Improvement In Fibrosis Scores Research Articles

Comparison of Efficacy of Glycyrrhiza Glabra (Licorice Extract) and Vitamin E in Decreasing Fibrosis Score in patients with Non-Alcoholic Fatty Liver Disease

Aim: To compare the efficacy of Glycyrrhiza glabra and vitamin E in decreasing fibrosis score in patients with non-alcoholic fatty liver disease (NAFLD). Method: This randomized controlled trial was carried out in the Medical Wards of Mayo Hospital/King Edward Medical University, Lahore. Two hundred and twelve patients with NAFLD were divided via random assignment into Group A that was given 800IU of vitamin E per day and Group B that received Glycyrrhiza Glabra in a dose of 10 mg per day. Both groups received treatment for 3 months and were re-evaluated monthly for improvement in fibrosis scores and liver transaminases. Data was analyzed using version 26.0 of SPSS. Results: Out of 212 patients, 53.4% were male and 46.6% were female. Mean age of patients in Group A was 35.8±14.26 and 41.93±14.2 in Group B. Fibrosis score in Group A decreased from 0.19± 1.02 to -0.14± 1.09 while reduction in Group B was from 0.29± 0.93 to -0.67± 0.97 (p-value <0.000). Only patients in Group B showed significant reduction in alanine transaminase (ALT 62.3± 15.3 to 57.2± 14.58, p-value <0.000). In lowering fibrosis score, vitamin E was effective in 11.3% of patients, whereas Glycyrrhiza glabra was effective in 34% patients (p-value 0.000). Practical Implication: With the global increase in the cases of NAFLD, it has become imperative to devise new treatment strategies to overcome this burden. No definitive treatment modality provides an ultimate cure for these patients. This study proves a superior role of Glycyrrhiza glabra (licorice extract) in terms of lowering fibrosis score and reduction of ALT levels. Conclusion: Both Glycyrrhiza glabra and vitamin E were effective in lowering fibrosis scores in patients with NAFLD, however, Glycyrrhiza glabra was more superior in terms of efficacy than vitamin E and also caused a considerable decrease in ALT levels. Keywords: Glycyrrhiza glabra, Vitamin E, Fibrosis Score, Non-alcoholic fatty liver disease

Effects of one-year supplementation with Phyllanthus niruri on fibrosis score and metabolic markers in patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial

Background and purposeand purpose: Non-alcoholic fatty liver disease (NAFLD) is a significant global health concern with limited pharmacotherapy options. This study aimed to evaluate the effectiveness of a standardized extract of Phyllanthus niruri in mild-to-moderate NAFLD. Materials and methodsThis was a 12-month randomized controlled trial, in which adults with a controlled attenuation parameter (CAP) score >250 dB/m and a fibrosis score <10 kPa were randomly assigned to receive a standardized P. niruri extract at a dose of 3,000 mg daily (n = 112) or a placebo (n = 114). The primary outcomes were changes in CAP score and liver enzyme levels, while the secondary outcomes were changes in other metabolic parameters. The analysis was performed on an intention-to-treat basis. ResultsAfter 12 months, there was no significant difference in the change of CAP score between the intervention and control groups (−15.05 ± 36.76 dB/m vs. −14.74 ± 41.08 dB/m; p = 0.869). There was also no significant difference in the changes of liver enzyme levels between the two groups. However, the intervention group showed a significant reduction in fibrosis score, which was not observed in the control group (−0.64 ± 1.66 kPa versus 0.10 ± 1.61 kPa; p = 0.001). No major adverse events were reported in either group. ConclusionThis study showed that P. niruri did not significantly reduce CAP score and liver enzyme levels in patients with mild-to-moderate NAFLD. However, a significant improvement in fibrosis score was observed. Further research is needed to determine its clinical benefits at different dosages for NAFLD treatment.

ODP181 Diabetes Mellitus and Advanced Liver Fibrosis – is Cirrhosis Reversible and Who Should We Screen?

