Drug repurposing in MASLD and MASH-cirrhosis: Targets and treatment approaches based on pathways analysis.

Designing and predicting novel drug targets to accelerate drug discovery for treating metabolic dysfunction-associated steatohepatitis (MASH)-cirrhosis is a challenging task. The presence of superimposed (nested) and co-occurring clinical and histological phenotypes, namely MASH and cirrhosis, may partly explain this. Thus, in this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Here, we used gene/protein and set enrichment analysis to predict druggable pathways for the treatment of MASH-cirrhosis. Our findings indicate that the pathogenesis of MASH-cirrhosis can be explained by perturbations in multiple, simultaneous, and overlapping molecular processes. In this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Therefore, we used systems biology modeling to provide evidence that MASH and cirrhosis paradoxically present unique and distinct as well as common disease mechanisms, including a network of molecular targets. More importantly, pathway analysis revealed straightforward results consistent with modulation of the immune response, cell cycle control, and epigenetic regulation. In conclusion, the selection of potential therapies for MASH-cirrhosis should be guided by a better understanding of the underlying biological processes and molecular perturbations that progressively damage liver tissue and its underlying structure. Therapeutic options for patients with MASH may not necessarily be of choice for MASH cirrhosis. Therefore, the biology of the disease and the processes associated with its natural history must be at the forefront of the decision-making process.

A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease.

BACKGROUND: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11. METHODS: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members. RESULTS: A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%). CONCLUSIONS: This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision.

Resmetirom for treatment of MASH.

Resmetirom is an oral selective THR-ß agonist conditionally approved for the treatment of patients with noncirrhotic MASH with moderate to advanced fibrosis. Resmetirom restores mitochondrial and hepatic metabolic function; reduces atherogenic lipids; improves hepatic steatosis, inflammation, and fibrosis; and has no significant effect on THR-α. To view this Bench to Bedside, open or download the PDF.

Cross talk between the liver microbiome and epigenome in patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease), including its severe clinical forms, involves complex processes at all levels of biological organization. This study examined the potential link between the liver microbiome profile and epigenetic factors. METHODS: Liver microbial DNA composition was analysed using high throughput 16S rRNA gene sequencing in 116 individuals, with 55% being female, across the spectrum of liver disease severity. Total activity of histone deacetylases (HDACs) and acetyltransferases (HATs) was assayed in nuclear extracts from fresh liver samples. In addition, we measured the global 5-hydroxymethylcytosine (5-hmC) levels of liver DNA. FINDINGS: Patients with MASLD showed a 2.07-fold increase (p = 0.013) in liver total HAT activity. Moreover, a correlation was observed between liver total HAT activity and the score for histological steatosis (Spearman's R = 0.60, p = 1.0E-3) and disease severity (R = 0.40, p = 2.0E-2). Liver HAT and HDAC activities also showed associations with the abundance of several liver bacterial DNAs. Additionally, liver global levels of 5-hmC showed negative correlation with the read number of Bacteroidetes (R = -0.62, p = 9.3E-4) and Gammaproteobacteria (R = -0.43, p = 3.2E-2), while it was positively correlated with the abundance of Acidobacteria (R = 0.42, p = 4.1E-2) and Actinobacteria (R = 0.47, p = 1.8E-2). INTERPRETATION: The host liver epigenome, including the activity of enzymes involved in maintaining the balance between protein acetylation and deacetylation and the global DNA hydroxy-methylation status, may be the target of microbial signals. FUNDING: Agencia Nacional de Promoción Científica y Tecnológica, FonCyT.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

The serum uric acid/creatinine ratio is associated with nonalcoholic fatty liver disease in the general population

