Interplay between metabolic dysfunction-associated fatty liver disease and renal function: An intriguing pediatric perspective

Over recent years,the nomenclature of non-alcoholic fatty liver disease has undergone significant changes.Indeed,in 2020,an expert consensus panel proposed the term“Metabolic(dysfunction)associated fatty liver disease”(MAFLD)to underscore the close association of fatty liver with metabolic abnormalities,thereby highlighting the cardiometabolic risks(such as metabolic syndrome,type 2 diabetes,insulin resistance,and cardiovascular disease)faced by these patients since childhood.More recently,this term has been further replaced with metabolic associated steatotic liver disease.It is worth noting that emerging evidence not only supports a close and independent association of MAFLD with chronic kidney disease in adults but also indicates its interplay with metabolic impairments.However,comparable pediatric data remain limited.Given the progressive and chronic nature of both diseases and their prognostic cardiometabolic implications,this editorial aims to provide a pediatric perspective on the intriguing relationship between MAFLD and renal function in childhood.

Magnetic resonance spectroscopy to study hepatic metabolism in diffuse liver diseases, diabetes and cancer

This review provides an overview of the current state of the art of magnetic resonance spectroscopy (MRS) in in vivo investigations of diffuse liver disease. So far, MRS of the human liver in vivo has mainly been used as a research tool rather than a clinical tool. The liver is particularly suitable for static and dynamic metabolic studies due to its high metabolic activity. Furthermore, its relatively superfi cial position allows excellent MRS localization, while its large volume allows detection of signals with relatively low intensity. This review describes the application of MRS to study the metabolic consequences of different conditions including diffuse and chronic liver diseases, congenital diseases, diabetes, and the presence of a distant malignancy on hepatic metabolism. In addition, future prospects of MRS are discussed. It is anticipated that future technical developments such as clinical MRS magnets with higher fi eld strength (3 T) and improved delineation of multicomponent signals such as phosphomonoester and phosphodiester using proton decoupling, especially if combined with price reductions for stable isotope tracers, will lead to intensifi ed research into metabolic syndrome, cardiovascular disease, hepato-biliary diseases, as well as non-metastatic liver metabolism in patients with a distant malignant tumor.

Association between IgG N-glycans and Nonalcoholic Fatty Liver Disease in Han Chinese

Nonalcoholic fatty liver disease（NAFLD） is a major public health issue worldwide. Immunoglobulin G（IgG） N-glycans are associated with risk factors for NAFLD, such as obesity and diabetes. A cross-sectional study involving 500 Han Chinese adults recruited from a community in Beijing was carried out to explore the association between IgG N-glycans and NAFLD. IgG N-glycosylation was significantly associated with NAFLD, with the disease showing a negative correlation with galactosylation（GP14, GP14n, and G2n）, positive correlation with fucosylation（FBG2n/G2n）, and positive correlation with bisecting N-acetylglucosamine（Glc NAc） [FBG2n/FG2n and FBG2n/（FG2n＋FBG2n）], after controlling age, gender, and prevalence of obesity, type 2 diabetes mellitus, hypertension, and hyperlipidemia. In other words, the present study showed a possible association between NAFLD and the loss of galactose and elevations of fucose and bisecting GlcNAc. Aberrant IgG glycosylation might therefore be a potential biomarker for the primary or secondary prevention of NAFLD.

Relation Between Cellular Senescence and Liver Diseases

Cellular senescence refers to a process that cellular proliferation and differentiation modulated by the multiple stimulating factors gradually decline. Aging cells present the irreversible stop of proliferation and differentiation and change in secretory function because the cell cycle of aging cells is steadily blocked at some point. It has have been shown that cellular senescence plays an important role in the occurrence and development of liver diseases. In this paper, we review the advances in relations between cellular senescence and liver diseases.

