Evaluation and comparison of thirty noninvasive models for diagnosing liver fibrosis in chinese hepatitis B patients

The limitations of liver biopsy have led to the development of indirect noninvasive models for liver fibrosis assessment. We aimed to evaluate and compare the performance of 30 noninvasive models to predict fibrosis stage in treatment‐naïve and treated chronic hepatitis B (CHB) patients. A total of 576 Chinese treatment‐naïve CHB patients and 236 treated CHB patients who had undergone percutaneous liver biopsy were included in the analysis. Histological grading and staging was assessed by the Ishak scoring system. The diagnostic accuracies of 30 noninvasive models were assessed by area under the receiver operating characteristic curves (AUROCs). In treatment‐naïve CHB patients, the AUROCs of the 30 noninvasive models for discriminating significant fibrosis (SF) were less than 0.800, and only the AUROC of the PP score for diagnosing advanced fibrosis (AF) was more than 0.800, while the AUROCs of FIB‐4, FibroQ, HB‐F, Lok index, PHP score and PP score for predicting cirrhosis were greater than 0.800. In treated CHB patients, only the AUROCs of APRI, GUCI, King's score and Wang I for identifying cirrhosis were more than 0.800. The Spearman correlation analysis identified that only the changes in FCI and Virahep‐C model values were weakly correlated with changes in Ishak fibrosis scores before and after treatment (r = 0.206, p = 0.008; r = 0.187, p = 0.016, respectively). In conclusion, in Chinese CHB patients, the 30 existing noninvasive models were not suitable for assessing each stage of fibrosis except cirrhosis before and after antiviral therapy, especially in gauging progression and regression of liver fibrosis following therapy.     

慢性乙肝患者HBV-DNA、肝功能指标与肝纤维化的关系

[目的]探究慢性乙型病毒性肝炎患者乙肝病毒脱氧核糖核酸(HBV-DNA)、肝功能指标与肝纤维化的关系.[方法]入选65例慢性乙肝患者为患者组;同期选取肝功能合格的体检者65例作为对照组;检测2组肝纤维化指标[血清透明质酸(HA)、层粘连蛋白(LN)、Ⅲ型胶原(PCⅢ)、Ⅳ型胶原(Ⅳ-C)],HBV-DNA,肝功能指标[...     

Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B.

BACKGROUND/AIM: Accurate histological assessment of liver fibrosis is essential in the management of chronic hepatitis B (CHB). Although semi-quantitative scoring systems describe well the pathological patterns of hepatic structure, they produce fibrosis evaluation that is not very precise. Image analysis or morphometry has the theoretical advantage of providing truly quantitative data. PATIENTS AND METHODS: The present study aimed at validating a new image analysis system, Bioquant Nova Prime, in estimating collagen content in liver biopsy samples from patients with CHB. The biopsies were stained with picrosirius red and the areas of collagen were measured. The results were correlated with laboratory parameters and Ishak modified histological scores. Discriminative reliability of morphometry was determined using receiver operating characteristics (ROC) analysis. RESULTS: There was excellent interobserver agreement (r=0.84-0.94, P<0.01) in the morphometric analysis. Significant correlations between the quantitative morphometric data and the semi-quantitative score (Spearman's r=0.68-0.78, P<0.001) were also demonstrated. Excellent discriminative power of morphometry in differentiating mild from advanced fibrosis and cirrhosis from absence of cirrhosis was shown by the ROC analysis. CONCLUSIONS: Our results validated the use of Bioquant Nova Prime in estimating collagen content in liver biopsies. We showed that morphometry is a sensitive method of liver fibrosis quantification in CHB and complements semi-quantitative histological scoring system. This tool, with its reliable intraassay variability, could be of special value in assessing histological response to treatment after anti-viral or anti-fibrotic therapy.     

