Active Liver Disease Research Articles

Effect of berberine and bicyclol on Chinese patients with non-alcoholic fatty liver disease: a retrospective study

Objectives To compare the effect of berberine and bicyclol on patients with non-alcoholic fatty liver disease (NAFLD). Methods Chinese non-alcoholic and non-viral hepatitis patients with a hepatic lipid content > 13% and non-alcoholic fatty liver disease activity score (NAS) ≥ 2 were treated with 500 mg berberine thrice daily, together with dietary modification (low-fat diet) and Tai Chi exercise for 4 months (BT cohort; n = 112), or 25 mg bicyclol thrice daily plus dietary modification and Tai Chi exercise for 4 months (CT cohort, n = 145), or dietary modification and Tai Chi exercise for 4 months (DT cohort, n = 128). Results Patients in the BT and the CT cohorts had improved anthropometric measurements (weight, height, body mass index, and waist-to-hip ratio), biochemical parameters (blood sugar, lipid profile, and liver functions tests), liver/spleen computed tomography findings, and liver biopsy results after 4 months of intervention (p < 0.05 for all). Bicyclol decreased the NAS in the CT cohort to a significantly greater degree than berberine in the BT cohort (p < 0.0001, q = 3.879). Patients in the DT cohort had reduced body mass index and waist-to-hip ratio (p < 0.05 for both). During the 4-month intervention, patients in the BT cohort had abdominal distension, mild diarrhea, constipation, nausea, and dyspepsia; patients in the CT cohort had dizziness and abdominal distension. Conclusions Berberine or bicyclol plus dietary modification and Tai Chi exercise could control NAFLD without serious adverse effects. Dietary modification and Tai Chi exercise alone for 4 months are insufficient for the management of NAFLD. It is possible to reduce body weight by administering berberine or bicyclol.

Fat signal fraction assessed with MRI predicts hepatic recurrence following hepatic resection for colorectal liver metastases.

The effect of hepatic steatosis on the development of colorectal liver metastases (CRLM) remains unknown. This study evaluated the usefulness of fat signal fraction assessed with magnetic resonance imaging (MRI) and the effect of hepatic steatosis on hepatic recurrences following initial hepatectomy for CRLM. Between January 2013 and December 2019, 64 patients underwent initial hepatectomy for CRLM. The medical records of these patients were reviewed to evaluate the recurrence and survival outcomes. The fat signal fraction was positively correlated with the nonalcoholic fatty liver disease activity score and liver-spleen ratio. Recurrence following the initial hepatectomy was observed in 48/64 patients, and hepatic recurrence was observed in 30/64 patients. The fat signal fraction was significantly higher in patients with hepatic recurrence after initial hepatectomy. The hepatic recurrence rate was 69.2% in patients with fat signal fraction ≥ 0.0258, which was significantly higher than that in patients with fat signal fraction < 0.0258. Hepatic recurrence-free survival rate was significantly higher in patients with fat signal fraction < 0.0258 than in those with fat signal fraction ≥ 0.0258. Multivariate analyses revealed that fat signal fraction ≥ 0.0258 was an independent risk factor for hepatic recurrence. The fat signal fraction assessed with MRI was significantly associated with hepatic recurrence following initial hepatectomy for CRLM.

Interrelationship between physical activity and depression in nonalcoholic fatty liver disease.

BACKGROUNDNonalcoholic fatty liver disease (NAFLD) is associated with a sedentary lifestyle and depressive symptoms. It is also well established that physical inactivity and depressive symptoms are related. However, an investigation of the interaction between all of these factors in NAFLD has not been previously conducted.AIMTo investigate the interrelationship between physical inactivity and depressive symptoms in individuals with NAFLD.METHODSData from the Rancho Bernardo Study of Healthy Aging were utilized. 589 individuals were included in the analyses (43.1% male; 95.8% non-Hispanic white; aged 60.0 ± 7.0 years). NAFLD was defined by using the hepatic steatosis index, depression using the Beck Depression Inventory, and physical activity by self-report of number of times per week of strenuous activity. Multivariable generalized linear regression models with Gamma distribution were performed to investigate the proposed relationship.RESULTSAbout 40% of the sample had evidence of NAFLD, 9.3% had evidence of depression, and 29% were physically inactive. Individuals with NAFLD and depression were more likely to be physically inactive (60.7%) compared to individuals with neither NAFLD nor depression (22.9%), individuals with depression without NAFLD (37.0%), and individuals with NAFLD without depression (33.3%). After accounting for various comorbidities (i.e., age, sex, diabetes, hypertension, obesity), individuals with NAFLD and higher levels of physical activity were at a decreased odds of having depressive symptoms [16.1% reduction (95% confidence interval: -25.6 to -5.4%), P = 0.004], which was not observed in those without NAFLD.CONCLUSIONIndividuals with NAFLD have high levels of physical inactivity, particularly those with depressive symptoms. Because this group is at high risk for poor outcomes, practitioners should screen for the coexistence of depressive symptoms and NAFLD. This group should receive appropriate interventions aimed at increasing both participation and levels of intensity of physical activity.

