Metabolic dysfunction-associated steatotic liver disease: Navigating terminological evolution, diagnostic frontiers and therapeutic horizon-an editorial exploration

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), once known as non-alcoholic fatty liver disease (NAFLD), represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes. The redefinition of NAFLD in 2023 marked a significant reposition in terminology, emphasizing a broader understanding of liver steatosis and its associated risks. MASLD is now recognized as a major risk factor for liver cirrhosis, hepatocellular carcinoma, and systemic complications such as cardiovascular diseases or systemic inflammation. Diagnostic challenges arise, particularly in identifying MASLD in lean individuals, necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools. Therapeutically, there is an urgent need for effective treatments targeting MASLD, with emerging pharmacological options focusing on, among others, carbohydrate and lipid metabolism. Additionally, understanding the roles of bile acid metabolism, the microbiome, and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches. There is a strong need to emphasize the importance of collaborative efforts in understanding, diagnosing, and managing MASLD to improve physicians’ approaches and patient outcomes.

Key Words: Metabolic dysfunction-associated steatotic liver disease, Diagnostics, Pathophysiology of metabolic dysfunction-associated steatotic liver disease, Therapy of metabolic dysfunction-associated steatotic liver disease, Therapeutic innovations

Core Tip: The transition from non-alcoholic fatty liver disease to metabolic dysfunction-associated steatotic liver disease (MASLD) reflects a broader understanding of liver steatosis beyond obesity-related factors. Early recognition and diagnosis of MASLD are essential. Updated diagnostic protocols and exploration of novel therapeutic avenues focusing on metabolic dysregulation are critical for improving outcomes in MASLD management. Cross-disciplinary collaboration is key to addressing the complexities of this disease effectively.

INTRODUCTION

The field of hepatology experienced a transformative moment in June 2023 with the redefinition of non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction-associated steatotic liver disease (MASLD), during the European Association for the Study of the Liver Congress in Vienna. The term SLD was chosen as a term to encompass the diverse causes of steatosis, and the proposed replacement for NAFLD is MASLD. This refined definition includes, at least one of the five cardiometabolic risk factors, with individuals lacking metabolic disease and no other known cause being diagnosed with cryptogenic SLD[1]. At present, MASLD is recognized as a risk factor for liver cirrhosis and a source of systemic complications. The disease progression initiates with liver steatosis, resulting from lipid accumulation inside hepatocytes. Excess fat leads to lipotoxicity, accompanied by unfavorable genetic factors, triggering inflammation. The subsequent stage, metabolic associated steatotic hepatitis (MASH), is characterized by an inflammatory response activating various cells, including macrophages and stellate cells, contributing to excessive intercellular matrix synthesis responsible for liver fibrosis[2]. In some cases, advanced liver fibrosis leads to cirrhosis and its complications, including hepatocellular carcinoma (HCC).

EMERGING CHALLENGES IN MASLD DIAGNOSIS AND MANAGEMENT

With its widespread occurrence (even 30%), MASLD may become a leading cause of liver fibrosis and HCC[3]. Recent reports also suggest a distinct familial clustering of adverse liver-related outcomes in families of individuals with biopsy-proven MASLD, with higher relative risks of HCC, progressive liver disease, and liver-related mortality, though absolute risks remain low[4].

A crucial consideration arises for individuals with a lean physique, as historical associations of fatty liver disease with obesity may lead to the oversight of MASLD in slender patients, posing diagnostic challenges. Healthcare practitioners are urged to recognize the unique diagnostic challenges faced by this subset of patients and proactively seek signs of SLD[5-7].

Revolutionizing diagnostic approaches for MASLD

The evolving terminology underscores the need for a paradigm shift in diagnostic approaches, especially within primary healthcare settings. Aligning with the guidelines established by the American Association for the Study of Liver Diseases[8], healthcare practitioners are urged to reassess and recalibrate diagnostic protocols. Understanding how these changes resonate at the foundational level of healthcare and the necessary adjustments for early and precise diagnosis, particularly in light of the challenges posed by MASLD, requires careful consideration. Advancements in diagnostic technologies, including non-invasive laboratory tests for liver fibrosis such as enhanced liver fibrosis or FIBROSpect II, offer hope for improved diagnostic accuracy and efficiency. These tests go beyond commonly used measures like liver function parameters (i.e., transaminase level or FIB-4 assessment), providing a more comprehensive approach to liver diagnostics. Non-invasive imaging studies such as FibroScan or elastography, as well as less commonly available magnetic resonance imaging derived proton density fat fraction, in addition to routinely performed ultrasound, contribute to enhanced sensitivity in imaging diagnostics. The potential of these innovative tools to usher in a new era in the detection and monitoring of MASLD, especially in primary care settings, raises important questions about seamless integration into existing diagnostic pathways[8].

