Active Liver Disease Research Articles

β-Sitosterol Attenuates Dexamethasone-Induced Muscle Atrophy via Regulating FoxO1-Dependent Signaling in C2C12 Cell and Mice Model.

Sarcopenia refers to a decline in muscle mass and strength with age, causing significant impairment in the ability to carry out normal daily functions and increased risk of falls and fractures, eventually leading to loss of independence. Maintaining protein homeostasis is an important factor in preventing muscle loss, and the decrease in muscle mass is caused by an imbalance between anabolism and catabolism of muscle proteins. Although β-sitosterol has various effects such as anti-inflammatory, protective effect against nonalcoholic fatty liver disease (NAFLD), antioxidant, and antidiabetic activity, the mechanism of β-sitosterol effect on the catabolic pathway was not well known. β-sitosterol was assessed in vitro and in vivo using a dexamethasone-induced muscle atrophy mice model and C2C12 myoblasts. β-sitosterol protected mice from dexamethasone-induced muscle mass loss. The thickness of gastrocnemius muscle myofibers was increased in dexamethasone with the β-sitosterol treatment group (DS). Grip strength and creatine kinase (CK) activity were also recovered when β-sitosterol was treated. The muscle loss inhibitory efficacy of β-sitosterol in dexamethasone-induced muscle atrophy in C2C12 myotube was also verified in C2C12 myoblast. β-sitosterol also recovered the width of myotubes. The protein expression of muscle atrophy F-box (MAFbx) was increased in dexamethasone-treated animal models and C2C12 myoblast, but it was reduced when β-sitosterol was treated. MuRF1 also showed similar results to MAFbx in the mRNA level of C2C12 myotubes. In addition, in the gastrocnemius and tibialis anterior muscles of mouse models, Forkhead Box O1 (FoxO1) protein was increased in the dexamethasone-treated group (Dexa) compared with the control group and reduced in the DS group. Therefore, β-sitosterol would be a potential treatment agent for aging sarcopenia.

GS012 - A non-calorie restricted low carbohydrate high fat diet improves non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and HbA1c in type 2 diabetes: a six-month randomised controlled trial

GS012 - A non-calorie restricted low carbohydrate high fat diet improves non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and HbA1c in type 2 diabetes: a six-month randomised controlled trial

RWD116 Reduced Lysosomal Acid Lipase Activity in Non-Alcoholic Fatty Liver Disease: A Systematic Review of Current Evidence and Future Directions

Non-alcoholic fatty liver disease (NAFLD) presents with accumulation of excessive intra-hepatic fat and acts as a major health burden globally. A multifactorial pathogenesis is reported to be involved. Reduced Lysosomal Acid Lipase (LAL) activity is suggested as one of the involved pathogenic mechanisms. This review summarizes the available evidence on role of reduced LAL activity in the pathogenesis of NAFLD.

Quality of life assessment in chronic viral hepatitis

Chronic viral hepatitis has a significant impact on morbidity, quality of life and mortality and is characterized by a growing economic and social burden in the context of disability of the population and an increase in life expectancy. Chronic viral hepatitis can significantly worsen health-related quality of life indicators (HRQoL), which are a reflection of the influence of the disease and therapy on the physical and emotional components of the patient's health, especially in patients with progressive liver disease and/or active viral activity. To assess the quality of life related to health, you can use general tools and tools for specific diseases. Common tools available in the scientific literature include the Short Form 36 questionnaire (SF-36) and the Euroqol five-point questionnaire (EQ-5D). However, since general instruments cannot always detect the subtle effects of a particular condition on the quality of life, the use of special instruments is of great value, due to their ability to clinically characterize the quality of life in patients with chronic viral hepatitis. The use of recently developed special tools for assessing the quality of life will greatly assist in the verification of preventive and therapeutic interventions in this area. One of the priorities of any measures for the prevention and treatment of chronic viral hepatitis is to improve the quality of life in this category of patients.

