代谢相关脂肪性肝病慢加急性肝衰竭的过去、现状与未来

代谢相关脂肪性肝病(MAFLD)是目前脂肪性肝病领域的热议话题,它已成为全球最常见的慢性肝病。预计在未来的20年内,MAFLD及相关肝硬化的发病率仍将不断增加,成为新的全球性健康问题。慢加急性肝衰竭(ACLF)是指在慢性肝病基础上,短期内发生的急性或亚急性肝功能失代偿状态,以腹水、黄疸、凝血功能障碍和肝性脑病为主要表现的临床症候群。在有限的资料基础上,对MAFLD-ACLF的流行病学、发病机制和治疗管理策略等问题进行讨论和展望。

LC-MS-based lipidomic analysis in distinguishing patients with nonalcoholic steatohepatitis from nonalcoholic fatty liver

Background: Nonalcoholic fatty liver disease(NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver(NAFL) and nonalcoholic steatohepatitis(NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. Methods: Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson’s trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score(NAS) was analyzed. Results: Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine(PC)(P-22:0/18:1), sphingomyelin(SM)(d14:0/18:0), SM(d14:0/24:0), SM(d14:0/22:0), phosphatidylethanolamine(PE)(18:0/22:5), PC(O-22:2/12:0), and PC(26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC(14:0/18:2), PE(18:0/22:5) and PC(26:1/11:0)] or plasmalogens [PC(O-22:0/0:0), PC(O-18:0/0:0), PC(O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC(14:0/18:2), phosphatidic acid(18:2/24:4) were positively correlated with NAS;whereas PC(18:0/0:0) was correlated positively with fibrosis score. Conclusions: The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The correlations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.

Glycemic control predicts the risk of hepatic fibrosis in biopsy-proven NAFLD:a possible mediating role for leukemia inhibitory factor?

Background:Despite the clear link between nonalcoholic fatty liver disease(NAFLD)and type 2 diabetes mellitus,little is understood about how glycemic control impacts histological severity.We aimed to investigate the deeper association between hemoglobin A1c(HbA1c)and the histologic severity of liver fibrosis.Methods:A total of 568 adults with biopsy-proven NAFLD from the PERSONS cohort in Wenzhou were enrolled.The association between mean HbA1c and hepatic histological features was investigated with ordinal logistic regression.Generalized additive models were used to identify the non-linear relationship between HbA1c and increased fibrosis stage(stage F
3).Causal mediation analysis was performed to calculate the indirect effect of the relationship between HbA1c and hepatic fibrosis mediated by cytokines.Results:Every 1%increase in mean HbA1c was associated with 16%higher odds of increased fibrosis stage(odds ratio 1.16,95%CI 1.04–1.30),even after adjustment for confounding factors.There was a non-linear association between HbA1c and increased fibrosis stage(stage F
3),and the HbA1c inflection point was 9.2%.In particular,the ORs on the left and right sides of this inflection point were 2.1(95%CI 1.4–3.3)and 0.1(95%CI 0–4.8),respectively.7%of the association(OR 1.07,95%CI 1.01–1.12)between HbA1c and liver fibrosis was mediated by leukemia inhibitory factor.Conclusions:Glycemic control predicts severity of hepatic fibrosis and leukemia inhibitory factor plays an intermediary role between them,and thus optimizing glycemic control may be a means of modifying the risk of fibrosis progression in NAFLD.

Non-alcoholic steatohepatitis and risk of hepatocellular carcinoma

The emergence of non-alcoholic fatty liver disease(NAFLD)as the leading chronic liver disease worldwide raises some concerns.In particular,NAFLD is closely tied to sedentary lifestyle habits and associated with other metabolic diseases,such as obesity and diabetes.At the end of the disease spectrum,non-alcoholic steatohepatitis(NASH)may progress to cirrhosis and hepatocellular carcinoma(HCC),representing a serious health problem to modern society.Recently,an increasing number of HCC cases originating from this progressive disease spectrum have been identified,with different levels of severity and complications.Updating the current guidelines by placing a bigger focus on this emerging cause and highlighting some of its unique features is necessary.Since,the drivers of the disease are complex and multifactorial,in order to improve future outcomes,having a better understanding of NASH progression into HCC may be helpful.The risks that can promote disease progression and currently available management strategies employed to monitor and treat NASH-related HCC make up the bulk of this review.

