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.

Sarcopenia and metabolic dysfunction associated steatotic liver disease:Time to address both

Sarcopenia and metabolic dysfunction associated steatotic liver disease(MASLD)are closely intertwined.Sarcopenia,traditionally a disease of the older adult and chronic disease population,has been closely studied as one of the pathophysiologic conditions at play in the development of MASLD.They share similar risk factors of insulin resistance and physical inactivity.Given similar pathophysiology along the liver-muscle axis,sarcopenia has been studied as a risk factor for MASLD,and vice versa.Current research suggests a bidirectional relationship.Given the chronicity of MASLD as a chronic inflammatory liver disease,it can break down muscle mass and lead to sarcopenia,while sarcopenia promotes intramuscular lipid accumulation that releases cytokines that can aggravate inflammation in the liver.However,for the longest time,a lack of consensus definition for MASLD and sarcopenia made it difficult to study their relationship and outcomes.A recent nomenclature update to diagnosing MASLD has made it easier for researchers to identify cohorts for study.However,no gold standard technique to measure muscle mass or consensus sarcopenia definition has been identified yet.Future studies are needed to reach a consensus and reduce diagnostic variation.With similar pathophysiology and shared risk factors between the two diseases,future research may also identify potential therapeutic targets along the liver-muscle axis that would benefit both sarcopenia and MASLD in order to maximize their outcomes.

Metabolic dysfunction-associated steatotic liver disease:A silent pandemic

The worldwide epidemiology of non-alcoholic fatty liver disease(NAFLD)is showing an upward trend,parallel to the rising trend of metabolic syndrome,owing to lifestyle changes.The pathogenesis of NAFLD has not been fully understood yet.Therefore,NAFLD has emerged as a public health concern in the field of hepatology and metabolisms worldwide.Recent changes in the nomenclature from NAFLD to metabolic dysfunction-associated steatotic liver disease have brought a positive outlook changes in the understanding of the disease process and doctor-patient communication.Lifestyle changes are the main treatment modality.Recently,clinical trial using drugs that target‘insulin resistance’which is the driving force behind NAFLD,have shown promising results.Further translational research is needed to better understand the underlying pathophysiological mechanism of NAFLD which may open newer avenues of therapeutic targets.The role of gut dysbiosis in etiopathogenesis and use of fecal microbiota modification in the treatment should be studied extensively.Prevention of this silent epidemic by spreading awareness and early intervention should be our priority.

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.

Implications of metabolic dysfunction associated fatty liver disease in COVID-19

Metabolic associated fatty liver disorder(MAFLD)characterizes the contributing etiologies(i.e.,type 2 diabetes mellitus,metabolic syndrome,overweight)of individuals with fatty liver disease that affects 1/3rd of the world population.In 2020,the coronavirus disease 2019(COVID-19)crisis was unprecedented,and people with different comorbidities became more susceptible to the infection caused by severe acute respiratory syndrome coronavirus 2.MAFLD patients are frequently obese with added metabolic menace like diabetes,hypertension,and dyslipidemia leading to greater jeopardy of COVID-19.MAFLD patients are 4 to 6-fold more prone towards infections.COVID-19 induces liver injury with elevated levels of aspartate aminotransferase and alanine aminotransferase and insignificantly elevated bilirubin.Hence,MAFLD in COVID-19 patients worsens the condition significantly.The evidence highlighting the interaction between MAFLD and altered liver functioning in COVID-19 suggested that COVID-19 patients with pre-existing MAFLD are at greater risk of morbidity or intensive care unit admission.Direct hepatic injury,enhanced levels of inflammatory cytokines,declined hepatic mitochondrial activity,and compromised immunity are considered as some underlying mechanisms.The main focus of this review is to discuss the implications of metabolic dysfunction associated with fatty liver disease in COVID-19 patients.The review systematically analyzes the effect of striking two worldwide pandemics(MAFLD and COVID-19)together in the present era.

