Histological Activity Index Score Research Articles

Histopathology and the predominantly progressive, indeterminate and predominately regressive score in hepatitis C virus patients after direct-acting antivirals therapy.

BACKGROUNDHistological changes after direct-acting antivirals (DAAs) therapy in hepatitis C virus (HCV) patients has not been elucidated. Whether the predominantly progressive, indeterminate and predominately regressive (P-I-R) score, evaluating fibrosis activity in hepatitis B virus patients has predictive value in HCV patients has not been investigated.AIMTo identify histological changes after DAAs therapy and to evaluate the predictive value of the P-I-R score in HCV patients.METHODSChronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included. Sustained virologic response (SVR) was defined as an undetectable serum HCV RNA level at 24 wk after treatment cessation. The Ishak system and P-I-R score were assessed. Inflammation improvement and fibrosis regression were defined as a ≥ 2-points decrease in the histology activity index (HAI) score and a ≥ 1-point decrease in the Ishak fibrosis score, respectively. Fibrosis progression was defined as a ≥ 1-point increase in the Ishak fibrosis score. Histologic improvement was defined as a ≥ 2-points decrease in the HAI score without worsening of the Ishak fibrosis score after DAAs therapy. The P-I-R score was also assessed. “absolutely reversing or advancing” was defined as the same directionality implied by both change in the Ishak score and posttreatment P-I-R score; and “probably reversing or advancing” was defined as only one parameter showing directionality.RESULTSThirty-eight chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included. The mean age of these patients was 40.9 ± 14.6 years and there were 53% (20/38) males. Thirty-four percent (13/38) of patients were cirrhotic. Eighty-two percent (31/38) of patients achieved inflammation improvement. The median HAI score decreased significantly after SVR (pretreatment 7.0 vs posttreatment 2.0, Z = -5.146, P = 0.000). Thirty-seven percent (14/38) of patients achieved fibrosis improvement. The median Ishak score decreased significantly after SVR (pretreatment 4.0 vs posttreatment 3.0, Z = -2.354, P = 0.019). Eighty-two percent (31/38) of patients showed histological improvement. The P-I-R score was evaluated in 61% (23/38) of patients. The progressive group showed lower platelet (P = 0.024) and higher HAI scores (P = 0.070) before treatment. In patients with stable Ishak stage after treatment: Progressive injury was seen in 22% (4/18) of patients, 33% (6/18) were classified as indeterminate and regressive changes were seen in 44% (8/18) of patients who were judged as probably reversing by the Ishak and P-I-R systems.CONCLUSIONSignificant improvement of necroinflammation and partial remission of fibrosis in HCV patients occurred shortly after DAAs therapy. The P-I-R score has potential in predicting fibrosis in HCV patients.

The synergy of dietary supplements Lactobacillus salivarius LI01 and Bifidobacterium longum TC01 in alleviating liver failure in rats treated with D-galactosamine.

Lactobacillus salivarius (L. salivarius) has been widely used in dietary supplements and clinical treatments. Previous studies demonstrated the protective effect of L. salivarius LI01 on liver injury induced by D-galactosamine (D-GaIN) in rats. Accumulating evidence indicates that Lactobacillus and Bifidobacterium are highly coordinated; so in this study, we focus on the synergistic effect of L. salivarius LI01 and B. longum TC01 on the alleviation of liver injury caused by D-GaIN in rats and aim to find out the underlying interaction between the two strains. We observed reduced hepatic damage in the D-GaIN-treated rats with probiotic pre-administration, characterized by lower levels of AST and ALT (p < 0.05) and decreased HAI (Histological Activity Index) scores. Moreover, cotreatment with LI01 and TC01 more effectively decreases proinflammatory cytokines TNF-α, MCP-1 and M-CSF (p < 0.05) so as to inhibit systemic inflammation. Gut barrier dysfunction was ameliorated with compound probiotic pretreatment, as evidenced by the ultrastructure integrity, decreased histological score and elevated TJP-1 expression. What's more, supplementation with LI01 and TC01 markedly alleviates gut dysbiosis in the G-DaIN-treated rats, with enrichment of short chain fatty acid (SCFA) producers Faecalibaculum and Eubacterium_xylanophilum_group, a decreased Firmicutes/Bacteroidetes (F/B) ratio and depletion of proinflammatory microbes, such as Peptococcaeae and Ruminococcaceae_UCG-005. This study highlights the synergistic effect of dietary supplements LI01 and TC01 on the protection against liver failure, which is probably via altering gut microbiota.