新型降糖药物在代谢相关脂肪性肝病中的适应证、作用和地位

代谢相关脂肪性肝病(MAFLD)是最常见的慢性肝病之一,由其导致的肝硬化和肝细胞癌发病率也在逐年增加。MAFLD的重要危险因素之一就是糖尿病,尤其是2型糖尿病(T2DM),二者互为因果。由于MAFLD的发病机制尚未完全明确,目前仍没有特异性治疗药物。近年来在各种新型降糖药物的临床试验中发现,胰高血糖素样肽-1受体激动剂(GLP-1RAs)、二肽基肽酶-4(DPP-4)抑制剂、钠-葡萄糖共转运体-2(SGLT-2)抑制剂和噻唑烷二酮类(TZDs)等对MAFLD具有减轻肝脏脂肪变性、炎症和纤维化程度的潜力,但尚未被公认。本文就这4类新型降糖药物在MAFLD治疗中的研究进展、作用地位、有效性和安全性等方面进行综述。

COVID-19 and Liver Dysfunction:Current Insights and Emergent Therapeutic Strategies

The outbreak of coronavirus disease 2019(COVID-19),caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has attracted increasing worldwide attention.Cases of liver damage or dysfunction(mainly characterized by moderately elevated serum aspartate aminotransferase lev-els)have been reported among patients with COVID-19.However,it is currently uncertain whether the COVID-19-related liver damage/dysfunction is due mainly to the viral infection per se or other coexisting conditions,such as the use of potentially hepatotoxic drugs and the coexistence of sys-temic inflammatory response,respiratory distress syndrome-induced hypoxia,and multiple organ dysfunction.Based on the current evidence from case reports and case series,this review article focuses on the demographic and clinical characteristics,potential mechanisms,and treatment options for COVID-19-related liver dysfunction.This review also describes the geo-graphical and demographic distribution of COVID-19-related liver dysfunction,as well as possible underlying mechanisms linking COVID-19 to liver dysfunction,in order to facilitate future drug development,prevention,and control measures for COVID-19.

The uprising of metabolic dysfunction-associated fatty liver disease(MAFLD)in acute-on-chronic liver failure(ACLF)

Metabolic dysfunction-associated fatty liver disease(MAFLD)(1)is currently the leading cause of chronic liver disease in the United States(US)and Europe,and the second leading cause for liver transplantation(2).Despite advancements in knowledge over the past decade,MAFLD-related cirrhosis is the most rapidly growing etiology for acute-on-chronic liver failure(ACLF)in the US(3-5).ACLF is a syndrome characterized by acute deterioration of cirrhosis and extrahepatic failure of 1 or more organs.ACLF represents a significant healthcare burden,and is associated with high short-term mortality.Recently,an epidemiology study showed a 3-fold increase in MAFLD-related ACLF waitlisted patients in the United Network for Organ Sharing(UNOS)database from 2005 to 2017(4),and a similar trend was observed in the European Liver Transplant Registry(ELTR)database(5).This is particularly concerning,as the quick rise in MAFLD-related ACLF has created a major gap between the number of patients requiring a liver transplant and the number of available liver donors.

Metabolic Acidosis in Critically Ill Cirrhotic Patients with Acute Kidney Injury

Background and Aims:The metabolic acid-base disorders have a high incidence of acute kidney injury(AKI)in critically ill cirrhotic patients(CICPs).The aims of our study were to ascertain the composition of metabolic acidosis of CICPs with AKI and explore its relationship with hospital mortality.Methods:Three-hundred and eighty consecutive CICPs with AKI were eligible for the cohort study.Demographic,clinical and laboratory parameters were recorded and arterial acid-base state was analyzed by the Stewart and Gilfix methodology.Results:Net metabolic acidosis,lactic acidosis,acidosis owing to unmeasured anions,acidemia,and dilutional acidosis were less frequent in the non-survival group compared to the survival group of CICPs.The presence of acidemia,acidosis owing to unmeasured anions,and lactic acidosis were independently associated with increased risk of intensive care unit 30-day mortality,with hazard ratios of 2.11(95%confidence interval(CI):1.43–3.12),3.38(95%CI:2.36–4.84),and 2.16(95%CI:1.47–3.35),respectively.After full adjustment for confounders,the relationship between acidosis owing to unmeasured anions with hospital mortality was still significant,with hazard ratio of 2.29(95%CI:1.22–4.30).Furthermore,arterial lactate concentration in combination with chronic liver failure-sequential organ failure assessment and BEUMA had the strongest ability to differentiate 30-day mortality(area under the receiver operating characteristic curve:0.79,95%CI:0.74–0.83).