Long-term exposure to air pollution, habitual physical activity and risk of non-alcoholic fatty liver disease: A prospective cohort study

BackgroundEmerging studies suggest a positive association between air pollution exposure and risk of non-alcoholic fatty liver disease (NAFLD), however, the combined effects of long-term exposure to air pollution, physical activity (PA), and risk of NAFLD is unclear. MethodsWe included 58,026 Taiwan residents who received a standard medical screening program between 2001 and 2016. Levels of fine particulate matter (PM2.5) at each participant’s residential address were estimated using multiple satellite-based aerosol optical depth data combined with a chemical transport model. PA volume was calculated as hours of metabolic equivalent tasks per week (MET-h/week) based on a standard self-administered questionnaire. Incident NAFLD was defined as the first occurrence of a fatty liver index (FLI) value > 30 or a hepatic steatosis index (HSI) value > 36 in participants without NAFLD at the baseline. Time-varying Cox regression was used to evaluate the combined effects of PA and PM2.5. ResultsExposure to PM2.5 was positively associated with NAFLD. A 1 μg/m3 increase in PM2.5 above 23.5 μg/m3 was associated with a hazard ratio (HR) of 1.06 (95% CI: 1.04, 1.09) and 1.05 (95% CI: 1.03, 1.07) for NAFLD identified by FLI and HSI, respectively. Performing PA was inversely associated with NAFLD. Compared with participants in high PM2.5 [≥ 27.5 μg/m3]–very low PA [< 3.75 MET-h/week] group, low PM2.5 [< 23.5 μg/m3]–very high PA [≥ 25.50 MET-h/week] group had a 57% (95% CI: 50%, 63%) and 42% (95% CI: 33%, 50%) lower risk of NAFLD defined by FLI and HSI, respectively. We found no evidence of any additive or multiplicative interaction between PA and PM2.5. ConclusionLong-term PM2.5 exposure was positively associated with NAFLD, whereas performing PA was inversely associated with NAFLD. The benefits of PA on NAFLD remained stable in participants exposed to various PM2.5 levels.

Meta-analysis: analysis of mechanistic pathways in the treatment of non-alcoholic steatohepatitis. Evidence from a Bayesian network meta-analysis.

Non-alcoholic steatohepatitis (NASH) is the most common cause of liver disease. However, there is lack of comparison of efficacy between different NASH drug classes. We conducted a network meta-analysis evaluating drug classes through comparing histological outcomes and targets of drugs. Medline, EMBASE and CENTRAL were searched for randomised controlled trials evaluating NASH drugs in biopsy-proven NASH patients. Primary outcomes included NASH resolution without worsening of fibrosis, at least 2-point reduction in Non-alcoholic fatty liver disease Activity Score (NAS) without worsening of fibrosis and at least 1-point reduction in fibrosis. Treatments were classified into inflammation, energy, bile acid and fibrosis modulators. The analysis was conducted with Bayesian network model and surface under the cumulative ranking curve (SUCRA) analysis. Among 49 included trials, treatments modulating energy (Risk ratio (RR): 1.92, Credible intervals (Crl): 1.59-2.34) were most likely to achieve NASH resolution followed by treatments modulating fibrosis (RR 1.66, Crl: 0.65-4.50), bile acids (RR: 1.37, Crl: 0.99-1.92) and inflammation (RR: 1.00, Crl: 0.75-1.33). Energy and bile acids modulation were effective in at least 2-point NAS reduction without worsening of fibrosis (RR: 1.52, Crl 1.30-1.77; RR: 1.69, Crl 1.41-2.03) and at least 1-point reduction in fibrosis (RR: 1.26, Crl:1.05-1.49; RR: 1.54, Crl: 1.20-1.97). This network analysis demonstrates the relative superiority of drugs modulating energy pathways and bile acids in NASH treatment. This guides the development and selection of drugs for combination therapies.