Serum uric acid-to-creatinine ratio (sUA/CrR) may be associated with metabolic syndrome components, but limited evidence exists on a relationship between sUA/Cr and NAFLD. Here, we investigated the association between sUA/CrR and NAFLD. We performed a cross-sectional analysis in 3359 subjects who participated in the NHANES 2017–2018 survey and consumed less than 30 and 20 g alcohol (men and women, respectively), with no positive tests of viral hepatitis. Liver steatosis was defined by controlled attenuation parameter and fibrosis by stiffness measurements obtained via transient elastography. We modeled the relationship between NAFLD and relevant demographic, anthropometric, and biochemical variables. sUA/CrR was significantly higher in participants with NAFLD than those without NAFLD. LASSO logit regression showed that only logarithmized age (p = 1.2e-3), waist circumference (WC) (p = 1.8e-5), triglycerides (p = 5e-6), and sUA/CrR (p = 3e-5) were retained in the model. Multivariate logistic analysis demonstrated a significant association between sUA/CrR and NAFLD; the OR for NAFLD of one log(sUA/CrR) increase was 2.61 (95% CI: 1.86–3.68, p < 3e-8) after adjusting for relevant covariables, including aminotransaminase levels and the effect of sUA/CrR remained significant for highest WC quintiles. The model’s predictive power with vs. without sUA/CrR was slightly but significantly better (Auroc: 0.859 ± 0.006 vs. 0.855 ± 0.007, p < 1.1e-2). Mediation analysis showed that SUA/CrR modestly mediates the effect of WC and insulin resistance but not glycohemoglobin on NAFLD. In conclusion, elevated sUA/CrR was significantly associated with NAFLD in the general population. Therefore, kidney function should be closely monitored in NAFLD patients. (AU)

SARS-CoV-2 targets the liver and manipulates glucose metabolism.

A recent publication by Barreto and colleagues showed that SARS-CoV-2 directly triggers hyperglycemia by infecting hepatocytes and inducing phosphoenolpyruvate carboxykinase (PEPCK)-dependent gluconeogenesis. Here, we discuss the biological importance of these findings, including the hepatic tropism of SARS-CoV-2. We also comment on the clinical implications of the bidirectional connection between COVID-19 and noncommunicable diseases.

Non-alcoholic fatty liver disease mediates the effect of obesity on arterial hypertension.

BACKGROUND: It has been consistently shown that obesity contributes directly to arterial hypertension and cardiovascular disease (CVD), independently of other risk factors. Likewise, non-alcoholic fatty liver disease (NAFLD) is acknowledged as a contributor and a risk enhancer for CVD. OBJECTIVES: We tested the hypothesis of a causal role of NAFLD in the effect of obesity on arterial hypertension. METHODS: Using causal mediation analysis, we quantified the magnitude of the body mass index (BMI) effect on arterial hypertension and CV-traits mediated by NAFLD. First, we analysed data from 1348 young adults in the Bogalusa Heart Study (BHS), a cohort aimed at assessing the natural history of CVD. Then, we used data from 3359 participants of the National Health and Nutrition Examination Survey (2017-2018 cycle, NHANES) to replicate the findings. RESULTS: We found that roughly 92% of the effects of BMI on arterial hypertension in the BHS and 51% in the NHANES population are mediated by NAFLD. In addition, indirect effects of BMI on systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) through NAFLD explained up to 91%, 93%, and 100% of the total effect, respectively, in the BHS. In the NHANES survey, indirect effects of BMI through NAFLD on CV traits explain a significant proportion of the total effects (SBP = 60.4%, HR = 100%, and pulse pressure = 88%). CONCLUSION: NAFLD mediates a substantial proportion of the effect of obesity on the presence of hypertension and CV-parameters independently of relevant covariates. This conclusion has implications for clinical management.

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.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

Advances in our understanding of the molecular heterogeneity of fatty liver disease: toward informed treatment decision making.

