Markers Of Hepatic Fibrosis Research Articles

Acanthoic acid modulates lipogenesis in nonalcoholic fatty liver disease via FXR/LXRs-dependent manner

Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae), with anti-inflammatory and hepatic-protective effects. The present study intended to reveal the effect and mechanism of AA on nonalcoholic fatty liver disease (NAFLD) associated with lipid accumulation by activating Farnesoid X receptor (FXR) and liver X receptors (LXRs) signaling. C57BL/6 mice were received a modified Lieber-DeCarli diet with 71% high-fat (L-D) and treated with AA (20 and 40 mg/kg) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid (PA). When L-D diet-fed mice were treated with AA, loss in body weight, liver index, and liver lipid droplet were observed along with reduced triglyceride (TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1 (SREBP-1) and target genes expression, regulated PPARα and PPARγ expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones (FXR antagonist) or GW3965 (LXR agonist). Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.

Serum Mac-2-binding protein (M2BPGi) as a marker of chronological liver fibrosis in biliary atresia patients with cirrhosis.

Biliary atresia (BA) is characterized by progressive liver fibrosis, but it is difficult to assess the progression after the patient develops cirrhosis. Mac-2-binding protein glycosylation isomer (M2BPGi) is a new marker for hepatic fibrosis. We examined the chronological changes in M2BPGi levels in BA patients with cirrhosis. Patients with cirrhosis were selected from among pediatric BA patients who had their native livers. Serum M2BPGi levels and Child-Pugh classification were evaluated. A total of 11 pediatric BA patients with cirrhosis were recruited. Initial M2BPGi level after diagnosis of liver cirrhosis based on liver biopsy was on average 3.4, and the most recent M2BPGi level under observation was on average 4.3. The follow-up period from the initial M2BPGi measurement averaged 22.6months. The ratio of the initial and most recent values (M2BPGi ratio) was on average 1.3 (0.5-2.4). Three cases with improved fibrosis (M2BPGi ratio < 1.0) remained in Child A, as did six cases (1.0 ≤ M2BPGi ratio < 2.0), but two cases with marked fibrosis progression (2.0 ≤ M2BPGi ratio) advanced to decompensated cirrhosis Child B. M2BPGi is useful as a prognostic factor for BA patients with liver cirrhosis. In addition, fibrosis improved even after the development of cirrhosis.

The association between a non-invasive hepatic fibrosis score and urolithiasis among non-alcoholic fatty liver disease (NAFLD) patients in China: a cross-sectional study

ObjectiveMounting data now support a strong link between the presence of non-alcoholic fatty liver disease (NAFLD) and an increased risk of urolithiasis. However, little is known on the association between...

Fructose Promotes Leaky Gut, Endotoxemia, and Liver Fibrosis Through Ethanol-Inducible Cytochrome P450-2E1-Mediated Oxidative and Nitrative Stress.

Fructose intake is known to induce obesity, insulin resistance, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the effects of fructose drinking on gut leakiness, endotoxemia, and NAFLD and study the underlying mechanisms in rats, mice, and T84 colon cells. Levels of ileum junctional proteins, oxidative stress markers, and apoptosis-related proteins in rodents, T84 colonic cells, and human ileums were determined by immunoblotting, immunoprecipitation, and immunofluorescence analyses. Fructose drinking caused microbiome change, leaky gut, and hepatic inflammation/fibrosis with increased levels of nitroxidative stress marker proteins cytochrome P450-2E1 (CYP2E1), inducible nitric oxide synthase, and nitrated proteins in small intestine and liver of rodents. Fructose drinking significantly elevated plasma bacterial endotoxin levels, likely resulting from decreased levels of intestinal tight junction (TJ) proteins (zonula occludens 1, occludin, claudin-1, and claudin-4), adherent junction (AJ) proteins (β-catenin and E-cadherin), and desmosome plakoglobin, along with α-tubulin, in wild-type rodents, but not in fructose-exposed Cyp2e1-null mice. Consistently, decreased intestinal TJ/AJ proteins and increased hepatic inflammation with fibrosis were observed in autopsied obese people compared to lean individuals. Furthermore, histological and biochemical analyses showed markedly elevated hepatic fibrosis marker proteins in fructose-exposed rats compared to controls. Immunoprecipitation followed by immunoblot analyses revealed that intestinal TJ proteins were nitrated and ubiquitinated, leading to their decreased levels in fructose-exposed rats. Conclusion: These results showed that fructose intake causes protein nitration of intestinal TJ and AJ proteins, resulting in increased gut leakiness, endotoxemia, and steatohepatitis with liver fibrosis, at least partly, through a CYP2E1-dependent manner.