Role of Hepatic Macrophages in Acute and Chronic Injury and Repair

Under optimal physiologic conditions, liver resident macrophages, such as Kupffer cells, are abundant in maintaining homeostasis. They orchestrate postinjury inflammatory tissue remodeling, surveil malignant microbial organisms, and remove toxins. Nevertheless, during chronic inflammation and wound healing in the liver, hepatic infiltration of immune cells from the bone marrow, peritoneum, and lymph nodes can promote the maintenance of macrophages subsets that exacerbate liver injury. Depending on the span of the inflammation and the extent of the damage, the liver can undergo acute liver injury or chronic liver injury. In this review, we explain the role of macrophages in the innate immune system, specifically discussing the role of the immune innate system and the description of Kupffer cells. The review also discusses macrophage activity in acute and chronic liver diseases, such as acetaminophen-induced injury, nonalcoholic steatohepatitis/nonalcoholic fatty liver disease, and alcoholic liver disease. Finally, the review also discuss Kupffer cell mechanisms for liver repair and regeneration.

Human Immunodeficiency Virus Is Associated With Elevated FibroScan-Aspartate Aminotransferase (FAST) Score.

Whether human immunodeficiency virus (HIV) infection is associated with the development of nonalcoholic steatohepatitis (NASH) remains unclear. The FibroScan-aspartate aminotransferase (FAST) score was developed to identify patients who have histologic NASH with high nonalcoholic fatty liver disease activity score (NAS ≥4) and significant liver fibrosis (≥F2), which has been associated with higher risk of end-stage liver disease. We examined whether HIV infection is associated with elevated FAST score in a large United States (US) cohort. Vibration-controlled transient elastography was performed in 1309 women without history of chronic viral hepatitis enrolled from 10 US sites: 928 women with HIV (WWH) and 381 women without HIV (WWOH). We used multivariable logistic regression to evaluate associations of HIV, demographic, lifestyle, and metabolic factors with an elevated (>0.35) FAST score. Median age of WWH and WWOH was 51 years and 48 years, respectively. Most (90%) WWH were on antiretroviral therapy and 72% had undetectable HIV RNA. Prevalence of elevated FAST score was higher among WWH compared to WWOH (6.3% vs 1.8%, respectively; P = .001). On multivariable analysis, HIV infection was associated with 3.7-fold higher odds of elevated FAST score (P = .002), and greater waist circumference (per 10 cm) was associated with 1.7-fold higher odds (P < .001). In analysis limited to WWH, undetectable HIV RNA and current protease inhibitor use were independently associated with lower odds of elevated FAST score. Our findings suggest that HIV is an independent risk factor for NASH with significant activity and fibrosis. Studies validating FAST score in persons with HIV are warranted.

Prospects of transient elastography’ using in the veterinary hepatology

Elastography is the qualitative and quantitative analysis of tissue’ elastic characteristics. The diagnostic of hepatopathies is based on the puncture biopsy of the liver. At the same point, the low biochemical activity of liver diseases is not always associated with the analogic histologic pattern. There were not excluded the advance of hepatic pathology. The primary hypothesis of this research was the prospects of transient elastography used in the diagnosis of hepatic disorder in animals. The methodology is about the formation of rotational waves in the determinate organ and measuring their velocity. The rotational wave has generated by a special detector which has the source of mechanical vibrations. The detector is located on the patient’s body surface in the zona of the organ’s projection. The studies were carried out in the laboratory animals, which were rabbits (n=20). The tool was used iLIvTouch. Standard methods also performed the liver biopsy and histological examination. Thus, we have detected the correlation between parameters of liver stiffness and the biopsy’ results performing transient elastography. The histology was pointing to the specific diagnosis: the fatty hepatosis with liver stiffness in 3.8‐4.2 kPa (n=10, the normal range was 5.8 kPa). Liver fibrosis was also diagnosed with liver stiffness in 6.2‐6.8 kPa (n=5) and toxic hepatitis with liver stiffness in 3.2‐3.6 kPa (n=5). The results of our research on laboratory animals after hepatopathies’ induction with different pathogenesis showed that the parameters of liver stiffness using transient elastography correlated with the results of the morphological evaluation. So, we can assume prospects of transient elastography using equally with standard methods.