INTRODUCTION: nonalcoholic fatty liver disease (NAFLD) is a complex disorder resulting from intricate relationships with diverse cardiometabolic risk factors and environmental factors. NAFLD may result in severe chronic liver damage and potentially declining liver function. AREAS COVERED: Accumulated knowledge over the last decade indicates that the disease trajectory presents substantial heterogeneity. In addition, overlapping features with the diseases of the metabolic syndrome, combined with heterogeneity in disease mechanisms, further complicates NAFLD diagnosis and prognosis, and hampers progress in biomarker and pharmacological discoveries. Here, we explore solving the heterogeneous clinical landscape of NAFLD by cluster analysis of molecular signatures that serve as a proxy for disease stratification into molecular sub-types. First, we collected information on NAFLD and metabolic syndrome-associated protein-coding genes by data mining the literature. Next, we performed pathways enrichment and cluster analyses to decipher and dissect the different patterns of phenotypic heterogeneity. Our approach showed unique biological pathways for every clinical subtype/group, namely NAFLD + obesity, NAFLD + arterial hypertension, NAFLD + dyslipidemia, and NAFLD + type 2 diabetes. EXPERT OPINION: Patients with NAFLD may be benefited by a better understanding of the disease biology, which involves 'dissection' of the molecular sub-phenotypes that drive the disease progression.

COVID-19 and non-alcoholic fatty liver disease: Biological insights from multi-omics data.

We explored the shared pathophysiological mechanisms between COVID-19 and non-alcoholic fatty liver disease (NAFLD) by integrating multi-omics data. We studied common genetic risk factors and underlying biological processes using functional enrichment analysis. To understand the sex-specific pathways involved in the clinical course of SARS-CoV-2 infection, we processed sex-stratified data from COVID-19 genome-wide association datasets. We further explored the transcriptional signature of the liver cells in healthy and COVID-19 tissue specimens. We also integrated genetic and metabolomic information. We found that COVID-19 and NAFLD share biological disease mechanisms, including pathways that regulate the inflammatory and lipopolysaccharide response. Single-cell transcriptomics revealed enrichment of complement-related pathways in Kupffer cells, syndecan-mediated signalling in plasma cells, and epithelial-to-mesenchymal transition in hepatic stellate cells. The strategy of pathway-level analysis of genomic and metabolomic data uncovered l-lactic acid, Krebs cycle intermediate compounds, arachidonic acid and cortisol among the most prominent shared metabolites.

The serum uric acid/creatinine ratio is associated with nonalcoholic fatty liver disease in the general population.

Serum uric acid-to-creatinine ratio (sUA/CrR) may be associated with metabolic syndrome components, but limited evidence exists on a relationship between sUA/Cr and NAFLD. Here, we investigated the association between sUA/CrR and NAFLD.We performed a cross-sectional analysis in 3359 subjects who participated in the NHANES 2017-2018 survey and consumed less than 30 and 20 g alcohol (men and women, respectively), with no positive tests of viral hepatitis. Liver steatosis was defined by controlled attenuation parameter and fibrosis by stiffness measurements obtained via transient elastography. We modeled the relationship between NAFLD and relevant demographic, anthropometric, and biochemical variables.sUA/CrR was significantly higher in participants with NAFLD than those without NAFLD. LASSO logit regression showed that only logarithmized age (p = 1.2e-3), waist circumference (WC) (p = 1.8e-5), triglycerides (p = 5e-6), and sUA/CrR (p = 3e-5) were retained in the model. Multivariate logistic analysis demonstrated a significant association between sUA/CrR and NAFLD; the OR for NAFLD of one log(sUA/CrR) increase was 2.61 (95% CI: 1.86-3.68, p < 3e-8) after adjusting for relevant covariables, including aminotransaminase levels and the effect of sUA/CrR remained significant for highest WC quintiles. The model's predictive power with vs. without sUA/CrR was slightly but significantly better (Auroc: 0.859 ± 0.006 vs. 0.855 ± 0.007, p < 1.1e-2). Mediation analysis showed that SUA/CrR modestly mediates the effect of WC and insulin resistance but not glycohemoglobin on NAFLD.In conclusion, elevated sUA/CrR was significantly associated with NAFLD in the general population. Therefore, kidney function should be closely monitored in NAFLD patients.

