Knodell Histological Activity Index Research Articles

The Hepatoprotective Effect of Curcuma longa Extract on Dengue Virus Serotype-2 infected BALB/c Mice

BACKGROUND: Dengue infection has a wide clinical spectrum ranging from asymptomatic infection to severe form with organ damage. Liver is among the common organ affected. Curcuma longa is a widely used herb that exhibits a hepatoprotective effect. AIM: This study aimed to investigate effect of C. longa on liver necroinflammatory activity and alanine aminotransferase (ALT) levels in dengue virus serotype-2 (DENV-2) infected BALB/c mice. MATERIALS AND METHODS: BALB/c mice were assigned into Group 1 (healthy mice), Group 2 (without C. longa administration), and Group 3 (C. longa administered). DENV-2 was inoculated intraperitoneally in Groups 2 and 3. C. longa extract was given at dose of 0.147 mg/mL intraorally in the 1st to 7th day. Liver histopathology and ALT level were assessed on the 7th day. Necroinflammatory activity was assessed with a Knodell histology activity index (HAI) score. RESULTS: The median Knodell HAI score in Group 1, Group 2, and Group 3 were 1.0 (0–5), 7.0 (4–10), and 3.5 (0–8), respectively. The mean difference of Knodell HAI score between Group 2 and Group 3 is 4.1 (95% CI 1.75–6.45, p = 0.002). The mean ALT in Groups 1, 2, and 3 were 58.22 ± 18.31 IU/L, 58.26 ± 18.31 IU/L, and 57.00 ± 10.71 IU/L, respectively. One-way analysis of variance test showed no significant differences in ALT level levels among the three groups (F = 0.26, p = 0.974). CONCLUSION: This study showed the hepatoprotective effect of C. longa that might decrease the liver necroinflammatory activity in dengue infection.

Liver histological changes in patients with hepatitis B e antigen-negative chronic hepatitis B virus infection with low hepatitis B virus load

Objective To determine the predictive factors for antiviral therapy in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection [HBeAg(-) CHBI] patients with HBV DNA<4.3 lg IU/mL. Methods A total of 179 HBeAg(-) CHBI patients were retrospective analyzed. Histology activity index (HAI) and fibrosis (S) were scored according to the Knodell HAI scoring system, and HAI>3 and/or S≥3 was adopted as indications for treatment. Univariate and multiple regression analysis were used to assess factors associated with treatment indications. Receiver operating curves (ROC) and area under curve (AUC) were used to determine the predictive value of relevant factors. Results There were 81 cases with HAI>3 (45.3%) and 72 with S≥3 (40.22%), and the proportion of patients with indications for treatment was 54.7%. Multiple regression analysis showed that age, γ-glutamyl transpeptadase (γ-GT), platelet (PLT) and albumin (Alb) were the predictive factors for the severity of liver damage and indication for treatment (all P<0.05). The AUC for age, PLT, γ-GT and Alb were 0.655, 0.657, 0.726 and 0.65, respectively, and the corresponding Yoden index for age, PLT, γ-GT, and Alb were 0.297, 0.426, 0.03 and 0.012, respectively, the sensitivities of predicting HBeAg(-)CHBI for treatment indications were 0.643, 0.842, 0.705 and 0.653, respectively. Conclusions This study shows that 54.7% of HBeAg(-)CHBI patients with HBV DNA<4.3 lg IU/mL have significant liver histological changes and require antiviral treatment. Older age, higher γ-GT, lower PLT and lower Alb levels are the predictive factors for treatment. Key words: Hepatitis B, chronic; Hepatitis B e antigens; Viral load; Liver biopsy

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.

Effect of Methylprednisolone on Liver Injury and Endotoxin Levels Following Brain Death in Rats

Background and aimBrain death impairs liver function in potential donors and is associated with inflammatory activation. Methylprednisolone treatment after brain death has been shown to reduce inflammatory activity. The aim of the present study was to evaluate the effects of methylprednisolone on liver injury and endotoxin levels in brain-dead rats. MethodsThirty-two rats were randomly divided into 4 groups: a sham-operation group (Sham group), a brain death with methylprednisolone treatment group (Methy group), a brain death with saline treatment group (Saline group), and a brain death group (BD group). The rats were anesthetized and induced by gradually increasing the intra-cranial pressure using a Fogarty catheter balloon for brain death. All of the animals were observed and ventilated for 6 h prior to being euthanized. Hepatic pathologic histology (Knodell histology activity index), liver inflammatory cytokine levels, liver function and endotoxin levels were assessed. ResultsAfter brain death, methylprednisolone markedly alleviated the Knodell histology activity index of liver injury (P < .05). Additionally, significant reductions in the levels of TNF-α, IL-1β, and IL-10 were observed in the Methy group compared to those in the Saline and BD groups (P < .01), whereas no significant differences were found between the Saline and BD groups (P > .05). Interestingly, although the rate of liver injury after brain death in the methylprednisolone treatment group improved, the endotoxin level did not decline in the Methy group compared to the levels in the Saline and BD groups (P > .05). ConclusionThe present study verified that methylprednisolone was protective for liver injury in rats subjected to brain death. This protection appeared to be due to reduced inflammatory activity with no influence on the endotoxin level.