Insulin resistance and adipose tissue interactions as the cornerstone of metabolic(dysfunction)-associated fatty liver disease pathogenesis

The relationship between metabolic derangements and fatty liver development are undeniable,since more than 75% of patients with type 2 diabetes mellitus present with fatty liver.There is also significant epidemiological association between insulin resistance(IR)and metabolic(dysfunction)-associated fatty liver disease(MAFLD).For little more than 2 years,the nomenclature of fatty liver of non-alcoholic origin has been intended to change to MAFLD by multiple groups.While a myriad of reasons for which MAFLD is thought to be of metabolic origin could be exposed,the bottom line relies on the role of IR as an initiator and perpetuator of this disease.There is a reciprocal role in MAFLD development and IR as well as serum glucose concentrations,where increased circulating glucose and insulin result in increased de novo lipogenesis by sterol regulatory elementbinding protein-1c induced lipogenic enzyme stimulation;therefore,increased endogenous production of triglycerides.The same effect is achieved through impaired suppression of adipose tissue(AT)lipolysis in insulin-resistant states,increasing fatty acid influx into the liver.The complementary reciprocal situation occurs when liver steatosis alters hepatokine secretion,modifying fatty acid metabolism as well as IR in a variety of tissues,including skeletal muscle,AT,and the liver.The aim of this review is to discuss the importance of IR and AT interactions in metabolic altered states as perhaps the most important factor in MAFLD pathogenesis.

Lower abundance of Bacteroides and metabolic dysfunction are highly associated with the post-weaning diarrhea in piglets

Growing evidences show a direct link between diarrhea and disorders of gut microbiota in pigs.However,whether there are microbial markers associated with post-weaning diarrhea remains unknown.In the current study,we compared the microbial community,functions and metabolites between healthy weaned piglets(group H,n=7)and piglets with post-weaning diarrhea(group D,n=7),in order to find out diarrhea associated microbial markers.Each of 7 fecal samples was collected from H and D piglets(weaned at 21 d and sampled at 26 d).The metagenomic and untargeted metabolomic analysis revealed that the microbial composition,function and metabolic profile in D pigs was considerably reshaped,including the reduced abundance and number of Bacteroides,which significantly correlated with the diarrhea status of host.The carbohydrate metabolism,biosynthesis and metabolism,lipid metabolism,amino acid metabolism,and the activity of glycan and carbohydrates digestion related enzymes showed extensively down-regulated in D pigs compared with H pigs.Diarrhea significantly changed the metabolic profiles of fecal microbiota,and most of the altered metabolites were negatively or positively correlated with the change in the abundance of Bacteroides.In conclusion,the lower abundance of Bacteroides and its associated metabolic dysfunction may be regarded as microbial markers of physiological post-weaning diarrhea in piglets.

Impact renaming non-alcoholic fatty liver disease to metabolic associated fatty liver disease in prevalence,characteristics and risk factors

BACKGROUND Recently,a group of hepatologists proposed to rename non-alcoholic fatty liver disease(NAFLD)as metabolic associated fatty liver disease(MAFLD)with modified diagnostic criteria.It is important to note,however,that there are some differences between the diagnostic criteria used for NAFLD and MAFLD.Since the research on MAFLD is just beginning,however,evidence on its incidence and prevalence in the general population and in speci
c subpopulations remains limited.AIM To assess epidemiology of fatty liver in new definition and compare MAFLD with NAFLD.Exploring risk factors of MAFLD individuals.METHODS This was a retrospective,cross-sectional study.A total of 85242 adults were selected from the Chinese health management database in 2017–2022.The data of general information,laboratory indicators,lifestyle management and psychological status were obtained.MAFLD was diagnosed as ultrasound diagnosis of fatty liver and at least one between these three conditions:Overweight/obesity,type 2 diabetes mellitus(T2DM)or metabolic dysregulation.Metabolic factors were not considered in NAFLD diagnosis standard.The clinical characteristics of MAFLD and NAFLD were analysed using descriptive statistics.Continuous variables normally distributed were expressed as means±SD.Categorical variables were expressed as frequencies and proportions.Binary logistic regression was used to determine risk factors of the MAFLD.RESULTS The prevalence of MAFLD and NAFLD was 40.5%and 31.0%,respectively.The MAFLD or NAFLD population is more likely to be older(M:47.19±10.82 vs 43.43±11.96;N:47.72±11.17 vs 43.71±11.66),male(M:77.21%vs 44.43%;N:67.90%vs 53.12%)and high body mass index(M:26.79±2.69 vs 22.44±2.48;N:26.29±2.84 vs 23.29±3.12)than the non-MAFLD or non-MAFLD population.In multivariate analysis,general information(e.g.,≥2 metabolic abnormalities OR=3.38,(95%CI:2.99-3.81),P<0.001;diastolic blood pressure OR=1.01,(95%CI:1.00–1.01),P=0.002),laboratory results[e.g.,total bilirubin(TBIL)OR=0.98,(95%CI:0.98-0.99),P<0.001;serum uric acid(SUA)OR=1.01,(95%CI:1.01-1.01),P<0.001],and lifestyle factors[e.g.,drink beverage OR=0.32,(95%CI:0.17-0.63),P=0.001]were influence factors for MAFLD.Our study results offer new insight into potential risk factors associated with fatty liver disease,including SUA,TBIL and creatinine,all of which are related to chronic renal disease(CKD).CONCLUSION MAFLD is more prevalent than NAFLD,with two-fifths of individuals meeting the diagnosis criteria.MAFLD and NAFLD populations have different clinical characteristics.CKD may be related with MAFLD.

