COMMENTED ARTICLES

Commentary

In this retrospective cohort study of 1158 patients with biopsy-proven fibrotic NASH without cirrhosis, bariatric surgery was significantly associated with a lower risk of major adverse liver outcomes and major adverse cardiovascular events.

For the authors, in this study, “among patients with nonalcoholic steatohepatitis and obesity, bariatric surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident major adverse liver outcomes and major adverse cardiovascular events.

Commentary

Macrophage-mediated inflammation is critical in the pathogenesis of NASH. T-cell immunoglobulin domain and mucin domain-4 (TIM-4) is selectively expressed on antigen-presenting cells and modulates various immune responses. However, the role of TIM-4 expressed by Kupffer cells in liver fibrosis remains unclear. In this article, S. Daemen et al. (Washington University School of Medicine, St. Louis, MI, USA) describe that, with high-fat, high-sucrose-diet feeding, mature TIM4pos Kupffer cells decrease in number, while Tim4neg macrophages, which are monocyte-derived, accumulate.

Taken together, their data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.

Commentary

The progression of NASH was initially defined according to a two-hit model involving an initial development of steatosis, followed by a process of lipid peroxidation and inflammation. In contrast, current evidence proposes a “multi-hit” or “multi-parallel hit” model that includes multiple pathways promoting progressive fibrosis and oncogenesis.

Commentary

The present study aimed to investigate the relationship between NAFLD risk and a dementia diagnosis in a large population-based sample aged >65 years.

These findings suggest that “an increased NAFLD risk may be associated to dementia and cognitive decline in older age. Considering the high NAFLD prevalence, the possible adverse disease effects on cognitive performance pose a health problem with significant social and economic implications.”

Commentary

In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations. The resulting consensus statements and recommendations address a broad range of topics that have general relevance for policymakers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD.

Commentary

Lifestyle modification designed to achieve sustained, modest weight loss remains hopelessly difficult to accomplish for many of patients with NAFLD.

Mobile health application use to augment current educational practices will achieve meaningful dietary change and regular physical activity.

Commentary

There have been several arguments put forward by the proponents of MAFLD in favour of a name change. The objections to NAFLD are that NAFLD should be defined by inclusion rather than by exclusion, the heterogeneity of NAFLD implies that it is difficult to manage it as a single entity, and the effects of non-significant amounts of alcohol consumed by NAFLD patients on hepatic steatosis have not yet been clearly defined.

The diagnosis of MAFLD requires radiological evidence of hepatic steatosis and the presence of any one of the following three conditions: overweight/obesity, presence of diabetes mellitus, or evidence of metabolic dysregulation. In fact, in their algorithm, the diagnosis of MAFLD is essentially identical to the diagnosis of NAFLD.

Commentary

In this “hypothesis and theory” section of Frontiers in Psychiatry, Q. Shao et al. (Beijing University of Chinese Medicine, China) aimed to investigate the interaction mechanisms between Major depressive disorder and NAFLD.

For the authors, “there is a significant correlation between MDD and NAFLD, and they mediate and promote each other, gradually forming a vicious circle, which is particularly obvious in patients with MDD- associated NAFLD.”

Commentary

In this cross-sectional analysis of the National Health and Nutrition Examination Surveys, 2017-2018, E. Vilar-Gomez et al. (University School of Medicine, USA) examined the association between diet quality, physical activity, socioeconomic status, and NAFLD risk.

It appears that high-quality diet, increased physical activity, and college education are associated with lower NAFLD risk in the US population.

Commentary

The effects of coffee consumption on hepatic outcomes are controversial. This study investigated the associations between coffee consumption and the incidence of NAFLD in the general population and the reduction of liver fibrosis among patients with NAFLD.

As the authors conclude, “there are contrasting results on the effects of coffee on NAFLD prevention in the general population. Benefits of coffee consumption on liver fibrosis were seen among patients with NAFLD.”

Commentary

In this study, S. Ciardullo et al. (Università degli Studi di Milano Bicocca, Italy) present a population-based cross-sectional study including 2734 US adults using data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey.

The authors show that “patients with NAFLD have a worse cardio-metabolic risk profile and a higher prevalence of CVD. Nonetheless, the association between VCTE-diagnosed NAFLD and liver fibrosis and CVD was not significant after adjustment for known cardiovascular risk factors.”

Commentary

This article describes the complex interactions occurring between diet, the gut microbiome, and bile acids in the aetiology of fatty liver disease.

Emerging new molecular technologies may provide guidance in unraveling the complex physiological pathways driving fatty liver disease and better approaches to prevention and treatment

Commentary

In this review, Yumi Ando and Janice H. Jou (Portland, OR, USA) summarise updated guidelines and guidance recommendations for the management of adult NAFLD. Interestingly, the authors highlight key difference between US, Asian, and European recommendations; and provide key updates.