Effects of gadolinium-based MRI contrast agents on liver tissue.

MRI with contrast is often used clinically. However, recent studies have reported a high accumulation of gadolinium-based contrast agents (GBCAs) in kidney, liver, and spleen tissues in several mouse models. To compare the effects on liver tissue of gadolinium-based MRI contrast agents in the light of biochemical and histopathological evaluation. Institutional Review Board (IRB)-approved controlled longitudinal study. In all, 32 male Sprague-Dawley rats were divided into a healthy control group subjected to no procedure (Group 1), a sham group (Group 2), a gadodiamide group (Group 3), and a gadoteric acid group (Group 4). Not applicable. Liver tissues removed at the end of the fifth week and evaluated pathologically (scored Knodell's histological activity index [HAI] method by two histopathologists) immunohistochemical (caspase-3 and biochemical tests (AST, ALT, TAS, TOS, and OSI method by Erel et al) were obtained. Differences between groups were analyzed using the nonparametric Kruskal-Wallis test followed by the Tamhane test, and one-way analysis of variance (ANOVA) followed by Turkey's HSD test. An increase was observed in histological activity scores in sections from rats administered gadodiamide and gadoteric acid, and in caspase-3, AST and ALT values (P < 0.05). In contrast, we determined no change in TOS (P = 0.568 and P = 0.094, respectively), TAS (P = 0.151 and P = 0.055, respectively), or OSI (P = 0.949 and P = 0.494, respectively) values. These data suggest that gadodiamide and gadoteric acid trigger hepatocellular necrosis and apoptosis by causing damage in hepatocytes, although no change occurs in total antioxidant and antioxidant capacity. 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1367-1374.

Diagnosis of Liver Fibrosis With Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein (WFA-M2BP) Among Chronic Hepatitis B Patients.

BackgroundWisteria floribunda agglutinin-positive Mac-2 binding protein (WFA-M2BP) is a protein with altered glycosylation that reacts with lectin, and was recently identified as a useful non-invasive biomarker for the diagnosis of liver fibrosis in patients with hepatitis C virus infection.This study aimed to evaluate the diagnostic efficacy of WFA-M2BP for liver fibrosis in the context of hepatitis B virus (HBV).MethodsWe enrolled 151 patients infected with HBV. Liver biopsy and elastography (Fibroscan) were performed during the initial visit. Fibrosis was graded according to the Knodell histologic activity index (F0–3). WFA-M2BP levels were determined with an automated immunoassay analyzer (M2BPGi, HISCL-5000, Sysmex, Japan). The diagnostic efficacy of WFA-M2BP was compared with those of various conventional or composite biomarkers, including enhanced liver fibrosis (ELF) score, Fibroscan, aspartate transaminase (AST)-to-platelet ratio index (APRI), and FIB-4, based on the area under the ROC curve (AUC) value.ResultsThe majority of patients were at fibrosis stages F1 and F2. The F2 and F3 AUC values for WFA-M2BP were similar to those for FIB-4, APRI, ELF, and Fibroscan, although the latter showed the best diagnostic efficacy. The diagnostic accuracy of all tested biomarkers for F2 and F3 was 60–70%. In multivariate analysis, WFA-M2BP, ELF, and platelet count significantly predicted stage ≥F2, whereas only platelet count significantly predicted F3.ConclusionsWFA-M2BP can support a diagnosis of liver fibrosis with similar diagnostic efficacy to other biomarkers, and predicted liver fibrosis stage ≥2 among patients with chronic hepatitis B.

PET/CT with 18F Fluorocholine as an Imaging Biomarker for Chronic Liver Disease: A Preliminary Radiopathologic Correspondence Study in Patients with Liver Cancer.