Dietary Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA) Operate by Different Mechanisms to Modulate Hepatic Steatosis and Hyperinsulemia in fa/fa Zucker Rats.

Hepatic steatosis, an early stage of non-alcoholic fatty liver disease, is commonly present in obesity and type 2 diabetes, and is associated with reduced hepatic omega-3 polyunsaturated fatty acid (n3-PUFA) status that impacts on the anti-inflammatory and insulin sensitizing functions of n3-PUFA. Our objective was to directly compare plant- and marine-based n3-PUFA (α-linoleic acid (ALA)), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)) for their effects on hepatic steatosis, markers of hepatic inflammation and fibrosis, and insulinemia in obese rats. Fa/fa Zucker rats were provided diets containing ALA, EPA, DHA, or linoleic acid (LA, n6-PUFA) for eight weeks and compared to baseline fa/fa rats and lean Zucker rats fed LA-rich diet for eight weeks. Both DHA and EPA groups had liver lipid similar to baseline, however, DHA was more effective than EPA for reducing hepatic fatty acid synthase (FAS), increasing the proportion of smaller lipid droplets, reversing early fibrotic damage, and reducing fasting hyperinsulinemia. EPA was more effective for reducing FoxO1. Dietary ALA did not attenuate hepatic steatosis, most inflammatory markers or FAS. In summary, amongst the n3-PUFA, DHA was the most effective for elevating hepatic DHA levels, and preventing progression of hepatic steatosis via reductions in FAS and a marker of fibrosis.

The Inhibitory T Cell Receptors PD1 and 2B4 Are Differentially Regulated on CD4 and CD8 T Cells in a Mouse Model of Non-alcoholic Steatohepatitis.

Infiltrating CD4 and CD8 T cells have been shown to worsen inflammatory liver damage in non-alcoholic steatohepatitis (NASH). Inhibitory T cell receptors such as the programmed cell death protein 1 (PD1) and the natural killer cell receptor 2B4 regulate the activity of CD4 and CD8 T cells and therefore play an important role in immune tolerance required in the liver. In this study, we investigated the expression profile of inhibitory T cell receptors on CD4 and CD8 T cells in a mouse model of NASH. Male B57BL/6J mice were fed a Western diet for 24 weeks. The expression levels of inhibitory receptors on the surface of intrahepatic and peripheral T cells were measured and correlated with markers of activation (CD107a, CD69, and CD44), metabolic disorder (serum triglycerides, serum cholesterol, γ-glutamyl transferase, hepatic triglycerides), inflammation (serum alanine aminotransferase and aspartate aminotransferase) and hepatic fibrosis (collagen 1A1, α-smooth muscle actin, hydroxyproline). Under Western diet, PD1 is exclusively upregulated on intrahepatic and peripheral CD8+ T cells, whereas the expression level on CD4 T cells is unaffected. In contrast, 2B4 is upregulated liver-specifically on both CD4 and CD8 T cells and unchanged on peripheral T cells. Upregulation of PD1 on CD8 T cells is restricted to CD8 effector memory T cells and correlates with lower levels of degranulation. Similarly, the inhibitory function of PD1 on intrahepatic CD4 T cells is shown by a lower CD69 and CD44 expression on PD1-positive CD4 T cells. In murine steatohepatitis, the upregulation of PD1 on CD8 T cells and 2B4 on CD4 and CD8 T cells potentially limits T cell-mediated liver damage. Therefore, these inhibitory T cell receptors could serve as promising targets of immune-modulatory NASH therapy.

Observation of the effect of bone marrow mesenchymal stem cell transplantation by different interventions on cirrhotic rats.