Investigating the Effect of Metabolic Phenotypes on Health Events in Alcoholic and Nonalcoholic Fatty Liver Disease

Background and Aims:Metabolic dysfunction and obe-sity commonly coexist with both alcoholic and nonalcoholic fatty liver disease(AFLD and NAFLD).The association of AFLD and NAFLD with incident diseases in individuals with different metabolic phenotypes are unclear.Methods:UK Biobank study participants were screened for the presence of fatty liver at baseline.Body mass index and metabolic dysfunction were used to define metabolic phenotypes.Cox regression model was performed to examine the associations of AFLD and NAFLD with incident significant liver diseases(SLDs),cardiovascular diseases(CVDs),chronic kidney dis-eases(CKDs),and cancers,respectively.Results:A total of 43,974 AFLD and 103,248 NAFLD cases were identified.Both AFLD and NAFLD were associated with an increased risk of diseases of interest.The effects were amplified by obesity and metabolic abnormalities and modified by metabolic phe-notypes.Compared to individuals free of fatty liver and with phenotype of metabolically healthy-normal weight,AFLD[hazard ratio(HR 3.27;95%CI:1.95-5.47)]and NAFLD(HR 2.25;95%CI:1.28-3.94)cases with phenotype of met-abolically obese-normal weight had the greatest risk of SLDs.For CVDs,CKDs,and cancer,the greatest risks were detected in AFLD and NAFLD cases with phenotype of metabolically obese-overweight/obesity.In this subpopulation,AFLD and NAFLD conferred a 2.75-fold(95%CI:2.32-3.25)and 4.02-fold 95%CI:(3.64-4.43)increased risk of CVDs,4.37-fold 95%CI:(3.38-5.64)and 6.55-fold 95%CI:(5.73-7.48)increased risk of CKDs,and 1.19-fold 95%CI:(1.08-1.27)and 1.21-fold 95%CI:(1.14-1.28)increased risk of cancers,respectively.Conclusions:Metabolic phenotypes modified the association of AFLD and NAFLD with intrahepatic and ex-trahepatic diseases.

Biomarkers of Metabolic(Dysfunction)-associated Fatty Liver Disease:An Update

The prevalence of metabolic(dysfunction)-associated fatty liver disease(MAFLD)is rapidly increasing and affects up to two billion individuals globally,and this has also resulted in increased risks for cirrhosis,hepatocellular carcinoma,and liver transplants.In addition,it has also been linked to extrahepatic consequences,such as cardiovascular disease,diabetes,and various types of cancers.However,only a small proportion of patients with MAFLD develop these complications.Therefore,the identification of high-risk patients is paramount.Liver fibrosis is the major determinant in developing these complications.Although,liver biopsy is still considered the gold standard for the assessment of patients with MAFLD.Because of its invasive nature,among many other limitations,the search for noninvasive biomarkers for MAFLD remains an area of intensive research.In this review,we provide an update on the current and future biomarkers of MAFLD,including a discussion of the associated genetics,epigenetics,microbiota,and metabolomics.We also touch on the next wave of multiomic-based biomarkers.

Fibroscan-AST(FAST)score and other non-invasive tests for the diagnosis of fibrotic non-alcoholic steatohepatitis

The Fibroscan-AST(FAST)score was developed based on the data of patients who had a liver biopsy for non-alcoholic fatty liver disease(NAFLD)at several liver centres in England,and it was validated using data from seven clinical studies from North America,Europe and Asia(1).The FAST score requires only controlled attenuation parameter(CAP)and liver stiffness measurement(LSM)from a vibration-controlled transient elastography(VCTE)examination and serum aspartate aminotransferase(AST)level in its calculation.

Fatty liver disease and risk of all cause and cause-specific mortality outcomes in the older population

Accumulating evidence in recent years has reinforced the notion that non-alcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease/metabolic dysfunction steatotic liver disease(NAFLD/MAFLD/MASLD)is a multisystem disease that increases the risk of all-cause and disease-specific mortality(1,2).

