuan Jia and Dr. Xin-Yu Zhang for their involvement in the MRI analysis. We also thank Prof. Aileen Wee and Guang-De Zhou for their involvement in the liver pathology confirmation. We also thank Hui-Xin Liu, MD, for help with the statistical review.

    FOOTNOTES

    Author contributions:Li XH, Rao HY and Wei L designed the protocol of this study; Li XH, Huang R, Yang M, Wang J, Gao YH, Jin Q and Ma DL collected the data; Li XH analyzed and interpreted the patient data and was major contributors in writing the manuscript; Wei L and Rao HY give advice in study design, statistical analysis and writing the manuscript; All authors read and approved the final manuscript.

    Supported byNational Natural Science Foundation of China, No. 81870406 ; and Nature Science Foundation of Beijing Municipality, No. 7182174 .

    Institutional review board statement:This study was reviewed and approved by the Institutional Review Board of Peking University People’s Hospital (2020 PHB039 -01 ), and the requirement for patient informed consent was waived.

    Informed consent statement:Patients were not required to provide informed consent for this study, as the analysis used anonymous clinical data. The Institutional Review Board of Peking University People’s Hospital approved waiving the requirement for patient informed consent.

    Conflict-of-interest statement:Prof. Rao reports grants from National Natural Science Foundation of China (NSFC),No. 81870406 , and Beijing Natural Science Foundation, No. 7182174 during the conduct of the study.

    Data sharing statement:No additional data are available.

    Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4 .0 ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4 .0 /

    Country/Territory of origin:China

    ORCID number:Xiao-He Li 0000 -0001 -6600 -6067 ; Rui Huang 0000 -0001 -5561 -8746 ; Ming Yang 0000 -0001 -5765 -3844 ; Jian Wang 0000 -0002 -9578 -8288 ; Ying-Hui Gao 0000 -0003 -4532 -3412 ; Qian Jin 0000 -0002 -5213 -8680 ; Dan-Li Ma 0000 -0002 -0936 -6792 ; Lai Wei 0000 -0003 -2326 -1257 ; Hui-Ying Rao 0000 -0003 -2431 -3872 .