Correlation of liver biochemistry with liver stiffness in chronic hepatitis B and development of a predictive model for liver fibrosis

Aim: To correlate liver stiffness with demographical factors and routine liver biochemistry and to assess the predictive value of these as potential markers of fibrosis. Methods: Transient elastography was performed in 1268 chronic hepatitis B (CHB) patients. According to a previous validated study for CHB, liver stiffness of >8.1 and >10.3 kPa were used as cut‐off values for defining severe fibrosis and cirrhosis respectively. Results: Liver stiffness correlated positively with bilirubin, alkaline phosphatase (ALP), γ‐glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), globulin, α‐fetoprotein (AFP) and HBV DNA levels and negatively with albumin and platelet levels (P<0.05 for all correlations). From 13 parameters (age, sex, platelet, AST, ALT, GGT, AFP, albumin, globulin, bilirubin, ALP, HBV DNA and hepatitis B e‐antigen), four best parameters (AST, platelet, GGT and AFP) were used to derive a liver stiffness model. Using log (index)=1.44+0.1490(GGT)+0.3308 log (AST)−0.5846 log (platelets)+0.1148 log (AFP+1) to predict both severe fibrosis and cirrhosis had area under the receiver operating characteristics curve of 0.85. Conclusion: Routine liver biochemistry correlated well with liver stiffness in Asian CHB patients. A model using simple serum markers can predict liver stiffness, and further studies are required to validate the usefulness of these simple tests as non‐invasive markers of fibrosis in CHB.     

慢性乙肝患者肝组织纤维化程度与细胞因子相关性

探讨慢性乙肝患苦血清细胞因子(TGF-β1、TNF-α、IFN-γ)在肝纤维化中的作用机制。采用ELISA和 RIA方法检测95例慢性乙肝患者血清TGF-β1、TNF-α、IFN-γ、HA、PCⅢ、C-Ⅳ的水平,并与肝组织病理学变化进 行对照研究。结果显示慢性乙肝患者血清TGF-β1、TNF-α、IFN-γ、HA、PCⅢ、C-Ⅳ的含量均不同程度高于对照 组,且随肝损害程度的加重而升高,与肝损害程度呈正相关;并且其水平与肝纤维化程度具有明显的相关性(P< 0．05)。血清TGF-β1水平与血清HA、PCⅢ、C-Ⅳ水平具有直线相关性,而IFN-γ与血清HA、PCⅢ、C-Ⅳ水平呈 负相关。慢性乙肝患者血清TCF-β1、TNF-α、IFN-γ水平可以作为诊断肝纤维化的血清学指标。     

Serum lincRNA‐p21 as a potential biomarker of liver fibrosis in chronic hepatitis B patients

Serum long non‐coding RNAs (lncRNAs) are emerging as promising biomarkers for various human diseases. The aim of this study was to investigate the feasibility of using serum long intergenic non‐coding RNA‐p21 (lincRNA‐p21) as a biomarker for chronic hepatitis B patients. Serum lincRNA‐p21 levels were quantified using real‐time PCR in 417 CHB patients and 363 healthy controls. The promoter methylation level of lincRNA‐p21 was detected using bisulphite‐sequencing analysis in primary hepatic stellate cells (HSCs). Sera from hepatitis B‐infected patients contained lower levels of lincRNA‐p21 than sera from healthy controls. Serum lincRNA‐p21 levels negatively correlated with stages of liver fibrosis in infected patients. Receiver operating characteristic (ROC) curve analyses suggested that serum lincRNA‐p21 had a significant diagnostic value for liver fibrosis in these patients. It yielded an area under the curve of ROC of 0.854 with 100% sensitivity and 70% specificity in discriminating liver fibrosis from healthy controls. There was additionally a negative correlation between serum lincRNA‐p21 level and the markers of liver fibrosis including α‐SMA and Col1A1. However, there was no correlation of serum lincRNA‐p21 level with the markers of viral replication, liver inflammatory activity, and liver function. Notably, during primary HSCs culture, loss of lincRNA‐p21 expression was associated with promoter methylation. Serum lincRNA‐p21 could serve as a potential biomarker of liver fibrosis in CHB patients. Down‐regulation of lincRNA‐p21 in liver fibrosis may be associated with promoter methylation.     