Porcine circovirus type 2(PCV2)and Campylobacter infection induce diarrhea in piglets:Microbial dysbiosis and intestinal disorder

Diarrhea is considered to be associated with microbial dysbiosis caused by infection of pathogens but poorly understood.We herein characterized the colonic microbiota of diarrheal early-weaning piglets infected with porcine circovirus type 2(PCV2)and Campylobacter.Campylobacter infection significantly decreased species richness and Shannon diversity index of colonic microbiota together with a significant increase in the proportion of Campylobacter and Enterobacteriaceae,whereas no significant difference on the above indexes was observed in piglets infected with PCV2 compared with healthy piglets,PCV2 and Campylobacter infection could disturb the homeostasis of colonic microbiota through deterioration of ecological network within microbial community,and specially Campylobacter performed as a module hub in ecological networks.The microbial dysbiosis caused metabolic dysfunction and led to a remarkable reduction in production of short chain fatty acids,following by a higher pH level in colon cavity.Campylobacter infection disturbed the function of colonic tract barrier observed in terms of significant lower relative expression of claudin-1,occluding,and zonula occludens protein-1 genes,and PCV2 infection induced intestinal inflammation together with a higher permeability of colon.Generally,these results suggested that PCV2 and Campylobacter infection could induce microbial dysbiosis and metabolic dysfunction,and cause intestinal disorder,all of which finally were associated to contribute to the diarrhea of early-weaning piglets.

High-fat diet-induced adipose tissue expansion occurs prior to insulin resistance in C57BL/6J mice

Background::To date,there is only scare evidence characterizing the temporal features and progression of metabolic dysfunction in high-fat diet(HFD)-fed obese mice.Hence,its specific pathogenesis remains unclear.Methods::Sixty 6-week-old male C57BL/6J mice were randomly divided into HFD and control diet(CD)groups and sacrificed at 1,5,9,13,17,and 21 weeks,respectively.At weekly intervals,intraperitoneal glucose tolerance testing(IPGTT)and intraperitoneal insulin tolerance testing(IPITT)were performed in both groups.A detailed time course in HFD-fed mice was investigated by evaluating the initiation of glucose homeostasis impairment,dyslipidemia,systemic insulin sensitivity,monocyte chemoattractant protein-1(MCP-1)levels,epididymal white adipose tissue(eWAT)expansion,macrophage content changes,proinflammatory(M1)/anti-inflammatory(M2)macrophage imbalance,lipid accumulation in the liver,andβ-cell morphometry in the pancreas.Results::In the HFD group,progressive weight gain and impairments in glucose metabolism(elevated fasting blood glucose and area under the curve(AUC)of IPGTT)were observed from the 3rd week,and a significantly elevated AUC of IPITT was first detected after week 7 of HFD feeding.As for dyslipidemia,after 9 weeks of feeding,the low-density lipoprotein cholesterol level and total cholesterol level in HFD group were significantly higher than those in the CD group(all P<0.05),whereas no significant differences were shown in triglyceride level.Adipocyte size increased significantly in the HFD group in the 1st week,a phenotypic switch in eWAT from anti-inflammatory(M2)to pro-inflammatory(M1)macrophages was observed in the 5th week,and the metabolic inflammation was distinct in eWAT in the 9th week.Additionally,liver steatosis was considerably obvious at the 17th week and pancreaticβ-cell morphometry did not change during 21 weeks of HFD feeding.Conclusion::The eWAT expansion was detected early in HFD-induced obese mice,which occurred prior to obvious insulin resistance.

Exercise as a therapy for cancer-induced muscle wasting

Cancer cachexia is a progressive disorder characterized by body weight,fat,and muscle loss.Cachexia induces metabolic disruptions that can be analogous and distinct from those observed in cancer,obscuring both diagnosis and treatment options.Inflammation,hypogonadism,and physical inactivity are widely investigated as systemic mediators of cancer-induced muscle wasting.At the cellular level,dysregulation of protein turnover and energy metabolism can negatively impact muscle mass and function.Exercise is well known for its anti-inflammatory effects and potent stimulation of anabolic signaling.Emerging evidence suggests the potential for exercise to rescue muscle's sensitivity to anabolic stimuli,reduce wasting through protein synthesis modulation,myokine release,and subsequent downregulation of proteolytic factors.To date,there is no recommendation for exercise in the management of cachexia.Given its complex nature,a multimodal approach incorporating exercise offers promising potential for cancer cachexia treatment.This review's primary objective is to summarize the growing body of research examining exercise regulation of cancer cachexia.Furthermore,we will provide evidence for exercise interactions with established systemic and cellular regulators of cancer-induced muscle wasting.