The preventive effect of recombinant human hepatocyte growth factor for hepatic steatosis in a rat model of short bowel syndrome

PurposeShort bowel syndrome (SBS) patients require total parenteral nutrition (TPN) following massive small bowel resection (SBR), which may cause intestinal failure-associated liver disease (IFALD), a life-threatening complication. Hepatocyte growth factor (HGF) acts as a potent hepatocyte mitogen with anti inflammatory and antioxidant actions. The present study evaluated the effect of recombinant human HGF (rh-HGF) on SBR and subsequent IFALD using a parentally fed rat model of SBS. MethodsRats underwent jugular vein catheterization for continuous TPN and 90% SBR. They were divided into 2 groups: TPN alone (SBS/TPN group: n = 7) or TPN plus the intravenous administration of rh-HGF (0.3 mg/kg/day) (SBS/TPN+HGF group: n = 7). On day 7, their tissues and stool were harvested to evaluate the effects of HGF. ResultsRegarding the histological findings, based on the nonalcoholic fatty liver disease (NAFLD) activity score, the SBS/TPN+HGF group showed significantly less hepatic steatosis and inflammatory cell infiltration than the SBS/TPN group (NAFLD activity score, 4.00 ± 1.83 vs. 1.00 ± 0.82; p < 0.01). The SBS/TPN+HGF group showed a higher expression of Farnesoid X receptor in the liver and lower expression of Toll-like receptor 4 in the ileum than the SBS/TPN group. Regarding the composition of the bacterial gut microbiota, Actinobacteria, Bacteroidetes and Proteobacteria were decreased in the SBS/TPN+HGF group compared with the SBS/TPN group. ConclusionIn our SBS with TPN rat model, rh-HGF administration had a preventive effect against hepatic steatosis and dysbiosis. rh-HGF may therefore be a potentially effective therapeutic agent for SBS and subsequent IFALD. Type of studyExperimental research.

Safety of Tocilizumab in COVID-19 Patients and Benefit of Single-Dose: The Largest Retrospective Observational Study.

Severe acute respiratory coronavirus-2 (SARS-CoV-2) still presents a public threat and puts extra strain on healthcare facilities. Without an effective antiviral drug, all available treatment options are considered supportive. Tocilizumab as a treatment option has to date shown variable results. In this retrospective study, we aimed to assess predictors of mortality of COVID-19 patients (n = 300) on tocilizumab and the clinical effectiveness of this drug. The results showed that ICU admission OR = 64.6 (95% CI: 8.2, 507.4); age of the patient OR = 1.1 (95% CI: 1.0, 1.1); and number of tocilizumab doses administered by the patient OR(two doses) = 4.0 (95% CI: 1.5, 10.9), OR(three doses) = 1.5 (95% CI: 0.5, 5.1), and OR(four doses or more) = 7.2 (95% CI: 2.0, 25.5) presented strong correlation factors that may be linked to COVID-19 mortality. Furthermore, our study showed the beneficial effects of early administration of tocilizumab OR = 1.2 (95% CI: 1.1, 1.4) and longer hospital length of stay OR = 0.974 (95% CI: 0.9, 1.0) in reducing COVID-19 mortalities. High blood D-dimer concentration OR = 1.1 (95% CI: 1.0, 1.2) and reciprocal blood phosphate concentration OR = 0.008 (95% CI: 0.0, 1.2) were correlated to high mortality under SARS-CoV-2 infection. The short-term effect of a single dose of tocilizumab was a significant increase in blood BUN and liver enzymes (ALT, AST, and LDH) above their normal ranges. Furthermore, it significantly reduced CRP blood concentration, but not to normal levels (13.90 to 1.40 mg/dL, p < 0.001). Assessing the effect of different doses of tocilizumab (in terms of the number of doses, total mg, and total mg/kg administered by the patients) indicated that administering more than one dose may lead to increases in ICU length of stay and hospital length of stay of up to 14 and 22 days after the last dose of tocilizumab (6 to 14, p = 0.06, and 10 to 22, p < 0.001), with no improvement in 28- and 90-day mortality, as confirmed by Kaplan–Meier analysis. There were also clear correlations and trends between the number of doses of tocilizumab and increased blood CO2, MCV, RDW, and D-dimer concentrations and between number of doses of tocilizumab and decreased CRP, AST, and hemoglobin concentrations. Microbiology analysis showed a significant increase in the incidence of infection after tocilizumab administration (28 to 119, p < 0.001) with a median time of incidence within 6 days of the first dose of tocilizumab. A significant correlation was also found between the number of tocilizumab doses and the number of incidences of infections after tocilizumab administration r (298) = 0.396, p = 1.028 × 10−12. Based on these results and depending on the pharmacokinetic parameters of the drug, we recommend single-dose administration of tocilizumab as the optimal dosage for COVID-19 patients who do not have active bacterial infection or liver diseases, to be administered as soon as the patient is admitted to the hospital.

Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans.

Hepatocyte nuclear factor 4 alpha (HNF4α) is indispensable for hepatocyte differentiation and critical for maintaining liver health. Here, we demonstrate that loss of HNF4α activity is a crucial step in the pathogenesis of chronic liver diseases (CLDs) that lead to development of HCC. We developed an HNF4α target gene signature, which can accurately determine HNF4α activity, and performed an exhaustive in silico analysis using hierarchical and K-means clustering, survival, and rank-order analysis of 30 independent data sets containing over 3500 individual samples. The association of changes in HNF4α activity to CLD progression of various etiologies, including HCV- and HBV-induced liver cirrhosis (LC), NAFLD/NASH, and HCC, was determined. Results revealed a step-wise reduction in HNF4α activity with each progressive stage of pathogenesis. Cluster analysis of LC gene expression data sets using the HNF4α signature showed that loss of HNF4α activity was associated with progression of Child-Pugh class, faster decompensation, incidence of HCC, and lower survival with and without HCC. A moderate decrease in HNF4α activity was observed in NAFLD from normal liver, but a further significant decline was observed in patients from NAFLD to NASH. In HCC, loss of HNF4α activity was associated with advanced disease, increased inflammatory changes, portal vein thrombosis, and substantially lower survival. In conclusion, these data indicate that loss of HNF4α function is a common event in the pathogenesis of CLDs leading to HCC and is important from both diagnostic and therapeutic standpoints.

Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH.

Non‐alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence‐based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra‐Amylin NASH (GAN) diet‐induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO‐NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose, and cholesterol for 28–88 weeks. GAN DIO‐NASH mice with biopsy‐confirmed NASH and fibrosis received low‐caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within‐subject change in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning‐based image analysis. GAN DIO‐NASH mice showed clear and reproducible progression in NASH, fibrosis stage, and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, whereas only lanifibranor induced regression in the fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of semaglutide, lanifibranor, and dietary intervention was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO‐NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO‐NASH mice in preclinical drug development.

Contribution of classification based on ferroptosis-related genes to the heterogeneity of MAFLD

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is a highly heterogeneous disease and its heterogeneity might be associated with ferroptosis because ferroptosis plays an important role in the development of MAFLD. We aimed to perform integrative analysis of ferroptosis related genes and MAFLD subtypes using bioinformatics.MethodsA differential expression analysis was performed to identify key ferroptosis-related genes associated with the clinical characteristics of MAFLD. Furthermore, consensus k clustering was utilized to distinguish ferroptosis-related clinical subtypes of MAFLD and assess the association of ferroptosis-related gene expression and clinical features between patients with different subtypes of MAFLD. Moreover, the variation in the immune status and regulatory relationship of ferroptosis-related genes in individuals with MAFLD was also explored using single sample gene set enrichment analysis, weighted gene coexpression network analysis and enrichment analyses.ResultsEight ferroptosis-related genes were identified as closely associated with both the hepatic steatosis grade and non-alcoholic fatty liver disease activity score. Two subtypes of MAFLD based on ferroptosis-related genes were identified by consensus clustering. They exhibited significantly different clinical features, immune statuses, biological processes and outcomes. The progression of the two subtypes was associated with immunity.ConclusionsTwo highly heterogeneous subtypes of MAFLD with significantly distinct clinical features, biological processes and immune statuses were identified based on ferroptosis-associated genes, which strongly supports the hypothesis that ferroptosis plays an important role in the development of MAFLD.