Commentary

Although liver fat is associated with cardiovascular risk factors, the association between hepatic fibrosis and cardiovascular risk factors is less clear. M. T. Long et al. (Boston University School of Medicine, USA) performed vibration-controlled transient elastography, assessing controlled attenuation parameter and liver stiffness measurement in 3,276 Framingham Heart Study adult participants presenting for a routine study visit.

After a multivariable-adjusted logistic regression, vibration-controlled transient elastography-defined hepatic fibrosis appeared associated with multiple cardiovascular risk factors, including obesity, metabolic syndrome, diabetes, hypertension, and HDL cholesterol.

Commentary

NAFLD is an increasingly prevalent and potentially severe liver disease, emphasising the need for implementation of widely supported care paths for patients at risk for advanced stages of NAFLD.

In this review article by A. M. van Dijk et al. (Amsterdam University Medical Centre, The Netherlands), after a brief clinical case, the authors summarise NAFLD natural history, diagnostic modalities, and finally development and implementation of clinical care paths and guidelines for NAFLD.

As underlined by the authors, “broad acceptance and implementation of interdisciplinary care paths in the near future will bring enhanced identification of those patients that benefit from surveillance, intensive lifestyle management, and empirical or investigational pharmacotherapy and enhance our epidemiological grasp of NAFLD in relation to lifestyle, genetic background, and cardiometabolic comorbidities related to NAFLD.”

Commentary

This brief review by Kathleen E. Corey et al. (Liver Center, Massachusetts General Hospital, Boston, MA, USA) provides a pragmatic guide of cardiovascular disease in NAFLD, with a focus on coronary heart disease.

Commentary

These Korean guidelines, organised in accordance with proposals by the approval of the Korean Association for the Study of the Liver (KASL) Board of Executives, provide clinical information and direction to healthcare providers involved in the diagnosis and treatment of NAFLD patients.

They also provide practical information to resident physicians, practitioners, and trainers.

Commentary

Using a meta-analytic approach, J. Park et al. (Santa Clara Valley Medical Center, San Jose, CA, USA) aimed to describe NAFLD incidence and prevalence, NAFLD fibrosis prevalence, and incidence of non-liver comorbidities.

In this study, the overall prevalence of NAFLD was 31.46% with an incidence rate of 42.8 per 1,000 person-years, and NASH prevalence was 52%. The prevalence and incidence of non-liver comorbidities was high especially for cardiovascular disease incidence.

Commentary

The majority of NAFLD patients die of cardiovascular disease. For this reason, management of this condition requires a multidisciplinary team.

However, important misconceptions remain among primary care providers. NAFLD should be understood as part of a systemic disease characterized for abnormal accumulation of fat in tissues other than the adipose tissue, which produces organ dysfunctions.

This review by E. Godinez-Leiva et al. (University of Alabama, Birmingham, USA) “focuses on the extrahepatic manifestations of NAFLD and its metabolic and cardiovascular implications.”

Commentary

Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including cardiovascular diseases such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation.

In this review, J. Gutiérrez-Cuevas et al. (University of Guadalajara, Jalisco, Mexico) summarise the evidence linking obesity with MAFLD, NASH, and CVD, and discuss the association of MAFLD and NASH with the development and progression of CVD.

Commentary

Exercise could mediate its beneficial effects directly on the liver and indirectly via extrahepatic pathways, forming a dose-response relationship with NAFLD in terms of prevalence and disease severity.

This mini-review addresses three major points regarding physical activity and NAFLD: prevention, treatment, and extrahepatic benefits, offering recommendations on type and intensity of exercise in liver disease.

Commentary

The authors evaluated the impact of NAFLD on the risk of low muscle mass and low muscle strength in a nationwide multicentre study in a total of 1595 community-dwelling people aged 70-84 years were followed for 2 years in the Korean Frailty and Aging Cohort Study.

According to the conclusion, “the presence of NAFLD may predict future risk of low muscle mass and low muscle strength, with greater impact on low muscle strength than on low muscle mass.

Commentary

General strategies have been proposed to manage NAFLD. They include: (a) lifestyle change in order to promote weight loss by diet and physical activity, (b) control of the main cardiometabolic risk factors, (c) correction of all modifiable risk factors leading the development and progression of advanced forms of NAFLD, (d) and prevention of hepatic and extra-hepatic complications.

This narrative review discusses in detail the different available approaches with the potential to prevent and treat NAFLD and its advanced forms.

Commentary

A few studies investigated the Mediterranean diet in developing countries, especially middle east countries where dietary patterns are different from other parts of the world. This case-control study aimed to examine the association between adherence to the Mediterranean diet and NAFLD in Iranian adults.

For the authors, “high adherence to the Mediterranean diet was associated with a 64 % reduction in NAFLD odds before some anthropometric variable adjustments. However, further prospective studies are required, particularly in BMI-stratified models.”

