Biochemical and Anthropometric Indices of Insulin Resistance in Obese and Overweight Children with Metabolic Dysfunction-Associated Fatty Liver Disease.

BACKGROUND The prevalence of metabolic (dysfunction)-associated fatty liver disease (MAFLD) increases together with the epidemic of childhood obesity. An important mechanism in the phenomenon appears to be insulin resistance (IR), the assessment of which in children is problematic. The homeostatic model assessment of IR (HOMA-IR), commonly used for this, is not standardized and appears not to correlate with IR in the pediatric population. Therefore, our study aimed to evaluate potential substitute indices of IR, including the triglyceride-glucose index (TyG), triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), modified TyG indices: TyG-waist circumference (TyG-WC) and TyG-body mass index (TyG-BMI) as surrogate markers of MAFLD in obese children suspected to have liver disease. MATERIAL AND METHODS The retrospective study included 264 obese children admitted to the Department to diagnose suspected liver disease. MAFLD was diagnosed according to the International Expert Consensus Statement. Anthropometric measurements and laboratory tests were made and the indices were calculated. Receiver operating characteristics analysis was performed to calculate the power of the indices. RESULTS MAFLD was diagnosed in 184 patients (70%). Obese children with MAFLD showed significantly higher activity of liver enzymes and concentration of total cholesterol, TG, WC, and waist-to-hip ratio compared to non-hepatopathic obese controls (n=80). The most important indices in identifying MAFLD were: TyG (AUC=0.641, p<0.001, cut-off =8.41, sensitivity=57.4%, specificity=68.8%), and TG/HDL-C (AUC=0.638, p<0.001, cut-off=2.5, sensitivity=48.6%, specificity=76.3%). TyG-BMI and HOMA-IR were not useful predictors. CONCLUSIONS TyG and TG/HDL-C can be considered as potential surrogate biomarkers in predicting MAFLD in obese children.

Tocilizumab for the treatment of COVID-19.

INTRODUCTION: Since the beginning of the COVID-19 pandemic, the repurposing of medicines has been pursued to find interventions effective in preventing fatal outcome of the disease. One of these drugs was tocilizumab, an interleukin-6 inhibiting monoclonal antibody, previously used to treat several immune-related disorders. AREAS COVERED: In this article, we present the results of the initial observational studies and subsequent randomized clinical trials on the efficacy and safety of tocilizumab in the treatment of COVID-19. Despite conflicting results, possibly due to the heterogeneity of the studied populations, large studies have ultimately proven that preventing IL-6 from attaching to its receptors can effectively reverse the fatal course of the disease. We also discuss the meta-analyses, which mostly supported the validity of tocilizumab therapy. We show how tocilizumab found its place in the most important recommendations on COVID-19 treatment and obtained authorization from the major regulatory authorities. EXPERT OPINION: The criteria for optimizing tocilizumab therapy in COVID-19 still need to be established. They are also important considering the existing risks of future zoonotic spillovers and epidemics that may trigger hyperinflammation that could be efficiently blocked. The experience gained with tocilizumab shall be perceived as preparedness for future challenges.

Thrombospondin-2 as a potential noninvasive biomarker of hepatocyte injury but not liver fibrosis in children with MAFLD: A preliminary study.

Aim of the study: Metabolic-associated fatty liver disease (MAFLD) requires close monitoring due to its increased incidence and progression to fibrosis, cirrhosis and even hepatocellular carcinoma. The search for non-invasive markers to diagnose liver fibrosis is ongoing. The aim of our study was to evaluate the serum levels of growth differentiation factor-15 (GDF-15), thrombospondin-2 (TSP2), pentraxin 3 (PTX3) and angiopoietin-like protein 8 (ANGPTL8) in children with MAFLD. Material and methods: Fifty-six overweight/obese children with suspected liver disease were included in this prospective study. MAFLD was diagnosed according to the latest consensus. Vibration-controlled transient elastography (TE) was performed to detect clinically significant liver fibrosis. Serum concentrations of GDF-15, TSP2, PTX3 and ANGPTL8 were measured by enzyme-linked immunosorbent assay (ELISA). Results: Liver steatosis was diagnosed in abdominal ultrasound in 31 (55.36%) overweight/obese patients who were classified as the MAFLD group. Aspartate aminotransferase (AST)/platelet ratio (APRI) and liver stiffness measurement (LSM) values and TSP2 concentrations showed significantly higher values in patients in MAFLD than in the non-MAFLD group. TSP2 was significantly positively correlated with alanine transaminase (ALT), AST, γ-glutamyltransferase (GGT) and APRI in the study group. The receiver operating characteristics (ROC) analysis showed that the area under the curve (AUC) of LSM, APRI and serum TSP2 was significant for predicting MAFLD in obese children. In the multivariable regression model, LSM was the only significant parameter associated with the diagnosis of MAFLD in children. Conclusions: TSP2 may be a potential biomarker of hepatocyte injury in pediatric patients with MAFLD. None of the examined biomarkers were found to be effective non-invasive markers of liver fibrosis in children.