Stage-dependent expression of fibrogenic markers in alcohol-related liver disease

Alcohol-related liver disease (ALD) is the primary cause of liver-related mortality and morbidity. Liver fibrosis remains the best validated surrogate marker for patient prognosis and is usually assessed in liver biopsies using histochemical stains detecting collagen as the major extracellular matrix (ECM) component in ALD. Distinction of collagen subtypes is of clinical interest, as they, including their cleavage products, have different functions. Changes in production, distribution, and composition of specific collagen subtypes and other extracellular matrix (ECM) components as well as markers for their main cellular source (activated hepatic stellate cells (aHSCs) and myofibroblasts (MFBs)) have not been fully elucidated in ALD. Our aims were to investigate the stage-dependent expression of collagen subtypes and markers for aHSCs and MFBs in ALD. We included liver biopsies from 49 ALD patients with fibrosis stages F0–F4. Biopsies were classified according to the semi-quantitative non‐alcoholic fatty liver disease (NAFLD) activity score (NAS‐CRN). Slides were stained with H&E, Sirius Red, and immunohistochemically with antibodies against collagen types I, III, IV and VI, and aHSC/MFB markers α-SMA, osteonectin, and CD271. Expression was examined using automated digital imaging analysis (DIA), by calculating the positive area relative to the total liver biopsy area (proportionate area). Likewise, collagen-proportionate area (CPA) was assessed using DIA of Sirius Red stained slides. CPA correlated highly with fibrosis stage (rs = 0.88, P = 5.9E-17) and moderately with activity score (rs = 0.58, P = 0.00001). Collagen type I proportionate area increased from 0.3% (± 0.1) at F1 to 10.2% (± 1.6) at F4 (P < 0.001). Collagen type III proportionate area increased from 0.6% (± 0.2) at F0 to 11.9% (± 1.7) at F4 (P < 0.001). Collagen type IV proportionate area increased from 17.0% (± 2.5) at F0 to 27.0% (± 3.9) at F4 (P = 0.079). Collagen type VI proportionate area increased from 14.8% (± 1.4) at F0 to 31.4% (± 2.4) at F4 (P < 0.001). Proportionate areas for α-SMA and CD271 increased from 10.7% (± 1.6) and 6.5% (± 1.0) at F0 to 29.5% (± 3.4) and 22.1% (± 2.2) at F4 (P < 0.001). Proportionate area for osteonectin increased from 1.4–1.8% at F0–F2 to 3.1% (± 0.5) at F3 and 3.2% (± 0.6) at F4 (P < 0.05). In conclusion, our data indicate that collagen types I, III and VI and the aHSC/MFB markers α-SMA and CD271 show a stage-dependent increase in ALD. In early ALD, collagen types IV and VI are important components of the perisinusoidal and pericellular fibrosis. Immunohistochemistry is a valuable additional tool to characterize the ECM changes in ALD. Further research is needed to explore the functional role of CD271 and the stage-dependent expression of other collagen subtypes in ALD.

Shear wave elastography and shear wave dispersion imaging in primary biliary cholangitis-a pilot study.

