• <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

    日韩三级伦理在线观看| 精品久久久久久久久av| 国产 一区精品| 婷婷色麻豆天堂久久| 在线天堂最新版资源| 国产高清不卡午夜福利| 亚洲中文av在线| 亚洲欧美日韩东京热| 国产毛片在线视频| 人妻 亚洲 视频| 熟妇人妻不卡中文字幕| 国产亚洲一区二区精品| 一本一本综合久久| 日韩免费高清中文字幕av| 免费观看无遮挡的男女| 日日爽夜夜爽网站| 91精品国产国语对白视频| 亚洲,一卡二卡三卡| 欧美日韩视频高清一区二区三区二| 国产日韩一区二区三区精品不卡 | 国产欧美日韩精品一区二区| 夜夜爽夜夜爽视频| 国产日韩欧美亚洲二区| 丝瓜视频免费看黄片| 欧美成人午夜免费资源| 老熟女久久久| 久久精品国产鲁丝片午夜精品| 乱人伦中国视频| av在线app专区| 午夜影院在线不卡| 一个人免费看片子| 免费黄频网站在线观看国产| 亚洲第一av免费看| 男人添女人高潮全过程视频| 日韩视频在线欧美| 精品视频人人做人人爽| av视频免费观看在线观看| 精品视频人人做人人爽| 两个人免费观看高清视频 | 日韩中文字幕视频在线看片| 七月丁香在线播放| 亚洲经典国产精华液单| 久久女婷五月综合色啪小说| 国产一区二区三区综合在线观看 | 亚洲va在线va天堂va国产| 99久国产av精品国产电影| 老司机亚洲免费影院| 亚洲国产色片| 黄色视频在线播放观看不卡| 日韩 亚洲 欧美在线| 国产视频内射| 嘟嘟电影网在线观看| 亚洲精品456在线播放app| 色视频www国产| 美女视频免费永久观看网站| 欧美成人精品欧美一级黄| 丝瓜视频免费看黄片| 国产亚洲av片在线观看秒播厂| 久久精品国产亚洲av天美| 观看免费一级毛片| 青春草视频在线免费观看| 亚洲无线观看免费| 国产免费又黄又爽又色| 国产伦精品一区二区三区四那| 国产成人午夜福利电影在线观看| 亚洲,欧美,日韩| 国产伦在线观看视频一区| 秋霞伦理黄片| 国产伦精品一区二区三区四那| 国产精品99久久久久久久久| 亚洲成色77777| 全区人妻精品视频| 国产免费一级a男人的天堂| 日韩av在线免费看完整版不卡| 亚洲精品自拍成人| 国产黄色免费在线视频| freevideosex欧美| 欧美日本中文国产一区发布| 久久久久久久久久人人人人人人| 国产女主播在线喷水免费视频网站| 国产永久视频网站| 极品教师在线视频| 欧美3d第一页| 国产欧美日韩一区二区三区在线 | 涩涩av久久男人的天堂| 欧美精品高潮呻吟av久久| 人人妻人人看人人澡| 亚洲中文av在线| 我的老师免费观看完整版| 一区在线观看完整版| 久久久久久久久大av| 久久ye,这里只有精品| 在线观看免费高清a一片| 日韩亚洲欧美综合| 色视频www国产| 免费看日本二区| 国产日韩欧美在线精品| 久久鲁丝午夜福利片| 国产av精品麻豆| av在线观看视频网站免费| 草草在线视频免费看| 九色成人免费人妻av| 国产精品女同一区二区软件| 成人无遮挡网站| 老司机影院成人| 蜜桃久久精品国产亚洲av| 国产日韩欧美在线精品| 在线精品无人区一区二区三| 熟女电影av网| 91aial.com中文字幕在线观看| 亚洲av成人精品一二三区| 国产精品欧美亚洲77777| 天美传媒精品一区二区| 嫩草影院新地址| 亚洲精品日本国产第一区| 欧美日韩亚洲高清精品| 99热这里只有是精品50| 亚洲精品一二三| 免费av不卡在线播放| 国内少妇人妻偷人精品xxx网站| 99热国产这里只有精品6| 久久久精品94久久精品| 99久久精品国产国产毛片| 人妻系列 视频| 99热这里只有是精品50| 久久久久久久久久成人| 在线看a的网站| 26uuu在线亚洲综合色| 久久久精品94久久精品| 亚洲综合精品二区| 亚洲精品中文字幕在线视频 | .