Purpose To determine the relationship between hepatic uptake at preoperative fluorine 18 (18F) fluorocholine combined positron emission tomography (PET) and computed tomography (CT) and the histopathologic features of chronic liver disease in patients with Child-Pugh class A or B disease who are undergoing hepatic resection for liver cancer. Materials and Methods Forty-eight patients with resectable liver tumors underwent preoperative 18F fluorocholine PET/CT. Mean liver standardized uptake value (SUVmean) measurements were obtained from PET images, while histologic indexes of inflammation and fibrosis were applied to nontumor liver tissue from resection specimens. Effects of histopathologic features on liver SUVmean were examined with analysis of variance. Results Liver SUVmean ranged from 4.3 to 11.6, correlating significantly with Knodell histologic activity index (ρ = -0.81, P < .001) and several clinical indexes of liver disease severity. Liver SUVmean also differed significantly across groups stratified by necroinflammatory severity and Metavir fibrosis stage (P < . 001). The area under the receiver operating characteristic curve for 18F fluorocholine PET/CT detecting Metavir fibrosis stage F1 or higher was 0.89 ± 0.05, with an odds-ratio of 3.03 (95% confidence interval: 1.59, 5.88) and sensitivity and specificity of 82% and 93%, respectively. Conclusion Correlations found in patients undergoing hepatic resection for liver cancer between liver 18F fluorocholine uptake and histopathologic indexes of liver fibrosis and inflammation support the use of 18F fluorocholine PET/CT as a potential imaging biomarker for chronic liver disease. © RSNA, 2018.

Non-ALT biomarkers for markedly abnormal liver histology among Chinese persistently normal alanine aminotransferase-chronic hepatitis B patients.

AIMTo determine incidence and clinical biomarkers of marked necroinflammation and fibrosis characteristics among chronic hepatitis B (CHB) patients with persistently normal alanine aminotransferase (PNALT).METHODSLiver biopsy was performed on 115 CHB patients with PNALT. Necroinflammation and fibrosis were graded by the Knodell histologic activity index and the Ishak fibrosis score, respectively. Correlations between the available clinical parameters and necroinflammation and fibrosis were analysed.RESULTSMarked necroinflammation (Knodell activity index ≥ 7) and fibrosis (Ishak fibrosis score ≥ 3) were found in 36.5% and 15.5% of CHB patients with PNALT, respectively. Following a univariate logistic regression analysis, multiple logistic regression analysis indicated that aspartate transaminase (AST) (AUROC = 0.852, cut-off value = 22.5 U/L) serves as an independent predictor of notable liver inflammation, while platelet (PLT) count (AUROC = 0.905, cut-off value = 171.5 ×109/mL) and gamma-glutamyl transpeptidase (GGT) (AUROC = 0.909, cut-off value = 21.5 U/L) level serve as independent predictors of notable liver fibrosis.CONCLUSIONA considerable proportion of marked histological abnormalities existed in our cohort, who will benefit from optimal therapeutic strategies administered according to predictive indication by AST, PLT and GGT levels.

Bushenjianpi formula combined with entecavir for HBeAg-negative chronic hepatitis B patients: a multicentre, randomised, double-blind, placebo-controlled trial