    S-Editor:Fan JR

    L-Editor:A

    P-Editor:Chen YX

    久久性视频一级片| 欧美+亚洲+日韩+国产| 18禁国产床啪视频网站| 久久久久国内视频| 成熟少妇高潮喷水视频| 韩国av一区二区三区四区| 少妇粗大呻吟视频| 亚洲精品美女久久久久99蜜臀| 一级片免费观看大全| 国产97色在线日韩免费| 日韩国内少妇激情av| 波多野结衣高清无吗| 免费高清视频大片| 在线观看日韩欧美| 波多野结衣巨乳人妻| 国产一区二区三区视频了| 两个人免费观看高清视频| 国产伦人伦偷精品视频| 人妻久久中文字幕网| 欧美乱码精品一区二区三区| 久久人人精品亚洲av| 久久久国产精品麻豆| 在线观看日韩欧美| 男男h啪啪无遮挡| 不卡一级毛片| 久久久久久国产a免费观看| 亚洲色图 男人天堂 中文字幕| 国产片内射在线| 午夜福利影视在线免费观看| 国产精品久久久av美女十八| 欧美成人性av电影在线观看| 婷婷丁香在线五月| 亚洲av五月六月丁香网| 少妇被粗大的猛进出69影院| 久久天躁狠狠躁夜夜2o2o| 色综合欧美亚洲国产小说| 国产亚洲精品一区二区www| www.自偷自拍.com| 亚洲av日韩精品久久久久久密| 18禁裸乳无遮挡免费网站照片 | 人成视频在线观看免费观看| 亚洲avbb在线观看| 手机成人av网站| 国产一区在线观看成人免费| 久久久久久久久久久久大奶| 欧美大码av| 侵犯人妻中文字幕一二三四区| 一区福利在线观看| 欧美成人性av电影在线观看| 亚洲avbb在线观看| 亚洲人成网站在线播放欧美日韩| 国产精品二区激情视频| av福利片在线| 91在线观看av| av天堂在线播放| 成人免费观看视频高清| aaaaa片日本免费| 成人精品一区二区免费| 久久久久久人人人人人| 一个人免费在线观看的高清视频| 亚洲免费av在线视频| 91九色精品人成在线观看| 国产精品影院久久| 少妇裸体淫交视频免费看高清 | 亚洲激情在线av| 中文字幕色久视频| 美女国产高潮福利片在线看| 欧美午夜高清在线| 禁无遮挡网站| 日日夜夜操网爽| 老司机靠b影院| 亚洲成av片中文字幕在线观看| 1024视频免费在线观看| 色尼玛亚洲综合影院| 9热在线视频观看99| 精品国产一区二区三区四区第35| 高清毛片免费观看视频网站| 国产在线精品亚洲第一网站| 欧美一区二区精品小视频在线| 在线天堂中文资源库| 别揉我奶头~嗯~啊~动态视频| 国产99久久九九免费精品| 女人被躁到高潮嗷嗷叫费观| 精品国产乱码久久久久久男人| 首页视频小说图片口味搜索| 亚洲av五月六月丁香网| 国产私拍福利视频在线观看| 波多野结衣一区麻豆| 欧美最黄视频在线播放免费| 嫩草影视91久久| 国产一区二区在线av高清观看| 日本免费a在线| 在线观看免费午夜福利视频| 亚洲色图综合在线观看| 91成人精品电影| 满18在线观看网站| 久久国产精品人妻蜜桃| 亚洲专区中文字幕在线| 成在线人永久免费视频| 国产麻豆69| 韩国av一区二区三区四区| 在线视频色国产色| 欧美成人一区二区免费高清观看 | 国产精品亚洲美女久久久| 老熟妇仑乱视频hdxx| 国产精品香港三级国产av潘金莲| 免费观看人在逋| 老司机福利观看| 免费无遮挡裸体视频| 1024香蕉在线观看| 国产国语露脸激情在线看| 国产亚洲精品综合一区在线观看 | 国产成人免费无遮挡视频| 侵犯人妻中文字幕一二三四区| 国产av在哪里看| 久久精品影院6| 日本a在线网址| 亚洲免费av在线视频| 