Early Treatment Consideration in Patients with Hepatitis B 'e' Antigen-Positive Chronic Infection: Is It Time for a Paradigm Shift?

Chronic hepatitis B (CHB) is associated with significant morbidity and mortality, due to the adverse sequelae of cirrhosis and hepatocellular carcinoma (HCC). To date, antiviral therapy has been reserved for patients with ostensibly active liver disease, fibrosis or cirrhosis, and/or increased risk of HCC. Historically, patients with hepatitis B ‘e’ antigen (HBeAg)-positive chronic infection, were not offered antiviral therapy. Nevertheless, there has been compelling evidence emerging in recent years, demonstrating that this disease phase is in fact not characterized by immunological tolerance. HBV integration into the human genome is a frequent event found in these patients. Additionally, it may well be associated with active inflammation and fibrosis, even in the presence of persistently normal liver enzymes. Likewise, it appears that the mechanisms of hepatocarcinogenesis are already present during this early stage of the disease. This was reflected in the European Association for the Study of the Liver (EASL) guidelines, where treating patients above the age of 30 years with HBeAg-positive chronic infection was proposed. Lowering the treatment threshold to broaden treatment eligibility is likely to slow disease progression and reduce the risk of developing HCC. The current review discusses the reasons to consider early antiviral therapy in HBeAg-positive chronic infection.

Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis

Body weight loss of ≥ 10% improves the metabolic derangements and liver disease in the majority of non-alcoholic steatohepatitis (NASH) patients, suggesting metabolic modulators may be effective in controlling disease. The pharmacodynamics of ALT-801, a GLP-1/glucagon receptor dual agonist optimized for NASH and weight loss, were compared to semaglutide (GLP-1 receptor agonist) and elafibranor (peroxisome proliferator-activated receptor, PPAR-α/δ, agonist) in a biopsy-confirmed, diet-induced obese (DIO) mouse model of NASH (DIO-NASH). Male C57BL/6J mice were fed Amylin Liver NASH (AMLN) diet for 32 weeks. Animals with biopsy-confirmed steatosis and fibrosis received ALT-801, semaglutide, elafibranor, or vehicle daily for 12 weeks while maintained on the AMLN diet. Study endpoints included body and liver weight, liver and plasma total cholesterol and triglycerides, plasma aminotransferases, histological analysis of liver steatosis, inflammation (galectin-3) and fibrosis (collagen type 1 alpha 1), and evaluation of individual animal changes in composite Non-alcoholic Fatty Liver Disease Activity Score (NAS), and fibrosis stage. ALT-801 demonstrated significant reductions in body weight (approx. 25%), plasma aminotransferases, plasma total cholesterol and liver triglycerides/total cholesterol in conjunction with improved liver steatosis, with greater reductions (p < 0.05) compared to semaglutide and elafibranor. ALT-801 significantly reduced the inflammation marker galectin-3 and the fibrosis marker collagen type 1 alpha 1 vs. vehicle (p < 0.05), with ALT-801 producing greater reductions in galectin-3 vs. elafibranor (p < 0.05). Importantly, all animals treated with ALT-801 significantly improved composite NAS compared to the active controls. This study provides evidence for a potential role for ALT-801 in the therapeutic treatment of NASH.

Co-occurrence of Wilson disease and Auto-Immune Hepatitis in 14-year-old female: A case report

Unusual cases of coexistence between Wilson's disease and autoimmune hepatitis have occurred. There are characteristics of both diseases in this community of patients, and laboratory and histo pathological findings can be misleading. Wilson disease's clinical appearance can differ widely; thus,&#x0D; there is not always an easy diagnosis. In addition to being childhood and young adult illnesses, Wilson's disease can also be triggered at any age. Liver disease and cirrhosis, neuropsychiatric disorders, Kayser-Fleischer(KF.) rings, and acute hemolysis events are the primary characteristics of Wilson's disease, frequently in combination with acute liver failure. Diagnosis is extremely difficult for children and adults with active liver disease. None of the latest Wilson's disease laboratory tests are optimal and may not be specific. Therefore, by taking into account acute hepatitis similar to Wilson's disease and autoimmune hepatitis, concomitant treatment with immunosuppression and penicillamine may have a superior impact.

Defective endoplasmic reticulum stress response via X box-binding protein 1 is a major cause of poor liver regeneration after partial hepatectomy in mice with non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Poor regeneration after hepatectomy in NAFLD is well recognized, but the mechanism is unclear. Endoplasmic reticulum (ER) stress plays an important role in the development of NAFLD. Here, we show that an impaired ER stress response contributes to poor liver regeneration in partially hepatectomized mice. Non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) was induced in mice using our patented feed and 70% partial hepatectomy (PH) was performed. Mice were sacrificed 0, 4, 8, 24, or 48hours, or 7 days after PH, and liver regeneration and the mRNA expression of ER stress markers were assessed. Non-alcoholic fatty liver disease activity score was calculated as 4-6 points for NAFL and 7 points for NASH. NASH was characterized by inflammation and high ER stress marker expression before PH. After PH, NASH mice showed poorer liver regeneration than controls. High expression of proinflammatory cytokine genes was present in NASH mice 4 hours after PH. Xbp1-s mRNA expression was high in control and NAFL mice after PH, but no higher in NASH mice. Dysfunction of the ER stress response might be a cause of poor liver regeneration in NASH.

Hepatitis B Virus Genotypes and Antiviral Resistance Mutations in Romanian HIV-HBV Co-Infected Patients.

Background and Objectives: Romania has one of the highest prevalence of hepatitis B virus (HBV) infection in human immunodeficiency virus (HIV) patients, mostly in those parenterally infected during childhood; nevertheless, there are scarce data on the virological profile of co-infection. The objective of this study was to assess the prevalence of HBV genotypes and antiviral resistance-associated mutations (RAMs) in these co-infected patients, in order to monitor the viral factors associated with the evolution of liver disease. Materials and Methods: HBV genotypes and RAMs were detected using nested PCR and line probe assays (INNO-LiPA HBV genotyping assay, and INNO-LiPA HBV DR v2, Innogenetics). Results: Out of 117 co-infected patients, 73.5% had detectable HBV-DNA, but only 38.5% presented an HBV viral load >1000 IU/mL. HBV genotype A was present in 66.7% of the cases and was dominant in patients parenterally infected during early childhood, who experienced multiple treatment regimens, with a mean therapy length of 15.25 years, and present numerous mutations associated with lamivudine (LAM) resistance, but very rarely active liver disease. HBV genotype D was detected in 33.3% of the cases, mostly in recently diagnosed injecting drug users who are treatment naïve, but, nevertheless, present RAMs in 63.5% of the cases, suggesting transmitted drug resistance, and display more frequently advanced liver fibrosis (36.1% vs. 12.3%; p = 0.033). The most frequently encountered RAMs are M204V/I: 48.8%, L180M: 33.3%, L80V: 28.8%, and V173L: 42.2%. There are no significant differences in the distribution of RAMs in patients infected with different HBV genotypes, except for the L80V and N236T mutations, which were more frequently found in HBV genotype A infections (p = 0.032 and p = 0.004, respectively). Conclusions: HBV genotypes A and D are the only genotypes present in HIV–HBV co-infected patients from Romania, with different distributions according to the infection route, and are frequently associated with multiple RAMs, conferring extensive resistance to LAM.

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.