Abstract Recent evidence shows an association between type 2 diabetes mellitus (T2DM) and liver steatosis, fibrosis, and hepatocellular carcinoma. Studies suggest that improved glycemic control, weight loss, and GLP-1 agonists may halt progression and even improve non-alcoholic fatty liver disease (NAFLD); however, little is known about the extent of improvement these factors have on liver fibrosis. ADA guidelines suggest only patients with T2DM or pre-DM and elevated liver enzymes (or fatty liver on ultrasound) should be evaluated for NAFLD and fibrosis. Three patients ages 65-71 with long-standing T2DM, HLD, obesity, and no history of liver disease or current alcohol use were followed in our diabetic clinic and referred for screening for liver steatosis and fibrosis. The transient elastography method (fibroscan) was used to determine the degree of liver fibrosis. On initial fibroscans, all three patients were found to have F4 scores consistent with liver cirrhosis. The first patient is a 71-year-old male with T2DM (BMI 37.5kg/m 2), treated with semaglutide, empagliflozin, glipizide, and insulin. Over two years, he experienced a 4-lb weight loss and improvement in HbA1c(7.8% to 7.1%). Repeat fibroscan after two years showed improved fibrosis score – F3 (11.6 kPa to 10.2 kPa), consistent with moderate fibrosis. The second patient is a 69-year-old female with T2DM (BMI 37.3kg/m 2) and transient mild LFT abnormalities, found to have cirrhosis on fibroscan – F4 score. She was managed with semaglutide, empagliflozin, metformin, and insulin; weight decreased 9-lbs over two years and HbA1c improved(10.8% to 7.8%). Repeat fibroscan showed improvement in fibrosis score to F2 (15.1 kPa to 8.9 kPa), and her LFT abnormalities resolved. The third patient is a 65-year-old male with T2DM (BMI 35kg/m 2). His initial fibroscan showed cirrhotic liver – F4 score. He was maintained on empagliflozin and dulaglutide- then switched to semaglutide. He experienced a 10-lb weight loss during this time and had a stable HbA1c(6.6%). Repeat fibroscan after one year showed improvement to F0-F1(11.3 kPa to 6.1 kPa) consistent with little to no liver scarring. These cases highlight two important factors: 1) ADA liver screening guidelines should be expanded to include obesity and dyslipidemia; and 2) advanced liver fibrosis in patients with diabetes is, to some degree, reversible. Not all of the patients initially met standard ADA screening criteria, mostly without elevated liver enzymes and no prior abnormal liver imaging. Yet, all were diabetic and obese with dyslipidemia, which are independent risk factors for NAFLD. Additionally, patients with improved glycemic control on GLP-1 treatment as well as some weight loss have promising results on repeat fibroscan. These findings may improve screening and management of diabetes-related liver disease. Further studies are needed to investigate to what extent GLP-1 agonists alone or in combination with glycemic control and weight loss contribute to these improvements. Presentation: No date and time listed

Response-Related Factors of Bone Marrow-Derived Mesenchymal Stem Cells Transplantation in Patients with Alcoholic Cirrhosis.

Liver cirrhosis leads to hepatic dysfunction and life-threatening conditions. Although the clinical efficacy of autologous bone marrow-derived mesenchymal stem cells (BM-MSC) transplantation in alcoholic cirrhosis (AC) was demonstrated, the relevant mechanism has not been elucidated. We aimed to identify the predictive factors and gene/pathways for responders after autologous BM-MSC transplantation. Fifty-five patients with biopsy-proven AC underwent autologous BM-MSC transplantation. The characteristics of responders who showed improvement in fibrosis score (≥1) after transplantation were compared with those of non-responders. BM-MSCs were analyzed with cDNA microarrays to identify gene/pathways that were differentially expressed in responders. Thirty-three patients (66%) were responders. A high initial Laennec score (p = 0.007, odds ratio 3.73) and performance of BM-MSC transplantation (p = 0.033, odds ratio 5.75) were predictive factors for responders. Three genes (olfactory receptor2L8, microRNA4520-2, and chloride intracellular channel protein3) were upregulated in responders, and CD36 and retinol-binding protein 4 are associated with the biologic processes that are dominant in non-responders. Eleven pathways (inositol phosphate, ATP-binding cassette transporters, protein-kinase signaling, extracellular matrix receptor interaction, endocytosis, phagosome, hematopoietic cell lineage, adipocytokine, peroxisome proliferator-activated receptor, fat digestion/absorption, and insulin resistance) were upregulated in non-responders (p < 0.05). BM-MSC transplantation may be warranted treatment for AC patients with high Laennec scores. Cell-based therapy utilizing response-related genes or pathways can be a treatment candidate.