Radiofrequency ablation combined with transcatheter arterial chemoembolization for recurrent liver cancer

BACKGROUND The recurrence rate of liver cancer after surgery is high.Radiofrequency ablation(RFA)combined with transcatheter arterial chemoembolization(TACE)is an effective treatment for liver cancer;however,its efficacy in recurrent liver cancer remains unclear.AIM To investigate the clinical effect of TACE combined with RFA in the treatment of recurrent liver cancer.METHODS Ninety patients with recurrent liver cancer were divided into 2 groups according to treatment plan:Control(RFA alone);and experimental[TACE combined with RFA(TACE+RFA)].The incidence of increased alanine aminotransferase levels,complications,and other indices were compared between the two groups before and after the procedures.RESULTS One month after the procedures,the short-term efficacy rate and Karnofsky Performance Status scores of the experimental group were significantly higher than those of the control group(P<0.05).Alpha-fetoprotein(AFP)and total bilirubin levels were lower than those in the control group(P<0.05);The overall response rate was 82.22%and 66.67%in the experimental and control groups,respectively;The disease control rate was 93.33%and 82.22%in the experimental and control groups,respectively,the differences are statistically significant(P<0.05).And there were no statistical differences in complications between the two groups(P>0.05).CONCLUSION TACE+RFA was effective for the treatment of recurrent liver cancer and significantly reduced AFP levels and improved various indices of liver function.

Role ofγδT cells in liver diseases and its relationship with intestinal microbiota

γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity.Based on the composition of T cell receptor and the cytokines produced,γδT cells can be divided into diverse subsets that may be present at different locations,including the liver,epithelial layer of the gut,the dermis and so on.Many of these cells perform specific functions in liver diseases,such as viral hepatitis,autoimmune liver diseases,non-alcoholic fatty liver disease,liver cirrhosis and liver cancers.In this review,we discuss the distribution,subsets,functions ofγδT cells and the relationship between the microbiota andγδT cells in common hepatic diseases.AsγδT cells have been used to cure hematological and solid tumors,we are interested inγδT cell-based immunotherapies to treat liver diseases.

Primary sclerosing cholangitis associated colitis: Characterization of clinical, histologic features, and their associations with liver transplantation

BACKGROUND Primary sclerosing cholangitis(PSC)associated inflammatory bowel disease(IBD)is a unique form of IBD(PSC-IBD)with distinct clinical and histologic features from ulcerative colitis(UC)and Crohn disease(CD).In patients with PSC and IBD,the severity of the two disease processes may depend on each other.AIM To study the histologic and clinical features of PSC patients with and without IBD.METHODS We assessed specimens from patients with UC(n=28),CD(n=10),PSC and UC(PSC-UC;n=26);PSC and CD(PSC-CD;n=6);and PSC and no IBD(PSC-no IBD;n=4)between years 1999-2013.PSC-IBD patients were matched to IBD patients without PSC by age and colitis duration.Clinical data including age,gender,age at IBD and PSC diagnoses,IBD duration,treatment,follow-up,orthotopic liver transplantation(OLT)were noted.RESULTS PSC-UC patients had more isolated right-sided disease(P=0.03),and less active inflammation in left colon,rectum(P=0.03 and P=0.0006),and overall(P=0.0005)compared to UC.They required less steroids(P=0.01)and fewer colectomies(P=0.03)than UC patients.The PSC-CD patients had more ileitis and less rectal involvement compared to PSC-UC and CD.No PSC-CD patients required OLT compared to 38%of PSC-UC(P=0.1).PSC-IBD(PSC-UC and PSCCD)patients with OLT had severe disease in the left colon and rectum(P=0.04).CONCLUSION PSC-UC represents a distinct form of IBD.The different disease phenotype in PSC-IBD patients with OLT may support liver-gut axis interaction,however warrants clinical attention and further research.

Comprehensive Understanding of Immune Cells in The Pathogenesis of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,defined by several phases,ranging from benign fat accumulation to non-alcoholic steatohepatitis(NASH),which can lead to liver cancer and cirrhosis.Although NAFLD is a disease of disordered metabolism,it also involves several immune cell-mediated inflammatory processes,either promoting and/or suppressing hepatocyte inflammation through the secretion of pro-inflammatory and/or anti-inflammatory factors to influence the NAFLD process.However,the underlying disease mechanism and the role of immune cells in NAFLD are still under investigation,leaving many open-ended questions.In this review,we presented the recent concepts about the interplay of immune cells in the onset and pathogenesis of NAFLD.We also highlighted the specific non-immune cells exhibiting immunological properties of therapeutic significance in NAFLD.We hope that this review will help guide the development of future NAFLD therapeutics.

