Incorporating fatty liver disease in multidisciplinary care and novel clinical trial designs for patients with metabolic diseases

Summary

With the global epidemics of obesity and associated conditions, including type 2 diabetes, metabolic dysfunction-associated fatty liver disease, chronic kidney disease, hypertension, stroke, cardiovascular disease, osteoporosis, cancer, and cognitive changes, the prevalence of multimorbidity is rapidly increasing worldwide. In this Review, a panel of international experts from across the spectrum of metabolic diseases come together to identify the challenges and provide perspectives on building a framework for a virtual primary care-driven, patient-centred, multidisciplinary model to deliver holistic care for patients with metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. We focus on clinical care and innovative trial design for metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. This work represents a call to action to promote collaboration and partnerships between stakeholders for improving the lives of people with, or at risk of, metabolic dysfunction-associated fatty liver disease and associated metabolic diseases.

Introduction

Non-communicable diseases constitute the leading cause of disability worldwide and are responsible for up to approximately 75% of total deaths; consequently, the global economic burden of non-communicable diseases is immense and growing rapidly, especially in resource-poor settings where a large proportion of this disease burden will reside.¹ Not surprisingly, the Sustainable Development Goal set by the UN aims to reduce the number of premature deaths from non-communicable diseases by a third by 2030.² The emergence of the obesity epidemic is associated with a myriad of clinical manifestations, including rising rates of type 2 diabetes, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, hypertension, chronic kidney disease (CKD), cerebrovascular disease, osteoporosis, cancer, and cognitive changes (figure 1). A substantial increase in multimorbidity has been noted, with prevalence of multimorbidity increasing with age and, consequently, reducing life expectancy.3, 4, 5 It has been estimated that approximately one in four individuals in the UK has two or more long-term comorbid conditions,³ and by 2035, the prevalence of people with four or more non-communicable diseases is projected to increase from nearly 10% to 17%.⁶

These clinical manifestations represent end-organ damage from underlying metabolic dysregulation driven by a myriad of signals including chronic metabolic inflammation, endothelial dysfunction, intestinal dysbiosis, and hepatic or systemic insulin resistance. Other well described drivers include altered lipid metabolism; dysregulated production or secretion of adipokines, cytokines, and hepatokines; increased oxidative stress; platelet activation; and other processes that are associated with ageing. The shared genetic basis and possible pleiotropy between these metabolic abnormalities is a contributing factor,⁷ with a role for epigenetics and bone marrow stem cells (figure 2).

Recognising this complexity, the effective prevention and management of common non-communicable diseases to achieve the 2030 UN Sustainable Development Goals requires the establishment of a strategic framework of multidisciplinary and patient-centred care and management, where health professionals from different specialties work in partnership with patient advocacy groups and with buy-in from all stakeholders. It has been established that there are intimate and bidirectional interactions between MAFLD and CKD, type 2 diabetes, and cardiovascular disease.⁸ Unfortunately, unlike other chronic vascular complications of diabetes, systematic case-finding protocols have not been widely adopted into the routine clinical care of patients with established type 2 diabetes and other cardiometabolic conditions to assess for the presence and severity of MAFLD. Similarly, there are no widely accepted criteria for screening and diagnosing MAFLD among populations who are at high risk with other coexisting metabolic diseases. This absence of criteria inevitably leads to discordance in patient care and delays in diagnosis, linkage to care, and medical interventions. These interconnections between the metabolic diseases require a multidisciplinary care model but also provide an opportunity for shared clinical trials and drug repurposing. In this Review, a panel of international experts from across the spectrum of metabolic diseases come together to pinpoint the challenges and to provide perspectives on building a framework for multidisciplinary care focusing on two key aspects: improving care and clinical trial designs for MAFLD and associated metabolic diseases.