国产精品久久| 国产成人精品久久久久久| 精品久久久久久久久亚洲| 欧美国产精品一级二级三级 | 波野结衣二区三区在线| 国产真实伦视频高清在线观看| 亚洲精品乱久久久久久| 少妇裸体淫交视频免费看高清| 好男人视频免费观看在线| 嘟嘟电影网在线观看| 青春草视频在线免费观看| 国产精品.久久久| 伊人亚洲综合成人网| 国产一区二区在线观看日韩| 中文精品一卡2卡3卡4更新| 亚洲,一卡二卡三卡| 国产淫片久久久久久久久| 色视频www国产| 精品视频人人做人人爽| 国产一区二区三区综合在线观看 | 水蜜桃什么品种好| 亚洲精品国产av蜜桃| 久久久精品免费免费高清| h日本视频在线播放| 在线观看av片永久免费下载| 国产精品秋霞免费鲁丝片| 国产精品一区二区在线不卡| 国产精品嫩草影院av在线观看| 久久久久久久亚洲中文字幕| 久久久久国产网址| 汤姆久久久久久久影院中文字幕| 久久久久视频综合| 国语对白做爰xxxⅹ性视频网站| 亚洲av综合色区一区| 最近的中文字幕免费完整| 美女cb高潮喷水在线观看| 热re99久久精品国产66热6| 国产精品麻豆人妻色哟哟久久| 女性生殖器流出的白浆| 国产精品偷伦视频观看了| 九色成人免费人妻av| 亚洲高清免费不卡视频| 欧美3d第一页| 国产欧美日韩精品一区二区| 久久韩国三级中文字幕| 亚洲,一卡二卡三卡| 国产 精品1| 国产日韩欧美亚洲二区| 一个人看视频在线观看www免费| 欧美三级亚洲精品| 日韩中字成人| 日韩强制内射视频| 老司机影院成人| 高清毛片免费看| 国产伦理片在线播放av一区| 亚洲精品aⅴ在线观看| 色婷婷av一区二区三区视频| 亚洲欧美日韩卡通动漫| 在线免费观看不下载黄p国产| 欧美精品高潮呻吟av久久| 三级经典国产精品| 欧美日韩视频精品一区| 18禁在线播放成人免费| 色婷婷久久久亚洲欧美| 乱人伦中国视频| 女人久久www免费人成看片| 免费人妻精品一区二区三区视频| 久久久久人妻精品一区果冻| 亚洲欧美一区二区三区国产| 大又大粗又爽又黄少妇毛片口| 夜夜看夜夜爽夜夜摸| 亚洲av成人精品一二三区| 美女福利国产在线| 国产精品伦人一区二区| 亚洲,欧美,日韩| 亚洲天堂av无毛| 国产精品一区二区在线不卡| 免费黄网站久久成人精品| 午夜免费观看性视频| 国产精品一区二区在线观看99| 国产熟女午夜一区二区三区 | 黑人高潮一二区| 午夜91福利影院| 国产爽快片一区二区三区| 日韩在线高清观看一区二区三区| 日本黄大片高清| 色婷婷av一区二区三区视频| 一区二区三区四区激情视频| 在线免费观看不下载黄p国产| 亚洲av成人精品一区久久| 国产黄片美女视频| 在线观看免费日韩欧美大片 | 国产精品三级大全| 日韩免费高清中文字幕av| 精品99又大又爽又粗少妇毛片| 不卡视频在线观看欧美| av福利片在线| 成人18禁高潮啪啪吃奶动态图 | 天美传媒精品一区二区| 韩国高清视频一区二区三区| 日韩一区二区视频免费看| 永久网站在线| 成人国产av品久久久| 久久人人爽人人片av| 久久精品国产亚洲av天美| 欧美激情极品国产一区二区三区 | 女性被躁到高潮视频| 国产无遮挡羞羞视频在线观看| 国产伦在线观看视频一区| 国产亚洲5aaaaa淫片| 国产亚洲最大av| 一本大道久久a久久精品| 