Comparison of the efficacy of Ursodeoxycholic acid (UDCA) versus vitamin E plus vitamin C in non-diabetic patients with nonalcoholic Steatohepatitis (NASH)

Introduction: Nonalcoholic steatohepatitis (NASH) is a frequent liver disease that can progress to cirrhosis and for which effective therapy is still lacking. Despite an important role of oxidative stress in the pathogenesis of NASH, antioxidant approaches have not been investigated sufficiently. The aim of the study was to compare ursodeoxycholic acid (UDCA) versus vitamin E plus vitamin C in non-diabetic patients with nonalcoholic steatohepatitis. Method: Patients with elevated aminotransferase levels and drinking, less than 40g alcohol/week with NASH diagnose were randomly assigned to receive either UDCA 15 mg/per kg/day (group A) or vitamin E 800 mg/day plus vitamin C 500 mg/day (group B) for 12 months and control group, which did not receive any medical treatment. Lifestyle modification was advised to all groups. The primary study end point was improvement in alanine transaminase (ALT) levels, secondary end points were improvement in steatosis score and improvement in fibrosis score. Result: 107 patients were included 35 in the group A, 52 in the group B and 20 in control group, 11 patients dropped out, non because of side effects. Baseline characteristics were not significantly different between groups. After 12 months treatment with vitamin E plus C, as compared with UDCA, was associated with a significant reduction of mean alanine aminotransferase (ALT) levels. Similarly, there was significant reduction of both mean steatosis score and fibrosis score. Conclusion: Vitamin E plus C combination is an effective, safe and inexpensive treatment option in patients with NASH and may be useful to reduce damage from oxidative stress and slow the process leading to cirrhosis

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.

Liver stiffness reduction and serum fibrosis score improvement in HIV/hepatitis C virus-coinfected patients treated with direct-acting antivirals.

Only a few studies have addressed liver stiffness dynamics after hepatitis C virus (HCV) treatment in patients with HIV/HCV coinfection. The aim was to evaluate the variation in liver stiffness and in serum liver fibrosis scores in HIV/HCV-coinfected patients before and after treatment with direct-acting antivirals (DAAs). Liver stiffness measured using transient elastography as well as serum liver fibrosis scores [fibrosis-4 (FIB-4) score and the aspartate aminotransferase to platelet ratio index (APRI)] were evaluated before and at 6-12months after DAA treatment. Variation in the outcome variables was evaluated using the Wilcoxon nonparametric test. Univariate analysis and multivariate regression models were used. A total of 78 HIV/HCV-coinfected subjects were included in the study. Median values of hepatic stiffness significantly decreased after DAA treatment compared with baseline [16.8 (interquartile range (IQR) 10.2-27.0) kPa at baseline vs. 9.4 (IQR 6.7-15.0) kPa after DAA treatment; P<0.01). Further, a decrease in median FIB-4 score [2.8 (IQR 1.5-4.8) vs. 2.0 (IQR 1.3-3.2), respectively; P<0.01] and APRI [0.9 (IQR 0.5-2.2) vs. 0.4 (IQR 0.2-0.7), respectively; P<0.01] was found. In univariate analysis, liver stiffness decrease was associated with increasing age, 'other' HCV genotype (vs. G1), the presence of cirrhosis, higher pre-DAA liver stiffness, sofosbuvir-based regimens and longer DAA treatment (all P<0.05). Multivariate regression confirmed the significance of the association only with higher baseline liver stiffness (P<0.01). Greater FIB-4 and APRI reductions were associated with higher respective baseline values, while the presence of hepatic steatosis correlated with lower score reduction after DAA. A reduction in liver stiffness and an improvement in fibrosis scores were observed in HIV/HCV-coinfected patients soon after DAA treatment. The clinical implications of these observations need to be evaluated in larger populations with longer follow-up.