午夜福利影视在线免费观看| 午夜福利高清视频| 国产又爽黄色视频| 香蕉国产在线看| 国产99久久九九免费精品| 波多野结衣高清无吗| 国产一区二区在线av高清观看| 波多野结衣一区麻豆| 国产成人精品久久二区二区免费| 亚洲国产精品sss在线观看| а√天堂www在线а√下载| 两人在一起打扑克的视频| 岛国在线观看网站| 老汉色av国产亚洲站长工具| 在线av久久热| 99久久99久久久精品蜜桃| 此物有八面人人有两片| 亚洲国产欧美一区二区综合| 窝窝影院91人妻| 涩涩av久久男人的天堂| 18禁裸乳无遮挡免费网站照片 | 搞女人的毛片| 亚洲精品久久成人aⅴ小说| 亚洲人成电影观看| 精品久久久精品久久久| 亚洲视频免费观看视频| 日本撒尿小便嘘嘘汇集6| 又黄又爽又免费观看的视频| 91精品三级在线观看| 老司机午夜十八禁免费视频| 成年版毛片免费区| 色综合站精品国产| 校园春色视频在线观看| 女人被躁到高潮嗷嗷叫费观| 日韩av在线大香蕉| 午夜免费鲁丝| 久久国产精品男人的天堂亚洲| 欧美成人一区二区免费高清观看 | 久久精品国产亚洲av高清一级| 国产片内射在线| 亚洲成人久久性| 色综合站精品国产| 正在播放国产对白刺激| 婷婷精品国产亚洲av在线| 久久久久久久精品吃奶| 精品一区二区三区av网在线观看| 天天躁狠狠躁夜夜躁狠狠躁| 青草久久国产| 亚洲国产精品合色在线| 久久久久久久午夜电影| 正在播放国产对白刺激| 韩国精品一区二区三区| 变态另类丝袜制服| 国产麻豆69| 手机成人av网站| 涩涩av久久男人的天堂| 亚洲五月天丁香| 99精品在免费线老司机午夜| 久久精品国产亚洲av香蕉五月| 欧美成狂野欧美在线观看| 精品卡一卡二卡四卡免费| 亚洲精品久久成人aⅴ小说| 久9热在线精品视频| av电影中文网址| 丰满的人妻完整版| 欧美黄色淫秽网站| 久久国产精品影院| 免费观看人在逋| 久久人妻av系列| 韩国精品一区二区三区| 午夜免费激情av| 91在线观看av| 男女床上黄色一级片免费看| 国产亚洲欧美精品永久| 伊人久久大香线蕉亚洲五| 99国产精品一区二区蜜桃av| 国产成人免费无遮挡视频| 午夜福利欧美成人| 日本vs欧美在线观看视频| 变态另类成人亚洲欧美熟女 | 又黄又爽又免费观看的视频| 国产精品爽爽va在线观看网站 | 国产激情欧美一区二区| 91成人精品电影| 久久久久久久精品吃奶| 欧美一级a爱片免费观看看 | 男女午夜视频在线观看| 国产色视频综合| 亚洲av成人一区二区三| 国产一卡二卡三卡精品| 欧美一级毛片孕妇| 国产精品影院久久| 国产熟女午夜一区二区三区| 岛国在线观看网站| 亚洲精品粉嫩美女一区| 中文字幕最新亚洲高清| 久久狼人影院| 两人在一起打扑克的视频| 国产视频一区二区在线看| 国产精品自产拍在线观看55亚洲| 多毛熟女@视频| 亚洲中文字幕一区二区三区有码在线看 | 久久精品国产99精品国产亚洲性色 | 国产精品久久久人人做人人爽| 国产欧美日韩综合在线一区二区| 国产亚洲av高清不卡| 国产成人精品在线电影| 国产成人av激情在线播放| 免费少妇av软件| 欧美人与性动交α欧美精品济南到| 欧美国产精品va在线观看不卡| 欧美黑人欧美精品刺激| 成人18禁在线播放| av中文乱码字幕在线| 亚洲人成电影观看| 国产乱人伦免费视频| 女性生殖器流出的白浆| 人人澡人人妻人| 国产xxxxx性猛交| 午夜精品久久久久久毛片777| 成人国产综合亚洲| 少妇裸体淫交视频免费看高清 | 亚洲一卡2卡3卡4卡5卡精品中文| 精品不卡国产一区二区三区| 