Serum rheumatoid factor is correlated with liver fibrosis in patients with chronic hepatitisB.

Non-invasive methods are being developed to evaluate liver fibrosis. In this study, we aimed to evaluate the diagnostic performance of rheumatoid factor (RF) to predict liver fibrosis in chronic hepatitisB (CHB). Atotal of 235 non-arthritic, treatment-naive patients with hepatitis B virus (HBV) were enrolled in this study. The RF level was analyzed concurrently with HBV-DNA and routine biochemical tests. The liver biopsies were scored by using the Knodell modified histology activity index (HAI) and the Ishak fibrosis score. Mean age, ALT, AST, ALP, GGT, INR, and HBV-DNA levels were significantly higher, and mean albumin and platelet levels were significantly lower in the RF positive group than the RF negative group. Liver biopsy was performed in 112 (47.66%) patients, and the RF positivity rate was 18 (15.38%) in the infection subgroup and 73 (61.86%) in the hepatitis subgroup. Along with the RF positivity rate, the fibrosis and HAI scores were also increased. Ahigh fibrosis score is associated with ahigh RF positivity rate. In the current study, we found that there was asignificant positive correlation between RF and liver fibrosis stage in patients with CHB. The RF that is easily obtained with low cost may be considered as an alternative biomarker for predicting liver fibrosis in CHB.

The role of diffusion tensor imaging for the assessment of liver fibrosis and inflammation in chronic viral hepatitis: A preliminary study

Objective: To evaluate the role of magnetic resonance (MR) diffusion tensor imaging (DTI) in the assessment of liver fibrosis andinflammation in chronic viral hepatitis by measuring apparent diffusion coefficient (ADC) and fractional anisotropy (Fa) values.Material and Methods: Twenty-seven patients (5 women and 22 men;mean age39.8±11.3) with hepatic fibrosis were included inour study. The relationship between ADC, Fa values and histological activity index (HAI) score were evaluated using Spearman’scorrelation coefficient. Patients were subgrouped as group A (fibrosis score 1) and group B (fibrosis score 3). The mean ADC and Favalues of groups A and B were compared using Student’s t-test. To evaluate the use of ADC and Fa values in distinguishing group Afrom group B, ROC analysis was applied; sensitivities and specificities were calculated.Results: Fa values correlated with HAI scores significantly (r=0.397, p&amp;lt;0.05) The difference was significant between the mean ADCvalues (group A:1.46± 0.191x103mm2/s; group B:1.105± 0.141x10-3 mm2/s; p&amp;lt;0.001) and Fa values (group A: 0.473±0.091; groupB: 0.643± 0.007; p&amp;lt;0.001) between the groups. For distinguishing group A from group B, ADC had a sensitivity of 81.8% and aspecificity of 93.8%. The sensitivity and specificity of Fa were 90.9% and 100%, respectively.Conclusion: Diffusion tensor imaging may play a role in the evaluation of fibrosis and HAI scores in patients with liver fibrosis.

The relationship of Serum Histone H3.3 and H4 with chronic Hepatitis B.