Bone marrow mesenchymal stem cells (BMSCs) transplantation has attracted attention for the treatment of liver cirrhosis and end-stage liver diseases. Therefore, in this study, we evaluated the effect of different methods of BMSCs transplantation in the treatment of liver cirrhosis in rats. Seventy-two male Sprague-Dawley rats were divided into 7 groups: 10 were used to extract BMSCs, 10 were used as normal group, and the remaining 52 rats were randomly divided into five groups for testing: control group, BMSCs group, BMSCs+granulocyte colony-stimulating factor (G-CSF) group, and BMSCs+Jisheng Shenqi decoction (JSSQ) group. After the end of the intervention course, liver tissue sections of rats were subjected to hematoxylin and eosin (H&E) and Masson staining, and pathological grades were scored. Liver function [aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB)] and hepatic fibrosis markers [hyaluronidase (HA), laminin (LN), type III procollagen (PCIII), type IV collagen (CIV)] were measured. BMSCs+JSSQ group had the best effect of reducing ALT and increasing ALB after intervention therapy (P<0.05). The reducing pathological scores and LN, PCIII, CIV of BMSCs+G-CSF group and BMSCs+JSSQ group after intervention therapy were significant, but there was no significant difference between the two groups (P>0.05). The effect of JSSQ on improving stem cell transplantation in rats with liver cirrhosis was confirmed. JSSQ combined with BMSCs could significantly improve liver function and liver pathology scores of rats with liver cirrhosis.

Gender and age peculiarities of the level of hyaluronic acid in the blood serum of patients with chronic hepatitis C virus infection at different degrees of hepatic fibrosis

Timely diagnostics of the early stages of fibrosis in chronic hepatitis C infection and the possibility to control it in patients with liver cirrhosis remains a topical issue in modern medicine. Hyaluronic acid (HA) takes a special place among direct hepatic fibrosis markers and is largely related to fibrogenesis, but is also involved in fibrinolysis, reflecting extra-cellular matrix remodeling. The aim of our research is to specify hepatic fibrosis diagnostics in patients with chronic hepatitis C infection through determination of gender and age peculiarities of the hyaluronic acid level in the blood serum. 66 patients with CHC of the 1st virus genotype have been examined. The diagnosis is confirmed by PCR results (RNA HCV +). The control group included 21 healthy individuals. The patients were also distributed by age and gender. All patients and control group individuals underwent ultra-sound fibroesophagography using FibroScan device. The results of fibroesophagography were evaluated by the METAVIR scale. The level of HA in the blood serum was determined both for patients with CHC and control group individuals with a set ‘HyaluronicAcid’ (Corgenix, Inc., the USA)). Statistical processing of the results was carried out in the statistical package “STATISTICA 5.5” (licensed number AXXR 910А374605FA). A method of correlation-regression analysis was used to develop a model of the dependence of the level of GA (on the duration (stage) of triple antiviral therapy). The validity of the difference between the comparable sample results was carried out according to the Student's criterion. Revealed that the level of HA in the blood serum of patients with CHC was higher than in the group of healthy individuals. The HA level in the blood serum of patients with CHC of the younger age group was lower than in people of the older age group. The analysis made by us showed that the HA level in the blood serum of patients with CHC increased in correspondence with the intensification of fibrotic changes in liver tissue in both age groups. So, a tendency was traced to the increase of HA in the blood serum of patients with CHC as compared to healthy individuals (2.61 times in the younger age group and 2.82 times — in the older age group), as well as, respectively, intensification of fibrotic changes in liver tissue in both age groups (2.03–4.26 times in the younger age group and 2.15–4.83 — in the older age group). No reliable difference between the levels of HA in the blood serum of patients with CHC depending on the gender has been traced.

Significance of biglycan and osteopontin as non-invasive markers of liver fibrosis in patients with chronic hepatitis B virus and chronic hepatitis C virus

Several studies were performed to evaluate the degree of liver fibrosis by non-invasive markers. We aimed to assess the diagnostic value of both biglycan (BGN) and osteopontin (OPN) as non-invasive...