Primary biliary cholangitis (PBC) is a chronic liver disease that can lead to liver fibrosis and cirrhosis. Two-dimensional shear wave elastography (2D-SWE) is a modern technique for fibrosis assessment. However, data regarding its performance in PBC is sparse. We aimed to characterize severity of liver disease in PBC patients using non-invasive 2D-SWE and the new methods of attenuation imaging (ATI) and shear wave dispersion imaging (SWD). Twenty two PBC patients were examined with 2D-SWE, SWD and ATI, alongside established non-invasive fibrosis and steatosis assessment methods as well as liver function tests. Median 2D-SWE values were 1.48 m/s (range, 1.14-2.13 m/s) and 6.7 kPa (range, 3.8-14.7 kPa), respectively. Median SWD, ATI, transient elastography (TE) and controlled attenuation parameter (CAP) values were 13.9 m/s/kHz (range, 11.6-21 m/s/kHz), 0.57 dB/cm/MHz (range, 0.5-0.68 dB/cm/MHz), 7 kPa (range, 3.7-14.6 kPa), and 208 dB/m (range, 107-276 dB/m), respectively. 2D-SWE displayed a significant correlation with spleen length, platelet count, non-invasive fibrosis scores (FIB-4, APRI) and with TE. SWD correlated with alkaline phosphatase (ALP) levels, which is a prognostic marker in PBC. Our findings add further evidence that 2D-SWE is a reliable method for fibrosis assessment in PBC. Even though the cohort size was small, the correlation of SWD with the prognostic marker ALP suggests a potentially valuable role of this new non-invasive method in evaluating liver disease activity in PBC.

Role of Mitochondrial Cytochrome P450 2E1 in Healthy and Diseased Liver.

Cytochrome P450 2E1 (CYP2E1) is pivotal in hepatotoxicity induced by alcohol abuse and different xenobiotics. In this setting, CYP2E1 generates reactive metabolites inducing oxidative stress, mitochondrial dysfunction and cell death. In addition, this enzyme appears to play a role in the progression of obesity-related fatty liver to nonalcoholic steatohepatitis. Indeed, increased CYP2E1 activity in nonalcoholic fatty liver disease (NAFLD) is deemed to induce reactive oxygen species overproduction, which in turn triggers oxidative stress, necroinflammation and fibrosis. In 1997, Avadhani’s group reported for the first time the presence of CYP2E1 in rat liver mitochondria, and subsequent investigations by other groups confirmed that mitochondrial CYP2E1 (mtCYP2E1) could be found in different experimental models. In this review, we first recall the main features of CYP2E1 including its role in the biotransformation of endogenous and exogenous molecules, the regulation of its expression and activity and its involvement in different liver diseases. Then, we present the current knowledge on the physiological role of mtCYP2E1, its contribution to xenobiotic biotransformation as well as the mechanism and regulation of CYP2E1 targeting to mitochondria. Finally, we discuss experimental investigations suggesting that mtCYP2E1 could have a role in alcohol-associated liver disease, xenobiotic-induced hepatotoxicity and NAFLD.

Association Between Neutrophil-to-Lymphocyte Ratio with Inflammatory Activity and Fibrosis in Non-alcoholic Fatty Liver Disease.

Inflammation plays an important role in the development and progression of non-alcoholic steatohepatitis (NASH), and NASH is a powerful driving force for the progression of fibrosis. The neutrophil-to-lymphocyte ratio (NLR) is a simple emerging indicator of inflammation. We aimed to assess the potential association between NLR and histological severity of non-alcoholic fatty liver disease (NAFLD). This retrospective study consisted of 231 patients with biopsy-proven NAFLD in China from August 2017 to September 2019. The steatosis, activity, and fibrosis scoring system were used to evaluate liver biopsy tissue. Of the 231 patients with NAFLD, advanced inflammatory activity was present in 43.3% and significant fibrosis in 25.5% of patients. Multivariate logistic regression analysis showed NLR to be correlated with advanced inflammatory activity (Odds ratio (OR): 0.62, 95% CI: 0.42-0.94, P = .025) and significant fibrosis (OR: 0.57, 95% CI: 0.35-0.94, P = .028). The NLR was inversely associated with the degree of steatosis, lobular inflammation and fibrosis (r = -0.16, P = .014; r = -0.15, P = .019; r = -0.13, P = .046, respectively), but had no association with the severity of ballooning. The multivariate-adjusted models had good predictability for advanced inflammatory activity (area under curves (AUC) 0.790, 95% CI: 0.730-0.850) and for significant fibrosis (AUC 0.798, 95% CI: 0.728-0.868). This study showed negative correlations between elevated NLR levels with advanced inflammatory activity and significant fibrosis in patients with NAFLD. Our results also suggested that NLR could be considered as a simple and noninvasive mark to identify high-risk populations in NAFLD.

Role of serum hyaluronic acid in predicting necroinflammatory activity of the nonalcoholic fatty liver disease.