Exploring novel pharmacotherapies for MASLD

Shifting attention to therapeutics, there is an urgent need for effective therapies against MASLD, especially in its early phases. Current recommendations include vitamin E and pioglitazone, but their use is more prevalent in advanced stages of MASLD (i.e., MASH), with limited improvements in steatosis. Thus, exploring additional therapeutic options that address concomitant conditions in patients with features of metabolic syndrome is crucial.

Therapeutic innovations and considerations for MASLD

The convergence of MASLD with obesity and diabetes introduces a new dimension in pharmaceutical interventions. Will medications designed for managing these co-morbidities prove efficaciousness in the treatment of MASLD, and how can their benefits be optimized while ensuring patient-centered care? There are various medications considered or under the studies in the treatment of MASLD[9], including drugs affecting carbohydrate metabolism like: Sodium/glucose cotransporter-2 inhibitors, agonists of glucagon-like peptide-1 receptors, dual agonists of incretin receptors (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide as well as glucagon-like peptide-1 and glucagon), triple incretin receptor agonists, glitazones, ketohexokinase inhibitors, metformin, alongside with drugs affecting lipid metabolism like: Core cholesterol-lowering therapy (statins or/and ezetimibe), PCSK9 inhibitors, peroxisome proliferator-activated receptors alpha agonists, selective peroxisome proliferator-activated receptor modulators, multiple peroxisome proliferator-activated receptor agonists, acetyl-CoA carboxylase inhibitors, fatty-acid synthase inhibitors, diacylglycerol acyltransferase inhibitors, fibroblast growth factor 21[9]. Given the above, will the use of semaglutide (GLP-1 analog) or tirzepatide (dual agonist of incretin receptor) yield tangible benefits in the treatment of SLD, given the current lack of effective therapy for MASLD?

Unraveling the role of bile acid metabolism in MASLD

Other studies suggest a potential link between bile acid metabolism and the development of MASLD[10]. The influence on bile acid metabolism might play a crucial role in the pathogenesis of the disease, adding another layer of complexity to our understanding.

Targeting iron metabolism for MASLD therapy

As we explore the multifaceted aspects of MASLD, considering the impact on bile acid metabolism becomes imperative, opening avenues for further research and potential therapeutic interventions. Can targeting iron metabolism and its involvement in oxidative stress be a goal of anti-steatotic, anti-fibrotic, and anti-carcinogenic therapies in MASLD[11]?

Microbiome dynamics in MASLD: Implications and therapeutic prospects

A nuanced exploration of the microbiome’s role in MASLD introduces an additional stratum of intricacy[12]. The intricate interplay between gut health and metabolic liver conditions prompts profound questions. Can the modification of the microbiota emerge as a therapeutic avenue, and how might this influence the overall management of patients with MASLD? Can the microbiota modulation by dietary components prevent SLD progression[13]?

Harnessing dietary interventions and functional foods in MASLD management

Physical activity has been the cornerstone in preventing and managing therapeutic interventions in MASLD so far as the non-pharmacological approach. However, there are emerging voices suggesting that the impact of dietary interventions, including functional food, is gaining significance in managing the disease. Incorporating functional food into the therapeutic approach holds promise as an adjunct to conventional treatments[9,13].

CONCLUSION

This editorial invites collective reflection on the multifaceted aspects of MASLD. As we navigate through nomenclature changes, diagnostic innovations, therapeutic possibilities, and the microbiome’s influence, we envision a comprehensive understanding that transcends disciplinary boundaries. Contributions and collaborative endeavors are encouraged as we collectively strive to enhance the care and outcomes for individuals grappling with the complexities of metabolic-associated fatty liver disease.