Sasa veitchii extract protects against carbon tetrachloride-induced hepatic fibrosis in mice

BackgroundThe current study aimed to investigate the hepatoprotective effects of Sasa veitchii extract (SE) on carbon tetrachloride (CCl4)-induced liver fibrosis in mice.MethodsMale C57BL/6J mice were intraperitoneally injected with CCl4 dissolved in olive oil (1 g/kg) twice per week for 8 weeks. SE (0.1 mL) was administered orally once per day throughout the study, and body weight was measured weekly. Seventy-two hours after the final CCl4 injection, mice were euthanized and plasma samples were collected. The liver and kidneys were collected and weighed.ResultsCCl4 administration increased liver weight, decreased body weight, elevated plasma alanine aminotransferase, and aspartate aminotransferase and increased liver oxidative stress (malondialdehyde and glutathione). These increases were attenuated by SE treatment. Overexpression of tumor necrosis factor-α was also reversed following SE treatment. Furthermore, CCl4-induced increases in α-smooth muscle actin, a marker for hepatic fibrosis, were attenuated in mice treated with SE. Moreover, SE inhibited CCl4-induced nuclear translocation of hepatic nuclear factor kappa B (NF-κB) p65 and phosphorylation of mitogen-activated protein kinase (MAPK).ConclusionThese results suggested that SE prevented CCl4-induced hepatic fibrosis by inhibiting the MAPK and NF-κB signaling pathways.

Impact of Sustained Viral Remission in Patients With Chronic Hepatitis C Infection on Surrogate Markers of Hepatic Fibrosis

Introduction: Direct-acting antivirals (DAAs) have resulted in improvement in the virologic cure rate of HCV infection. However, tools to measure regression of hepatic fibrosis after HCV eradication are not perfect. Liver biopsy is not always appropriate and transient elastography has limited availability. Alternative ways to monitor for regression of fibrosis are required in clinical practice. The AST-to-Platelet-Ratio-Index (APRI) and Fibrosis-4 (Fib-4) are validated tools that predict presence of hepatic fibrosis. We examined if treatment of HCV infection resulted in sustained improvement in the APRI and Fib-4 scores. Methods: Clinic records of adult patients with chronic HCV infection who received treatment in a single center were reviewed over a 5-year period. Sustained virologic response (SVR) was achieved if the HCV RNA titer was undetected 12 weeks or more after treatment completion. APRI and Fib-4 scores were calculated before and 12-24 weeks after treatment completion. Cirrhosis was ascertained based on laboratory and imaging data or biopsy. Continuous variables are reported as mean (± SD). Multivariable linear and stepwise linear regression analyses were performed to examine the association between SVR12 and the APRI/FIB-4 scores 12-24 weeks after treatment completion. The analyses were adjusted for baseline APRI/FIB-4 scores, BMI, cirrhosis, use of peg-interferon, and genotype 3. Results: 153 patients were identified. Mean age was 51.2 ± 14.0 years. Mean treatment duration was 14.7 ± 8.2 weeks. 68% were men, 3.3% were HIV co-infected. Genotype 1 was predominant (1a 46%, 1b 17%), followed by genotype 2 (18%), genotype 3 (16%), and genotypes 4-6 (3%). 22% of patients had cirrhosis, 14% received an interferon containing regimen. In the unadjusted analysis, patients who achieved SVR12 had a significant decline in the mean APRI and Fib-4 scores compared to those who did not achieve SVR12. These results remained robust in the multivariable linear regression analyses where all the covariates of interest were forced into the models, as well as in the stepwise analyses where non-significant covariates were eliminated from the models. Conclusion: We herein demonstrate that treatment of chronic HCV infection results in improvement in the APRI and Fib-4 scores among patients who achieved SVR12 suggesting regression of hepatic fibrosis. In the absence of transient elastography, physicians should consider relying on these surrogate markers for risk stratification.847_A Figure 1 No Caption available.847_B Figure 2 No Caption available.

Association between HLA-DQA1/DRB1 polymorphism and development of hepatocellular carcinoma during entecavir treatment.

It remains unclear whether there is an association between single-nucleotide polymorphisms (SNPs) and development of hepatocellular carcinoma (HCC) during entecavir (ETV) treatment in nucleos(t)ide analog-naïve patients with chronic hepatitis B virus infection. We investigated the risk factors for HCC, especially host factors, during ETV treatment. A total of 127 Japanese patients undergoing ETV treatment were enrolled in this study. Univariate and multivariate analyses for clinical factors, hepatic fibrosis markers, and SNPs associated with HCC development were analyzed. A total of 10 patients developed HCC during the follow-up period (median duration, 3.3years). The 3-, 5-, and 7-year cumulative rates of HCC development were 4.8%, 10.6%, and 13.6%, respectively. Liver fibrosis (cirrhosis; P=0.0005), age (≥49years; P=0.0048), platelet count (≤115×10/mm3 ; P=0.0007), α-fetoprotein (≥8.0ng/mL; P=0.030), type IV collagen (≥200ng/mL; P=0.043), fibrosis-4 index (≥4.14; P=0.0006), and human leukocyte antigen (HLA)-DQA1/DRB1-SNP (AA genotype; P=0.0092) were significantly associated with HCC development according to the log-rank test. In multivariate analysis, AA genotype in the HLA-DQA1/DRB1 gene (P=0.013; hazard ratio 4.907; 95% confidence interval 1.407-17.113) and cirrhosis (P=0.019; hazard ratio 4.789; 95% confidence interval 1.296-17.689) were significantly associated with HCC development. Our findings suggested that patients with AA genotype in the HLA-DQA1/DRB1 gene or cirrhosis should be carefully followed up as a population potentially at higher risk of HCC during ETV treatment.