FibroScan对慢性乙型肝炎肝纤维化诊断的临床价值

目的探讨肝脏瞬时弹性扫描仪(FibroScan)对慢性乙型肝炎(chronic hepatitis B,CHB)肝纤维化的诊断价值。方法对80例行肝脏穿刺检查的CHB患者进行FibroScan检测,记录所检测到的肝脏硬度值。肝纤维化程度分为无或轻度肝纤维化(S0~S1期)、显著肝纤维化(S2~S4期)、严重肝纤维化(S3~S4期)和早期肝硬化(S4期)。以肝脏活体组织检查病理结果为"金标准",绘制受试者工作特征曲线(receiver-operating characteristic curve,ROC曲线),计算ROC曲线下面积(area under ROC curve,AUROC),评价FibroScan对CHB患者肝纤维化的诊断价值。结果肝脏硬度值与肝脏病理分期呈正相关(rs=0.739,P0.01)。FibroScan对显著肝纤维化、严重肝纤维化和早期肝硬化的AUROC值分别为0.865、0.940和0.944。结论 FibroScan可以较准确地估计CHB患者的肝纤维化程度,部分替代有创性的肝脏活体组织检查,对CHB患者肝纤维化的诊断和治疗有指导意义。     

Diabetes mellitus in chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis

Diabetes mellitus has been reported to have an increased prevalence and to be associated with more severe fibrosis in patients with chronic hepatitis C. We evaluated the prevalence of diabetes mellitus in patients with chronic hepatitis B or C as well as the possible association between presence of diabetes and extent of liver fibrosis. In total, 434 consecutive patients with histologically documented hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (n = 174) or chronic hepatitis C (n = 260) were studied. The relationships of diabetes and epidemiological, somatomorphic, laboratory and histological patient characteristics were evaluated. Liver histological lesions were blindly evaluated according to the Ishak's classification. Diabetes was present in 58 (13%) patients, without any difference between those with chronic hepatitis B (14%) or C (13%). Diabetes was observed significantly less frequently in patients with fibrosis score 0-2 (7.7%) than 3-4 (10.4%) than 5-6 (29.2%) (P < 0.001). The presence of diabetes was independently associated with higher gamma-glutamyl-transpeptidase (GGT) levels and more severe fibrosis or presence of cirrhosis (P < 0.001) as well as with presence of hepatic steatosis and increased serum triglycerides levels (P < 0.02). In the noncirrhotic patients, diabetes was significantly associated with older age and higher GGT levels, but not with the extent of fibrosis. In conclusion, diabetes mellitus is observed in more than 10% of patients with either HBeAg-negative chronic hepatitis B or chronic hepatitis C. The presence of diabetes is strongly associated with more severe liver fibrosis, but such an association may be related to the high prevalence of diabetes in patients with cirrhosis.     

瞬时弹性成像在慢性乙型肝炎肝纤维化诊断中的应用

目的：探讨瞬时弹性成像（ FS）在慢性乙型肝炎（乙肝）肝纤维化诊断中的应用价值。方法选取慢性乙肝患者165例,其中轻度肝纤维化者77例,中度肝纤维化者47例,重度肝纤维化及肝硬化者41例;另选同期健康体检者50例。采用FS扫描仪检测所有受试者肝脏硬度值;采用常规及临床生化检查检测血小板、AST、谷氨酰转肽酶及胆固醇,计算APRI指数、Forns指数。采用受试者工作特征（ ROC）曲线分析FS、APRI、Forns单独及联合诊断慢性乙肝肝纤维化的准确性。结果在诊断中度肝纤维化时,FS、Forns、APRI的ROC曲线下面积（ AUC）值分别为0．807、0．786、0．767,诊断界值分别为8．5 kPa及8．1、11．7,敏感度分别为83．3％、60．0％、73．3％,特异度分别为81．6％、92．1％、76．3％;在诊断重度肝纤维化及肝硬化时,FS、Forns、APRI的AUC值分别为0．896、0．886、0．829,诊断界值分别为16．3 kPa及8．4、9．3,敏感度分别为73．3％、80．0％、73．3％,特异度分别为90．6％、83．0％、88．7％。在诊断中度肝纤维化时,FS＋APRI ＋Frons、FS＋Frons、FS＋APRI、FS 的AUC 值分别为0．851、0．832、0．826、0．807,敏感度分别为66．7％、76．7％、70．0％、83．3％,特异度分别为97．4％、81．6％、89．5％、81．6％;在诊断重度肝纤维化及肝硬化时,FS＋APRI＋Frons、FS＋Frons、FS＋APRI、FS的AUC值分别为0．922、0．904、0．907、0．896,敏感度分别为86．7％、86．7％、80．0％、73．3％,特异度分别为88．7％、83．0％、88．7％、90．6％。结论 FS对慢性乙肝肝纤维化诊断准确性高,联合血清学检测诊断效能增高,具有良好的临床应用价值。     