BackgroundThe treatment combination of traditional Chinese medicine with western medicine results in significant decrease of serum hepatitis B virus (HBV) DNA and increase of HBeAg loss in patients with HBeAg-positive chronic hepatitis B (CHB) without any serious adverse events. We aimed to assess whether the Bushenjianpi Formula combined with entecavir could increase the HBsAg loss rate in patients with HBeAg-negative CHB. MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, we recruited patients with HBeAg-negative CHB from ten third-level grade-A hospital of Traditional Chinese Medicine. The inclusion criteria included a history of HBV or HBsAg positive for more than 6 months; positivity for HBsAg or HBV DNA; persistent HBeAg-negativity or HBeAb positivity; HBV DNA concentration of 1 × 104 copies per mL or higher by PCR assay at least 4 weeks before screening; alanine aminotransferase (ALT) concentrations of 2 × ULN or greater, or 1 × ULN≤ALT<2 × ULN and Knodell histology activity index of 4 points or greater at least 4 weeks before screening; no treatment with any nucleoside analogues or interferon at least 12 months before screening; and age 18–65 years. The exclusion criteria included being co-infected with other hepatitis viruses; hepatocellular carcinoma and other forms of liver disease; having other severe primary disease or mental disorder disease, and being pregnant and lactating. By using a block randomisation method, patients were randomly assigned (1:1) to receive Bushenjianpi Formula combined with entecavir (treatment group) or placebo combined with entecavir (control group) for 96 weeks. All patients were treated with entecavir 0·5 mg daily and the Bushenjianpi Formula or placebo (4·5 g twice daily, oral administration). The primary outcome was the of rate of HBsAg negative conversion and the secondary outcomes were the decline range of HBsAg, and the level of cccDNA. We used χ2 tests and independent-sample t-test to assess differences between groups. This study was conducted in accordance with the ethics principles of the Declaration of Helsinki and approved by the Ethical Committee of Shuguang Hospital, Shanghai University of Traditional Chinese Medicine. All patients were written informed consent. FindingsBetween Dec 1, 2012, and March 31, 2016, 620 patients with HBeAg-negative CHB were recruited, and they were randomly assigned to the treatment group (320 patients) and the control group (320 patients). After 96 weeks of treatment, the percentage of patients who had reduction in serum HBsAg concentrations decreased more than 1Log10 in the treatment group (11·76%), which was significantly higher than that in control group (6·41%; p=0·043). The rate of HBsAg negative conversion was determined by the ratio between the number of patients whose HBsAg level was lower than 0·1 IU/mL and the total number of patients in every group after treatment. The rate of HBsAg negative conversion was significantly greater in the treatment group (5·13%) than in control group (2·10%; p=0·046). The cccDNA level of liver tissue after treatment was lower than that before treatment in both groups (p=0·001). In this study, there were five cases of adverse events in treatment group and six cases of adverse events in control group. The symptoms in adverse events included cold, fever, and diarrhoea. InterpretationThe combination of Bushenjianpi Formula with entecavir could result in a decrease of serum HBsAg and liver tissue cccDNA, as well as increase of HBsAg negative conversion for patients with HBeAg-negative CHB. FundingNational Natural Science Foundation of China (81473477, 81403354, 81473629, 81403351, 81503545), Science Research Project of Twelve Five-year Plan (2012ZX10005004–002), Shanghai Rising-Star Program (13QA1403500), the Key Technology Research of Shanghai Municipal Science (13401902900), Three-year action plan of development of TCM in Shanghai (ZYSNXD-CC-ZDYJ015 and ZY3-CCCX-3–3027), Training plan of outstanding young medical talents, Shanghai Municipal Health Bureau (XYQ2013093), Shanghai Sailing Program (14YF1411600, 15YF1412300), Wang Baoen liver fibrosis research fund of China foundation for Hepatitis Prevention and Control (CFHPC20131045, CFHPC20131046) and the Budgeted Projects of Shanghai University of Traditional Chinese Medicine (2013JW40, 2014YSN39).

Non-invasive fibrosis tests are correlated with necroinflammatory actvity of liver in patients with chronic hepatitis B.

The gold standarda method used for assessing necroinflammatory activity and fibrosis in the liver is a liver biopsy which has many disadvantages. Therefore, many investigators have been trying to develop non-invasive tests for predicting liver fibrosis score (LFS) of these patients. The aim of this study is to describe the relationship between certain non-invasive fibrosis markers with LFS and histological activity index (HAI) detected histopathologically by liver biopsy in chronic hepatitis B patients. A total of 54 patients who had undergone a liver biopsy with the diagnosis of chronic HBV infection were included in the study. Ishak scoring was used for the evaluation of liver fibrosis, and a modified Knodell HAI was used for demonstration of necroinflammation. In this study, non-invasive fibrosis tests were calculated as described in previous studies. Histological acitivity index was positively correlated with age, age/platelet index, cirrhosis discriminant score (CDS), AST/platelet ratio index (APRI), AST/platelet/GGT/AFP index (APGA), fibro-quotient (Fibro-Q), Goteburg University Cirrhosis Index (Guci), and Platelet/Age/Phosphatase/AFP/AST index (PAPAS). When divided into two groups according to HAI, Guci and APGA were found significantly different both in >4 and >4 HAI groups than the other group. In ROC analysis performed for LFS; PAPAS, APGA, FFI and APRI were the markers having the highest AUC levels, and in ROC analysis performed for HAI; Guci, APRI and APGA were the markers with the highest AUC levels. APRI, APGA and GUCI tests may be helpful in prediction of necroinflammatory scores in the liver.

Abstract 1486: Fatty acid and phospholipid profiling of liver tumor tissue: correlation with in vivo molecular PET imaging of phosphocholine synthesis