Improvement of liver stiffness measurement, acoustic radiation force impulse measurements, and noninvasive fibrosis markers after direct-acting antivirals for hepatitis C virus G4 recurrence post living donor liver transplantation: Egyptian cohort.

Progression of recurrent hepatitis C is accelerated in liver transplant (LT) recipients. Direct-acting antivirals (DAAs) have recently emerged as a promising therapeutic regimen for the treatment of hepatitis C virus infection. Rates of sustained virological response (SVR) have drastically improved since the introduction of DAAs. The aim is to elucidate the changes in liver stiffness measurement (LSM) by transient elastography (TE) as well as acoustic radiation force impulse (ARFI) elastography and fibrosis scores after DAA treatment in LT recipients with hepatitis C virus recurrence. A single-center, prospective study including 58 LT recipients with hepatitis C recurrence who received different sofosbuvir-based treatment regimens. Transient elastography and ARFI elastography values were recorded as well as fibrosis 4 score (FIB-4) and aspartate aminotransferase-to-platelet ratio index were calculated at baseline and SVR at week 24 (SVR24). The outcome was improvement in LSM and at least a 20% decrease in LSM at SVR24 compared with baseline. The sustained virological response was 98.1%. There was improvement of platelet counts, alanine aminotransferase, and aspartate aminotransferase, which in turn caused improvement in fibrosis scores at SVR24. LSM by TE and ARFI elastography decreased from the baseline median value of 6.3 kPa (interquartile range [IQR]; 4.6 to 8.8 kPa) and 1.28 m/s (IQR; 1.07 to 1.53 m/s) to an SVR24 median value of 6.2 kPa (IQR; 4.85 to 8.9 kPa) and 1.12 (IQR; 0.97 to 1.30 m/s), respectively. Logistic regression analysis showed that baseline viral load was the only significant predictor of improvement in LS after DAA therapy at SVR24. Sofosbuvir-based treatment resulted in an early improvement in parameters of liver fibrosis in post-LT patients with hepatitis C recurrence.

Topical superoxide dismutase in posttreatment fibrosis in patients with head and neck cancer.

Topical superoxide dismutase (SOD) has been shown to decrease postradiation fibrosis in some cancers but has not demonstrated an effect in patients with head and neck cancer. The purpose of this study was to determine if topical SOD is an effective treatment for postradiation neck fibrosis. This was a randomized prospective blinded clinical study of topical SOD versus placebo for the treatment of neck fibrosis. Measures of fibrosis grade and quality of life were obtained at baseline and after 3 months of treatment. Improvement in fibrosis score was comparable between the 2 study arms at 3 months. Both study groups showed improvement but the differences between groups was not statistically significant. Topical SOD likely has limited benefit for posttreatment neck fibrosis but this study confirms other published evidence of benefit from active physical therapy of posttreatment fibrosis in patients with head and neck cancer.

Treating nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a review of efficacy and safety.