Background and Aim:Hyaluronic acid (HA), a fundamental component of the extracellular matrix, is associated with chronic liver diseases. The aim of this study was to investigate quantitative HA measurement as a noninvasive marker for steatosis and fibrosis staging in nonalcoholic fatty liver disease (NAFLD) with biopsy evidence.Materials and Methods:In this study, 52 NAFLD patients with biopsy evidence and who met the inclusion criteria were included. Hepatic enzyme levels, HA levels, and other laboratory findings were examined. In addition, the degree of steatosis was determined via computed tomography (CT).Results:According to the degree of steatosis, HA levels were 29.17±22.66, 39.85±60.28, and 32.05±19.40, respectively, and no significant difference was found between the groups (p=0.584). In addition, HA levels were not found to be significant according to the degrees of steatohepatitis (p=0.860). However, a statistically significant relationship was found between steatosis levels detected by CT and biopsy (p<0.01).Conclusion:Serum HA level, other biochemical parameters, and steatosis severity measurement via CT did not appear to have any diagnostic value for nonalcoholic steatohepatitis. In this context, novel markers that may be useful for NAFLD diagnosis and severity assessment in risky individuals should be investigated.

CME/Answers: Metformin - Dos and Don'ts

CME/Answers: Metformin - Dos and Don'ts Abstract. CME/Answers: Metformin - Dos and Don'ts In the absence of contraindications metformin is still considered the initial medication in patients with diabetes mellitus type 2, although diabetes therapy is rapidly changing. Metformin is used both as monotherapy and in combination with any other diabetic medication. As a biguanide metformin improves glycemic control by inhibiting gluconeogenesis and increasing insulin-mediated glucose utilization in peripheral tissues. Metformin promotes modest weight reduction and provides several other advantages: no risk of hypoglycemia, excellent general tolerability, well-known long-term safety profile and low-cost. The most common gastrointestinal side effects are usually mild and transient, but vitamin B12 deficiency may develop. Metformin-associated lactic acidosis (MALA) is a rare, but relevant and life-threatening complication. The risk increases with renal impairment; therefore the metformin dose must be adjusted to the eGFR. The use of metformin is contraindicated with an eGFR <30 ml/min/1.73 m2. There are other contraindications: concurrent active or progressive severe liver disease, active alcohol abuse, unstable or acute heart failure, hypoperfusion and hemodynamic instability, as well as a past history of lactic acidosis. Since metformin remains a modern therapy, it is important to be aware of its indications and contraindications.

A Selective Adenosine A3 Receptor Antagonist, HL3501, Has Therapeutic Potential in Preclinical Liver and Renal Fibrosis Models.

Adenosine and 4 G-protein-associated membrane receptors (A1, A2A, A2B, and A3) and their derivatives regulate the central nervous, cardiovascular, peripheral, and immune system. We developed a novel selective A3 AR antagonist, HL3501, and examined its anti-fibrotic effects across various models. The anti-fibrotic activity of HL3501 was evaluated in three cell lines (HK2, LX2, and Primary hepatic stellate cell) and a methionine-choline-deficient (MCD) model including use of mouse pharmacokinetics (PK). HL3501 decreased alpha-smooth muscle actin (α-SMA) and collagen 1 in TGF-β1-induced pro-fibrotic activation in HK2 cells. HL3501 also inhibited TGF-β1-induced HSC activation, which resulted in reduction of α-SMA and fibronectin in LX2 and human primary HSCs. In the nonalcoholic fatty liver disease activity score (NAS) analysis, HL3501 showed improved anti-steatosis and anti-inflammatory activity. The mouse PK study revealed the oral bioavailability (%F) of HL3501 at 30 mg/kg and 60 mg/kg as 92.5 and 107.2%, respectively. HL3501 presents anti-fibrotic effects in in vitro and in vivo studies. We also demonstrated that HL3501 is orally available and has a good bioavailability (BA >90%) profile from in mouse PK. HL3501, therefore, has a therapeutic potential for various fibrotic diseases, including those of liver and kidney tissues.

Structural elucidation and anti-nonalcoholic fatty liver disease activity of Polygonatum cyrtonema Hua polysaccharide.