Abstract Alterations in phospholipid and fatty acid metabolism may play key roles in hepatocarcinogenesis. Phosphocholine synthesis can be imaged and quantified in-vivo by positron emission tomography (PET) using radiopharmaceuticals bearing the choline moiety. Results from this PET assessment of tissue phospholipid metabolism were compared to phospholipid and fatty acid profiles of both tumor and liver parenchymal tissues in patients with liver cancer undergoing hepatectomy. Fluorine-18 fluorocholine PET/CT of the liver was completed &amp;lt;2 weeks prior to surgery as part of a clinicaltrials.gov-registered (NCT01395030) IRB-approved clinical study with written informed consent. Paired tumor and parenchymal tissue samples were collected in liquid nitrogen (20 hepatocellular carcinoma, 3 with intrahepatic cholangiocarcinoma), freeze-dried, homogenized and extracted with methanol/CHCl3/water containing BHT as preservative. The organic phase was analyzed by orbitrap LCMS after electrospray ionization in positive mode to quantify fatty acids (after derivatization) and phospholipid metabolites. Tumor and liver standardized uptake value (SUV) measurements were obtained from static PET images. Tumors exhibited significantly lower levels of docosahexaenoic acid, docasopentanoic acid, alpha-linolenic acid and significantly higher levels of palmitoleic acid, eicosadienoic acid, arachadonic acid, and linoleic acid than peritumoral liver tissue. Tumors also exhibited significantly higher SUVs than surrounding liver. Highest tumor SUV correlated significantly with tumor levels of palmitoleic acid, gamma linolenic acid, CDP choline, phosphatidylcholine, phosphatidylethanolamine and phosphatidylinsolitol. In contrast, no significant correlations were noted between tumor SUV and peri-tumoral levels of these compounds. Peritumoral liver SUV was significantly correlated with levels of myristic acid, eicosaptaenoic acid, gamma-linolenic acid, palmitoleic acid, docosapentaenoic acid, linoleic acid, oleic acid, and palmitic acid in peritumoral liver tissue. Furthermore, parenchymal liver SUV was inversely correlated with the Knodell histologic activity index (HAI), as well as histologic features of portal inflammation, piecemeal necrosis, and fibrosis. These histology features were also inversely correlated with liver tissue concentrations of docosahexaenoic acid, CDP-choline, total phosphaticylcholine, and total phosphatidylinositol. No significant correlations were found between tumor fatty acid/phospholipid levels and Edmonson-Steiner tumor grade. These preliminary results may indicate multiple inter-related metabolic alterations involving phospholipid and fatty acid metabolism in primary liver cancer. Chronic liver disease appears to be associated with diminishing hepatic phospholipid reserve. Note: This abstract was not presented at the meeting. Citation Format: Sandi Alexander Kwee, Adrian A. Franke, Laurie J. Custer, Xingnan Li, Linda L. Wong. Fatty acid and phospholipid profiling of liver tumor tissue: correlation with in vivo molecular PET imaging of phosphocholine synthesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1486. doi:10.1158/1538-7445.AM2015-1486

Association between vitamin D level and viral load or fibrosis stage in chronic hepatitis B patients from Southern China

The role of vitamin D playing in patients with chronic hepatitis C has been intensively studied. However, studies on the potential interaction between vitamin D level and chronic hepatitis B are still limited. This study aimed to explore whether any association existed between serum vitamin D level and liver histology or virological parameters in patients with chronic hepatitis B infection in Southern China. 25-Hydroxyvitamin D serum levels were determined in a cohort of 242 treatment-naïve chronic hepatitis B patients. Histologic assessment was based on Knodell histologic activity index and Ishak fibrosis staging. Predictors of vitamin D insufficiency were identified using multivariate analysis. Mean 25-hydroxyvitamin D value was 33.90 ng/mL. The percentage of patients with different concentration of 25-hydroxyvitamin D (≥ 30 ng/mL, 20-30 ng/mL, < 20 ng/mL) were 59.9%, 31.4%, and 8.7%, respectively. Gender, season, age, and viral genotype were independent predictors of vitamin D insufficiency (< 30 ng/mL). Patients with genotype B virus infection had a lower mean 25-hydroxyvitamin D level (P = 0.023) and higher prevalence of vitamin D insufficiency than those with genotype C (P = 0.021), while no association was found between vitamin D status and viral load. In addition, 25-hydroxyvitamin D level did not significantly vary according to activity grade or fibrosis stage. The prevalence of vitamin D insufficiency is relatively low in our cohort. Patients infected with genotype B had a higher prevalence of vitamin D insufficiency than genotype C. 25-Hydroxyvitamin D serum level is not associated with viral load or fibrosis stage in chronic hepatitis B patients.

