Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis:an international registry study

Background:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis(NASH)is limited by its inherent invasiveness and possible sampling errors.Some studies have shown that cytokeratin-18(CK-18)concentrations may be useful in diagnosing NASH,but results across studies have been inconsistent.We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.Methods:Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease(NAFLD),and in all patients,circulating CK-18 M30 levels were measured.Individuals with a NAFLD activity score(NAS)≥5 with a score of≥1 for each of steatosis,ballooning,and lobular inflammation were diagnosed as having definite NASH;individuals with a NAS≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver(NAFL).Results:A total of 2571 participants were screened,and 1008(153 with NAFL and 855 with NASH)were finally enrolled.Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL(mean difference 177 U/L;standardized mean difference[SMD]:0.87[0.69–1.04]).There was an interaction between CK-18 M30 levels and serum alanine aminotransferase,body mass index(BMI),and hypertension(P<0.001,P=0.026 and P=0.049,respectively).CK-18 M30 levels were positively associated with histological NAS in most centers.The area under the receiver operating characteristics(AUROC)for NASH was 0.750(95%confidence intervals:0.714–0.787),and CK-18 M30 at Youden’s index maximum was 275.7 U/L.Both sensitivity(55%[52%–59%])and positive predictive value(59%)were not ideal.Conclusion:This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.

An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease

Background:With the rising global prevalence of fatty liver disease related to metabolic dysfunction,the association of this common liver condition with chronic kidney disease(CKD)has become increasingly evident.In 2020,the more inclusive term metabolic dysfunction-associated fatty liver disease(MAFLD)was proposed to replace the term non-alcoholic fatty liver disease(NAFLD).The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD.However,to date,there is no appropriate guidance on CKD in individuals with MAFLD.Furthermore,there has been little attention paid to the link between MAFLD and CKD in the Nephrology community.Methods and Results:Using a Delphi-based approach,a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD.Conclusions:This Delphi-based consensus statement provided guidance on the epidemiology,mechanisms,management and treatment of MAFLD and CKD,as well as the relationship between the severity of MAFLD and risk of CKD,which establish a framework for the early prevention and management of these two common and interconnected diseases.

Comparative associations of non-alcoholic fatty liver disease and metabolic dysfunction-associated steatotic liver disease with risk of incident chronic kidney disease:a cohort study

Background:We examined the comparative associations between non-alcoholic fatty liver disease(NAFLD)and metabolic dysfunction-associated steatotic liver disease(MASLD)definitions with risk of developing chronic kidney disease(CKD)and abnormal albuminuria.Methods:We conducted a cohort study of 214,145 Korean adults with normal kidney function at baseline who underwent liver ultrasonography.Participants were further subdivided into no steatotic liver disease(no-SLD),NAFLD-only,MASLD-only,both NAFLD and MASLD,and SLD not categorized as NAFLD or MASLD groups.Cox proportional hazards models were used to analyze the risk of incident CKD and albuminuria.Results:Compared with either the no-NAFLD or no-MASLD groups,the NAFLD and MASLD groups were associated with a higher risk of incident CKD(NAFLD:adjusted hazard ratio(HR),1.18[95%CI,1.01-1.38];MASLD:adjusted HR,1.21[95%CI,1.04-1.39]).Among the five subgroups,both NAFLD and MASLD group had the strongest association with risk of incident CKD(adjusted HR,1.21[95%CI,1.04-1.42]).The MASLD-only group had the strongest association with incident abnormal albuminuria,with an adjusted HR comparable to that of the both NAFLD and MASLD group(adjusted HR 1.96[95%CI,1.44-2.67]for the MASLD-only,and adjusted HR 1.98[95%CI,1.58-2.49]for the both NAFLD and MASLD group versus the no-SLD group).The NAFLD-only group was not independently associated with risk of CKD or abnormal albuminuria.Conclusions:These findings suggest that MASLD definition identifies individuals at high risk of developing incident CKD or abnormal albuminuria better than NAFLD definition.

LEARN algorithm:a novel option for predicting non-alcoholic steatohepatitis

Background:There is an unmet need for accurate non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH).Since impedance-based measurements of body composition are simple,repeatable and have a strong association with non-alcoholic fatty liver disease(NAFLD)severity,we aimed to develop a novel and fully automatic machine learning algorithm,consisting of a deep neural network based on impedance-based measurements of body composition to identify NASH[the bioeLectrical impEdance Analysis foR Nash(LEARN)algorithm].Methods:A total of 1,259 consecutive subjects with suspected NAFLD were screened from six medical centers across China,of which 766 patients with biopsy-proven NAFLD were included in final analysis.These patients were randomly subdivided into the training and validation groups,in a ratio of 4:1.The LEARN algorithm was developed in the training group to identify NASH,and subsequently,tested in the validation group.Results:The LEARN algorithm utilizing impedance-based measurements of body composition along with age,sex,pre-existing hypertension and diabetes,was able to predict the likelihood of having NASH.This algorithm showed good discriminatory ability for identifying NASH in both the training and validation groups[area under the receiver operating characteristics(AUROC):0.81,95%CI:0.77-0.84 and AUROC:0.80,95%CI:0.73-0.87,respectively].This algorithm also performed better than serum cytokeratin-18 neoepitope M30(CK-18 M30)level or other non-invasive NASH scores(including HAIR,ION,NICE)for identifying NASH(P value<0.001).Additionally,the LEARN algorithm performed well in identifying NASH in different patient subgroups,as well as in subjects with partial missing body composition data.Conclusions:The LEARN algorithm,utilizing simple easily obtained measures,provides a fully automated,simple,non-invasive method for identifying NASH.

The gut microbiome and nicotine metabolism in NAFLD

A history of cigarette smoking is present in approximately 40%of patients with chronic liver diseases and there is considerable interest in better understanding if and how cigarette smoking may affect chronic liver diseases[1].Non-alcoholic fatty liver disease(NAFLD)is currently the most common cause of chronic liver disease,affecting up to 30%of the world’s adults[2].Genetic and environmental factors contribute to the development and progression of NAFLD,and increasing evidence shows that smoking is associated with more severe liver disease in NAFLD[3,4].Despite convincing evidence of this association between smoking and liver disease,the underlying mechanism(s)linking smoking with NAFLD is still poorly understood.

Metabolic dysfunction-associated fatty liver disease and hepatocellular carcinoma:present and future

Metabolic dysfunction-associated fatty liver disease(MAFLD),previously termed non-alcoholic fatty liver disease,is one of the most common causes of chronic liver disease,affecting around 30%of the world’s adults(1).MAFLD encompasses a spectrum of liver conditions,ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis(MASH),which can progress to cirrhosis and hepatocellular carcinoma(HCC)(2,3).