To determine the role of serum histone H3.3 and H4 in patients with chronic hepatitis B to explore any relationship between the two. The prospective controlled clinical pilot study was conducted in the Gastroenterology Clinic of Bezmialem Vakif University, Istanbul, Turkey, from January to October 2017, and comprised biopsy-proven patients with chronic hepatitis B and healthy controls. Demographics, hepatitis B virus deoxyribonucleic acid quantity, hepatitis B e-antigen, aspartate aminotransferase, alanine transaminase, international normalized ratio, total/direct bilirubin, albumin and thrombocyte counts as well as histological activity index and fibrosis scores were noted. Data was analysed using SPSS 22. Of the 140 subjects, 70(50%) each were cases and controls. The overall mean age of the sample was 43.38±15.07 years (range: 18-70 years). There was positive correlation of histone H3.3 with hepatitis B virus deoxyribonucleic acid, aspartate aminotransferase, alanine transaminase and international normalized ratio levels. Histone H4 levels only correlated with hepatitis B virus deoxyribonucleic acid and international normalized ratio. Hepatitis B e-antigen positivity was present in 14(20%) of the cases. Histone H3.3 levels appeared to be associated with pathophysiological changes in chronic hepatitis B patients, suggesting that future treatments should target H3.3.

Histopathological features of chronic hepatitis B reactivation

It was aimed to investigate histopathological changes in acute hepatic exacerbations. A total of 20 patients, who developed acute hepatic exacerbation on the base of chronic hepatitis B infection, were enrolled in the study and liver biopsy was performed. Histological activity index (HAI) and its components, fibrosis scores and total HAI score were calculated according to the Ishak scoring system. All of the patients enrolled in the study had portal inflammation and spotty necrosis. Fibrosis was present in 17 patients. The median grade, stage and total HAI scores of the patients were 7 (2-14), 2 (0-3) and 8.5 (4-16), respectively. Positive correlation was determined between necroinflammation and ALT. While grade and total HAI score did not show significant difference among genders, fibrosis was significantly higher in males (p=0.008). The findings of this study showed that there are significant correlation between histopathologic changes (grade and total HAI score) in liver biopsy and plasma ALT, AST and Total bilirubin levels during acute hepatic exacerbation in patients with chronic hepatitis B infection.

Probiotic Mixture VSL#3 Alleviates Dextran Sulfate Sodium-induced Colitis in Mice by Downregulating T Follicular Helper Cells.

Clinical trials have shown beneficial effects of probiotics on inflammatory bowel diseases (IBD), although the exact mechanism remains unknown. VSL#3, a mixture of 8 probiotic bacteria, has been confirmed to have adjunctive therapeutic effects on colitis. T follicular helper (Tfh) cells, a new separate subset of CD4+ T helper cells, have been proved to play a vital role in autoimmunity. The present study aimed to identify the beneficial effect of the probiotic mixture VSL#3 on the mouse model of colitis by regulating Tfh cells. Dextran sulfate sodium (DSS) was used to induce chronic colitis in C57BL/6 mice. VSL#3 (3×109 live bacteria) was given to C57BL/6 mice every other day for 60 days by gavage. The disease activity index (DAI), histological activity index (HAI), colon length and myeloperoxidase (MPO) activity were detected. Immunofluorescence was used to visualize the location of Tfh cells. Immunoglobulins, Tfh cells and plasma cells were quantified by enzyme-linked immunosorbent assay (ELISA), flow cytometry, real-time PCR or Western blotting. The results showed that after DSS treatment, the humoral immunity was disordered in C57BL/6 mice, with increased IgM, IgG and IgA levels in colonic mucus and increased Tfh cells in mesenteric lymph nodes (MLN). VSL#3 treatment showed anti-inflammatory effects as evidenced by reduced DAI score, HAI score and MPO activity. IgM, IgG and IgA levels were significantly reduced in colon mucus, and the number of Tfh cells was markedly decreased in MLN after VSL#3 treatment. It was concluded that VSL#3 alleviates DSS-induced colitis by downregulating Tfh cells, and Tfh cells may become a potential therapeutic target for IBD.