Association of sociodemographical features, antiviral treatment, and necroinflammatory activity with depression and anxiety in chronic hepatitis B patients

Objective: Psychiatric disorders like depression and anxiety are known to be more prevalent in patients with chronic hepatitis B than healthy individuals. This increased prevalence may be due to multiple factors such as psychological distress associated with having a chronic disease, necroinflammatory activity in liver, side effects of treatment with antiviral agents or interferons, and/or direct effect of hepatitis viruses on central nervous system. Purpose of this study was to evaluate several risk factors that may be associated with anxiety and depression in patients with chronic hepatitis B. Methods: This study included 195 chronic hepatitis B patients. A psychiatrist made clinical interviews with the patients and filled Sociodemographic Data Form, Hamilton Anxiety Rating Scale (HARS), and Hamilton Depression Rating Scale (HDRS). Needle biopsies were performed to 175 patients who met biopsy criteria of American Association for the Study of Liver Diseases. Knodell Histological Activity Index was used to evaluate biopsy materials. HBV DNA and ALT levels were measured from patients’ sera. Findings: In the study sample, 119 patients were males and 76 were females. Mean HARS score was 7.3±6.2 and mean HDRS score was 8.8±6.6. Both HARS and HDRS scores were higher in females than males. HARS score was higher in patients with a family history of chronic hepatitis and both HARS and HDRS scores were higher in patients with comorbid medical illness. Alanine aminotransferase, HBV DNA levels, and level of fibrosis in liver biopsy didn’t affect HARS or HDRS scores. Also, there wasn’t a difference in HARS or HDRS scores according to patients’ usage of pegylated interferon, or oral antiviral therapy. Conclusion: Multiple factors affect the relation between chronic hepatitis and psychiatric disorders like anxiety and depression. Results of our study suggest that female sex, presence of a family history for chronic hepatitis B, comorbidity of other medical diseases, and ethnic origin affect more than the level of necro-inflammatory activity and cellular damage in the liver or antiviral treatments.

Reelin expression by hepatic stellate cells and ductular reaction in HCV related liver fibrosis

Reelin is a secreted extracellular glycoprotein that is thought to guide migrat- ing neurons during brain development and maturation cooperating with Disabled-1 (Dab1), an adaptor protein obligate effector of reelin signalling pathway (1). Reelin is also expressed in human liver by hepatic stellate cell(HSC)s that following liver injury become activated, migrating and fibrogenic cells (2). The cross-talk between HSCs and other cells such as those of ductular reaction (DR) is believed to rule liver fibrogenesis leading to cirrhosis (3). In order to better understand the role of ree- lin in human liver tissue with ongoing fibrosis, we aim to analyse the hepatic reelin expression and its relationship with the main histological determinants of the dis- ease activity and severity. Eighty-one liver biopsies of patients with chronic hepatitis C were studied. The expression of Reelin, Dab1, and HSC markers was investigated by immunohistochemistry and immunofluorescence. The Knodell histology activity index and DR score were evaluated. Activated HSC were frequently reelin positive and a statistical correlation was found between the number of reelin positive HSCs and Knodell’s stage (r= 0,3; p<0,05). Dab1 was expressed by cells of DR and the number of reelin positive HSCs correlated with DR score in mild/moderate fibrosis (r=0,4; p<0,05). Since reelin expression by HSCs correlates with increasing fibrosis and DR, whose cells in turn express Dab1, it might act as mediator in DR activation by HSCs. Further studies are needed to test reelin as useful biomarker for liver fibrosis assess- ment.

Does low‐dose prolonged steroid therapy affect the natural history of chronic hepatitis C?

Chronic hepatitis C patients may require steroids due to other comorbidities. However, there is not enough information to consider steroids as beneficial or harmful drugs on natural history of chronic hepatitis C. The aim of the present study was to examine the effect of low-dose prolonged therapy with corticosteroids with or without azathioprine on these study patients. A retrospective-prospective observational study was established. Twenty-eight patients with chronic hepatitis C and treated with corticosteroids at low-dose (≤30 mg/day) with or without azathioprine for more than 6 months were included. AST, ALT, HCV RNA, and liver fibrosis were determined, and results were compared with a control group of non-treated chronic hepatitis C patients. The mean age was 47 ± 10 years. The male proportion was 43%. The mean dose of prednisone was 9 ± 5 mg/day (range: 2.5-30 mg/day). The mean treatment time was 76 ± 80 months (range: 7-349 months). Thirty six percent received concomitant azathioprine. Transaminases decreased significantly only within the first 3 months of treatment, with non-significant changes thereafter. Corticosteroids led to a non-significant increase in HCV RNA. Knodell Histology Activity Index decreased (from 8.5 ± 3.7 to 4.7 ± 1.7; P = 0.1). Fibrosis progression per year (final fibrosis stage-initial fibrosis stage/time between explorations, in years), was lower in treated cases than in control group (0.054 ± 0.25 units vs. 0.196 ± 0.6 units, P = 0.26). In conclusion, corticosteroid treatment caused a significant initial decrease in transaminases, non-significant changes in HCV RNA, and a trend to a slower fibrosis progression in comparison to a control group. Therefore, corticosteroids did not accelerate progression of chronic hepatitis C.