Updates in Management of SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide since the beginning of 2020 [...].

Ways to Eliminate Viral Hepatitis as a Global Health Threat.

Hepatitis B (HBV) and C (HCV) have been recognized by the World Health Organization [...].

Celiac Disease in Conjunction with Hereditary Fructose Intolerance as a Rare Cause of Liver Steatosis with Mild Hypertransaminasemia-A Case Report.

Celiac disease (CD) has been associated with several genetic and autoimmune disorders, but its association with hereditary fructose intolerance (HFI) is very rare. The possibility of an association between CD and HFI should be considered, especially in patients with a lack of improvement after a gluten-free diet. Children with HFI often present with a wide range of symptoms, however, data about a strong aversion to fruits and sweets may be helpful to establish the diagnosis. The diagnosis of HFI should be confirmed in genetic testing. Both CD and HFI may present with liver steatosis with hypertransaminasemia. In patients with these two disorders, the dietary restrictions of gluten and fructose improve clinical symptoms and protect them from secondary complications. We report the case of a child with the concurrence of these two disorders.

From Nonalcoholic Fatty Liver Disease (NAFLD) to Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)-New Terminology in Pediatric Patients as a Step in Good Scientific Direction?

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, which predispose to more serious hepatic conditions. It ranges from simple liver steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, and even end-stage liver disease. Since obesity became one of the most important health concerns wordwide, a considerable increase in the prevalance of NAFLD and other metabolic implications has been observed, both in adults and children. Due to the coexistence of visceral obesity, insulin resistance, dyslipidemia, NAFLD is considered to be the hepatic manifestation of metabolic syndrome (MetS). These relationships between NAFLD and MetS led to the set up in adults of a new term combining both of these conditions, called metabolic dysfunction-associated fatty liver disease (MAFLD). Based on these findings, we propose a set of criteria, which may be useful to diagnose MAFLD in children and adolescents.

Lack of change in serum sCD36 concentration in children with non-alcoholic fatty liver disease - A preliminary study.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is increasingly being recognized in the pediatric population, therefore, the search for non-invasive parameters to predict progression of NAFLD is of great interest. The aim of this study was to assess serum concentration of sCD36 in children with obesity and to determine its diagnostic value in pediatric NAFLD. PATIENTS AND METHODS: The study group consisted of 50 children with obesity aged 8-17.5 years, admitted to our Department because of suspected liver pathology. Selected liver diseases were excluded in the examined group. Anthropometry, laboratory tests (including the concentration of sCD36) and liver ultrasound, were performed in all subjects. RESULTS: NAFLD was confirmed in 16 out of 50 patients with obesity. There was significantly higher activity of ALT, AST, GGT, and increased waist-hip ratio WHR in individuals with NAFLD in comparison to non-hepatopathic children with obesity. We did not find a significant difference between sCD36 concentration in patients with obesity and NAFLD and non-hepathopathic patients with obesity. We also did not find a significant difference between sCD36 concentration in children with obesity in comparison to the control group and between mild (grade 1) vs. advanced (grade ≥2) steatosis. Correlation of sCD36 concentration with anthropometric, biochemical, and bioimpedance parameters in children with obesity was confirmed only with body fat percentage. CONCLUSIONS: sCD36 is not a suitable parameter to differentiate children with NAFLD from non-hepatopathic children with obesity and controls without obesity. Further studies on a larger pediatric population are needed to confirm these findings.