Importance of Prolidase Enzyme Activity and Serum Cytokeratin 18 Levels for Differential Diagnosis between Asymptomatic Hepatitis B Carriers and HBeAg Negative Chronic Hepatitis B Patients

Background: In this study, it was aimed to evaluate the relationship between the severity of necroinflammation in the liver and the stage of fibrosis and the serum levels of Serum Prolidase Activity (SPA) and Cytokeratin (CK)-18 in patients with active Chronic Hepatitis B (CHB) and asymptomatic Hepatitis B Virus (HBV) carriers. Methods: Biochemical analyses, serological parameters associated with HBV and serum prolidase activity and CK-18 levels were measured in asymptomatic HBV carriers (n=65), active CHB patients (n=60) and healthy controls (n=27). Liver biopsies were performed on asymptomatic HBV carriers and active CHB patients. Findings: SPA level was significantly higher in active CHB patients (819.92 ± 123.74 IU/L) compared to asymptomatic HBV carriers (732.99 ± 124.70 IU/L) and was higher in asymptomatic HBV carriers compared to healthy controls (529.4 ± 74.73 IU/L) (p=0.001). The diagnostic cut-off value of SPA level was found 751.15 U/L. When this cut-off value was taken to differentiate HBe-Ag negative CHB in asymptomatic HBV carriers, sensitivity and specificity of efficacy were 72% and 63% respectively (c-statistics: 0.707). A strong positive correlation was observed between serum prolidase level and the severity of fibrosis in asymptomatic HBV carriers (r=0.603, p=0.000). A positive correlation was determined between SPA level and Histological Activity Index (HAI) scores in patients with active CHB and asymptomatic HBV carriers. The serum CK-18 levels were significantly lower in the healthy control group when compared to the asymptomatic HBV carriers and active CHB patients (p=0.001). Conclusion: Prolidase enzyme may be beneficial in differentiating asymptomatic HBV carriers from HBeAg-negative CHB patients when used in combination with ALT and HBV-DNA levels.

Long-term histological change in chronic hepatitis C patients who had received peginterferon plus ribavirin therapy with sustained virological response

The improvement in liver histology is an important aim in the management of hepatitis C virus (HCV) infection. Previous studies suggest that antiviral treatment could reduce the progression of hepatic fibrosis, especially in patients with sustained virological response (SVR). However, most studies were limited by short-term evaluations and the liver stiffness was assessed by non-invasive methods. In our study, we performed a paired liver biopsy study aimed at analyzing the long-term histological changes in patients with SVR. We included 31 patients who had been previously treated with peginterferon plus ribavirin. All patients achieved SVR and had received pre- and post-treatment liver biopsies. The histological appearance of fibrosis and inflammation were assessed with METAVIR scoring system and Histological Activity Index (HAI) criteria. We analyzed several factors associated with the histological response. The median interval between two biopsies was 93.0 months. The percentage of patients with fibrosis regression, stable, and progression were 19%, 45%, and 36%. A total of 71% of patients achieved inflammation improvement, whereas 6% and 23% of patients had stable disease and disease-progression, respectively. We showed that the patients without baseline advanced fibrosis and those having a lower baseline HAI score had higher risk of fibrosis worsening. Baseline fibrosis and necroinflammation status did not influence HAI change significantly. The progression of hepatic fibrosis and inflammation can be reversed in some patients who had long-term virological suppression. Patients with advanced baseline fibrosis and higher inflammatory stages seemed to receive more histologic benefit from successful antiviral treatments.

Declining in liver stiffness cannot indicate fibrosis regression in patients with chronic hepatitis B: A 78-week prospective study.

Little reliable data are available about the liver stiffness measurement (LSM) for fibrosis monitoring in chronic hepatitis B (CHB) patients on antiviral therapy. We aimed to assess the accuracy of LSM in fibrosis monitoring during 78-week antiviral therapy in CHB patients. Five hundred fifty-six treatment-naïve CHB patients with qualified LSM and liver biopsy at baseline were analyzed. Patients receiving entecavir-based therapy were prospectively followed to 78weeks for second LSM and liver biopsy. Serologic detection, LSM, and liver biopsy were performed on the same day. Necro-inflammatory activity was also evaluated. Areas under receiver operating characteristics curves of LSM at baseline and week 78 for significant fibrosis (≥F3), advanced fibrosis (≥F4), and liver cirrhosis (≥F5) was 0.84, 0.87, 0.83 and 0.76, 0.85, 0.88, respectively. Patients with the same fibrosis stage but higher histology activity index score tend to have higher LSM at baseline. Liver stiffness decreased rapidly (3.8 [1.6-8.6] kPa) in parallel with baseline histology activity index scores from 11.3 (7.8-16.7) kPa at baseline to 6.4 (5.1-8.8) kPa at week 78. Greater decline of LSM in patients with only inflammation improvement was observed as compared with those without inflammation improvement (5.2 [2.5-9.7] vs 1.8 [0.2-8.1] kPa, P=0.013). Baseline Ishak fibrosis score was the only predictor of 78-week fibrosis improvement (odds ratio, 1.859; P=0.000). In CHB patients receiving 78-week antiviral treatment, LSM could diagnosis different liver fibrosis stages, decrease in absolute LSM value could reflect the remission of liver inflammation, and baseline Ishak fibrosis score was the only predictor for 78-week fibrosis reversion.