To review current literature for the efficacy and safety of treatment for nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). A PubMed literature search from January 1990 to June 2017 was conducted using the search terms nonalcoholic fatty liver disease, diabetes mellitus, type 2, therapy, treatment, treat, therapeutics, nonalcoholic fatty liver, nonalcoholic hepatosteatosis, NASH, NAFLD, metformin, and statin. Bibliographies of chosen articles were reviewed. Relevant articles on metformin, thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and statins for the treatment of NAFLD which included patients with T2DM were reviewed. A total of 23 relevant studies were found and included randomized controlled, observational, and open-label designs, as well as three meta-analyses. Metformin combined with weight loss provides a modest improvement in steatosis and no improvement in fibrosis in patients with NAFLD and T2DM. TZDs showed positive results on fibrosis and resolution of NASH but at least half of patients studied were nonresponders. GLP-1 RAs also showed favorable results on reductions in transaminases and steatosis and improvements in insulin sensitivity and weight loss but lack efficacy data for resolution of NASH or improvement in fibrosis scores. Statins showed favorable results on reductions in transaminases but mixed results for improvement in steatosis and fibrosis scores. All reviewed treatment options are safe for management of NAFLD in patients with T2DM but long-term histological improvements are minimal. TZDs are efficacious for resolution of NASH and improvements in fibrosis but long-term use is required to maintain these results.

Sustained Viral Response to Hepatitis C Direct Acting Anti-viral Therapy Is Associated With a Significant Regression of Fibrosis as Measured by Transient Elastography: Another Benefit of Cure

Introduction: Hepatitis C (HCV) direct acting anti-viral therapy (DAA) is associated with a >90% sustained virological response rate (SVR) as defined by an undetectable hepatitis C viral load 12 weeks after completing therapy. Prior to initiation of DAA therapy, determination of the baseline fibrosis level is considered standard of care. After virological cure, the determination of the effect of SVR on fibrosis is not typically assessed yet it is critical for development of long term care goals in these patients. This study evaluated post-SVR fibrosis scores as measured by transient elastography (TE) in HCV pts having an SVR to DAA therapy to assess the effect of SVR on baseline fibrosis. Methods: Patients who achieved an SVR to DAA therapy were enrolled from a period of 12/2014-12/2016. All pts had baseline demographics, BMI, HCV genotype, HCVRNA, and ALT collected. TE was performed prior to initiation of DAA therapy and at least 12 weeks after completion of therapy in pts with SVR. Fibrosis was reported by the Metavir score and TE scores in kPa. Bridging fibrosis (F3) was defined as 7.5 - 12.4 kPa. Cirrhosis (F4) was defined as > 12.5 kPa. Results: 106 pts were enrolled. The mean baseline and post-SVR kPa scores were 10 and 8, respectively. Overall, 57% had fibrosis regression, 40% remained at the same fibrosis score, 3% had fibrosis progression. 38% regressed by 1 fibrosis stage, 17% by 2 stages and 2% by 3 stages. Of the pts with baseline cirrhosis (F4), 16/23 (70%) were no longer cirrhotic at follow up. 2 regressed from F4 to F1, 9 regressed from F4 to F2, 5 regressed from F4 to F3. 2 pts showed an increase in kPa score. Of the pts with baseline F3, 12/15 (80%) showed fibrosis regression. 5 regressed from F3 to F2, 7 regressed from F3 to F1. Of the pts with baseline F2, 16/22 (73%) had fibrosis regression. 13 regressed from F2 to F1, 2 regressed from F2 to F0. 4 remained at F2. 3 had fibrosis progression. Of the pts with baseline F1, 40/41 (44%) showed fibrosis regression. 17 regressed from F1 to F0. 1 had fibrosis progression to F2. All baseline F0 pts remained at F0. Conclusion: SVR to HCV DAA therapy is associated with significant improvement in fibrosis scores as measured by TE at all stages. 70% of cirrhotics had regression to non-cirrhotic states. Measurement of fibrosis by TE following SVR should be considered a standard part of the post-treatment evaluation as fibrosis regression has significant positive and cost saving implications on long term management of these pts.Table: Table. Results of fibrosis regression post SVR by transient elastography

The fibrolytic potentials of vitamin D and thymoquinone remedial therapies: insights from liver fibrosis established by CCl4 in rats.

BackgroundVitamin D (VitD) and thymoquinone (TQ) are nutraceutical agents with well-known immunomodulatory and hepatoprotective properties. This study measured whether VitD and TQ, individually or combined, could have direct fibrolytic activities and/or enhanced performance during remedial treatment of liver fibrosis established by CCl4 in rats.MethodsEighty five male Wistar rats were used as 10 negative controls (NC) and the remainders were distributed equally into 5 groups: short (S-PC) and long (L-PC) positive controls, TQ, VitD and VitD/TQ groups. CCl4 was injected for 7 weeks followed by a week of no intervention. TQ and/or VitD were given orally (3 days/week) from week 9 and euthanasia was at week 17 for all groups except the S-PC was at week 9. Following histopathological and digital image analyses, TGF-β1, IL-6, IL-10, IL-22 and MMP-9 were measured by ELISA in liver homogenates while the corresponding cytokine receptors were measured by immunohistochemistry. The mRNA expressions of all molecules were measured by quantitative RT-PCR.ResultsFibrosis was evident in both PC-groups and was significantly more advanced in the L-PC than S-PC, reaching to cirrhosis. The concentrations of TGF-β1, IL-6, IL-22 and their receptors were significantly higher (P < 0.05) simultaneously with significantly lower (P < 0.05) concentrations of MMP-9, IL-10 and IL-10 receptors in the S-PC and L-PC than the NC-group. TQ and VitD monotherapies showed significantly less fibrosis than L-PC but were similar to S-PC. Both remedial monotherapies also resulted in significant decreases of TGF-β1, IL-6, IL-22 and their receptors together with significant increases of MMP-9 and IL-10 system compared with S-PC and L-PC groups. Interestingly, dual therapy resulted in the most significant improvement in fibrosis score and index, yet was significantly higher (P < 0.05) than the NC-group, and concurred with the utmost significant restorations of all candidate genes and proteins.ConclusionsVitD and TQ exhibited comparable anti-fibrogenic effects and modulated several pro- and anti-fibrotic mediators. Additionally, VitD/TQ dual therapy alleviated the previously established liver fibrosis simultaneously with significantly enhanced actions at the molecular level. More studies are required to explorer the therapeutic value of TQ and VitD against liver fibrosis in human.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1040-4) contains supplementary material, which is available to authorized users.

The effect of long-term entecavir therapy on liver histopathology in patients with chronic viral hepatitis B

Objectives: The aim of this study was to evaluate histopathological improvement and virological, biological and serological response rates in patients receiving long-term entecavir therapy who were followed with the diagnosis of chronic hepatitis B (CHB).Materials and Methods: Ninety-eight nucleoside(t)e-naive CHB patients who were receiving 0.5 mg/day entecavir (ETV) were included in the study. Virological, serological and biochemical test results were assessed baseline and every 12-week intervals. Liver biopsy specimens were assessed according to the modified Ishak scoring.Results: Forty-six CHB patients receiving ETV treatment underwent liver biopsy. The mean age of the patients was 44 ± 12.9, 26.1% of them were female. The mean duration of follow-up was 44.9 ± 10.8 months. All patients had hepatitis B virus (HBV) genotype D infection. Of 21 patients who were HBeAg positive at baseline, HBeAg loss occurred in 9 and seroconversion occurred in 5. HBsAg loss occurred in none of the patients. Serum HBV DNA levels became undetectable in 93.5% patients. Of the patients, 50% achieved ≥ 2 point improvement in HAI scores and 30.4% achieved ≥ 1 point improvement in fibrosis scores with treatment. The mean improvement in HAI and fibrosis score were 1.94 ± 1.93 and 0.11 ± 0.9 points, respectively.Conclusion: ETV is an effective treatment in histological improvement and virological response in CHB patients. Large-scale, long-term studies are still warranted to evaluate the long-term outcomes of entecavir therapy.

Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis.

Given the rising epidemics of obesity and metabolic syndrome, nonalcoholic steatohepatitis (NASH) is now the most common cause of liver disease in the developed world. Effective treatment for NASH, either to reverse or prevent the progression of hepatic fibrosis, is currently lacking. To define the predictors associated with improved hepatic fibrosis in NASH patients undergoing serial liver biopsies at prolonged biopsy interval. This is a cohort study of 45 NASH patients undergoing serial liver biopsies for clinical monitoring in a tertiary care setting. Biopsies were scored using the NASH Clinical Research Network guidelines. Fibrosis regression was defined as improvement in fibrosis score ≥1 stage. Univariate analysis utilized Fisher's exact or Student's t test. Multivariate regression models determined independent predictors for regression of fibrosis. Forty-five NASH patients with biopsies collected at a mean interval of 4.6 years (±1.4) were included. The mean initial fibrosis stage was 1.96, two patients had cirrhosis and 12 patients (26.7 %) underwent bariatric surgery. There was a significantly higher rate of fibrosis regression among patients who lost ≥10 % total body weight (TBW) (63.2 vs. 9.1 %; p = 0.001) and who underwent bariatric surgery (47.4 vs. 4.5 %; p = 0.003). Factors such as age, gender, glucose intolerance, elevated ferritin, and A1AT heterozygosity did not influence fibrosis regression. On multivariate analysis, only weight loss of ≥10 % TBW predicted fibrosis regression [OR 8.14 (CI 1.08-61.17)]. Results indicate that regression of fibrosis in NASH is possible, even in advanced stages. Weight loss of ≥10 % TBW predicts fibrosis regression.

Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study.

There is no licensed treatment for non-alcoholic fatty liver disease (NAFLD), a condition that increases risk of chronic liver disease, type 2 diabetes and cardiovascular disease. We tested whether 15-18 months treatment with docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) (Omacor/Lovaza) (4 g/day) decreased liver fat and improved two histologically-validated liver fibrosis biomarker scores (primary outcomes). Patients with NAFLD were randomised in a double blind placebo-controlled trial [DHA+EPA(n=51), placebo(n=52)]. We quantified liver fat percentage (%) by magnetic resonance spectroscopy in three liver zones. We measured liver fibrosis using two validated scores. We tested adherence to the intervention (Omacor group) and contamination (with DHA and EPA) (placebo group) by measuring erythrocyte percentage DHA and EPA enrichment (gas chromatography). We undertook multivariable linear regression to test effects of: a) DHA+EPA treatment (ITT analyses) and b) erythrocyte DHA and EPA enrichment (secondary analysis). Median (IQR) baseline and end of study liver fat% were 21.7 (19.3) and 19.7 (18.0) (placebo), and 23.0 (36.2) and 16.3 (22.0), (DHA+EPA). In the fully adjusted regression model there was a trend towards improvement in liver fat% with DHA+EPA treatment (β=-3.64 (95%CI -8.0,0.8); p=0.1) but there was evidence of contamination in the placebo group and variable adherence to the intervention in the Omacor group. Further regression analysis showed that DHA enrichment was independently associated with a decrease in liver fat% (for each 1% enrichment, β=-1.70 (95%CI -2.9,-0.5); p=0.007). No improvement in the fibrosis scores occurred. Conclusion. Erythrocyte DHA enrichment with DHA+EPA treatment is linearly associated with decreased liver fat%. Substantial decreases in liver fat% can be achieved with high percentage erythrocyte DHA enrichment in NAFLD. (Hepatology 2014;).

Insulin resistance and oxidative stress: Two therapeutic targets in non-alcoholic steatohepatitis

Background & Aims: Non-alcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. Methods: We randomly assigned 247 adults with non-alcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of non-alcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, p values of less than 0.025 were considered to indicate statistical significance. Results: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in non-alcoholic steatohepatitis (43% vs. 19%, p = 0.001 but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; p = 0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (p <0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (p = 0.005 for vitamin E and p <0.001 for pioglitazone) and lobular inflammation (p = 0.02 for vitamin E and p = 0.004 for pioglitazone) but not with improvement in fibrosis scores (p = 0.24 for vitamin E and p = 0.72 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions: Vitamin E was superior to placebo for the treatment of non-alcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes.