国产日韩欧美在线精品| 国产成人精品久久久久久| 最近最新中文字幕免费大全7| 一区二区三区免费毛片| 老熟女久久久| 国产男女超爽视频在线观看| 少妇丰满av| 少妇猛男粗大的猛烈进出视频| 九九爱精品视频在线观看| 久久久久国产网址| 99热国产这里只有精品6| 久久人人爽av亚洲精品天堂| 久久99热6这里只有精品| 成人午夜精彩视频在线观看| 纵有疾风起免费观看全集完整版| 日韩大片免费观看网站| 国产成人免费无遮挡视频| a级毛色黄片| 国产成人一区二区在线| 久久99精品国语久久久| 成人漫画全彩无遮挡| 国产精品国产三级国产专区5o| 久久毛片免费看一区二区三区| 男女边摸边吃奶| 亚洲,一卡二卡三卡| 秋霞在线观看毛片| 亚洲精华国产精华液的使用体验| 成人毛片a级毛片在线播放| 汤姆久久久久久久影院中文字幕| 亚洲国产欧美在线一区| 亚洲av免费高清在线观看| 国产日韩欧美在线精品| 久久99一区二区三区| 亚洲精品国产成人久久av| 亚洲精品第二区| 18+在线观看网站| 中文欧美无线码| 久久精品久久精品一区二区三区| 天堂俺去俺来也www色官网| 亚洲性久久影院| 欧美bdsm另类| 日韩欧美精品免费久久| 少妇精品久久久久久久| 你懂的网址亚洲精品在线观看| 一边亲一边摸免费视频| 日韩亚洲欧美综合| 精品视频人人做人人爽| 这个男人来自地球电影免费观看 | 少妇精品久久久久久久| 成年美女黄网站色视频大全免费 | 少妇的逼好多水| 日韩 亚洲 欧美在线| 国产在线男女| 久久久午夜欧美精品| 午夜久久久在线观看| 中文字幕精品免费在线观看视频 | 视频中文字幕在线观看| 美女视频免费永久观看网站| av天堂中文字幕网| 久久久国产一区二区| 麻豆乱淫一区二区| 日日摸夜夜添夜夜添av毛片| 深夜a级毛片| 天堂8中文在线网| 亚洲不卡免费看| 国产有黄有色有爽视频| 亚洲av福利一区| 一本一本综合久久| 人妻 亚洲 视频| 国产真实伦视频高清在线观看| 在线观看美女被高潮喷水网站| 热99国产精品久久久久久7| 蜜桃久久精品国产亚洲av| 女性生殖器流出的白浆| 极品人妻少妇av视频| 男人和女人高潮做爰伦理| av视频免费观看在线观看| 69精品国产乱码久久久| 亚洲综合精品二区| av专区在线播放| 亚洲精品久久久久久婷婷小说| 人人妻人人添人人爽欧美一区卜| 久久精品国产亚洲av天美| 成年美女黄网站色视频大全免费 | 免费av中文字幕在线| 麻豆精品久久久久久蜜桃| 欧美高清成人免费视频www| av福利片在线| 午夜老司机福利剧场| 又爽又黄a免费视频| h日本视频在线播放| 国产成人免费观看mmmm| 欧美日韩av久久| 国产精品人妻久久久久久| 亚洲欧美精品专区久久| 18禁在线播放成人免费| videos熟女内射| 国产成人精品无人区| 久久精品久久精品一区二区三区| 久久久a久久爽久久v久久| 欧美精品人与动牲交sv欧美| 中国国产av一级| 亚洲av在线观看美女高潮| a级片在线免费高清观看视频| 久久免费观看电影| av又黄又爽大尺度在线免费看| 成人二区视频| 美女脱内裤让男人舔精品视频| 亚洲国产精品专区欧美| 国产成人aa在线观看| 人人妻人人爽人人添夜夜欢视频 | 高清不卡的av网站| 久热久热在线精品观看| 女性生殖器流出的白浆| 亚洲怡红院男人天堂| 在线 av 中文字幕| 久久这里有精品视频免费| av免费观看日本| 久久国内精品自在自线图片| 一个人免费看片子| 只有这里有精品99| 久久 成人 亚洲| 亚洲av成人精品一区久久| 精品人妻偷拍中文字幕| 91在线精品国自产拍蜜月| 97在线人人人人妻| 男女边摸边吃奶| 嫩草影院入口| 在线观看免费视频网站a站| 久久国产乱子免费精品| 夜夜骑夜夜射夜夜干| 蜜桃在线观看..