Assessment of histopathological alterations in patients with chronic hepatitis B infection following long-term oral antiviral therapy.

Objectives:To evaluate the histopathological changes in the liver after oral antiviral therapy in patients with chronic hepatitis B.Methods:A total of 79 HBeAg-negative and positive patients who had been on lamivudine, entecavir, or tenofovir disoproxil for at least 3 years prior to inclusion were enrolled between March 2015 and 2016, retrospectively. There were 23 patients on lamivudine, 21 patients on entecavir, and 35 on tenofovir. All patients underwent a follow-up liver biopsy. Biochemical, serological, virological and histopathological data were recorded in all patients and were compared after at least 3 years of treatment with oral antiviral agents.Results:Histological activity index scores were reduced in patients who received lamivudine (p=0.011), entecavir (p=0.002), and tenofovir (p=0.001). Also, in contrast with a significant improvement in fibrosis scores in lamivudine (p=0.033) and tenofovir (p=0.001) groups no improvements were found in patients who received entecavir (p=0.090).Conclusion:Long term treatment with oral antiviral agents was associated with biochemical, virological, serological, and histopathological improvements. Long-term use of anti-viral agents as well as continuous suppression of HBV DNA are prerequisites for histopathological improvement.

Clinical and histopathological features of chronic hepatitis B virus infected patients with high HBV-DNA viral load and normal alanine aminotransferase level: A multicentre-based study in China.

BackgroundThe aim of this study is to reveal the clinical and histopathological features of HBsAg-positive and HBeAg-positive chronic hepatitis B infected patients with high level of HBV DNA, from 17 hospitals and medical centres in China, with alanine aminotransferase levels within the lower region of normal range versus those with levels within the upper region of normal range and to investigate the clinical risk factors for the requirement of treatment through the examination of liver biopsy.MethodsLiver biopsy was performed on high level of HBV DNA of 455 patients with HBsAg-positive and HBeAg-positive chronic hepatitis B infection and persistently normal alanine aminotransferase level. Liver necroinflammation and fibrosis were graded per the Knodell histological activity index and Ishak’s fibrosis score, respectively. Univariate analysis of the clinical parameters versus necroinflammation and fibrosis was carried out.ResultsOf the subjects in this multicentre-based study, 5.49% and 10.11% had significant necroinflammation with Knodell histological activity index ≥ 9 and hepatic fibrosis stages with Ishak scores ≥ 3, respectively. The subjects were stratified into three age groups (30–39, 40–49 and ≥ 50 years), and our data clearly suggested that age, particularly in the age group over 50, was an independent predictor of liver necroinflammation and fibrosis. Lower HBV-DNA viral levels were found in patients with Knodell histological activity index ≥ 9 or advanced fibrosis (Ishak scores ≥ 3).ConclusionOur results showed that histological changes in liver tissues were observed in a significant proportion of patients with persistently normal alanine aminotransferase level. According to the data evaluation results, liver biopsy is advisable for HBeAg-positive chronic hepatitis B infected patients aged older than 40 and high HBV-DNA viral load in China.

Incidentally detected asymptomatic hepatitis C virus infection with significant fibrosis: Possible impacts on management.