Cardiovascular Risk in Children with Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease in children. With the global obesity epidemic, the prevalence of NAFLD is increasing both in industrialized and developing countries. NAFLD is a multisystem disorder and a hepatic manifestation of the metabolic syndrome. Growing scientific evidence suggests that NAFLD is an independent risk factor for cardiovascular disease. This paper briefly describes the current knowledge concerning the association between NAFLD and cardiac dysfunction in children.

Management of hepatitis B and hepatitis C coinfection: an expert review.

INTRODUCTION: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections share common routes of transmission. HBV/HCV coinfection can lead to interactions affecting mechanisms of infection and therapy. AREAS COVERED: In the review, we present epidemiology of HBV/HCV coinfection and current therapeutic options for both viruses. The possibility of drug-drug interactions during the treatment of coinfected patients is discussed. However, the major part of the review is dedicated to interactions between viruses and risk of HBV reactivation during HCV treatment with direct-acting antivirals (DAA). Finally, we analyze available international and national guidelines for the management of HBV reactivations related to DAA administration. EXPERT OPINION: The most important international societies' guidelines include comments on HBV/HCV coinfection, but due to their inconsistency we present a proposal of management for HBV/HCV coinfected patients focusing mostly on HBV reactivation in patients treated for HCV. We provide some advice that should be considered in future guidelines for the management of HBV/HCV coinfection.

Update on pathogenesis, diagnostics and therapy of nonalcoholic fatty liver disease in children.

Nonalcoholic fatty liver disease (NAFLD) represents the most common cause of chronic liver disease. Increasing prevalence of NAFLD in children may be the cause of unfavorable metabolic implications and development of end stage liver disease. NAFLD is a "multiple-hit" disease mediated by several metabolic, environmental, genetic and microbiological mechanisms. Additionally, lipotoxicity, oxidative stress and inflammation predispose to progressive liver damage. According to current guidelines, liver biopsy is an imperfect gold standard for NAFLD diagnosis, but due to its invasive character its use is limited in children and it should be performed only in children who need exclusion of coexisting diseases. Noninvasive methods should be preferred and current research is focused on serum markers and novel imaging or elastographic techniques. Therapeutic approaches for NAFLD are currently focused on lifestyle modification, insulin resistance, dyslipidemia, oxidative stress and the gut microbiome. However, a number of clinical studies on novel therapeutic molecules are ongoing.

Can hepatokines be regarded as novel non-invasive serum biomarkers of intrahepatic lipid content in obese children?

PURPOSE: Hepatokines are proteins produced by the liver and involved in regulating glucose and lipid metabolism. However, their role as the biomarkers of intrahepatic lipid content is not clear. The aim of the study was to evaluate the serum concentration of selected hepatokines: fibroblast growth factor-21 (FGF-21), selenoprotein P (SELENOP) and sex hormone-binding globulin (SHBG) in obese children. PATIENTS AND METHODS: The cross-sectional study included 86 obese children with suspected liver disease. Nonalcoholic fatty liver disease (NAFLD) was diagnosed in children with liver steatosis in ultrasound with elevated alanine aminotransferase (ALT) serum activity and excluded other liver diseases. The total intrahepatic lipid content (TILC) was assessed by magnetic resonance proton spectroscopy (1H-MRS). RESULTS: The concentration of FGF-21 and SELENOP was significantly higher and SHBG significantly lower in children with NAFLD compared to controls. Only FGF-21 level was significantly higher in NAFLD children than in obese patients without NAFLD. The significant positive correlation of FGF-21 with ALT, gamma glutamyltransferase (GGT), triglycerides, homeostatic model assessment-insulin resistance (HOMA-IR), the degree of liver steatosis in ultrasound and TILC in 1H-MRS were found. The ability of serum FGF-21 to diagnose severe liver steatosis was significant. CONCLUSIONS: FGF-21 can be considered as a suitable biomarker in predicting TILC and fatty liver in obese children.