Consensus scoring systems for nonalcoholic fatty liver disease: an unmet clinical need

Noninvasive diagnosis of nonalcoholic fatty liver disease(NAFLD)has received increasing attention(1,2).Nowadays,when we search the item‘scoring system and fatty liver’in PubMed,we can see a sharp increase in the number of related papers in the past few years.In fact,an era of‘information explosion’of noninvasive tests(NITs)for NAFLD is coming.

Associations of Hydroxysteroid 17-beta Dehydrogenase 13 Variants with Liver Histology in Chinese Patients with Metabolicassociated Fatty Liver Disease

Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic Chinese is unknown.The aim of this study was to investigate the potential associations in Chinese patients.Methods:In total,427 Han Chinese with biopsy-confirmed MAFLD were enrolled.Two single nucleotide polymorphisms in HSD17B13 were genotyped:rs72613567 and rs6531975.Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.Results:In our cohort,the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis[odds ratio(OR):2.93(1.20–7.17),p=0.019 for the additive model;OR:3.32(1.39–7.91),p=0.007 for the recessive model],representing an inverse association as compared to the results from European cohorts.In contrast,we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant[OR:0.48(0.24–0.98),p=0.043 for the additive model;OR:0.62(0.40–0.94),p=0.025 for the dominant model].HSD17B13 variants were only associated with fibrosis but no other histological features.Furthermore,HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis.Conclusions:HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans.These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.

A novel radiomics signature based on T2-weighted imaging accurately predicts hepatic inflammation in individuals with biopsy-proven nonalcoholic fatty liver disease:a derivation and independent validation study

Background:Currently,there are no effective methods for assessing hepatic inflammation without resorting to histological examination of liver tissue obtained by biopsy.T2-weighted images(T2WI)are routinely obtained from liver magnetic resonance imaging(MRI)scan sequences.We aimed to establish a radiomics signature based on T2WI(T2-RS)for assessment of hepatic inflammation in people with nonalcoholic fatty liver disease(NAFLD).Methods:A total of 203 individuals with biopsy-confirmed NAFLD from two independent Chinese cohorts with liver MRI examination were enrolled in this study.The hepatic inflammatory activity score(IAS)was calculated by the unweighted sum of the histologic scores for lobular inflammation and ballooning.One thousand and thirty-two radiomics features were extracted from the localized region of interest(ROI)in the right liver lobe of T2WI and,subsequently,selected by minimum redundancy maximum relevance and least absolute shrinkage and selection operator(LASSO)methods.The T2-RS was calculated by adding the selected features weighted by their coefficients.Results:Eighteen radiomics features from Laplacian of Gaussian,wavelet,and original images were selected for establishing T2-RS.The T2-RS value differed significantly between groups with increasing grades of hepatic inflammation(P<0.01).The T2-RS yielded an area under the receiver operating characteristic(ROC)curve(AUROC)of 0.80[95%confidence interval(CI):0.71-0.89]for predicting hepatic inflammation in the training cohort with excellent calibration.The AUROCs of T2-RS in the internal cohort and external validation cohorts were 0.77(0.61-0.93)and 0.75(0.63-0.84),respectively.Conclusions:The T2-RS derived from radiomics analysis of T2WI shows promising utility for predicting hepatic inflammation in individuals with NAFLD.

Metabolic-associated Fatty Liver Disease

A panel of experts from 22 countries recently proposed a name change from nonalcoholic fatty liver disease(NAFLD)to metabolic-associated fatty liver disease,or MAFLD.1 Sub-sequently,new criteria for diagnosing MAFLD were provided to help guide clinicians in their clinical practice.2 The criteria are based on evidence of hepatic steatosis in the presence of one or more of overweight/obesity,type 2 diabetes,or metabolic dysregulation.3 The proposed novel diagnostic criteria represent a landmark in hepatology that combines our current understanding of obesity,metabolic syndrome and system biology into a single focus.

