Key Clinical Summary: Updates in Metabolic Dysfunction-Associated Steatohepatitis Management

This is a micro-learning module summary of Dr Amreen Dinani's MASH Academy session which you can find here.

Before participating please read our CME and disclosure information which can be found here.

The MASH Academy was supported by an independent medical education grant from Novo Nordisk.

Introduction:

This summary provides an overview of evidence-based strategies for the long-term management of Metabolic Dysfunction-Associated Steatohepatitis (MASH). It covers lifestyle and dietary modifications for sustainable improvements, as well as the latest pharmacological treatments based on current guidelines.

Epidemiology of MASLD:

• MASLD is a global epidemic with an estimated prevalence of 30% or higher worldwide.
• The highest rates are observed in the Middle East and Latin America.
• In the United States, the prevalence is also approximately 30%, which is a significant public health burden.
• MASLD prevalence is even higher in patients with type 2 diabetes, estimated to be as high as 70%.

Lifestyle and Dietary Modifications:

• Society guidelines (liver, cardiology, and diabetes) recommend weight loss through a healthy lifestyle, hypocaloric diet, and exercise to improve MASLD and associated metabolic diseases.
• Key Lifestyle Changes:
• Hypocaloric Mediterranean diet
• Regular physical activity (aiming for 5-10% weight reduction)
• Impact of Weight Loss:
• A meta-analysis of randomized controlled trials showed that weight loss improves hepatic steatosis and liver enzymes.
• A prospective study demonstrated that:
• As little as 5% weight loss improves steatosis and steatohepatitis.
• 7-10% weight loss has a more dramatic impact on steatosis and MASH resolution.
• 10% weight loss has the potential to reverse fibrosis.
• Post-hoc analysis suggests that weight loss of 7-10% is associated with higher rates of MASH resolution, but women, those with type 2 diabetes, and those with a BMI ≥ 35 may require more significant weight loss.
• Benefits of Weight Loss in MASH:
• Improvement in liver enzymes
• Improvement in metabolic parameters (fasting glucose, insulin sensitivity)
• Reduction in liver fat
• Improvement in steatohepatitis and fibrosis

Dietary Composition:

• Diet quality is crucial, focusing on macronutrient and micronutrient intake, as well as food preparation and processing.
• Ultra-processed foods (high in added sugars, low in nutritional value) should be limited.
• Minimally processed foods should be encouraged.
• Identifying Ultra-Processed Foods:
• Read labels for unrecognizable ingredients not typically found in a kitchen.
• Look for added high fructose corn syrup, artificial flavors and colors, and hydrogenated oils.
• Evidence on Diet and MASLD:
• A meta-systematic review showed a positive association between ultra-processed food consumption and MASLD/metabolic syndrome.
• A US-based study linked red and processed meat, and high cholesterol intake to MASLD, while fiber intake was protective.
• Overfeeding with saturated fats leads to more liver fat accumulation than overfeeding with simple sugars.

Role of Fructose and Sugar-Sweetened Beverages:

• Fructose, found in many processed foods and sugar-sweetened beverages, is primarily cleared by the liver and stimulates lipogenesis.
• Fructose metabolism leads to ATP consumption, ADP accumulation, uric acid formation, hepatic oxidative stress, and mitochondrial toxicity, contributing to liver damage.
• Studies have shown an association between fructose consumption and MASH in children.
• Sugar-sweetened beverages are associated with an increased risk of hepatocellular carcinoma and liver-related mortality.
• A study in adolescent boys with MASH showed that a low-sugar diet significantly reduced liver fat.

Healthy Diet Recommendations:

• A healthy diet, beneficial for both human health and the environment, emphasizes:
• Predominantly vegetables and fruits
• Very little animal protein
• Close to zero ultra-processed foods
• Non-animal protein sources (legumes, nuts)
• Limited animal protein (moderate portions, daily to weekly)
• Improving diet quality, even without weight loss, can decrease liver fat and reduce the incidence of new MASLD cases.
• A healthy diet can modify genetic risk for MASLD, which is particularly important for patients with a strong family history.
• Red meat, processed meat, and sugar-sweetened beverage consumption exceed recommended levels in most regions globally.
• Food insecurity is associated with increased consumption of ultra-processed foods and a higher prevalence of MASLD and advanced fibrosis.