Genetics in non-alcoholic fatty liver disease: The role of risk alleles through the lens of immune response.

The knowledge on the genetic component of non-alcoholic fatty liver disease (NAFLD) has grown exponentially over the last 10 to 15 years. This review summarizes the current evidence and the latest developments in the genetics of NAFLD and non-alcoholic steatohepatitis (NASH) from the immune system's perspective. Activation of innate and or adaptive immune response is an essential driver of NAFLD disease severity and progression. Lipid and immune pathways are crucial in the pathophysiology of NAFLD and NASH. Here, we highlight novel applications of genomic techniques, including single-cell sequencing and the genetics of gene expression, to elucidate the potential involvement of NAFLD/NASH-risk alleles in modulating immune system cells. Together, our focus is to provide an overview of the potential involvement of the NAFLD/NASH-related risk variants in mediating the immune-driven liver disease severity and diverse systemic pleiotropic effects.

Geographical similarity and differences in the burden and genetic predisposition of NAFLD.

NAFLD has become a major public health problem for more than 2 decades with a growing prevalence in parallel with the epidemic of obesity and type 2 diabetes (T2D). The disease burden of NAFLD differs across geographical regions and ethnicities. Variations in prevalence of metabolic diseases, extent of urban-rural divide, dietary habits, lifestyles, and the prevalence of NAFLD risk and protective alleles can contribute to such differences. The rise in NAFLD has led to a remarkable increase in the number of cases of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver-related mortality related to NAFLD. Moreover, NAFLD is associated with multiple extrahepatic manifestations. Most of them are risk factors for the progression of liver fibrosis and thus worsen the prognosis of NAFLD. All these comorbidities and complications affect the quality of life in subjects with NAFLD. Given the huge and growing size of the population with NAFLD, it is expected that patients, healthcare systems, and the economy will suffer from the ongoing burden related to NAFLD. In this review, we examine the disease burden of NAFLD across geographical areas and ethnicities, together with the distribution of some well-known genetic variants for NAFLD. We also describe some special populations including patients with T2D, lean patients, the pediatric population, and patients with concomitant liver diseases. We discuss extrahepatic outcomes, patient-reported outcomes, and economic burden related to NAFLD.

Alcohol consumption and metabolic syndrome: Clinical and epidemiological impact on liver disease.

Alcohol use and metabolic syndrome are highly prevalent in the population and frequently co-exist. Both are implicated in a large range of health problems, including chronic liver disease, hepatocellular carcinoma, and liver-related outcomes (i.e. decompensation or liver transplantation). Studies have yielded mixed results regarding the effects of mild-moderate alcohol consumption on the risk of metabolic syndrome and fatty liver disease, possibly due to methodological differences. The few available prospective studies have indicated that mild-moderate alcohol use is associated with an increase in liver-related outcomes. This conclusion was substantiated by systems biology analyses suggesting that alcohol and metabolic syndrome may play a similar role in fatty liver disease, potentiating an already existing dysregulation of common vital homeostatic pathways. Alcohol and metabolic factors are independently and jointly associated with liver-related outcomes. Indeed, metabolic syndrome increases the risk of liver-related outcomes, regardless of alcohol intake. Moreover, the components of metabolic syndrome appear to have additive effects when it comes to the risk of liver-related outcomes. A number of population studies have implied that measures of central/abdominal obesity, such as the waist-to-hip ratio, can predict liver-related outcomes more accurately than BMI, including in individuals who consume harmful quantities of alcohol. Many studies even point to synergistic interactions between harmful alcohol use and many metabolic components. This accumulating evidence showing independent, combined, and modifying effects of alcohol and metabolic factors on the onset and progression of chronic liver disease highlights the multifactorial background of liver disease in the population. The available evidence suggests that more holistic approaches could be useful for risk prediction, diagnostics and treatment planning.