慢性乙型肝炎患者肝纤维化程度与肝功能指标关系分析

目的 探讨慢性乙型肝炎肝纤维化程度与血清HBV DNA水平及肝功能的关系.方法 采用肝脏活体组织检查确定肝组织炎症活动度及纤维化程度,同时检测血清HBV DNA水平及肝功能.结果 肝组织病理的肝纤维化分级与炎症活动分期有关,肝脏炎症程度与纤维化程度呈正相关,P=0.000,rs=0.657.肝脏炎症分期与HBV DNA...     

Performance of noninvasive markers for liver fibrosis is reduced in chronic hepatitis C with normal transaminases

In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Few studies investigated noninvasive markers of liver fibrosis in hepatitis C virus (HCV) patients with normal alanine aminotrasferase (NALT). Eighty HCV patients with NALT and 164 HCV patients with elevated alanine aminotrasferase (EALT) who underwent a diagnostic liver biopsy were evaluated for AST-to-platelet ratio, Forns' index, AST-to-ALT ratio (AAR), Fibrotest and the recently proposed Fibroindex, using liver histology as reference standard. The primary end-point was the detection of significant fibrosis (> or =F2). Performance of noninvasive markers was expressed as specificity, sensitivity and positive (PPV) and negative (NPV) predictive value, accuracy and area under the receiver operating characteristic curve (AUROC). All noninvasive markers for liver fibrosis tested showed a poorer performance in NALT group than in EALT group. Overall, Fibrotest had the best performance in NALT group, as showed by AUROC of 0.70 and 73.5% accuracy. Performance of AAR, Forns' index and Fibroindex was poor in NALT group and it was significantly lower than in EALT group for Forns and Fibroindex (AUROC 0.6 vs 0.76 and 0.58 vs 0.74, respectively, P = 0.05). In NALT patients, PPV was high for all noninvasive markers (>87%) except for AAR, while NPV was low (<65%), thus none of them was able to reliably exclude significant fibrosis. In conclusion, performance of noninvasive-markers is significantly reduced in HCV patients with NALT. Liver biopsy may still be needed for many of these cases to correctly stage liver fibrosis. Specific noninvasive tools and possibly combination of markers should be developed and validated in this clinical setting.     

The predictive value of liver fibrosis in determining the effectiveness of interferon and lamivudine therapies for chronic hepatitis B

Backgound To determine the best indicator of the effective use of interferon and lamivudine for the treatment of hepatitis B e antigen-positive chronic hepatitis, we retrospectively analyzed histologic and virologic status in 200 patients who were treated with interferon and 45 patients who were treated with lamivudine.Methods Histological grading and staging scores were determined by international criteria and the METAVIR scoring system. The YMDD motif associated with lamivudine resistance was analyzed by the sequencing of hepatitis B virus (HBV) DNA.Results Of 200 interferon-treated patients, 62 (31%) seroconverted to anti-hepatitis B e (anti-HBe). Multivariate analysis showed that the significantly important predictors of response were a higher grading score (P = 0.0056) and lower staging score (P = 0.0010). Twenty (44%) of the 45 lamivudine-treated patients seroconverted to anti-HBe, and multivariate analysis showed that the significantly important predictors of response were a higher alanine aminotransferase (ALT) level (P = 0.0034) and lower hepatitis B e antigen levels (P = 0.0128). YMDD mutations occurred during therapy in 12 patients (27%). The significantly important predictor of the development of mutation was a higher staging score (P = 0.0226).Conclusions Both interferon and lamivudine were effective for patients with high ALT levels, but interferons efficacy appeared to be limited by the degree of fibrosis. Lamivudine appeared to be effective irrespective of the degree of fibrosis, but YMDD mutations seemed to develop sooner in patients with advanced liver fibrosis.     