The chemical structure and pharmacological activity of Polygonatum cyrtonema Hua polysaccharides have garnered significant attention in recent years. In this study, a homogeneous polysaccharide, PCP1, was extracted from P. cyrtonema Hua rhizomes and purified. Monosaccharide composition analysis showed that PCP1 is primarily composed of fructose, glucose, and mannose. Chemical structure analysis showed that the main chain of PCP1 is composed mainly of →1)-β-D-Fruf-(2→ and →1,6)-β-D-Fruf-(2→, with small amounts of →6)-α-D-Glcp-(1→, →4)-β-D-Manp-(1→, and β-D-Glcp-(1→. The side chain is β-D-Fruf-(2→ linked at C-6 of →1,6)-β-D-Fruf-(2→. In vivo experiments showed that PCP1 mitigates liver pathological damage, improves abnormal lipid metabolism and oxidative stress, promotes the production of short-chain fatty acids, and balances the composition of the intestinal microbiota in non-alcoholic fatty liver disease (NAFLD) mice. Thus, PCP1 can be used as a natural ingredient in functional foods for the treatment of NAFLD.

Prevalence of High-risk Nonalcoholic Steatohepatitis (NASH) in the United States: Results From NHANES 2017–2018

The population prevalence of high-risk non-alcoholic steatohepatitis (NASH), defined as nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2, is unknown. The FibroScan-AST (FAST) score, calculated using liver stiffness measurement and controlled attenuation parameter values from FibroScan and aspartate aminotransferase levels, is a validated algorithm to identify individuals with high-risk NASH. We estimated the prevalence of high-risk NASH using the FAST score in the United States population. Data were derived from the National Health and Nutrition Examination Surveys 2017-2018, which included a total of 4218 adults with valid elastography measurements. FAST scores of ≥0.35 (sensitivity, 90%) and ≥0.67 (specificity, 90%) were used to identify adults with high-risk NASH in the general population. At 90% sensitivity for the FAST score, the prevalence of age-adjusted high-risk NASH was 5.8% and was higher among men (8.2% vs 3.6% in women) and in Hispanics (9.2% vs. 5.8% non-Hispanic (N.H.) Asians, 5.2% in N.H. whites, and 3.8% in N.H. blacks). The prevalence of high-risk NASH was 11.7% in those with metabolic syndrome and 22.5% in individuals with type 2 diabetes mellitus (T2DM). At 90% specificity for the FAST score, the prevalence of age-adjusted high-risk NASH was 1.2% and was higher among men (1.7% vs 0.8% in women) and in Hispanics (2.2% vs 1.0% in N.H. Asians, 0.9% in N.H. whites, and 0.4% in N.H. blacks). The prevalence of high-risk NASH was 3.4% in those with metabolic syndrome and 8.7% in adults with T2DM. We estimate at least 2 million adults have high-risk NASH in the United States. Moreover, the prevalence of high-risk NASH among individuals with T2DM is higher, ranging between 8.7% and 22.5%, supporting the case for coordinated case-finding and management.

CME: Metformin - Dos and Don'ts

CME: Metformin - Dos and Don'ts Abstract. In the absence of contraindications metformin is still considered the initial medication in patients with diabetes mellitus type 2, although diabetes therapy is rapidly changing. Metformin is used both as monotherapy and in combination with any other diabetic medication. As a biguanide metformin improves glycemic control by inhibiting gluconeogenesis and increasing insulin-mediated glucose utilization in peripheral tissues. Metformin promotes modest weight reduction and provides several other advantages: no risk of hypoglycemia, excellent general tolerability, well-known long-term safety profile and low-cost. The most common gastrointestinal side effects are usually mild and transient, but vitamin B12 deficiency may develop. Metformin-associated lactic acidosis (MALA) is a rare, but relevant and life-threatening complication. The risk increases with renal impairment; therefore the metformin dose must be adjusted to the eGFR. The use of metformin is contraindicated with an eGFR <30 ml/min/1.73 m2. There are other contraindications: concurrent active or progressive severe liver disease, active alcohol abuse, unstable or acute heart failure, hypoperfusion and hemodynamic instability, as well as a past history of lactic acidosis. Since metformin remains a modern therapy, it is important to be aware of its indications and contraindications.