Genetic Variations and Nonalcoholic Fatty Liver Disease:Field Synopsis,Systematic Meta-Analysis,and Epidemiological Evidence

Objective To systematically summarize the published literature on the genetic variants associated with nonalcoholic fatty liver disease(NAFLD).Methods Literature from Web of Science,PubMed,and Embase between January 1980 and September 2022 was systematically searched.Meta-analyses of the genetic variants were conducted using at least five data sources.The epidemiologic credibility of the significant associations was graded using the Venice criteria.Results Based on literature screening,399 eligible studies were included,comprising 381 candidate gene association,16 genome-wide association,and 2 whole-exome sequencing studies.We identified 465 genetic variants in 173 genes in candidate gene association studies,and 25 genetic variants in 17 genes were included in the meta-analysis.The meta-analysis identified 11 variants in 10 genes that were significantly associated with NAFLD,with cumulative epidemiological evidence of an association graded as strong for two variants in two genes(HFE,TNF),moderate for four variants in three genes(TM6SF2,GCKR,and ADIPOQ),and weak for five variants in five genes(MBOAT7,PEMT,PNPLA3,LEPR,and MTHFR).Conclusion This study identified six variants in five genes that had moderate to strong evidence of an association with NAFLD,which may help understand the genetic architecture of NAFLD risk.

Metabolic dysfunction-associated fatty liver disease and low muscle strength: A comment

The diagnosis of non-alcoholic fatty liver disease(NAFLD)and metabolic dysfunction-associated fatty liver disease only on the basis of laboratory parameter score such as Hepatic Steatosis Index which includes liver enzymes,gender,basal metabolic index,and presence of diabetic mellitus is not sufficient to exclude other causes of deranged liver enzymes especially medications and autoimmune related liver diseases.As the guideline suggests ultrasound is the preferred first-line diagnostic procedure for imaging of NAFLD,as it provides additional diagnostic information and the combination of biomarkers/scores and transient elastography might confer additional diagnostic accuracy and evident from previous similar studies too.

Anti-tumor efficacy of Calculus bovis: Suppressing liver cancer by targeting tumor-associated macrophages

Despite significant advances in our understanding of the molecular pathogenesis of liver cancer and the availability of novel pharmacotherapies,liver cancer remains the fourth leading cause of cancer-related mortality worldwide.Tumor relapse,resistance to current anti-cancer drugs,metastasis,and organ toxicity are the major challenges that prevent considerable improvements in patient survival and quality of life.Calculus bovis(CB),an ancient Chinese medicinal drug,has been used to treat various pathologies,including stroke,convulsion,epilepsy,pain,and cancer.In this editorial,we discuss the research findings recently published by Huang et al on the therapeutic effects of CB in inhibiting the development of liver cancer.Utilizing the comprehensive transcriptomic analyses,in vitro experiments,and in vivo studies,the authors demonstrated that CB treatment inhibits the tumor-promoting M2 phenotype of tumor-associated macrophages via downregulating Wnt pathway.While multiple studies have been performed to explore the molecular mechanisms regulated by CB,this study uniquely shows its role in modulating the M2 phenotype of macrophages present within the tumor microenvironment.This study opens new avenues of future investigations aimed at investigating this drug’s efficacy in various mouse models including the effects of combination therapy,and against drug-resistant tumors.

Comparison between metabolic-associated fatty liver disease and nonalcoholic fatty liver disease:From nomenclature to clinical outcomes

As a result of the obesity epidemic,Nonalcoholic fatty liver disease(NAFLD)and its complications have increased among millions of people.Consequently,a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis;metabolic-associated fatty liver disease(MAFLD).This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD.This article discusses the rationale behind the nomenclature change,the main differences,and its clinical implications.