Physical Activity:

• Exercise/physical activity is beneficial for MASLD, even without weight loss.
• Studies have shown that exercise improves liver fat and liver enzymes.
• Emerging evidence suggests that exercise may also improve liver fibrosis.
• The type of physical activity (aerobic, anaerobic, resistance training, or a combination) is less important than the act of moving.

Implementing Effective Lifestyle Interventions:

• Successful implementation requires shifting the focus from weight reduction to sustainable healthy behaviors.
• Key strategies:
• Reiterate that MASLD is reversible with lifestyle changes.
• Emphasize the importance of dietary composition.
• Acknowledge the benefits of even small increases in physical activity.
• Empower patients to make changes.
• Set realistic weight loss goals (e.g., pounds/kg per month).
• Involve patients in goal setting.
• Educate patients on the "MyPlate" concept (half fruits and vegetables, quarter grains, quarter protein).
• Addressing Challenges to Lifestyle Change:
• Cost: Recommend buying fruits and vegetables in bags, frozen over canned, and seasonal produce.
• Knowledge/Misconceptions: Educate patients on food groups and macronutrients.
• Physical Limitations: Focus on increasing overall physical activity gradually (aiming for 150 minutes per week).
• Toxic Environments: Encourage shopping on the outer aisles of grocery stores to avoid processed foods.
• Socioeconomic Factors: Acknowledge the impact of food insecurity and limited resources on food choices.

Summary of Lifestyle Recommendations:

• Along the spectrum of MASLD, interventions include:
• Hypocaloric/isocaloric Mediterranean diet
• Physical activity (aiming for 150 minutes/week)
• Reduced fructose intake
• Reduced consumption of processed foods
• Increased fiber intake
• Lean protein sources (chicken, turkey, fish over red meat)
• Other modifiable risk factors: coffee, no alcohol (especially with advanced liver disease), and smoking cessation.

Pharmacological Interventions:

• Management of MASLD should include addressing cardiometabolic risk factors (cardiovascular disease, type 2 diabetes, obesity).
• Statin therapy is safe and recommended in patients with MASLD (except in decompensated cirrhosis) to address cardiovascular risk.
• Guidelines recommend using drugs approved for associated comorbidities that may also benefit MASLD

Specific Pharmacological Agents:

• Resmetirom:
• First medication approved for MASH with moderate to advanced fibrosis (F2-F3).
• Thyroid hormone receptor-beta agonist.
• Improves hepatic lipid metabolism, reduces LDL cholesterol, and has anti-inflammatory/anti-fibrotic effects.
• GLP-1 Receptor Agonists (e.g., Semaglutide):
• Approved for type 2 diabetes and obesity.
• Have pleiotropic effects, including cardioprotective and renoprotective benefits.
• Indirectly improve liver health by reducing appetite, body weight, postprandial lipoprotein secretion, systemic inflammation, and insulin resistance.
• Studies show improvement in hepatic steatosis and potential for MASH resolution.
• Generally safe with a similar profile to that seen in type 2 diabetes/obesity treatment.
• Combination Therapies (e.g., Tirzepatide):
• Tirzepatide (GIP and GLP-1 receptor agonist) has shown promise in improving MASH and metabolic parameters.
• Most common side effects are gastrointestinal events, which are usually mild to moderate.
• Pioglitazone:
• A PPAR-gamma agonist used to improve insulin resistance in type 2 diabetes.
• Studies have shown improvement in steatohepatitis features, but the effect on fibrosis is less clear.
• Statins:
• Safe and recommended in MASLD to reduce cardiovascular risk.
• May have beneficial effects on liver histology due to their anti-inflammatory and antioxidant properties.

Conclusion:

Effective management of MASH requires a comprehensive approach that combines lifestyle interventions with pharmacological therapies. Lifestyle modifications, including diet and exercise, remain the foundation of treatment. Emerging pharmacological therapies, such as resmetirom and GLP-1 receptor agonists, offer new options for addressing MASH resolution and fibrosis improvement, while also managing associated metabolic comorbidities.