COMMENTED ARTICLES

Commentary

R. Pais et al. (Hôpital Pitié-Salpêtrière, Paris, France) describe the histological outcome in patients with advanced NASH and its relationship with weight loss and metabolic improvement after bariatric surgery.

For the authors, “while bariatric surgery successfully reverses active steatohepatitis, advanced fibrosis can persist for many years and is associated with lesser weight-loss and metabolic improvement. Weight-loss alone may not be sufficient to reverse advanced fibrosis.”

Commentary

This review by C. H. Lee et al. (University of Hong Kong, Hong Kong) aims to provide a summary of the latest evidence that support NAFLD as an emerging diabetic complication of increasing importance, and to present the current recommendations, focusing on the assessment and therapeutic strategies, on the management of NAFLD among T2D patients.

Commentary

MicroRNA levels in blood may change in liver disease including NAFLD. K. Johnson et al. (Newcastle University, UK) carried out microRNA sequencing in a group of 183 patients with NAFLD. One particular microRNA miR-193a-5p consistently increased.
Measuring this microRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy.

Commentary

MAFLD might be considered as a multisystem disease that affects not only the liver but involves wider implications, relating to several organs and systems, the brain included.

The present study by S. Nucera et al. (University Magna Graecia of Catanzaro, Italy) aims to investigate changes associated with MAFLD-induced alteration of thalamic metabolism in vivo.

The experimental results suggest that thalamic energy metabolism is affected by MAFLD progression. This metabolic imbalance “might cause structural damage to brain cells and dysfunctions of neurotransmitter release.”

Commentary

Hepatocellular carcinoma is the most common type of liver cancer, increasingly arising in patients with NAFLD or MAFLD. S. Myers et al. (University of Geneva, Switzerland) assessed all patients with hepatocellular carcinoma between 1990 and 2014 in the canton of Geneva and found an increase in all hepatocellular carcinoma cases, particularly in women. They also found that hepatocellular carcinoma caused by NAFLD or MAFLD significantly increased over the years, particularly in women, possibly driving the increase in overall hepatocellular carcinoma cases.

Commentary

To investigate incidence and predictors of NAFLD and NASH by employing noninvasive testing in liver transplant recipients (i.e. controlled attenuation parameter and cytokeratin 18), A. Alhinai et al. (McGill University, Montreal, Canada) prospectively recruited 40 consecutive adult patients who received liver transplant at the McGill University Health Centre between 2015-2018.

During a median follow-up of 16.8 mo, 63% and 48% of patients developed NAFLD and NASH, respectively. As highlighted by the authors, “close follow-up and nutritional counselling should be planned in overweight patients.”

Commentary

Colorectal adenoma is linked to metabolic dysfunction. S. Fukunaga et al. (Kurume University School of Medicine, Japan) aimed to investigate the impact of MAFLD on the prevalence of colorectal adenoma by comparing it to NAFLD in health check-up examinees in a multicenter retrospective study.

According to this study, MAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.

Commentary

According to this article by D. Pfister et al. (German Cancer Research Center, Germany), the response to immunotherapy is better in patients with virus-induced HCC than in patients with non-viral HCC (that is, NASH). This might be due to the amount or quality of viral antigens or to a different liver micro-environment, possibly one that does not impair immune surveillance.

“These results might also have implications for patients with obesity and NALFD or NASH who have cancer at other organ sites”.

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.”