Liver biopsy may be considered in patients with hepatitis C virus (HCV) infection to assess the severity of liver injury and stage of fibrosis, thereby guiding therapeutic decisions. In addition, advanced stage also necessitates surveillance for hepatocellular carcinoma. The aim of this study was to assess whether transaminase (alanine transaminase [ALT]) levels and RNA titers correlate with the histological activity index (HAI) and fibrosis (F) stage in asymptomatic patients with incidentally detected HCV (IDHCV). Retrospective evaluation of liver biopsies was done in 113 patients with IDHCV, diagnosed during routine screening. Decision of liver biopsy was made on the basis of age, genotype, acceptable clinical, hematological, and biochemical profiles, and willingness of the patients to undergo treatment. Serum ALT levels, HCV RNA titers, and genotypes were correlated with HAI and F stage. Genotyping was done in 77 of the 113 patients, of which genotype 3 was seen in 43 and genotype 1 in 25 patients. A higher fibrosis stage (Ishak's >F2) was noted in 23.8% of the biopsies. Serum ALT showed a significant correlation with the HAI score on liver biopsy (P = 0.01) but not with the stage of fibrosis (P = 0.52). HCV RNA titers did not reveal any correlation with HAI score or fibrosis stage. Serum transaminases and HCV RNA titers are poor predictors of disease severity and fibrosis. Since HCV shows a slow disease progression, higher stage may predict a worse prognosis irrespective of the low viral RNA load. Liver biopsy may help guide therapeutic decisions in IDHCV infection.

Staging and grading chronic viral hepatitis: A teaching hospital experience using an objective histological activity index in a tropical population

Background: Chronic viral hepatitis (CVH) is the leading cause of chronic liver diseases (CLD) and exhibit diffuse parenchymal damage requiring a systematic assessment of disease extent and progression. Aims: The aim of this study is to determine the epidemiological pattern and grade/stage all cases of CVH using Ishaq Modified Histologic Activity Index (HAI); then share and to compare our experience with similar works elsewhere. Methods: Ten years (2006–2015) liver biopsies received in the Department of Pathology, Ahmadu Bello University Teaching Hospital Zaria, were fixed in formalin, embedded in paraffin and stained with routine and special stains were reviewed, graded and staged using Ishaq HAI. Data were analysed and presented in statistical frequency distribution tables and figures. Results: CVH formed 55.2% was the most common of liver diseases. There were119 male and 47 female with male-to-female ratio of 2.5: 1 and peaked in the third decade of life. Nearly 42.2% had modified Ishaq HAI score of 4–8, while 28.3% and 27.1% had score 1–3 and score 9–12, respectively. Only 2.4% had score of 13–18. Nearly 70.5% of cases were between Stages 0 and 2, 25.9% of cases were Stage 3and 4 while only 6% were in Stage 5. Hepatitis B virus (HBV) was the most common aetiology and found in 77.7% of cases, 13.3% were associated with hepatitis C virus (HCV) and HBV/HCV co infection in 9.0%. Conclusions: CVH was the most common form of CLD, peaked in the third decade of life. Nearly 42.2% were in mild grade disease while 70.5% had Stage 2 and below disease. HBV infection was the most common aetiology.

Liver tissue trace element levels in HepB patients and the relationship of these elements with histological injury in the liver and with clinical parameters