Diffusion Weighted MRI for Hepatic Fibrosis: Impact of b-Value

BackgroundHepatic fibrosis is a typical complication of chronic liver diseases resulting in cirrhosis that remains a major public health problem worldwide. Liver biopsy is currently the gold standard for diagnosing and staging hepatic fibrosis. Percutaneous liver biopsy; however, is an invasive procedure with risks of complications. Therefore, there is need for alternative non-invasive techniques to assess liver fibrosis and chronic liver diseases. In recent years, MRI techniques, including diffusion weighted imaging (DWI), have been developed for in vivo quantification of liver fibrosis.ObjectivesThe purpose of this study is to evaluate the utility of diffusion weighted MRI in the diagnosis and quantification of the degree of hepatic fibrosis and to investigate the influence of b-value.Patients and MethodsTwenty-four patients (13 males, 11 females), with a mean age of 46 years (36-73 years) diagnosed as chronic hepatitis and histopathologically proven liver fibrosis and 22 other patients (8 males, 14 females) with no clinical or biochemical findings of liver disease, with a mean age of 51.2 years (32-75 years) were included in the study. All patients with chronic hepatitis underwent percutaneous liver biopsy by an experienced hepatologist without sonographic guidance. The Knodell histology activity index (HAI) for grading of necroinflammatory changes and Metavir scoring system for staging of the liver fibrosis were used to record the severity of the disease. All patients were examined with a 1.5 Tesla MRI system and the patients underwent diffusion weighted imaging (DWI) with a routine hepatic MRI protocol. Different b-values including 250, 500, 750, and 1000 sec/mm 2 were used to calculate apparent diffusion coefficients.ResultsWe detected decreased apparent diffusion coefficient values in patients with hepatic fibrosis compared to patients without chronic hepatitis and there was a trend toward decrease in hepatic apparent diffusion coefficient values with an increasing degree of fibrosis.ConclusionsOur findings suggest that hepatic apparent diffusion coefficient measurement with a b-value of 750 sec/mm 2 or greater is useful in accurate quantification of liver fibrosis and necroinflammation.

A comparative evaluation of scoring systems for assessing necro-inflammatory activity and fibrosis in liver biopsies of patients with chronic viral hepatitis.

To compare the five scoring systems in assessing grading and staging of liver biopsies from patients with chronic viral hepatitis and their problems and pitfalls. Liver biopsies from 25 patients with chronic viral hepatitis were studied. Sections were stained with Haematoxylin and Eosin, Reticulin and Masson's Trichrome stains. Van Gieson, Perl's and Shikata's Orcein stains were used as and when required. Coded histological sections were scored independently by three histopathologists using the Knodell Histology Activity Index (HAI), the Scheuer scoring system, Ishak's system, Metavir system and Ishak modified HAI. There were 15 males and 10 females. Their mean age was 51.24 years. On histological examination, hepatocytes showed degenerative changes with varying grades of necrosis (spotty and confluent). Widening of portal tracts with varying severity of mononuclear inflammatory infiltrate and interface hepatitis was observed. Fibrosis appeared as periportal, portal-portal and portal-central septa. A significant agreement was found by kappa statistics for both grading (p< 0.001) as well as staging (p < 0.001) among all the five scoring systems. Lobular activity was the only parameter that showed some discrepancy. No significant intra observer difference was observed. It is concluded that all the scoring systems are equally good for grading and staging in the hands of an experienced hepatopathologists.

Inflammation in background cirrhosis evokes malignant progression in HCC development from HCV-associated liver cirrhosis

Objective. It is accepted that inflammation promotes malignant progression in the development of cancers. Whether, this is true for hepatocellular carcinoma (HCC) remains as an open question. We examined the relationship between the inflammatory histology activity index (HAI) in the background liver cirrhosis (LC) and the histological grading of the HCC in the hepatectomized HCC patients with HCV-associated LC. Material and methods. Out of 264 HCC patients who underwent curative hepatic resection, 197 had HCV-associated LC. Among them, 52 patients with a small solitary HCC nodule (< 5 cm in diameter) were studied. Inflammation in the background LC was evaluated by modified Knodell's HAI. To evaluate the inflammation, piece meal necrosis, intra lobular cellular degeneration and focal necrosis, portal cellular inflammation (0–4, each) were estimated. The average HAI was calculated. The grade of malignancy of HCC was determined by WHO classification. Results. The average HAI in the 15 patients with moderately differentiated HCC (4.3 ± 0.8, mean ± SD) was significantly larger than that in 11 patients with well differentiated HCC (3.5 ± 0.6, p = 0.036). The HAI in the 24 patients whose HCC nodules contained poorly differentiated HCC (5.2 ± 1.1) was significantly larger than that in patients with moderately differentiated HCC (p = 0.025). Thus, the HAI order was well differentiated group < moderately differentiated group < poorly differentiated group. Conclusions. Inflammation in the background non-cancerous cirrhotic portion would evoke malignant progression in HCC development from HCV-associated LC.