Serum bile acid levels as a predictor for the severity of liver fibrosis in patients with chronic hepatitis C

Summary. Serum bile acids (SBAs) are commonly elevated in cholestatic liver diseases, but it is unclear if SBA levels are also elevated in noncholestatic chronic liver diseases and whether those levels correlate with disease severity. We analysed SBA levels of 135 consecutive patients with chronic hepatitis C virus infection and correlated these levels with the degree of liver fibrosis as determined by liver biopsy. In addition, we assessed the accuracy of SBA levels as a noninvasive predictor for liver fibrosis by its comparison to the patients’ FibroTest scores. Two‐thirds (90/135 patients, 67%) of the study patients had nonsevere liver fibrosis (Metavir F0–F2), and the others (45/135, 33%) had severe fibrosis or cirrhosis (Metavir F3–F4). The SBA levels were significantly higher in patients with severe fibrosis as compared to nonsevere fibrosis (11.46 ± 10.01 vs 6.37 ± 4.69, P < 0.0001). Furthermore, a receiver operator characteristics curve based on a model that included serum bile acids, age, body mass index, serum AST, glucose and cholesterol levels suggested that this combination reliably predicts the degree of liver fibrosis and is not inferior to the current noninvasive FibroTest score (areas under the curve of 0.837 vs 0.83, respectively, P = 0.87). We conclude that measurement of SBA levels may have a clinical role as a simple noninvasive tool to assess the severity of HCV‐induced liver disease. Combined with widely available laboratory parameters, SBA levels can predict disease severity with a high degree of accuracy.     

Hepatic venous pressure gradient as a predictor of fibrosis in chronic liver disease because of hepatitis B virus

Background: Liver biopsy has been considered to be a gold standard for assessing hepatic fibrosis. Sample variability, interobserver variability and step‐wise evaluation limit its use. Hepatic venous pressure gradient (HVPG) correlates with hepatic fibrosis in chronic liver disease (CLD) because of hepatitis C. Aim: To evaluate the utility of HVPG for assessing hepatic fibrosis in patients with hepatitis B virus (HBV)‐related CLD. Patients and Methods: Sixty‐one patients with HBV‐related CLD who underwent both liver biopsy and hepatic haemodynamic studies were studied. Results: Forty‐nine (80.3%) patients had clinically significant portal hypertension (PHT) (HVPG≥10 mmHg), 39 (63.9%) severe PHT (i.e. HVPG≥12 mmHg), six (9.8%) HVPG≤5 mmHg and another six (9.8%) had preclinical PHT (i.e. HVPG>5 but <10 mmHg). A positive correlation between HVPG and fibrosis score was found (r=0.436, P<0.001). In patients with HVPG<10 or <12 mmHg there was a significant correlation with fibrosis score (r=0.603, P=0.029 and r=0.887, P<0.001 respectively). A positive correlation also existed in patients with HVPG≥10 mmHg and in patients with HVPG≥12 mmHg (r=0.512, P≤0.001 and r=0.543, P<0.001 respectively). Receiver operating characteristic curve of HVPG for the prediction of advanced fibrosis (stage≥3) had an area under curve of 0.906. HVPG value above 13.0 mmHg had a sensitivity of 79% and a specificity of 89% for predicting advanced fibrosis on histology. Conclusions: HVPG correlates well with the degree of histological fibrosis in patients with HBV‐related CLD.     

FibroScan在慢性乙型肝炎肝纤维化诊断中的应用

FibroScan的临床应用价值已在慢性丙型肝炎患者中得到广泛验证。近年来,FibroScan也用于慢性乙型肝炎患者肝纤维化的评价。但应注意的是,除操作者的因素外,患者生化指标改变、病毒学因素、代谢状态都有可能影响FibroScan检测值,因此,应进一步界定不同情况下FibroScan的诊断界值。本文对FibroScan在慢性乙型肝炎患者肝纤维化诊断中的应用进行综述。     

Non-invasive fibrosis markers for assessment of liver fibrosis in chronic hepatitis delta