免费观看人在逋| 免费观看精品视频网站| 久久天堂一区二区三区四区| 成熟少妇高潮喷水视频| 无遮挡黄片免费观看| 波多野结衣一区麻豆| 手机成人av网站| 露出奶头的视频| 久久影院123| 日本欧美视频一区| 欧美丝袜亚洲另类 | 美女 人体艺术 gogo| 亚洲专区国产一区二区| 亚洲av熟女| 精品久久久久久久人妻蜜臀av | 亚洲成国产人片在线观看| 黄色 视频免费看| 高清黄色对白视频在线免费看| 一区二区三区国产精品乱码| 亚洲第一青青草原| 国产高清videossex| 村上凉子中文字幕在线| 亚洲欧美激情综合另类| 老司机靠b影院| 色精品久久人妻99蜜桃| 中文字幕精品免费在线观看视频| 亚洲性夜色夜夜综合| 国产精品一区二区在线不卡| 精品人妻在线不人妻| 美女 人体艺术 gogo| 动漫黄色视频在线观看| 在线观看午夜福利视频| 亚洲精品一卡2卡三卡4卡5卡| 日韩欧美免费精品| 9191精品国产免费久久| 淫秽高清视频在线观看| 亚洲在线自拍视频| 国产91精品成人一区二区三区| 狂野欧美激情性xxxx| www.自偷自拍.com| 国产国语露脸激情在线看| 日本黄色视频三级网站网址| 18禁裸乳无遮挡免费网站照片 | 色哟哟哟哟哟哟| 一级,二级,三级黄色视频| 国产免费男女视频| 久久中文字幕一级| 精品高清国产在线一区| 琪琪午夜伦伦电影理论片6080| xxx96com| 亚洲男人天堂网一区| 国产精品 欧美亚洲| 国产成人系列免费观看| 国产97色在线日韩免费| 人人妻人人澡欧美一区二区 | 搡老岳熟女国产| 很黄的视频免费| 12—13女人毛片做爰片一| www.www免费av| 亚洲午夜精品一区,二区,三区| 久久中文字幕一级| 国产亚洲精品一区二区www| av有码第一页| 日日摸夜夜添夜夜添小说| 亚洲男人天堂网一区| 高清在线国产一区| 一a级毛片在线观看| 十分钟在线观看高清视频www| 亚洲专区中文字幕在线| 国产极品粉嫩免费观看在线| 99久久久亚洲精品蜜臀av| 这个男人来自地球电影免费观看| 麻豆成人av在线观看| 亚洲黑人精品在线| 国产乱人伦免费视频| 亚洲七黄色美女视频| 91九色精品人成在线观看| 视频区欧美日本亚洲| 午夜免费鲁丝| 国产欧美日韩精品亚洲av| 亚洲精品国产色婷婷电影| av欧美777| 久久久久国产一级毛片高清牌| 乱人伦中国视频| 欧美日韩福利视频一区二区| ponron亚洲| 国产色视频综合| 亚洲欧美激情在线| 禁无遮挡网站| 999精品在线视频| 在线观看免费日韩欧美大片| 在线观看www视频免费| 麻豆av在线久日| 97人妻天天添夜夜摸| 亚洲av熟女| 99国产精品一区二区三区| 国内毛片毛片毛片毛片毛片| 亚洲自偷自拍图片 自拍| av在线天堂中文字幕| 麻豆一二三区av精品| 亚洲熟妇中文字幕五十中出| 欧美最黄视频在线播放免费| 亚洲精品国产精品久久久不卡| 我的亚洲天堂| 亚洲精品粉嫩美女一区| 精品高清国产在线一区| 天天添夜夜摸| 亚洲专区字幕在线| 欧美成人性av电影在线观看| 成年版毛片免费区| 免费看十八禁软件| 亚洲电影在线观看av| 桃红色精品国产亚洲av| 精品一区二区三区视频在线观看免费| 在线观看免费日韩欧美大片| 亚洲精品在线美女| 精品欧美国产一区二区三| 夜夜看夜夜爽夜夜摸| 日韩大码丰满熟妇| 两性午夜刺激爽爽歪歪视频在线观看 | 动漫黄色视频在线观看| 真人一进一出gif抽搐免费| 国产亚洲精品久久久久久毛片| 久久亚洲真实| 国语自产精品视频在线第100页| 