Forty‐eight‐week retrospective study of telbivudine and lamivudine treatment in patients with hepatitis B‐related cirrhosis

The aim of this study was to evaluate the efficacy and safety of telbivudine 600 mg/day compared with lamivudine 100 mg/day for 48 weeks of treatment in patients with hepatitis B-related cirrhosis. Data were reviewed retrospectively from 165 hepatitis B-related cirrhotic patients (55 compensated patients and 110 decompensated) who received antiviral therapy with telbivudine or lamivudine. Serum alanine aminotransferase (ALT) and hepatitis B virus (HBV) DNA levels, hepatitis B e antigen (HBeAg) loss and seroconversion, histological improvement and various adverse events (AEs) were evaluated. Baseline characteristics were comparable. ALT levels declined but showed no significant difference in treatment with telbivudine or lamivudine (P > 0.05). Reduction in serum HBV DNA levels was evident by week 4 in compensated HBV-related cirrhosis patients (telbivudine, 2.34 log10 copies/mL; lamivudine, 2.07 log10 copies/mL; P = 0.02) and persisted by week 8. Patients administrated with telbivudine had slightly greater HBeAg loss and seroconversion than patients with lamivudine, but the difference was not statistically significant (P > 0.05). Accumulative HBeAg loss was seen at week 48 (25.0% vs 25.0% and 13.3% vs 10.0% for telbivudine vs lamivudine in compensated and decompensated cirrhotic groups, respectively), as well as HBeAg seroconversion (15.0% vs 8.3% and 8.9% vs 6.7%). Mean Knodell Histologic Activity Index scores decreased in both compensated and decompensated cirrhotic patients (3.92 vs 3.64, 3.85 vs 3.73, for telbivudine vs lamivudine). Telbivudine and lamivudine were both well tolerated with minor AEs. The results of this study support telbivudine as an effective therapy for patients with both compensated and decompensated HBV-related cirrhosis.

Portal Vein Thrombosis in Splenectomized Cirrhotic Patient: A Case Report

Purpose: Portal vein thrombosis (PVT) and systemic venous thromboembolism are significantly increased in cirrhotic patients even without hepatocellular carcinoma. The risk of developing such complications is usually associated with advanced cirrhosis. When cirrhosis is mild and compensated, other possible causes of PVT should also be considered. We present a case of PVT in chronic hepatitis C infection with focal cirrhosis and portal hypertension with history of splenectomy. A 47-year-old Caucasian woman presented with chronic hepatitis C, genotype 1. She was treated with pegylated interferon and ribavirin for 48 weeks, but developed viral relapse. She had splenectomy when she was young for unclear reason. Her findings on pathologic examination of the liver biopsy were consistent with focal cirrhosis in mild to moderate chronic hepatitis; the Knodell's histologic activity index (HAI) score was 7-9/22. Her MELD score was 6. An annual esophagogastroduodenoscopy revealed non-bleeding grade II esophageal varices and cardial gastric varices. A computerized tomography scan revealed the sub-occlusive thrombus at the bifurcation of the main portal vein. The workup for hypercoagulable state showed low protein C, protein S, and antithrombin III levels. The inferior vena caval venogram showed thrombotic occlusion in left, right, and common portal vein with a portal systemic pressure gradient of 11 mmHg. Collateralization was present at portal hiatus. The ultrasound guided thrombus removal with interventional thrombolysis was attempted in order to avoid systemic anticoagulation therapy. However, the guidewire failed to pass through the obstructed portal vein. She eventually was evaluated for liver transplantation. This is a case that demonstrates the presence of PVT in a patient with mild compensated cirrhosis (based on both histological and clinical evaluation) without hepatocellular carcinoma. The incidence of PVT in well-compensated cirrhosis is reported between 0.6-16%. An increased frequency is reported in decompensated cirrhosis and in up to 35% of cirrhotic patients with hepatocellular carcinoma. The origin of PVT is multifactorial in most cirrhotic patients. Low serum protein C, protein S, and antithrombin III level secondary to decreased protein synthesis in cirrhosis can contribute to a prothrombotic state. Splenectomy is another possible cause of PVT in this case, since PVT after splenectomy occurs in 6-8%. However, the late onset of presentation makes it a less likely cause since most PVT occurs in days to weeks after splenectomy.