Estimation of gamma-glutamyl transferase as a suitable simple biomarker of the cardiovascular risk in children with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a risk factor for cardiovascular disease (CVD). Research conducted in adults has proven that GGT can also be an independent risk factor for CVD. The aim of this study was to ascertain if GGT can be regarded as a simple biomarker of cardiovascular risk in obese children with NAFLD. One hundred obese children, aged 7-17 years, with suspected liver pathology were admitted to our Department. Viral hepatitis and autoimmune, toxic and selected metabolic liver diseases were excluded. Anthropometry, laboratory tests, 1HMR spectroscopy and evaluation of the common carotid artery intima-media thickness (IMT) were performed in all subjects. NAFLD was confirmed in 38 obese patients. There was a significantly higher activity of GGT and ALT, the concentration of total and LDL cholesterol, waist circumference, left coronary artery IMT, mean IMT value and total lipids in 1HMRS in children with NAFLD in comparison to non-hepatopathic obese children. Logistic regression analysis indicated that GGT, total cholesterol, LDL-cholesterol, left IMT and waist circumference significantly affected the development of NAFLD in obese children. In ROC analysis only GGT, waist circumference and left IMT allowed to differentiate children with NAFLD from those without steatosis with GGT having the highest result (AUC=0.94). GGT activity in patients revealed weak or at the upper limit of statistical significance correlation with traditional cardiovascular risk factors: glucose level, waist circumference, BMI, total cholesterol, LDL-cholesterol and insulin level. This allows to suggest, that GGT might be a potential reliable, simple and non-invasive biochemical marker for estimation of cardiovascular risk in obese children with NAFLD. However, further studies on larger population are necessary to confirm that observation.

Predictive Role of Interleukin-18 in Liver Steatosis in Obese Children.

Introduction: Interleukin-18 (IL-18) is a proinflammatory cytokine associated with metabolic syndrome (MS). Nonalcoholic fatty liver disease (NAFLD) can be recognized as a feature of MS. Material and Methods: Serum IL-18 concentration was evaluated in serum of 108 obese children, determined with ELISA, and referred to degree of liver steatosis in USG or total intrahepatic lipid content assessed by magnetic resonance proton spectroscopy (1HMRS). Results: Fatty liver was confirmed in 89 children with USG and in 72 with 1HMRS. IL-18 concentration demonstrated significantly higher values in patients than in controls. Significant correlations between IL-18 and ALT, GGT, triglycerides, hsCRP, and the degree of liver steatosis were demonstrated. NAFLD children had significantly higher level of IL-18, ALT, GGT, HOMA-IR, waist circumference, and total lipids content in 1HMRS than other obese children. IL-18 level was also significantly higher in obese children with advanced liver steatosis. Measurement of serum IL-18 showed ability to differentiate children with fatty liver from those without steatosis. Conclusion: Elevated serum IL-18 concentration and its correlation with hepatocyte injury, systemic inflammation, and degree of liver steatosis support role in NAFLD pathomechanism. IL-18 can be considered to play a role in predicting advanced liver steatosis and fatty liver in obese children.

Ombitasvir and paritaprevir boosted with ritonavir and combined with dasabuvir for chronic hepatitis C.

INTRODUCTION: Hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma responsible for almost 700,000 deaths worldwide annually. Until 2014, management of HCV infections was based on interferon alfa containing regimens, with efficacy of 40-70% and a high adverse event rate. Interferon-free therapeutic options improved sustained viral response (SVR) rate to >90% and safety profile to placebo-like levels. Areas covered: This article describes all-oral regimen consisting of three direct acting antivirals (DAA) - ombitasvir (OBV), paritaprevir (PTV) and dasabuvir (DSV), which in clinical practice is boosted with ritonavir (r) and sometimes with ribavirin (RBV). This combination is registered for treatment of patients infected with HCV genotype 1 and 4. We focused on the regimen characteristics, pharmacokinetics, risk of resistance as well as efficacy and safety in clinical trials and real world studies. Expert commentary: Combination of OBV/PTV/r±DSV±RBV provides SVR rate of about 95% and good safety profile even in patients with compensated liver cirrhosis and failure with previous therapy. Currently it should be of particular value in areas with a predominance of genotype 1b infections. Due to the complexity and risk of drug to drug interactions, it will probably be replaced in coming few years with pangenotypic combinations of next generation DAAs.