两个人视频免费观看高清| 在线十欧美十亚洲十日本专区| 成在线人永久免费视频| 热re99久久国产66热| 国产精品爽爽va在线观看网站 | 757午夜福利合集在线观看| 日本a在线网址| 不卡av一区二区三区| 搡老妇女老女人老熟妇| 少妇熟女aⅴ在线视频| 一夜夜www| 色婷婷久久久亚洲欧美| 一级,二级,三级黄色视频| 亚洲专区国产一区二区| 青草久久国产| 午夜精品国产一区二区电影| 欧美日韩福利视频一区二区| 亚洲精品在线观看二区| www国产在线视频色| 一级a爱片免费观看的视频| 自拍欧美九色日韩亚洲蝌蚪91| 啦啦啦免费观看视频1| 国产亚洲欧美精品永久| 一进一出好大好爽视频| 精品国产乱子伦一区二区三区| 99国产精品免费福利视频| 免费观看精品视频网站| 亚洲人成77777在线视频| 精品久久久精品久久久| 国产成人精品无人区| 97人妻天天添夜夜摸| 18美女黄网站色大片免费观看| 国产亚洲av高清不卡| 青草久久国产| 999久久久国产精品视频| 国产精品秋霞免费鲁丝片| www.自偷自拍.com| 狂野欧美激情性xxxx| 国产又色又爽无遮挡免费看| 午夜久久久久精精品| 99精品欧美一区二区三区四区| 高潮久久久久久久久久久不卡| 国产午夜精品久久久久久| 午夜日韩欧美国产| 搡老妇女老女人老熟妇| 欧美最新免费一区二区三区| 久久九九热精品免费| 亚洲成人久久性| 国产麻豆成人av免费视频| 99国产极品粉嫩在线观看| 又爽又黄无遮挡网站| 少妇被粗大猛烈的视频| 乱码一卡2卡4卡精品| 亚洲熟妇中文字幕五十中出| 18+在线观看网站| 我要搜黄色片| 亚洲精品一卡2卡三卡4卡5卡| 国产成人影院久久av| 国产精品一区二区性色av| 亚洲人与动物交配视频| 国产真实伦视频高清在线观看 | 免费高清视频大片| 在线播放无遮挡| 亚洲av第一区精品v没综合| h日本视频在线播放| 国产成人影院久久av| 免费在线观看影片大全网站| 亚洲欧美激情综合另类| 男人舔女人下体高潮全视频| 又黄又爽又刺激的免费视频.| 波多野结衣高清作品| 成人精品一区二区免费| 在线观看美女被高潮喷水网站| 黄色一级大片看看| 国产亚洲精品久久久com| 999久久久精品免费观看国产| 国产美女午夜福利| 亚洲精品成人久久久久久| 亚洲国产精品久久男人天堂| 十八禁网站免费在线| 久久久久久久亚洲中文字幕| 狂野欧美激情性xxxx在线观看| 日韩国内少妇激情av| 久久午夜福利片| 我的老师免费观看完整版| 99热6这里只有精品| 97人妻精品一区二区三区麻豆| 内地一区二区视频在线| 国产乱人伦免费视频| 啪啪无遮挡十八禁网站| 欧美三级亚洲精品| 非洲黑人性xxxx精品又粗又长| 久久人人精品亚洲av| 九九爱精品视频在线观看| 久久精品国产清高在天天线| 国产av麻豆久久久久久久| av在线天堂中文字幕| 伦理电影大哥的女人| 久久九九热精品免费| 国产三级中文精品| 精品久久久久久成人av| 国产高清视频在线观看网站| 日韩在线高清观看一区二区三区 | 18+在线观看网站| 狠狠狠狠99中文字幕| 熟女电影av网| 国内精品久久久久久久电影| 日韩中字成人| 又黄又爽又刺激的免费视频.