Serum Interleukin-8, Osteopontin, and Monocyte Chemoattractant Protein 1 Are Associated With Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

The severity of hepatic fibrosis is the primary predictor of liver‐related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD‐associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy‐proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0‐1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3‐4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin‐8 (IL‐8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, hepatocyte ballooning, age, sex, body mass index, diabetes mellitus, hypertension, and metabolic syndrome status, IL‐8 remained strongly associated with fibrosis (P = 0.001). Furthermore, IL‐8 was also a strong predictor of increased fibrotic liver injury compared to established markers of hepatic fibrosis. Hepatic gene expression from 72 patients with NAFLD (n = 40 mild fibrosis; n = 32 advanced fibrosis) from the Duke University Health System NAFLD Clinical Database and Biorepository revealed IL‐8, MCP1, and OPN gene expression to be increased and differentially expressed in patients with advanced hepatic fibrosis. Thus, serum IL‐8, MCP1, and OPN may reflect up‐regulated gene expression during liver fibrosis in NAFLD. Conclusion: Serum IL‐8, MCP1, and OPN may serve as a test for advanced hepatic fibrosis in NAFLD and thus reveal novel targets for antifibrotic therapies. The increased serum IL‐8, MCP1, and OPN that correspond with associated hepatic gene expression lend strength to such analytes as ideal surrogate serum biomarkers for severity of hepatic fibrosis.

Serum leptin and leptin resistance correlations with NAFLD in patients with type 2 diabetes.

Leptin/leptin resistance has been suggested to play a role in nonalcoholic fatty liver disease (NAFLD), and therefore we investigated the correlation of leptin/leptin-receptor system with markers of hepatic steatosis (HS) and fibrosis (HF) in patients with type 2 diabetes (T2D). In 159 T2D subjects with disease duration of 6.0 (0.0-27.0) years, HS was evaluated by semi-quantitative ultrasonographic scores and by clinical/biochemical variables: Fatty liver index and Hepatic steatosis index. HF was evaluated by NAFLD fibrosis score (NAFLD-FS). Serum leptin and leptin receptor (sObR) concentrations were measured and leptin resistance estimated by Free Leptin Index (FLpI). Both simple and multiple correlations between the HS and HF with the three parameters of interest were examined. Leptin levels and FLpI correlated with diabetes duration (0.25 [95%CI: 0.09-0.39] and 0.24 [95%CI: 0.08-0.39]; P<0.01 for both). 76.1% of T2D patients had HS and 29% had HF. The univariate analysis indicated positive correlations of HS indexes with serum leptin, FLpI, and negative correlations with serum sObR (P<0.0001 for all). In the multiple regression analysis leptin, sObR, FLpI, waist-to-hip ratio, HbA1c, lipids, and HOMA-IR correlated independently with HS (P<0.0001 for all). Although the univariate analyses indicated weak correlations of NAFLD-FS with leptin, sObR, and FLpI, in the multiple regression analyses, only age and waist independently predicted HF. In patients with T2D, HS correlated positively with serum leptin and leptin resistance, and negatively with sObR, along with variables of adiposity and metabolic control, but neither of them made a significant contribution to HF.

Effect of luseogliflozin on hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective, single-arm trial (LEAD trial).