Hepatitis C: efficacy and safety in real life.

Interferon-free combinations were registered in 2014 and 2015 for the treatment of chronic HCV infection. As a result, real-world experience has been gathered in the last year and this paper presents data available in September 2016. Real-world studies on the efficacy of the ledipasvir/sofosbuvir (LDV/SOF)±ribavirin (RBV) regimen showed a sustained virologic response (SVR) rate of between 91% and 98%. The SVR rate in the 13858 patients included in this paper was 94%, and 92% in the 3506 patients with cirrhosis. In a number of recently published real-world studies evaluating ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±RBV, the SVR rate was between 92% and 100%. The SVR rate of the 4260 patients included in the studies in this paper was 97% and the rate was the same in the 1647 patients with cirrhosis. Recently, data evaluating SOF/simeprevir±RBV showed an SVR rate >90%, while in combination with daclatasvir this rate reached approximately 95%. The safety data available for LDV/SOF±RBV and OBV/PTV/r±DSV±RBV show that discontinuation due to adverse events was necessary in no more than 3% of patients and the frequency of serious adverse events was between 0 and 11%, in particular in real-world studies. Because of the similar efficacy and safety, real-world data support the use of either the LDV/SOF±RBV or OBV/PTV/r±DSV±RBV regimen in patients with genotypes 1 or 4. There is still not enough real-world data in patients with genotype 3 and other genotypes.

Hepatokines and non-alcoholic fatty liver disease.

Nowadays non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver pathology both in adults and children. NAFLD manifestation ranges from a simple liver steatosis to steatohepatitis (nonalcoholic steatohepatitis - NASH), which may progress to advanced fibrosis, cirrhosis and end-stage liver disease. Due to the coexistence of visceral obesity, insulin resistance and dyslipidemia, NAFLD is considered to be the hepatic manifestation of metabolic syndrome. In recent years, in the pathogenesis of metabolic syndrome, type 2 diabetes mellitus, cardiovascular disease and also NAFLD, more and more attention has been paid to the so-called organokines, proteins with both paracrine or/and endocrine activities. These include most known adipokines (mainly produced by adipose tissue), myokines (mainly produced by skeletal muscles) and hepatokines exclusively or predominantly produced by the liver. It was shown that the liver may affect the lipids and glucose metabolism by hepatokines released into the blood and NAFLD seems to be associated with altered hepatokines production. Fetuin-A, fibroblast growth factor-21 (FGF-21), selenoprotein P, sex hormone-binding globulin (SHBG), angiopoietin-related growth factor (also known as angiopoietin-related protein 6) and leukocyte derived chemotaxin 2 (LECT2) are considered as the most important hepatokines. In this review, we provide an overview of the main hepatokines and we summarize the association of liver-derived proteins with the development and progression of NAFLD.

Current drugs in early development for treating hepatitis C virus-related hepatic fibrosis.

INTRODUCTION: More than 100 million people worldwide are infected with hepatitis C virus (HCV), which is responsible for chronic liver disease accompanied by progressive fibrosis of hepatic tissue, often leading to liver cirrhosis. Novel therapeutic options are able to clear the virus in almost all diagnosed patients. However, even after successful treatment, hepatic fibrosis may persist in many of them. There is no registered therapy specific for liver fibrosis, but numerous molecules are currently in development. AREAS COVERED: In this review, the authors look at drugs in early development for the treatment of HCV-related hepatic fibrosis. Their mechanism of action is based on the inhibition of hepatic inflammation, the modulation of cellular sources of extracellular matrix (ECM), the stimulation of ECM degradation and prevention of collagen crosslinking. Importantly, significant antifibrotic effects have been demonstrated with both IFN-based and IFN-free anti-HCV regimens. EXPERT OPINION: Successful future therapy is likely to be based on sequential administration of drugs leading initially to HCV clearance, followed by treatment for the possible reversal of liver fibrosis. The primary consideration with clinical trials carried out in patients with advanced liver disease is safety. Indeed, the evaluation of anti-fibrotic therapy depends on reliable noninvasive techniques for quantification of liver fibrosis, such as transient or shear-wave elastography or serologic tests which are able to replace liver biopsy.