Portal hypertension in nonalcoholic fatty liver disease: Challenges and perspectives

Nonalcoholic fatty liver disease(NAFLD)has become the most common chronic liver disease worldwide.NAFLD‐related cirrhosis is often complicated by portal hypertension(PHT).Recent evidence showed that portal venous pressure(PVP)starts to rise in the early stages of NAFLD,even in absence of advanced fibrosis or cirrhosis.However,the precise pathological mechanisms of this process are still poorly understood.Lipid accumulation,hepatocellular ballooning,sinusoidal endothelial cell dysfunction,capillarization,microthrombosis,increased angiogenesis,and pericellular fibrosis may all be involved in the early development of increased PVP in NAFLD.Direct measurement of PHT is invasive and impractical in noncirrhotic NAFLD individuals and may also underestimate its severity.Thus,the development and validation of noninvasive and more accurate measurements,including new serum biomarkers,scoring models,and imaging techniques(such as ultrasonography,elastography,and magnetic resonance imaging),are urgently needed.Owing to the increasing morbidity,challenges in the prevention and management of PHT in NAFLD are unprecedented.This review article aims to briefly discuss these challenges and summarizes the mechanisms,diagnosis,and emerging therapies for PHT in people with NAFLD.

MAFLD vs.NAFLD:shared features and potential changes in epidemiology,pathophysiology,diagnosis,and pharmacotherapy

Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide,placing an increasing burden on human health.NAFLD is a complex multifactorial disease involving genetic,metabolic,and environmental factors.It is closely associated with metabolic syndrome,obesity,and type 2 diabetes,of which insulin resistance is the main pathophysiological mechanism.Over the past few decades,investigation of the pathogenesis,diagnosis,and treatments has revealed different aspects of NAFLD,challenging the accuracy of definition and therapeutic strategy for the clinical practice.Recently,experts reach a consensus that NAFLD does not reflect the current knowledge,and metabolic(dysfunction)associated fatty liver disease(MAFLD)is suggested as a more appropriate term.The new definition puts increased emphasis on the important role of metabolic dysfunction in it.Herein,the shared features and potential changes in epidemiology,pathophysiology,diagnosis,and pharmacotherapy of the newly defined MAFLD,as compared with the formerly defined NAFLD,are reviewed for updating our understanding.

From MAFLD to hepatocellular carcinoma and everything in between

Metabolic(dysfunction)associated fatty liver disease(MAFLD),previously known as non-alcoholic fatty liver disease,is the most common cause of chronic liver disease worldwide.Many risk factors contribute to the pathogenesis of MAFLD with metabolic dysregulation being the final arbiter of its development and progression.MAFLD poses a substantial economic burden to societies,which based on current trends is expected to increase over time.Numerous studies have addressed various aspects of MAFLD from its risk associations to its economic and social burden and clinical diagnosis and management,as well as the molecular mechanisms linking MAFLD to end-stage liver disease and hepatocellular carcinoma.This review summarizes current understanding of the pathogenesis of MAFLD and related diseases,particularly liver cancer.Potential therapeutic agents for MAFLD and diagnostic biomarkers are discussed.

Pyrrolizidine alkaloids:An update on their metabolism and hepatotoxicity mechanism

Pyrrolizidine alkaloids(PAs)are among the most hepatotoxic natural compounds that are widely distributed throughout the world.Most PAs are metabolically activated to trigger toxicity.Exposure to herbal medicine containing PAs and food supplements contaminated by PAs is considered to be one of the two main causes of hepatic sinusoidal obstruction syndrome(HSOS),which is a rare hepatic vascular disease with a high mortality rate.PAs-induced HSOS cases have been reported worldwide.However,there is no clinically effective therapy for PAs-induced HSOS,which is partially because the toxic mechanism is not fully understood.This review focuses on updating the information on the metabolism and the molecular mechanisms of PAs hepatotoxicity,including oxidative stress,apoptosis,and dysfunction of bile acid metabolism,and their interactions.

Emerging mechanisms of non-alcoholic steatohepatitis and novel drug therapies

Non-alcoholic fatty liver disease(NAFLD)has become a leading cause of chronic liver disease globally.It initiates with simple steatosis(NAFL)and can progress to the more severe condition of non-alcoholic steatohepatitis(NASH).NASH often advances to end-stage liver diseases such as liver fibrosis,cirrhosis,and hepatocellular carcinoma(HCC).Notably,the transition from NASH to end-stage liver diseases is irreversible,and the precise mechanisms driving this progression are not yet fully understood.Consequently,there is a critical need for the development of effective therapies to arrest or reverse this progression.This review provides a comprehensive overview of the pathogenesis of NASH,examines the current therapeutic targets and pharmacological treatments,and offers insights for future drug discovery and development strategies for NASH therapy.