Commentary

In this review, L. J. M. Heyens et al. (Hasselt University, Belgium, Maastricht University, Netherlands, and, Ziekenhuis Oost-Limburg, Belgium) give an overview of the pathogenic mechanisms of the evolution from isolated steatosis to fibrosis. The authors also discuss of the current and future diagnostic biomarkers and anti-fibrotic drugs

Commentary

“Should we be concerned about the presence of increased portal pressure in non-cirrhotic NAFLD? What would be a safe, easy, and accurate way to detect subclinical portal hypertension and utilise it in risk assessment? How could an early rise in portal pressure contribute to NAFLD pathophysiology and could these mechanisms identify novel therapeutic targets?”

This article by G. Baffy (Harvard Medical School, USA) and J. Bosch (University of Bern, Switzerland, and University of Barcelona, Spain) is a review of recent advances on these controversial issues.

Commentary

While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, NAFLD) or NASH) are nowadays the leading causes of hepatic fibrosis worldwide. In this review, F. Tacke et al. (Charité University Medicine, Berlin, Germany) discuss recent advances in antifibrotic prevention and therapy.

For the authors, “tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.”

Commentary

In this review, J. L. Fraile et al. (University of Aberdeen, UK) have performed an exhaustive review of the current therapeutic landscape (drug classes, biologics vs small molecules, and target molecules) for NASH.

Regarding lanifibranor, the authors stated, “it’s an oral small molecule that activates all three PPAR isoforms, inducing anti-fibrotic, anti-inflammatory and other beneficial metabolic changes in the body, and delivers these outcomes by decreasing triglyceride levels and increasing high-density lipoprotein cholesterol levels and insulin sensitisation.”

Lanifibranor “is the only pan-PPAR agonist in clinical development for NASH.” The 24-week Phase 2b NATIVE clinical trial “demonstrated that the higher dose used in this study (1200 mg per day) reduced by at least two points the steatosis activity fibrosis (SAF) score (SAF is a measure that combines the degree of hepatocellular inflammation and cellular ballooning) with no worsening of fibrosis (primary endpoint). The study also met secondary endpoints with the same dose, which included resolution of NASH with no worsening of fibrosis and improvement of fibrosis without worsening of NASH.”

Commentary

In their systematic review and meta-analysis, V. Houttu et al. (Amsterdam University Medical Center, The Netherlands) summarise and assess the evidence for dietary interventions NAFLD patients.

In these patients, Mediterranean and hypocaloric dietary interventions favouring unsaturated fatty acids result in improvements in intrahepatic lipid content and transaminases. Nevertheless, many dietary intervention studies are combined with exercise interventions. There is a paucity of ample-sized studies on the clinically relevant stages of NAFLD, with multiparametric imaging and liver histology as outcome measures. Hence, the optimal dietary invention in NAFLD remains to be defined.

Commentary

S. Hassani Zadeh et al. (Shahid Sadoughi University of Medical Sciences, Yazd, Iran) carried out this meta-analysis to examine the association between dietary patterns and NAFLD. The authors selected three dietary patterns of Western, Prudent, and Mediterranean. The Prudent diet curtails the intake of eggs, whole milk, and whole milk-based dairy products, liver, shellfish, and commercial pastry products. Lean meats are permitted but preference is given to fish which is recommended for use at least four or five times a week.

According to this article, “western dietary patterns increased the risk of NAFLD by 56%, although the Prudent and Mediterranean dietary patterns reduced the risk of this disease by 22% and 23%, respectively.”

Commentary

In an ongoing, community-based, cohort-study in Sri Lanka, participants were randomly selected in 2007, and were reassessed in 2014 to evaluate new-onset metabolic traits and cardiovascular-events. M. A. Niriella et al. (University of Kelaniya, Sri Lanka) compared baseline characteristics, metabolic traits and cardiovascular-events after 7-years in NAFLD and MAFLD and vs. controls. Similarly, the authors compared these parameters in patients excluded by the NAFLD definition but captured by the MAFLD definition and vice versa, and vs. controls.

Although NAFLD and MAFLD had similar metabolic traits at baseline, and similar outcomes after 7-years, patients excluded by the NAFLD definition but captured by the MAFLD definition seem at higher risk of adverse outcomes than those excluded by the MAFLD definition but captured by the NAFLD definition. Redefining NAFLD as MAFLD seemed to improve clinical utility.

Commentary

In order to compare the outcomes of the two diagnostic criteria in a population-based study, Q. Huang et al. (Peking University People’s Hospital, Beijing, China) aimed to investigate the association of MAFLD or NAFLD with all-cause and cause-specific mortality. They recruited 12,480 participants from the Third National Health and Nutrition Examination Survey (NHANES III) with matched mortality data in 2015.

MAFLD patients “showed greater risk for all-cause mortality and equal risk for cause-specific mortality referring to NAFLD. The new terminology excluded participants with lower mortality risk and included participants with higher risk.”