Metabolic(dysfunction)associated fatty liver disease:more evidence and a bright future

Recently,metabolic(dysfunction)associated fatty liver disease(MAFLD)has been proposed as a name to replace non-alcoholic fatty liver disease(NAFLD)(1).Controversy over the name is in full swing and evidence-based debate will determine the outcome.Evidence-based medicine is predicated on rigorous scientific data,clinical experience and patient preferences.So how does MAFLD stack up?We briefly summarize the existing evidence and find that MAFLD does hold up to its promise as an advance in the terminology for the disease we all treat.

Interaction of SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409 Increases Susceptibility to Nonalcoholic Steatohepatitis

Background and Aims:Previous studies have reported that the single nucleotide polymorphisms(SNPs)of SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409 are associated with nonalcoholic fatty liver disease(NAFLD).However,no studies have examined the effect of interactions between these three genotypes to affect liver disease severity.We assessed the effect of these three SNPs on nonalcoholic steatohepatitis(NASH)and also examined the gene-gene interactions in a Chinese population with biopsy-confirmed NAFLD.Methods:We enrolled 415 consecutive adult individuals with biopsy-proven NAFLD.Multivariable logistic regres-sion analysis was undertaken to test associations between NASH and SNPs in SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409.Gene-gene interactions were ana-lyzed by performing a generalized multifactor dimensionality reduction(GMDR)analysis.Results:The mean±standard deviation age of these 415 patients was 41.3±12.5 years,and 75.9%were men.Patients with SAMM50-rs738491 TT,PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes had a higher risk of NASH,even after adjustment for age,sex and body mass index.GMDR analysis showed that the combination of all three SNPs was the best model for predicting NASH.Additionally,the odds ratio of the haplotype T-A-G for predicting the risk of NASH was nearly three times higher than that of the haplotype G-C-C.Conclusions:NAFLD patients carrying the SAMM50-rs738491 TT,PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes are at greater risk of NASH.These three SNPs may synergistically interact to increase susceptibility to NASH.

PNPLA3 rs738409 C>G Variant Influences the Association Between Visceral Fat and Significant Fibrosis in Biopsyproven Nonalcoholic Fatty Liver Disease

Background and Aims:Intra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3(PNPLA3)rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver disease(NAFLD).We examined whether the relationship between visceral fat accumulation and liver disease severity may be influenced by PNPLA3 rs738409 polymorphism.Methods:The variant of PNPLA3 rs738409 was genotyped within 523 Han individuals with biopsy-confirmed NAFLD.Visceral fat area(VFA)was measured by bioelectrical impedance.Significant liver fibrosis(SF),defined as stage F≥2 on histology,was the outcome measure of interest.Results:The distribution of PNPLA3 genotypes was CC:27.5%,CG:48.2%,and GG:24.3%.Higher VFA was associated with greater risk of having SF(adjusted-odds ratio[OR]:1.03;95%confidence interval[CI]:1.02–1.04,p<0.05),independent of potential confounders.Among subjects with the same VFA level,the risk of SF was greater among carriers of the rs738409 G genotype than among those who did not.Stratified analysis showed that PNPLA3 rs738409 significantly influenced the association between VFA and SF.VFA remained significantly associated with SF only among the rs738409 G-allele carriers(adjusted-OR:1.05;95%CI:1.03–1.08 for the GG group;and adjusted-OR:1.03;95%CI:1.01–1.04 for the GC group).There was a significant interaction between VFA and PNPLA3 rs738409 genotype(Pinteraction=0.004).Conclusions:PNPLA3 rs738409 G allele has a moderate effect on the association between VFA and risk of SF in adult individuals with biopsy-proven NAFLD.Existence of the PNPLA3 rs738409 G allele and VFA interact to increase risk of SF。

A Class Effect Network Meta-analysis of Lipid Modulation in Non-alcoholic Steatohepatitis for Dyslipidemia