AimIn this study, the relationship of liver tissue trace element concentrations with hepatitis B disease and the effects of several environmental factors were analysed. MethodThe liver tissue concentrations of Al, Fe, Cd, Mn, Cr, Cu, Pb, Ni, Zn, Ag, and Co were evaluated in 92 patients with hepatitis B using the Inductively Coupled Plasma − Mass Spectrometry (ICP/MS) method in the analyses. The patients were divided into the following two groups: low-high Ishak histologic activity index (HAI) (0–6: Low Histologic Activity, 7–18: High Histologic Activity) and low-high fibrosis (FS) (Fibrosis 1,1,2 and Fibrosis 3,4,5,6). The metal levels were compared between the groups. ResultsThe Cd concentration was found to be statistically higher in the group with low HAI scores (p=0.019). The hepatic Cu concentration was found to be higher in women than in men (p=0.046). The hepatic Fe concentration was found to be higher in the group with increased FS compared to the group with decreased FS (p=0.033). Cd was found to be higher in patients who worked in positions involving exposure to heavy metals and in individuals with an ALT level above 40 IU/L (p=0.008). Several correlations have been found between the hepatic tissue metal levels in our study. In a linear regression analysis, Fe and Zn were found to be correlated with the fibrosis scores (p=<0.001 and p=0.029), and Cu was correlated with HAI (p=0.023). In the linear regression model, Ni (p=0.018) and Cr (p=0.011) were correlated with gender. There was a correlation between the hepatic Fe level and the location where hepatitis B patients were living (village/city) (p=0.001), frequency of fish consumption (p=0.045) and smoking (p=0.018) according to the linear regression analysis. Using a logistic regression analysis, Cr (p=0.029), Ni (p=0.031) and Pb (p=0.027) were found to be correlated with smoking habit, and Zn (p=0.010), Ag (p=0.026), Cd (p=0.007) and Al (p=0.005) were correlated with fish consumption. ConclusionThe liver tissue trace element levels are correlated with disease activity and histologic damage in patients with HepB disease. Additionally, smoking, the environment in which the patient works and the amount of fish consumption affect the accumulation of trace elements in the liver.

Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/β-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial

BackgroundThere is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis. MethodsIn this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160mg/m2/day for six cycles of 1week on and 1week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440). FindingsBetween Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)].After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40mg/m2/day cohort, and improved in one patient by 3 points in the 160mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10mg/m2/day cohort, and improved in one patient in the 40mg/m2/day cohort. InterpretationThis study showed that administration of 10 or 40mg/m2/day intravenous PRI-724 over 12weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160mg/m2/day cohort. Funding SourceAMED.

Serum hepatitis B core antibody as a biomarker of hepatic inflammation in chronic hepatitis B patients with normal alanine aminotransferase

Our previous studies unexpectedly indicated that the level of serum hepatitis B core antibody (anti-HBc) was positively correlated with the serum alanine aminotransferase (ALT) level. The aim of this study was to determine whether anti-HBc could serve as a potential biomarker for the detection of liver inflammation in chronic hepatitis B (CHB) patients, especially in patients with normal ALT levels. Serum anti-HBc levels were quantified in 655 treatment-naïve CHB patients, including 45 patients who underwent two liver biopsies (baseline phase and the 78th weeks of antiviral-treatment). Serum anti-HBc levels increased significantly along with the increasing histology activity index (HAI) score. After antiviral-treatment, patients with HAI score reduction had significant decline in serum anti-HBc level. Multivariate analysis showed that anti-HBc was independently associated with moderate-to-severe hepatic inflammation in patients with normal ALT level. Furthermore, serum anti-HBc showed a high diagnostic accuracy for predicting moderate-to-severe inflammation in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB patients with normal ALT levels (area under the curve, AUC = 0.87 and 0.75; respectively). Thus, anti-HBc may be a strong indicator for assessing the hepatic inflammatory degree and used for antiviral treatment decisions in CHB patients with normal ALT levels.

Relationship between liver injury and serum cytokeratin 18 levels in asymptomatic hepatitis B virus carriers and in patients with chronic hepatitis B infection

Background and study aimsApoptosis represents a well-known mechanism of cell death involved in most chronic liver injuries. Our aim was to investigate the serum fragment level of cytokeratin 18 (CK18), M30, in asymptomatic hepatitis B virus (HBV) carriers and patients with chronic hepatitis B (CHB) and to evaluate the relationship between serum M30 levels and the severity of hepatic injury. Patients and methodsAsymptomatic HBV carriers (n=169), patients with CHB (n=100), and healthy control subjects (n=43) were enrolled in the study. Serum CK18 (M30) levels were analysed in all subjects. Liver biopsy for histopathological assessment was performed in asymptomatic HBV carriers and in patients with CHB infection. ResultsSerum CK18 (M30) levels were significantly higher in asymptomatic HBV carriers (198.77±77.62U/L) than in healthy control subjects (146.92±40.18U/L). Patients with CHB (283.02±147.45U/L) had significantly higher CK18 (M30) levels than asymptomatic HBV carriers (p=0.001). The diagnostic efficacy of CK18 (M30) levels in distinguishing patients with HBeAg-negative CHB from asymptomatic HBV carriers was found to be moderate (c-statistics: 0.695), and the diagnostic cut-off value of CK18 (M30) was 262U/L (specificity: 85%, sensitivity: 48%, positive likelihood ratio: 3.35, and negative likelihood ratio: 0.60). There was a positive correlation between serum CK18 (M30) levels and histological activity index scores in asymptomatic HBV carriers and patients with CHB. ConclusionsSerum CK18 (M30) levels may be a valuable indicator in distinguishing asymptomatic HBV carriers from patients with HBeAg-negative CHB when considered together with ALT and HBV-DNA levels.

