Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common liver disorder worldwide, with an estimated global prevalence of more than 31%. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide a comprehensive analysis of the extrahepatic manifestations of MASH, focusing on chronic diseases related to the cardiovascular, muscular, and renal systems. A systematic review of published studies and literature was conducted to summarize the findings related to the systemic impacts of MASLD and MASH. The review focused on the association of MASLD and MASH with metabolic comorbidities, cardiovascular mortality, sarcopenia, and chronic kidney disease. Mechanistic insights into the concept of lipotoxic inflammatory "spill over" from the MASH-affected liver were also explored. MASLD and MASH are highly associated (50%-80%) with other metabolic comorbidities such as impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, and hypertension. Furthermore, more than 90% of obese patients with type 2 diabetes have MASH. Data suggest that in middle-aged individuals (especially those aged 45-54), MASLD is an independent risk factor for cardiovascular mortality, sarcopenia, and chronic kidney disease. The concept of lipotoxic inflammatory "spill over" from the MASH-affected liver plays a crucial role in mediating the systemic pathological effects observed. Understanding the multifaceted impact of MASH on the heart, muscle, and kidney is crucial for early detection and risk stratification. This knowledge is also timely for implementing comprehensive disease management strategies addressing multi-organ involvement in MASH pathogenesis.

Keywords: Adipose tissue (AT); cardiovascular diseases (CVDs); chronic kidney diseases (CKDs); heart; metabolic dysfunction-associated steatohepatitis (MASH)/non-alcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatotic liver disease (MASLD)/non-alcoholic fatty liver disease (NAFLD); muscle; sarcopenia.

FIGURE 1

Systemic Impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH). Illustration depicts the progression from a metabolically healthy state (left side) to the development of MASLD and MASH and its subsequent systemic effects (right side). The left side shows the interconnectedness of healthy organs, including the heart, liver, muscle, and kidneys, maintaining metabolic balance. However, moving to the right, the impact of an unhealthy diet, environmental factors, and genetic predispositions contribute to the development of MASH, characterized by enlarged liver and visceral fat depot with the accumulated fat and inflammation. The hepatic and extra-hepatic consequences of MASH are evident, as the liver afflicted with MASH causally associated with the increased risk of cardiovascular diseases (CVDs), muscular disorders and chronic kidneys diseases (CKDs). All of which may also adversely impacted by the inflamed visceral fat associated with MASH. This representation highlights the systemic pathological nature of MASH, highlighting the importance of a holistic approach to its management and treatment. The illustration was made on BioRender.com.

FIGURE 2

MASLD/MASH pathogenesis and its systemic implications. Illustration depicts the pathophysiological mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic associated steatohepatitis (MASH), and its systemic consequences. Dietary fats and carbohydrates (fructose in particular) contribute to fat import and de novo lipogenesis respectively within the liver, leading to triglyceride (TG) and cholesterol biosynthesis, and subsequent fatty acid accumulation. Increased flux of free fatty acids to mitochondria causes mitochondrial burnout, leading to inadequate disposal of metabolic substrates due to impaired beta-oxidation. These processes result in; i) increased lipid droplets (LDs) causing steatosis, ii) increased very-low-density lipoprotein (VLDL) production, iii) oxidative stress marked by reactive oxygen species (ROS), and iv) endoplasmic reticulum (ER) stress, promoting lipotoxicity deriving hepatic inflammation and fibrosis. The systemic “spill over” of inflammation from the liver impacts other organs, including the heart, muscles, and kidneys. This “spill over” leads to extrahepatic pathologies such as cardiovascular diseases (CVDs), muscular dystrophy, and chronic kidney disease (CKD). Additionally, visceral fat (with inflammation and fibrosis) in MASH, characterized by increased lipases activity, contributes to the systemic inflammatory responses, thereby exacerbating the cycle of metabolic dysfunction across multiple organ systems. The illustration was made on BioRender.com.

FIGURE 3

An Integrated holistic care model for managing patients with metabolic associated steatohepatitis (MASH) and other MASH-associated effects. Illustration proposed an integrated care model for patients with MASH who also have systemic indications such as obesity, diabetes, cardiovascular diseases (CVDs), chronic kidney disease (CKD), and muscular dystrophy. Clinical interventions proposed are outlined, showing a flow of care from a hepatologist/gastroenterologist to a team including a pathologist, endocrinologist, cardiologist, nephrologist, and rheumatologist, indicating the need for collaborative medical management across different organ systems affected during/by MASH. Lifestyle interventions are highlighted, with a nutritionist/dietitian and a medical exercise specialist playing key roles in managing the patient’s nutrition and physical activity, essential for the overall treatment strategy. This model highlights the importance of a multidisciplinary integrative team working in concert to provide comprehensive care that addresses the multifaceted aspects of MASH and its related systemic diseases. The illustration was made on BioRender.com.