Background and Aims:Pharmaceutical therapy for NASH is associated with lipid modulation,but the consensus on drug treatment is limited and lacks comparative analysis of effectiveness.A network meta-analysis was conducted to compare NASH drug classes in lipid modulation.Methods:Online databases were searched for randomized controlled trails(RCTs)evaluating NASH treatments in biopsy-proven NASH patients.Treatments were classified into four groups:(1)inflammation,(2)energy,(3)bile acids,and(4)fibro-sis based on the mechanism of action.A Bayesian network analysis was conducted with outcome measured by mean difference(MD)with credible intervals(Crl)and surface un-der the cumulative ranking curve(SUCRA).Results:Forty-four RCTs were included in the analysis.Bile acid modulat-ing treatments(MD:0.05,Crl:0.03-0.07)were the best treatment for improvement in high-density lipid(HDL)cho-lesterol,followed by treatments modulating energy(MD:0.03,Crl:0.02-0.04)and fibrosis(MD:0.01,Crl:−0.12 to 0.14)compared with placebo.The top three treatments for reduction in triglycerides were treatments modulating energy(MD:−0.46,Crl:−0.49 to−0.43),bile acids(MD:−0.22,Crl:−0.35 to−0.09),and inflammation(MD:−0.08,Crl:−0.13 to−0.03)compared with placebo.SUCRA found treatment modulating fibrosis(MD:−1.27,Crl:−1.76 to−0.79)was the best treatment for reduction in low-density lipid(LDL)cholesterol followed by treatment modulating in-flammation(MD:−1.03,Crl:−1.09 to−0.97)and energy(MD:−0.37,Crl:−0.39 to−0.34)compared with placebo,but LDL cholesterol was worsened by treatments modulat-ing bile acids.Conclusions:Network analysis comparing the class effects of dyslipidemia modulation in NASH found that treatment targets can include optimization of athero-genic dyslipidemia.Future studies are required to evaluate the cardiovascular outcomes.

Promotion of nonalcoholic steatohepatitis by RNA N^(6)-methyladenosine reader IGF2BP2 in mice

Nonalcoholic steatohepatitis(NASH)has emerged as the major cause of end-stage liver diseases.However,an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies.In the present study,through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis,we identified IGF2BP2,an N6-methyladenosine modification reader,as a key regulator that promotes NASH progression in mice.Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis,inflammation,and fibrosis in mice,at least in part,by increasing Tab2 mRNA stability.Besides,hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers.Of potential clinical significance,IGF2BP2 expression is significantly upregulated in the livers of NASH patients.Moreover,knockdown of IGF2BP2 substantially alleviated liver injury,inflammation,and fibrosis in diet-induced NASH mice.Taken together,our findings reveal an important role of IGF2BP2 in NASH,which may provide a new therapeutic target for the treatment of NASH.

Metabolic Dysfunction-associated Fatty Liver Disease is Associated with Greater Impairment of Lung Function than Nonalcoholic Fatty Liver Disease

Background and Aims:We compared lung function parameters in nonalcoholic fatty liver disease(NAFLD)and metabolic dysfunction-associated fatty liver disease(MAFLD),and examined the association between lung function parameters and fibrosis severity in MAFLD.Methods:In this cross-sectional study,we randomly recruited 2,543 middle-aged individuals from 25 communities across four cities in China during 2016 and 2020.All participants received a health check-up including measurement of anthropometric parameters,biochemical variables,liver ultrasonography,and spirometry.The severity of liver disease was assessed by the fibrosis(FIB)-4 score.Results:The prevalence of MAFLD was 20.4%(n=519)and that of NAFLD was 18.4%(n=469).After adjusting for age,sex,adiposity measures,smoking status,and significant alco-hol intake,subjects with MAFLD had a significantly lower predicted forced vital capacity(FVC,88.27±17.60%vs.90.82±16.85%,p<0.05)and lower 1 s forced expiratory volume(FEV1,79.89±17.34 vs.83.02±16.66%,p<0.05)than those with NAFLD.MAFLD with an increased FIB-4 score was significantly associated with decreased lung function.For each 1-point increase in FIB-4,FVC was diminished by 0.507(95%CI:-0.840,-0.173,p=0.003),and FEV1 was diminished by 0.439(95%CI:-0.739,-0.140,p=0.004).The results remained unchanged when the statistical analyses was performed separately for men and women.Conclusions:MAFLD was significantly asso-ciated with a greater impairment of lung function param-eters than NAFLD.

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.