Obesity and metabolic dysfunction-associated fatty liver disease: Understanding the intricate link
image: Hepatic steatosis is promoted by factors such as obesity, insulin resistance, de novo lipogenesis, high-calorie diets, genetic factors, and gut microbiome dysbiosis. In contrast, VLDL export, and increased fatty acid oxidation in the initial stages clear the excessively accumulated fat from hepatocytes. However, ongoing hepatic steatosis that exceeds the capacity of the liver to oxidize intracellular lipids in the mitochondria activates alternate oxidation pathways and generates reactive oxygen species, resulting in steatohepatitis. Both fatty liver stage and steatohepatitis can progress to cirrhosis and subsequent hepatocellular carcinoma unless the risk factors are modified. MAFLD, metabolic dysfunction-associated fatty liver disease; VLDL, very low-density lipoproteins.
Credit: Sandhiya Selvarajan, Pazhanivel Mohan, Jayavardhan Vulchi
Obesity, a persistent metabolic state characterized by an excess accumulation of adipose tissue, has emerged as a global health concern. One of the most significant comorbidities associated with obesity is metabolic dysfunction-associated fatty liver disease (MAFLD), which encompasses a spectrum of liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. This review delves into the intricate link between obesity and MAFLD, exploring their clinical implications on comorbidities, diagnosis, and treatment strategies.
Pathophysiology
The pathogenesis of MAFLD is multifactorial, with obesity, insulin resistance (IR), genetic predisposition, and gut microbiome dysbiosis playing pivotal roles. In obese individuals, increased lipogenesis in the liver, driven by insulin and the liver X receptor-mediated activation of sterol regulatory element-binding protein 1c (SREBP1c), leads to excessive fat accumulation. This, coupled with altered lipid metabolism and defective fatty acid oxidation, results in hepatic steatosis. Prolonged steatosis triggers oxidative stress and mitochondrial dysfunction, promoting inflammation and fibrosis.
Role of Gut Microbiome
The gut microbiome plays a crucial role in maintaining mucosal barrier integrity, facilitating nutrient absorption, and regulating energy balance. Intestinal dysbiosis, characterized by reduced bacterial diversity and richness, along with an increased Firmicutes to Bacteroidetes ratio, is prevalent in obesity. This dysbiosis contributes to MAFLD development by altering bile acid metabolism, enhancing lipogenesis, and promoting hepatic inflammation.
Diagnosis
Accurate diagnosis of MAFLD relies on a combination of clinical, biochemical, and imaging modalities. Blood tests, including liver enzymes (alanine aminotransferase, aspartate aminotransferase), lipid profile, and biomarkers like ferritin and haptoglobin, provide valuable information. Imaging techniques such as ultrasound, controlled attenuation parameter (CAP), magnetic resonance imaging-proton density fat fraction (MRI-PDFF), and vibration-controlled transient elastography (VCTE) aid in quantifying liver fat content and assessing fibrosis. However, each method has its limitations, necessitating a multimodal approach for comprehensive assessment.
Treatment
Currently, there are no medications specifically approved by the USA Food and Drug Administration for treating MAFLD. Management focuses on weight loss through lifestyle modifications, including dietary changes and increased physical activity. The Mediterranean diet, rich in omega-3 fatty acids, whole grains, fruits, and vegetables, has shown promising results in reducing the risk and progression of MAFLD. Pharmacological interventions are limited and primarily reserved for specific conditions. Drugs like GLP-1 receptor agonists, obeticholic acid, and tropifexor are under investigation for their potential in treating NASH. Bariatric surgery, though effective for weight loss, is not recommended as a primary treatment for MAFLD due to limited research and associated risks.
Clinical Implications and Comorbidities
Obesity and MAFLD interact in a vicious cycle, with one exacerbating the other. This interaction leads to a myriad of comorbidities, including type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, and certain infectious diseases. MAFLD patients exhibit higher infection rates, longer/complicated courses, and increased fatality from infections like COVID-19, bacterial pneumonia, and urinary tract infections.
Conclusions
In conclusion, obesity is intricately linked to MAFLD, with both conditions sharing a complex interplay of pathophysiological mechanisms. The multifactorial nature of MAFLD necessitates a holistic approach to management, encompassing lifestyle modifications, pharmacotherapy, and, in select cases, surgical interventions. Further research is warranted to develop novel therapeutic strategies and improve diagnostic accuracy, ultimately reducing the burden of MAFLD and its associated comorbidities.
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https://www.xiahepublishing.com/2994-8754/JTG-2023-00043
The study was recently published in the Journal of Translational Gastroenterology.
Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.
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