No pharmacological therapies are approved for non-alcoholic fatty liver disease (NAFLD). Luseogliflozin, a sodium glucose cotransporter 2 inhibitor, has been developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this prospective, single-arm study is to evaluate the efficacy of luseogliflozin on hepatic fat content and glycated hemoglobin (HbA1c) in T2DM patients with NAFLD. Forty T2DM patients with NAFLD were treated with luseogliflozin 2.5mg/day for 24weeks. Primary end-points were changes in HbA1c and hepatic steatosis evaluated by magnetic resonance imaging-hepatic fat fraction from baseline. Secondary end-points were changes in metabolic and hepatic function-related parameters, including hepatic fibrosis markers (Fibrosis-4 index, NAFLD fibrosis score, type IV collagen 7S. and Wisteria floribunda agglutinin-positive Mac-2 binding protein). Not only HbA1c and transaminase activities but also hepatic fat content were significantly decreased after 24weeks of therapy with luseogliflozin. The reduction of hepatic fat content was significantly correlated with the reduction of alanine aminotransferase. Although hepatic fibrosis markers were unchanged, serum ferritin levels reduced and serum albumin significantly increased after the treatment. Luseogliflozin can be a novel promising agent for the treatment of T2DM patients with NAFLD. Prospective randomized controlled trials are warranted to confirm this impact of luseogliflozin onT2DM with NAFLD.

Evaluation of the Impact of Preoperative Values of Hyaluronic Acid and Type IV Collagen on the Outcome of Patients with Hepatocellular Carcinoma After Hepatectomy

Recently, some reports have revealed a relationship between post-hepatectomy prognosis in hepatocellular carcinoma (HCC) and hepatic fibrosis markers. We evaluated the relationship between these markers of hepatic fibrosis, clinicopathological findings, and prognosis. Three hundred and sixty patients underwent hepatectomy for HCC in the Nippon Medical School Hospital between 1993 and 2013. We divided these patients into two groups: normal serum hyaluronic acid (HA) levels and abnormal levels. We also divided patients into groups with normal serum type IV collagen levels and abnormal levels. The overall survival rate and recurrence-free survival rate of the normal group were significantly higher than those of the abnormal group. In the normal hyaluronic acid group, serum albumin and prothrombin time were significantly higher than in the abnormal group, and age, hepatitis C virus antibody (HCV)-Ab positivity, Child-Pugh grade B, liver cirrhosis, indocyanine green retention rate at 15 min (ICGR15), type IV collagen level, and type IV collagen 7s level were significantly lower than those in the abnormal group. In the normal type IV collagen group, HCV-Ab positivity, liver cirrhosis, ICGR15, HA level, and type IV collagen 7s level were significantly lower than those in the abnormal group, and the serum albumin level was significantly higher than that in the abnormal group. Multivariate analysis independently revealed the significant effect of serum type IV collagen on the overall survival rate as well as the significant effect of serum HA on the recurrence-free survival rate in patients who underwent hepatectomy for HCC. Preoperative examinations of serum hyaluronic acid levels and type IV collagen levels are imperative for hepatic resection for HCC because these markers are significantly associated with liver function and prognosis.

Curcumin supplementation mitigates NASH development and progression in female Wistar rats.

Curcumin, a naturally occurring plant polyphenolic compound, may have beneficial effects in nonalcoholic steatohepatitis (NASH) development. We examined whether curcumin supplementation could be used in both prevention and treatment of NASH with fibrosis. Female Wistar rats were provided ad libitum access to a “western diet” (WD) high in fat (43% kcal), sucrose (29% kcal), and cholesterol (2% w/v), as well as 15% fructose drinking water. Intraperitoneal CC14 injections (0.5 mL/kg) were also administered at weeks 1, 2, 4, and 6 to accelerate development of a NASH with fibrosis phenotype. Rats were randomized to four groups (n = 9–12/group) and fed ad libitum: (1) WD for 8‐weeks (8WD), (2) WD enriched with curcumin for 8‐weeks (8WD+C; 0.2% curcumin, BCM‐95, DolCas Biotech) to assess prevention, (3) WD for 12‐weeks (12WD), (4) WD for 8‐weeks followed by 4‐weeks WD+C (12WD+C) to assess treatment. Curcumin prevention (8WD vs. 8WD+C) attenuated (P < 0.05) histological liver inflammation, molecular markers of fibrosis (Col1a1 mRNA) and a serum marker of liver injury (AST). Curcumin treatment (12WD vs. 12WD+C) reduced (P < 0.05) hepatocellular inflammation, steatosis, NAFLD Activity Scores, and serum markers of liver injury (AST, ALP). Moreover, curcumin treatment also increased hepatic pACC/ACC, ApoB100, and SOD1 protein, and decreased hepatic FGF‐21 levels; whereas, curcumin prevention increased hepatic glutathione levels. Both curcumin prevention and treatment reduced molecular markers of hepatic fibrosis (Col1a1 mRNA) and inflammation (TNF‐α, SPP1 mRNA). Curcumin supplementation beneficially altered the NASH phenotype in female Wistar rats, particularly the reversal of hepatocellular inflammation.