Chronic DON exposure and acute LPS challenge: effects on porcine liver morphology and function

The aim of the present study was to examine the role of chronic deoxynivalenol (DON) exposition on the liver morphology and function in combination with pre- and post-hepatic lipopolysaccharide (LPS) stress in young pigs fed for 4 weeks with a DON-contaminated diet (4.59 mg/kg feed). At the end of the experiment, LPS (7.5 μg/kg BW) was administered for 1 h pre-hepatically (Vena portae hepatis) or post-hepatically (Vena jugularis). Liver morphology was macroscopically checked and showed haemorrhage in all LPS groups, significantly higher relative liver weights, accompanied by marked oedema in the gallbladder wall. Histological changes were judged by a modified histology activity index (HAI). Liver HAI score was significantly increased in all LPS groups compared to placebo, primarily due to neutrophil infiltration and haemorrhage. DON feed alone was without effect on the liver HAI. Liver function was characterized by (i) hepatic biochemical markers, (ii) mitochondrial respiration and (iii) Ca2+ accumulation capacity of isolated mitochondria. Clinical chemical parameters characterizing liver function were initially (<3 h) slightly influenced by LPS. After 3 h, bilirubin and alkaline phosphatase were increased significantly, in DON-fed, jugular-infused LPS group. Respiration and Ca2+ accumulation capacity of isolated liver mitochondria was not impaired by chronic DON exposure, acute LPS challenge or combined treatments. DON-contaminated feed did not change macroscopy and histology of the liver, but modified the function under LPS stress. The different function was not linked to modifications of liver mitochondria.

Expression of Hepatocyte Hepatitis B Core Antigen and Hepatitis B Surface Antigen as a Marker in the Management of Chronic Hepatitis B Patients.

Background/AimsWe aimed to clarify the association of hepatitis B surface antigen (HBsAg)/hepatitis B core antigen (HBcAg) with the disease status and treatment response in patients with chronic hepatitis B (CHB).MethodsWe investigated 171 biopsy-proven entecavir-treated CHB patients (109 hepatitis B e antigen [HBeAg]-positive, 62 HBeAg-negative). HBcAg expression was positive when ≥10% of hepatocytes stained, and classified into nuclear, mixed, and cytoplasmic patterns. HBsAg expressions were intracytoplasmic (diffuse, globular, and submembranous) and membranous. The histologic activity index (HAI) and fibrosis stage followed Ishak system.ResultsIn HBeAg-positive patients, older age, increased HAI score, advanced fibrosis, and reduced viral load were observed when HBcAg expression shifted from nucleus to cytoplasm in HBcAg-positive patients, and HBsAg expression from non-submembranous to submembranous in HBcAg-negative patients (all, p<0.05). In HBeAg-negative patients, only intracytoplasmic HBsAg expression patterns had clinical relevance with decreased ALT levels and viremia. In HBeAg-positive patients without favorable predictors of virologic response, negative HBcAg and membranous HB-sAg expression predicted greater virologic response (both, p<0.05). The probability of HBeAg seroclearance was higher in patients with increased HAI or lacking HBcAg expression (both, p<0.05). Higher serum HBsAg levels and hepatocyte HBcAg positivity were associated with reduced serum HBsAg during first and post-first year treatment, respectively (both, p<0.05).ConclusionsHepatocyte HBcAg/HBsAg expression is a good marker for disease status and predicting treatment response.