| 欧美日韩中文字幕国产精品一区二区三区| 搞女人的毛片| 男人的好看免费观看在线视频| 91午夜精品亚洲一区二区三区 | 男人舔奶头视频| 乱系列少妇在线播放| 成人毛片a级毛片在线播放| 成人性生交大片免费视频hd| 亚洲国产精品sss在线观看| 久久久久精品国产欧美久久久| 国产黄a三级三级三级人| 色5月婷婷丁香| 色精品久久人妻99蜜桃| 在线观看av片永久免费下载| 色av中文字幕| 国产av不卡久久| 久久精品国产亚洲av涩爱 | 免费人成视频x8x8入口观看| 我的老师免费观看完整版| 国产69精品久久久久777片| 丰满的人妻完整版| 小蜜桃在线观看免费完整版高清| 色播亚洲综合网| 永久网站在线| 久久精品国产99精品国产亚洲性色| 亚洲综合色惰| 中文字幕av在线有码专区| 色播亚洲综合网| 日韩欧美 国产精品| 蜜桃亚洲精品一区二区三区| 亚洲自偷自拍三级| 国产免费男女视频| 国产亚洲精品久久久com| 国产三级在线视频| 中文字幕人妻熟人妻熟丝袜美| 九九热线精品视视频播放| 成年版毛片免费区| 麻豆成人午夜福利视频| 少妇被粗大猛烈的视频| 联通29元200g的流量卡| 成人午夜高清在线视频| 12—13女人毛片做爰片一| 99久国产av精品| 亚洲18禁久久av| 国产精品99久久久久久久久| 给我免费播放毛片高清在线观看| 亚洲精品一区av在线观看| av黄色大香蕉| av在线天堂中文字幕| 熟女电影av网| 美女高潮的动态| 精品乱码久久久久久99久播| 亚洲,欧美,日韩| 春色校园在线视频观看| 亚洲成人精品中文字幕电影| 国产精品一区二区免费欧美| 国产伦人伦偷精品视频| 色哟哟哟哟哟哟| 极品教师在线视频| 九色成人免费人妻av| 国产精品国产高清国产av| 午夜免费激情av| 日本五十路高清| 乱码一卡2卡4卡精品| 精品久久久久久久久av| 伊人久久精品亚洲午夜| 一本一本综合久久| 精品久久久久久久久亚洲 | 极品教师在线免费播放| 国产精品久久久久久久电影| 欧美中文日本在线观看视频| 欧美精品国产亚洲| 99久久九九国产精品国产免费| 国产美女午夜福利| 国产精品久久久久久精品电影| 在线播放无遮挡| 美女cb高潮喷水在线观看| 精品久久久久久,| 国内精品久久久久精免费| av视频在线观看入口| 动漫黄色视频在线观看| 又爽又黄无遮挡网站| 免费高清视频大片| 国产免费男女视频| 在现免费观看毛片| 久久精品久久久久久噜噜老黄 | 欧美一区二区亚洲| 一区二区三区激情视频| 男人狂女人下面高潮的视频| 国产亚洲91精品色在线| 黄色配什么色好看| 51国产日韩欧美| 91麻豆精品激情在线观看国产| 国产成人一区二区在线| 99在线视频只有这里精品首页| 国内揄拍国产精品人妻在线| 国产精品人妻久久久久久| 久久久久九九精品影院| 搡老岳熟女国产| 日日摸夜夜添夜夜添小说| 午夜福利在线观看吧| 亚洲真实伦在线观看| 亚洲在线自拍视频| 亚洲国产精品成人综合色| 久久热精品热| 亚洲欧美精品综合久久99| 国产精品三级大全| 国产视频一区二区在线看| 国产单亲对白刺激| 麻豆国产97在线/欧美| 一级黄色大片毛片| 欧美中文日本在线观看视频| 国产成人福利小说| 国产高清不卡午夜福利| 久久精品国产99精品国产亚洲性色| 99在线人妻在线中文字幕| 婷婷精品国产亚洲av| 色视频www国产| 99在线人妻在线中文字幕| 国产精品乱码一区二三区的特点| 简卡轻食公司| 亚洲av.av天堂| 天天一区二区日本电影三级| 欧美xxxx性猛交bbbb| 免费电影在线观看免费观看| 国内精品一区二区在线观看| 99热6这里只有精品| 精品午夜福利在线看| 国产黄片美女视频| 欧美丝袜亚洲另类 | 亚洲,欧美,日韩| 国产人妻一区二区三区在| 日日撸夜夜添| 人妻制服诱惑在线中文字幕| 精品无人区乱码1区二区| 天堂动漫精品| 亚洲经典国产精华液单| 欧美3d第一页| 久久久久久国产a免费观看|