Non-invasive aspartate aminotransferase to platelet ratio index correlates well with invasive hepatic venous pressure gradient in cirrhosis.

Hepatic venous pressure gradient (HVPG) is the best recommended tool to measure portal pressure, but is invasive. HVPG helps in prognosticating cirrhosis and predictits complications. Aminotransferase to platelet ratio index (APRI) is a simple non-invasive marker of hepatic fibrosis. We aimed to correlate APRI with HVPG and to determine the usefulness of APRI in predicting complication of cirrhosis. APRI and HVPG were measured in consecutive patients of cirrhosis aged 18 to 70 years. Spearman's rho was used to estimate their correlation; acut-off valueof APRI topredict severe portal hypertension (HVPG > 12mmHg) was determined. This study, conducted between August 2011 and December 2014, included 277 patients, median age 51 (range: 16-90) years, 84% males. Etiology of cirrhosis was alcohol in 135 (49%), cryptogenic/nonalcoholic steatohepatitis (NASH) in 104 (38%), viral in 34 (12%), and others in 4 (1%). Median Child-Turcott-Pugh (CTP) and model for end-stage liver disease (MELD) scores were 7 (5-11) and 11 (6-33), respectively. Median HVPG was 17.0 (1.5-33) mmHg and median APRI was 1.09 (0.21-12.22). There was positive correlation between APRI andHVPG (Spearman's rho 0.450, p < 0.001). The area under the receiver operating characteristic (ROC) curve of APRI for predicting severe portal hypertension was 0.763 (p < 0.01). Youden's index defined the cut-off of APRI for predicting HVPG > 12mmHg was 0.876 with a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 71%, 78%, 94%, 38%, and 73%, respectively. APRI also correlated well with CTP, variceal size, bleeding status, ascites but not with MELD. APRI score of 0.876 has an acceptable accuracy topredictsevere portal hypertension (HVPG > 12mmHg). High APRI also correlated with severity of cirrhosis and its complications. Thus, APRI may be used as a simple, bedside, non-invasive, and inexpensive tool for evaluating portal hypertension and complications of cirrhosis.

Metallothionein Expression in Horses With Chronic Liver Disease and Its Correlation With Ki-67 Immunoreactivity.

Chronic liver disease is an important cause of illness in horses, and treatment is mainly supportive. Research into new treatment modalities for humans has shown promising data regarding metallothionein (MT), which has been shown to possess regenerative, antifibrotic, and anti-inflammatory properties. This study aimed to examine the relationship between hepatic MT expression and the histopathologic markers of hepatic inflammation, fibrosis and bile duct proliferation, as well as cellular regeneration in 77 selected cases of chronic liver disease in horses. We hypothesized that higher MT expression would be associated with increased heptocellular proliferation and decreased fibrosis, inflammation, and bile duct proliferation. Hepatocellular MT expression was evaluated with immunohistochemistry. Additionally, cellular regeneration was evaluated with immunohistochemistry for Ki-67, a protein expressed during all active stages of the cell cycle. The severity of inflammation and fibrosis was scored, and bile duct proliferation was assessed by counting bile duct profiles. MT expression was observed in 73 of 77 (94.8%) cases of chronically diseased livers. Ki-67 expression was seen in resident Kupffer cells ( n = 42, 54.6%), lymphocytes ( n = 39, 50.7%), bile duct epithelium ( n = 10, 13.0%), and hepatocytes ( n = 8, 10.4%). MT expression was significantly associated with Ki-67 staining in bile duct epithelium and Kupffer cells. Additionally, median MT expression was higher in cases containing lymphocytic infiltrates as compared with cases with no lymphocytic infiltrate ( P < .05). These findings are the first known report of MT expression within chronic equine hepatic disease.

Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models

Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans.