Plasma sgp130 is an independent predictor of non-alcoholic fatty liver disease severity

Background: Nonalcoholic steatohepatitis (NASH) is a metabolic disease associated with liver failure and cancer. Accurate monitoring of advancing NASH is challenging. There are few reliable, non-invasive biomarkers of early NASH. Since liver inflammation is a main driver of fibrosis, we investigated relationships between circulating components of the interleukin-6 signaling pathway (IL-6, sIL-6R and sgp130) and liver pathology in subjects with NAFLD and NASH. Methods: Predictive performance of plasma IL-6, sIL-6R and sgp130 were investigated in two independent cohorts: 1) patients with biopsy-confirmed NASH (n=49), where magnetic resonance spectroscopy (MRS), imaging (MRI) and elastography (MRE) assessed liver fat, volume and stiffness; and 2) patients with morbid obesity (n=245) undergoing bariatric surgery where Bedossa algorithm and steatosis, activity, and fibrosis scores assessed NASH severity. Correlations were evaluated between circulating IL-6, sIL-6R and sgp130 and anthropomorphic characteristics, plasma markers of metabolic disease or liver pathology, adjusting for covariates of liver disease such as age, sex, BMI and diabetes. Results: In patients with NASH, plasma IL-6 and sgp130 strongly correlated with liver stiffness, which for sgp130, was independent of age, sex, BMI, and chronic disease (diabetes, hyperlipidemia, hypertension or history of HCC). Plasma sgp130 was the strongest predictor of liver stiffness compared to commonly used biomarkers and predictive algorithms. Plasma sIL-6R correlated with liver volume independent of age, sex, and BMI. In stepwise forward regression analysis, plasma sgp130 followed by NAFLD fibrosis score and plasma globulin, predicted up to 74% of liver stiffness with/without adjustment for sex. In morbidly obese subjects, circulating IL-6 correlated with hepatocellular ballooning and sgp130 correlated with advanced liver fibrosis. Conclusions: Circulating sgp130 could represent a robust biomarker of active NASH and may be used alone or in combination with other biomarkers as a non-invasive measure of liver disease severity.

Liver Stiffness, Albuminuria and Chronic Kidney Disease in Patients with NAFLD: A Systematic Review and Meta-Analysis

An association between liver stiffness, a surrogate measure of liver fibrosis, and chronic kidney disease (CKD) in patients with nonalcoholic fatty liver disease (NAFLD) has been proposed. However, most studies were small and had low statistical power. We systematically searched PubMed-MEDLINE and Scopus from inception to August 2021 for cross-sectional or cohort studies reporting the association between liver stiffness diagnosed by vibration controlled transient elastography (VCTE) and renal dysfunction. The primary outcome was CKD, defined as a composite of urinary albumin to creatinine ratio (UACR) ≥ 30 mg/g and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Measures of association from individual studies were meta-analyzed using random effects models. Of the 526 titles initially scrutinized, 7 cross-sectional studies fulfilled the criteria and were included. For CKD, risk was higher in patients with liver fibrosis assessed by VCTE, compared with patients without (n = 5 studies: OR 2.49, 95% CI 1.89–3.29; test for overall effect z = 6.475, p < 0.001). When increased UACR was considered as an outcome, elevated liver stiffness was associated with a significantly increased risk as well (n = 3 studies: OR 1. 98 95% CI 1.29–3.05; test for overall effect z = 3.113, p = 0.002). Neither analysis showed significant heterogeneity (I2 = 0% and I2 = 46.5%, respectively for the two outcomes). This meta-analysis indicates that elevated liver stiffness is associated with increased odds of kidney outcomes among patients with NAFLD. Wider use of VCTE to screen for advanced fibrosis might help identify patients at risk of end-stage renal disease.

Regression of liver fibrosis and hepatocellular carcinoma development after HCV eradication with oral antiviral agents

We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years. LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN). Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks. HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN.Clinical trials registration: ClinicalTrials.gov (NCT02865369).

Liver Fibrosis and Steatosis in Virally Suppressed HIV-Infected Patients with Cytomegalovirus Seropositivity

Background: Cytomegalovirus (CMV) is a human herpesvirus common in people with human immunodeficiency virus (HIV). In a patient with immunocompetence, long periodic asymptomatic CMV might affect to develop the abnormal liver function and contribute to non-AIDS defining morbidity, including chronic liver disease. This study aims to know the prevalence of liver fibrosis and steatosis in virally suppressed HIV infected patients with CMV reactive and summarize the correlation of clinical presentation with liver fibrosis and steatosis in these subjects.Method: A cross-sectional study in HIV Integrated Care Unit, Cipto Mangunkusumo Hospital, was conducted from April 2019 until June 2020. Subjects enrolled in this study were suppressed HIV patients aged between 30-40 years with positive IgG CMV and already using stable ART for at least one year. Transient elastography measured the liver stiffness. Patients with liver stiffness above 7 kPa were defined as having significant liver fibrosis. In addition, Spearman correlation was conducted to evaluate the correlation of clinical presentation of subjects related to liver fibrosis and steatosis. Results: A total of subjects was included in this study. Dominantly male (62.5%) with average age 38 ± 4.68 years. The median amount of CMV DNA was 466 (17-21284) copy/ml. Significant Fibrosis was found in 17/80 (21%) subjects. In this study, clinical parameters correlated with liver fibrosis were insulin, glucose fasting, Homa IR, triglyceride, HDL, and platelet. A medium positive correlation was found in insulin, and Homa IR, with coefficient correlation for insulin, was r = 0.475, p 0.001; and coefficient correlation for Homa IR was r = 0 .487, p 0.001.Conclusion: The prevalence of liver fibrosis was 12% in these subjects. In addition, insulin and Homa IR had a positive correlation with increasing liver fibrosis.

Prevalence of Elevated Liver Stiffness Among Potential Candidates for Bariatric Surgery in the United States

Purpose Obesity represents a well-known risk factor for metabolic-dysfunction associated fatty liver disease (MAFLD) and its progression towards cirrhosis. The aim of this study is to estimate the proportion of potential candidates to a bariatric surgery intervention that has an elevated liver stiffness on vibration-controlled transient elastography (VCTE). Materials and Methods This is a cross-sectional study performed using data obtained during the 2017–2018 cycle of the National Health and Nutrition Examination Survey. Potential candidates for a bariatric surgery intervention from the general US population were identified by applying criteria from international guidelines. All included participants were evaluated by VCTE. A controlled attenuation parameter (CAP) value ≥ 288 dB/m was considered indicative of steatosis while liver stiffness measurement (LSM) was considered elevated if ≥ 9.7 kPa. Multivariable logistic regression models were fitted to identify independent predictors of both outcomes. Results A total of 434 participants were included (mean age 42.9 ± 0.6 years; 54.4% women). Among them, 76.7% (95% CI 71.7–81.0) had steatosis, while 23.1% (95% CI 17.8–29.3) had an elevated LSM. Male sex, older age, γ-glutamyltranspeptidase levels, and body mass index (BMI) were independent predictors of steatosis, while BMI was the only independent predictor of elevated LSM. Non-Hispanic black participants were protected from both outcomes, while other ethnicities were not. Conclusion The prevalence of elevated LSM is high in potential candidates for a bariatric surgery intervention. Accurate screening for occult advanced liver disease might be indicated in this patient population. Graphical abstract

An-Luo-Hua-Xian Pill Can Improve the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated With Entecavir

Background & Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis even cancer, antiviral therapy can reverse liver fibrosis with limited effect, thus we aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with ETV.Methods: Treatment naïve patients with CHB from Oct 1st, 2013 to Dec 31st, 2020 were randomly treated with ETV alone or combined with ALHX (ETV+ALHX). Patients’ demographic, laboratory and liver histology data before and after 78 weeks of treatment were collected. Ishak fibrosis score (F) was used and fibrosis regression means F decreased ≥1 after treatment.Results: In total, 394 patients with a second liver biopsy after treatment were included in per-protocol population: 132 patients in ETV group and 262 patients in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group were significantly higher than ETV group in baseline F≥3 patients: 124/211 (58.8%) verse 45/98 (45.9%), p=0.035. The degradation rate of liver stiffness measurement (LSM) is also consistent with it: 154/262 (73.0%) in ETV+ALHX group and 60/132 (61.2%) in ETV group, p=0.037. Logistic regression analysis showed that combined with ALHX was related to fibrosis regression (OR=1.94, p=0.018), and family history of hepatocellular carcinoma was on the contrary (OR=0.41, p=0.031).Conclusions: ETV combined with ALHX can significantly increase liver fibrosis regression in CHB patients.