Vitamin E for nonalcoholic steatohepatitis: Ready for prime time?

BACKGROUND: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. METHODS: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. RESULTS: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. CONCLUSIONS: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes.

Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis

Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.)

Effects of interferon plus ribavirin treatment on NF-κB, TGF-β1, and metalloproteinase activity in chronic hepatitis C

Little is known about the cellular and molecular mechanisms underlying the effects of anti-viral therapy on the regression of liver inflammation and fibrosis in chronic hepatitis C. The aim of this study was to evaluate the effects of interferon alpha and ribavirin in combination therapy on the tissue expression of nuclear-factor kB (NF-κB) (a transcription factor coordinating the expression of stress genes involved in immune response and inflammation), of the polypeptide transforming growth factor beta-1 (TGF-β1) and matrix metalloproteinases 1 (MMP-1) (both of which play an important part in the pathological process of liver fibrogenesis), and on the serum levels of soluble TGF-β1, tissue inhibitors of metalloproteinases (TIMP)-1, and active endogenous MMP-2 and MMP-9 in paired (pre- and post-treatment) liver biopsy and serum samples of subjects with chronic hepatitis C. Serum levels of TGF-β1, TIMP-1, MMP-2, and MMP-9 were evaluated by enzyme-linked immunosorbent assay. Liver expression of muscle-specific α-actin, NF-κB, TGF-β1, and MMP-1 was studied immunohistochemically using commercially available mono- and polyclonal antisera in an avidin–biotin complex method. Combination therapy induced a reduction in the liver expression of TGF-β and NF-κB and an increased expression of MMP-1, regardless of the virological response to the treatment. The greater expression of MMP-1 and lesser expression of NF-κB were both associated with an improvement in fibrosis score. These effects paralleled the significant increase in soluble MMP-9/TIMP-1 ratio in post-therapy sera. Combination therapy with interferon and ribavirin affects the tissue expression of TGF-β-1 and NF-κB and favors metalloproteinase activity, and may thereby modulate hepatic fibrogenetic events.

Vitamin E attenuates biochemical and morphological features associated with development of chronic pancreatitis

The objective was to investigate the effects of vitamin E on collagen deposition induced by Cyclosporin A (CsA) administration in rats with caerulein (Cr) pancreatitis. CsA transforms the fully regenerative, self-limited form of Cr pancreatitis into a chroniclike disease in conjunction with increased transforming growth factor (TGF)-beta and myofibroblast proliferation. Vitamin E inhibits TGF-beta release in mesangial cells and reduces CsA cytotoxicity. Wistar rats received CsA daily (20 mg/kg), and CR pancreatitis was induced on days 1 and 8 (Cr + CsA group). In a separate group, vitamin E (600 mg.kg(-1).day(-1)) was administered starting 4 days before CsA. Three other groups received either vehicle, CsA, or Cr alone. Thiobarbituric acid-reactive substance (TBARS), 8-isoprostanes, and hyaluronic acid were measured in plasma obtained on the day the animals were killed (day 15). Pancreases were weighed and processed for light microscopy to assess connective tissue and myofibroblast number. Pancreatic homogenates were also assayed for collagen (hydroxyproline) and TBARS content. TBARS, 8-isoprostane, and TGF-beta were elevated in CsA and Cr + CsA rats. Vitamin E treatment greatly decreased these parameters. Vitamin E also decreased the fall in pancreatic weight observed in Cr + CsA pancreas. Pancreatic hydroxyproline and plasma hyaluronic acid were increased in Cr + CsA rats but were effectively reduced by vitamin E. Morphology showed improvement in fibrosis score and a decreased number of myofibroblasts in vitamin E-treated rats. Vitamin E reduces oxidative stress and collagen deposition during the development of experimental chronic pancreatitis. Adjuvant antioxidants may be of value in the treatment of chronic pancreatitis.