Assessment of liver fibrosis by non-invasive means is clinically important. Studies in chronic hepatitis delta (CHD) are scarce. We evaluated the performance of eight serum fibrosis markers [fibrosis-4 score (FIB-4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), age-platelet index (API), AST-to platelet-ratio-index (APRI), Goteborg University Cirrhosis Index (GUCI), Lok index, cirrhosis discriminant score (CDS) and Hui score] in CHD and chronic hepatitis B (CHB). Liver stiffness was assessed by transient elastography (TE) in CHD. The ability of fibrosis markers to detect significant fibrosis and cirrhosis were evaluated in 202 CHB and 108 CHD patients using published and new cut-offs through receiver operating characteristics (ROC) analysis. The latter was also applied to obtain cut-offs for TE. APRI, Fib-4, API and Hui score were assessed for significant fibrosis, and APRI, GUCI, Lok index, CDS and AAR for cirrhosis determination. Fibrosis markers displayed weak performance in CHB for significant fibrosis with area under ROC (AUROC) curves between 0.62 and 0.71. They did slightly better for CHD. TE displayed an AUROC of 0.92 and performed better than serum fibrosis markers (p < 0.05 for fibrosis markers). For cirrhosis determination, CDS and Lok Index displayed an AUROC of 088 and 0.89 in CHB and GUCI, Lok index and APRI displayed AUROCs around 0.90 in CHD. TE displayed the best AUROC (0.95). Hence TE is superior to serum fibrosis markers for diagnosing significant liver fibrosis and cirrhosis. GUCI, Lok index and APRI displayed a reasonable performance in CHD, which needs further confirmation.     

肝苏颗粒治疗慢性乙型肝炎肝纤维化的临床研究

目的：观察肝苏颗粒治疗慢性乙型肝炎肝纤维化的疗效。方法：选择慢性乙型肝炎肝纤维化患者160例,随机分为两组,对照组（78例）采用常规保肝治疗,治疗组（82例）在常规治疗的基础上加用肝苏颗粒,观察治疗后两组患者临床症状、体征、肝功能以及肝纤维化相关指标如PGA指数、肝纤3项（HA、LN、CⅣ）和肝血流动力学变化。结果：两组均能明显改善患者临床症状,但以治疗组为优（P〈0.01）;治疗组患者ALT、AST、γ-GT、TBil和肝纤3项、PGA指数均明显降低,且显著优于对照组（P〈0.01或0.05）;同时彩色多谱勒显示治疗组患者门、脾静脉内径、血流量值皆明显下降（P〈0.01）。结论：肝苏颗粒能较好地改善慢性乙型肝炎肝纤维化患者临床症状,具有降酶、退黄、促进肝功能恢复作用,且对阻断及逆转肝纤维化进程有一定疗效。     

Impact of interferon-alpha therapy on liver fibrosis progression in patients with HBeAg-negative chronic hepatitis B

The possible effect of interferon-alpha (IFNa) on liver fibrosis progression has not been adequately studied in chronic hepatitis B. We evaluated 147 patients with HBeAg-negative chronic hepatitis B who had > or =2 liver biopsies and had been treated with IFNa (n = 120) or had remained untreated (n = 27). The median interval between the two biopsies was 24 (12-160) months. All biopsies were scored blindly by a single liver histopathologist according to the classification of Ishak et al. (J Hepatol 1995; 22: 696-699). IFNa induced sustained biochemical response in 30, initial response and subsequent relapse in 57 and no response in 33 patients. Fibrosis improved in 17.5% of treated (sustained responders: 40%, relapsers: 9%, nonresponders: 12%) and 4% of untreated patients and worsened in 34% (sustained responders: 7%, relapsers: 40%, nonresponders: 48%) and 70% of cases, respectively (P = 0.002). The annual rate of fibrosis progression was worse in the untreated (0.427 +/- 0.119) than in treated patients (0.067 +/- 0.052, P = 0.001). However, the fibrosis progression rate in the untreated patients was not significantly different than the net fibrosis progression rate (after subtraction of IFNa duration) in nonresponders or relapsers. In multivariate analysis, worse fibrosis progression rate was associated with older age (P = 0.010), worse baseline grading score (P < 0.001), lower baseline fibrosis (P = 0.035) and the type of response to IFNa (P = 0.032). In conclusion, in HBeAg-negative chronic hepatitis B, IFNa significantly reduces the rate of fibrosis progression, but such an effect is mainly observed in patients with sustained biochemical responses. In relapsers and nonresponders, fibrosis benefit equals the treatment period. The strongest factor associated with fibrosis progression is the change in necroinflammatory activity.