| 色婷婷av一区二区三区视频| 欧美精品亚洲一区二区| 成人亚洲精品一区在线观看| 亚洲精品色激情综合| 在线观看www视频免费| 女人久久www免费人成看片| av又黄又爽大尺度在线免费看| a 毛片基地| 少妇高潮的动态图| 18禁裸乳无遮挡动漫免费视频| 国产精品国产三级国产专区5o| 黄色一级大片看看| 爱豆传媒免费全集在线观看| 一级黄片播放器| 精品国产一区二区三区久久久樱花| 欧美少妇被猛烈插入视频| 99久久人妻综合| 国产成人精品无人区| 国精品久久久久久国模美| av线在线观看网站| 久久久久久久久久久久大奶| 久久影院123| 国产乱人偷精品视频| 这个男人来自地球电影免费观看 | 丝袜喷水一区| 成人毛片a级毛片在线播放| 国产精品一区二区在线不卡| 下体分泌物呈黄色| 内射极品少妇av片p| xxx大片免费视频| 如何舔出高潮| freevideosex欧美| 夜夜骑夜夜射夜夜干| 性高湖久久久久久久久免费观看| 搡老乐熟女国产| 丁香六月天网| 欧美亚洲 丝袜 人妻 在线| 最近手机中文字幕大全| 日韩成人伦理影院| 日本vs欧美在线观看视频 | 久久99一区二区三区| 日本av手机在线免费观看| 国产高清三级在线| 国产午夜精品久久久久久一区二区三区| 国语对白做爰xxxⅹ性视频网站| 国产精品99久久久久久久久| 国产国拍精品亚洲av在线观看| 午夜精品国产一区二区电影| 男的添女的下面高潮视频| 少妇猛男粗大的猛烈进出视频| 亚洲人成网站在线观看播放| 九九久久精品国产亚洲av麻豆| 国产 精品1| 精品酒店卫生间| 国产视频首页在线观看| 中文字幕人妻熟人妻熟丝袜美| 最新的欧美精品一区二区| 婷婷色综合www| 久久久久久久久久成人| 国产成人精品婷婷| 丝瓜视频免费看黄片| 日本与韩国留学比较| 在现免费观看毛片| 女性生殖器流出的白浆| 国产亚洲最大av| 国产日韩欧美在线精品| 最黄视频免费看| 国产精品久久久久成人av| 国产探花极品一区二区| 亚洲国产欧美在线一区| 熟妇人妻不卡中文字幕| freevideosex欧美| 我要看黄色一级片免费的| 91精品一卡2卡3卡4卡| 精品国产一区二区久久| 国产 精品1| 最近中文字幕2019免费版| av国产精品久久久久影院| 亚洲精华国产精华液的使用体验| 精品一区二区免费观看| 一级av片app| 天天操日日干夜夜撸| av国产久精品久网站免费入址| 免费看不卡的av| 自拍欧美九色日韩亚洲蝌蚪91 | 男人舔奶头视频| 国产熟女欧美一区二区| 国产日韩一区二区三区精品不卡 | 久久99热6这里只有精品| 亚洲av欧美aⅴ国产| 一本大道久久a久久精品| www.av在线官网国产| 国国产精品蜜臀av免费| 99热这里只有是精品50| 日韩制服骚丝袜av| 极品教师在线视频| 免费观看a级毛片全部| 最近2019中文字幕mv第一页| 亚洲第一区二区三区不卡| 中文字幕av电影在线播放| 91精品一卡2卡3卡4卡| 一级a做视频免费观看| 日本欧美视频一区| 国产伦精品一区二区三区视频9| 国产69精品久久久久777片| 欧美精品人与动牲交sv欧美| av不卡在线播放| 久久人妻熟女aⅴ| 亚洲va在线va天堂va国产| 五月开心婷婷网| 一二三四中文在线观看免费高清| a级片在线免费高清观看视频| 黑人猛操日本美女一级片| 国产一区有黄有色的免费视频| 久久久久久伊人网av| 黑人巨大精品欧美一区二区蜜桃 | 男女无遮挡免费网站观看| 精品一区二区免费观看| 亚洲美女搞黄在线观看| 一区在线观看完整版| 丰满饥渴人妻一区二区三| 国产精品成人在线| 久久精品国产亚洲网站| 亚洲精品自拍成人| 亚洲国产色片| 天堂中文最新版在线下载| 亚洲精品国产av成人精品| 亚洲av二区三区四区| 黄色毛片三级朝国网站 | 噜噜噜噜噜久久久久久91| 久热这里只有精品99| 久久久国产一区二区| 十八禁高潮呻吟视频 | videossex国产| 免费看光身美女| 久久午夜综合久久蜜桃| 人人妻人人看人人澡| 大片电影免费在线观看免费| av黄色大香蕉| 自拍偷自拍亚洲精品老妇| 国产精品99久久99久久久不卡 | 伊人久久国产一区二区| 亚洲av成人精品一二三区| 在线亚洲精品国产二区图片欧美 | 18+在线观看网站| 色哟哟·www| a级一级毛片免费在线观看| 日韩av免费高清视频| 丁香六月天网| 日韩大片免费观看网站| 中文在线观看免费www的网站| www.色视频.com| 亚洲国产精品国产精品| 亚洲欧洲国产日韩| 秋霞在线观看毛片| 亚洲精品亚洲一区二区| 亚洲欧美一区二区三区国产| 日韩av不卡免费在线播放| 免费黄色在线免费观看| 三级国产精品欧美在线观看| 老司机亚洲免费影院| 熟女电影av网| 日韩免费高清中文字幕av| 中文字幕人妻丝袜制服| 高清欧美精品videossex| 中文天堂在线官网| 水蜜桃什么品种好| 久久久亚洲精品成人影院| 国产中年淑女户外野战色| 天天躁夜夜躁狠狠久久av| 国产精品久久久久久精品电影小说| 国产精品久久久久久久电影| 免费观看的影片在线观看| 制服丝袜香蕉在线| 亚洲欧美一区二区三区国产| 亚洲精品视频女| 亚洲欧美日韩另类电影网站| 国产精品福利在线免费观看| 亚洲人与动物交配视频| 午夜福利在线观看免费完整高清在| 久久午夜福利片| 夫妻性生交免费视频一级片| 男男h啪啪无遮挡| 亚洲欧美成人精品一区二区| 9色porny在线观看| 久久鲁丝午夜福利片| 嫩草影院入口| 欧美日韩一区二区视频在线观看视频在线| 五月天丁香电影| 日韩av在线免费看完整版不卡| 国产亚洲一区二区精品| 自拍偷自拍亚洲精品老妇| 国产69精品久久久久777片| 国产真实伦视频高清在线观看| 亚洲国产最新在线播放| 大话2 男鬼变身卡| 水蜜桃什么品种好| 亚洲av国产av综合av卡| 性色av一级| 国产熟女午夜一区二区三区 | av线在线观看网站| 国产精品人妻久久久影院| 男女无遮挡免费网站观看| av一本久久久久| 99re6热这里在线精品视频| 国产成人a∨麻豆精品| 人体艺术视频欧美日本| 女性被躁到高潮视频| 国产黄色免费在线视频| 国产亚洲一区二区精品| 26uuu在线亚洲综合色| av在线app专区| 高清av免费在线| 国产又色又爽无遮挡免| 嫩草影院新地址| 看十八女毛片水多多多| 成人无遮挡网站| 成人毛片60女人毛片免费| 国产日韩欧美视频二区| 国产欧美日韩综合在线一区二区 | 夫妻性生交免费视频一级片| 2021少妇久久久久久久久久久| 高清午夜精品一区二区三区| 国产淫片久久久久久久久| 男女啪啪激烈高潮av片| 51国产日韩欧美| 国产极品天堂在线| 曰老女人黄片| 2022亚洲国产成人精品| 国产视频内射| 国产精品秋霞免费鲁丝片| 99热这里只有是精品50| 噜噜噜噜噜久久久久久91| 亚洲国产日韩一区二区| 99九九在线精品视频 | av国产久精品久网站免费入址| 国产女主播在线喷水免费视频网站| 国产日韩欧美视频二区| 欧美日韩精品成人综合77777| av在线老鸭窝|