Blood cell counts and nonalcoholic fatty liver disease: Evidence from Mendelian randomization analysis

BACKGROUND Previous research has highlighted correlations between blood cell counts and chronic liver disease.Nonetheless,the causal relationships remain unknown.AIM To evaluate the causal effect of blood cell traits on liver enzymes and nonalcoholic fatty liver disease(NAFLD)risk.METHODS Independent genetic variants strongly associated with blood cell traits were extracted from a genome-wide association study(GWAS)conducted by the Blood Cell Consortium.Summary-level data for liver enzymes were obtained from the United Kingdom Biobank.NAFLD data were obtained from a GWAS meta-analysis(8434 cases and 770180 controls,discovery dataset)and the Fingen GWAS(2275 cases and 372727 controls,replication dataset).This analysis was conducted using the inverse-variance weighted method,followed by various sensitivity analyses.RESULTS One SD increase in the genetically predicted haemoglobin concentration(HGB)was associated with aβof 0.0078(95%CI:0.0059-0.0096),0.0108(95%CI:0.0080-0.0136),0.0361(95%CI:0.0156-0.0567),and 0.0083(95%CI:00046-0.0121)for alkaline phosphatase(ALP),alanine aminotransferase(ALT),aspartate aminotransferase,and gammaglutamyl transferase,respectively.Genetically predicted haematocrit was associated with ALP(β=0.0078,95%CI:0.0052-0.0104)and ALT(β=0.0057,95%CI:0.0039-0.0075).Genetically determined HGB and the reticulocyte fraction of red blood cells increased the risk of NAFLD[odds ratio(OR)=1.199,95%CI:1.087-1.322]and(OR=1.157,95%CI:1.071-1.250).The results of the sensitivity analyses remained significant.CONCLUSION Novel causal blood cell traits related to liver enzymes and NAFLD development were revealed through Mendelian randomization analysis,which may facilitate the diagnosis and prevention of NAFLD.

Protective links between vitamin D,inflammatory boweldisease and colon cancer

Vitamin D deficiency has been associated with a wide range of diseases and multiple forms of cancer including breast, colon, and prostate cancers. Relatively recent work has demonstrated vitamin D to be critical in immune function and therefore important in inflammatory diseases such as inflammatory bowel disease(IBD). Because vitamin D deficiency or insufficiency is increasingly prevalent around the world, with an estimated 30%-50% of children and adults at risk for vitamin D deficiency worldwide, it could have a significant impact on IBD. Epidemiologic studies suggest that low serum vitamin D levels are a risk factor for IBD and colon cancer, and vitamin D supplementation is associated with decreased colitis disease activity and/or alleviated symptoms. Patients diagnosed with IBD have a higher incidence of colorectal cancer than the general population, which supports the notion that inflammation plays a key role in cancer development and underscores the importance of understanding how vitamin D influences inflammation and its cancer-promoting effects. In addition to human epidemiological data, studies utilizing mouse models of colitis have shown that vitamin D is beneficial in preventing or ameliorating inflammation and clinical disease. The precise role of vitamin D on colitis is unknown; however, vitamin D regulates immune cell trafficking and differentiation, gut barrier function and antimicrobial peptide synthesis, all of which may be protective from IBD and colon cancer. Here we focus on effects of vitamin D on inflammation and inflammation-associated colon cancer and discuss the potential use of vitamin D for protection and treatment of IBD and colon cancer.

Reverse time-dependent effect of alphafetoprotein and disease control on survival of patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma

AIM To characterize the survival of cirrhotic patients with Barcelona Clinic Liver Cancer(BCLC) stage C hepatocellular carcinoma(HCC) and to ascertain the factors predicting the achievement of disease control(DC).METHODS The cirrhotic patients with BCLC stage C HCC evaluated by the Hepatocatt multidisciplinary group were subjected to the investigation. Demographic, clinical and tumor features, along with the best tumor response and overall survival were recorded. RESULTS One hundred and ten BCLC stage C patients were included in the analysis; the median overall survival was 13.4 mo(95%CI: 10.6-17.0). Only alphafetoprotein(AFP) serum level > 200 ng/m L and DC could independently predict survival but in a time dependent manner, the former was significantly associated with increased risk of mortality within the first 6 mo of follow-up(HR = 5.073, 95%CI: 2.159-11.916, P = 0.0002), whereas the latter showed a protective effect against death after one year(HR = 0.110, 95%CI: 0.038-0.314, P < 0.0001). Only patients showing microvascular invasion and/or extrahepatic spread recorded lower chances of achieving DC(OR = 0.263, 95%CI: 0.111-0.622, P = 0.002).CONCLUSION The BCLC stage C HCC includes a wide heterogeneous group of cirrhotic patients suitable for potentially curative treatments. The reverse and time dependent effect of AFP serum level and DC on patients' survival confers them as useful predictive tools for treatment management and clinical decisions.

Associating liver partition and portal vein ligation for staged hepatectomy in the treatment of colorectal cancer liver metastases

Colorectal cancer(CRC)is a common malignancy of the digestive system.Colorectal liver cancer metastasis(CRLM)occurs in approximately 50%of the patients and is the main cause of CRC mortality.Surgical resection is currently the most effective treatment for CRLM.However,given that the remnant liver volume after resection should be adequate,only a few patients are suitable for radical resection.Since Dr.Hans Schlitt first performed the associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)for CRLM in 2012,ALPPS has received considerable attention and has continually evolved in recent years.This review explains the technical origin of the ALPPS procedure for CRLM and evaluates its efficacy,pointing to its favorable postoperative outcomes.We also discuss the patient screening strategies and optimization of ALPPS to ensure long-term survival of patients with CRLM in whom surgery cannot be performed.Finally,further directions in both basic and clinical research regarding ALPPS have been proposed.Although ALPPS surgery is a difficult and high-risk technique,it is still worth exploration by experienced surgeons.

Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma:Lights and shadows

About one-fourth of adults globally suffer from nonalcoholic fatty liver disease(NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma(HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment(TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors(ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC.

Extragastric manifestations of Helicobacter pylori infection: Possible role of bacterium in liver and pancreas diseases

Helicobacter pylori(H. pylori) is an ancient microorganism that has co-evolved with humans for over 60000 years. This bacterium typically colonizes the human stomach and it is currently recognized as the most common infectious pathogen of the gastroduodenal tract. Although its chronic infection is associated with gastritis, peptic ulcer, dysplasia, neoplasia, MALT lymphoma and gastric adenocarcinoma, it has been suggested the possible association of H. pylori infection with several extragastric effects including hepatobiliary and pancreatic diseases. Since a microorganism resembling H. pylori was detected in samples from patients with hepatobiliary disorders, several reports have been discussed the possible role of bacteria in hepatic diseases as hepatocellular carcinoma, cirrhosis and hepatic encephalopathy, nonalcoholic fatty liver disease and fibrosis. Additionally, studies have reported the possible association between H. pylori infection and pancreatic diseases, especially because it has been suggested that this infection could change the pancreatic physiology. Some of them have related a possible association between the microorganism and pancreatic cancer. H. pylori infection has also been suggested to play a role in the acute and chronic pancreatitis pathogenesis, autoimmune pancreatitis, diabetes mellitus and metabolic syndrome. Considering that association of H. pylori to liver and pancreas diseases needs further clarification, our work offers a review about the results of some investigations related to the potential pathogenicity of H. pylori in these extragastric diseases.

Alcohol-related diseases and liver metastasis:Role of cell-free network communication

Alcohol intake is a risk factor for cancer development and metastatic disease progression.Extracellular vesicle(EV)-mediated interorgan communication is assumed to be significant in boosting tumorigenic pathways and disease progression.Recent research indicates that exosomes have a variety of roles in the development of cancer during pathophysiological conditions.The involvement of EV signaling during cancer progression in the alcohol environment is unknown.Therefore,understanding communication networks and the role of EVs as biomarkers can contribute significantly to developing strategies to address the serious public health problems associated with alcohol consumption and cancer.