Understanding the New EASL-EASD-EASO Guidelines on MASLD

Who are EASL, EASD, EASO?

EASL, EASD, and EASO are prominent European organizations in the field of health and medicine, each focusing on a specific area:

• The European Association for the Study of the Liver (EASL) is a professional association dedicated to the research and treatment of liver diseases. It provides a platform for hepatologists and other healthcare professionals to share knowledge, advance research, and promote the best practices in hepatology.
• European Association for the Study of Diabetes (EASD) is a professional association  focused on diabetes research and education. It aims to encourage and support research in diabetes, improve patient care, and facilitate the dissemination of knowledge among healthcare professionals dealing with diabetes.
• European Association for the Study of Obesity (EASO) is a professional association dedicated to obesity research and management. It works to improve understanding of obesity, enhance treatment options, and promote public health initiatives to address the obesity epidemic across Europe.

What are clinical practice guidelines (CPG) and why are they important?

Clinical practice guidelines are evidence-based recommendations developed through systematic review and consensus to help healthcare providers and patients make informed decisions about the most appropriate treatment options for specific health conditions.

The current Clinical Practice Guidelines for MASLD, developed jointly by EASL, EASD, and EASO, update the 2016 guidelines to reflect recent advancements in disease understanding and treatment. These guidelines emphasize the importance of early identification and intervention, leveraging improved diagnostic tools and therapeutic options to better manage MASLD and prevent clinical events. Created through a rigorous process involving literature reviews, expert consensus, and multi-stakeholder input, the CPG aims to provide a comprehensive framework for the diagnosis, treatment, and follow-up of MASLD, tailored to available resources and local regulations.

What is MASLD?

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a liver condition characterized by the accumulation of excessive triglycerides (a type of fat) in the liver, accompanied by at least one cardiometabolic risk factor. MASLD replaces the former term nonalcoholic fatty liver disease (NAFLD) and is now included in the broader definition of steatotic liver disease (SLD). In addition to MASLD, SLD encompasses MASLD with moderate alcohol intake (MetALD), alcohol-related liver disease (ALD), specific aetiologies of SLD (e.g., drug-induced, monogenic diseases), and cryptogenic SLD.

MASLD Spectrum

MASLD can range from simple fat accumulation in the liver to more severe conditions. The spectrum includes:

• Steatosis: Fat in the liver
• Metabolic dysfunction-associated steatohepatitis (MASH): Fat in the liver with inflammation and damage
• Fibrosis: Liver scarring
• Cirrhosis: Severe liver damage
• MASH-related hepatocellular carcinoma (HCC): Liver cancer associated with MASH

Defining the Population at Risk and Screening Strategies

When liver steatosis is discovered incidentally, it should prompt an assessment to confirm the presence of SLD and check for advanced fibrosis. This assessment is crucial as it helps determine the risk of liver-related and cardiovascular complications and guides appropriate care.

Routine screening for SLD in the general population is not recommended, as steatosis alone does not necessarily lead to liver-related outcomes.

What to Look For

• Individuals with cardiometabolic risk factors and consistently abnormal liver enzymes:
  • <1.0 mmol/L (<39 mg/dl) in men
  • <1.3 mmol/L (<50 mg/dl) in women
• Plasma triglycerides: ≥1.7 mmol/L (>150 mg/dl) or on lipid-lowering treatment
• HDL-Cholesterol:
• Blood Pressure: ≥130/85 mmHg or receiving treatment for hypertension
• Individuals who are overweight or have obesity:
  • ≥25 kg/m² (general population)
  • ≥23 kg/m² (Asian population)
  • 94 cm in men and >80 cm in women (Europeans)
  • 90 cm in men and >80 cm in women (South Asians and Chinese)
  • 85 cm in men and >90 cm in women (Japanese)
• BMI:
• Waist Circumference:
• In people with dysglycaemia or type 2 diabetes (T2D):
  • HbA1c: 39-47 mmol/mol (5.7-6.4%)
  • Fasting Plasma Glucose: 5.6-6.9 mmol/L (100-125 mg/dl)
  • 2-hour Plasma Glucose during OGTT: 7.8-11 mmol/L (140-199 mg/dl)
  • HbA1c: >48 mmol/mol (>6.5%)
  • Fasting Plasma Glucose: >7.0 mmol/L (>126 mg/dl)
  • 2-hour Plasma Glucose during OGTT: >11.1 mmol/L (>200 mg/dl)
  • Receiving treatment for T2D
• Prediabetes:
• T2D:

Key Risk Factors and Populations at Elevated Risk for MASLD Progression

• Type 2 diabetes and obesity, particularly abdominal obesity, significantly impact MASLD progression, including the risk of developing advanced fibrosis, cirrhosis, and HCC.
• Males over 50, postmenopausal women, and individuals with multiple cardiometabolic risk factors are at higher risk for progressive fibrosis and related complications.
• In the U.S., the prevalence of steatohepatitis, with or without T2D, is highest among the Hispanic population, due to the impact of genetic, cultural, and socioeconomic factors on MASLD progression .
• Smoking is linked to an increased risk of developing HCC, both generally and specifically in individuals with MASLD.

Prevention in the General Population and High-Risk Groups

• Recommend non-pharmacological measures, such as a healthy diet and physical activity, to prevent MASLD and HCC, especially in high-risk groups (obesity, T2D).
• Unhealthy diets, sedentary lifestyles, sugary drinks, and red meat increase MASLD risk.
• The Mediterranean diet and smoking cessation reduce the risk of MASLD, liver fibrosis, and HCC.
• Advocate for public policies to regulate unhealthy food marketing, promote healthy food options, and improve food literacy.

How is MASLD Diagnosed?

The suggested strategy for assessing the risk of advanced liver fibrosis in individuals with metabolic risk factors or signs of SLD involves a multi-step, noninvasive process.

For adults with MASLD, it is recommended to use noninvasive scores that combine blood tests and imaging techniques, as they are more accurate for detecting fibrosis than standard liver enzyme tests (e.g., ALT and AST).

The process includes:

1. Initial Screening: Use an established blood-based score like FIB-4 to identify potential fibrosis.
2. Further Assessment: If fibrosis is suspected or if the individual is high-risk, follow up with imaging techniques such as liver elastography to determine the stage of fibrosis.
3. Alternative Tests: In some cases, blood tests that measure collagen-related components, like the ELF (Enhanced Liver Fibrosis) test, can be used instead of imaging to detect advanced fibrosis. The Age, Diabetes, and Phosphatidylethanol Test (ADAPT) can also be used, providing an overview by combining clinical factors (age and presence of diabetes) and biomarkers to assess alcohol consumption, allowing for a more accurate assessment of liver fibrosis risk.

Considerations for MASH Diagnosis

• Non-invasive tools like blood biomarker scores, liver stiffness measurements, and imaging techniques can monitor MASH progression and predict liver-related outcomes in adults with MASLD.
• These methods can serve as surrogates for liver biopsy, effectively assessing fibrosis and predicting risk.
• Non-invasive techniques cannot evaluate specific microscopic features such as ballooning or lobular inflammation.
• Liver biopsy is generally not needed for managing MASLD but is required for a definitive diagnosis of steatohepatitis and to exclude other liver diseases.

Management and Treatment of MASLD

The guidelines suggest that doctors work closely with patients to manage MASLD effectively through a combination of lifestyle changes and medications when necessary.

• Pharmacotherapy:
• For T2D or obesity: Incretin-based therapies (e.g., semaglutide, tirzepatide) may be beneficial.
• Resmetirom may be an option for non-cirrhotic MASH with significant fibrosis (stage ≥2) and if it is available locally.
• MASH-targeted medications are not recommended for cirrhosis.

Doctors should evaluate various aspects of health, including:

• Metabolic Factors: Assess insulin resistance and sensitivity. Tests like the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) can clarify metabolic dysfunction.
• Cardiovascular Health: Pay attention to heart health, as MASH can increase the risk of cardiovascular problems.
• Many people with MASH may not reach the target heart rate during exercise tests, so additional pharmacological stress tests may be performed.
• Myocardial perfusion scintigraphy, a noninvasive nuclear imaging stress test, can be used to check for coronary artery disease.
• Noninvasive angiography (such as CCTA) is an alternative for high-risk MASH patients to evaluate heart health.

Adults with MASLD should be screened for associated conditions, includingT2D, dyslipidemia (abnormal cholesterol levels), hypertension (high blood pressure), kidney disease, sleep apnea, and polycystic ovary syndrome. Regular lab tests and physical exams are recommended to monitor these comorbidities. Extrahepatic cancer screening is advised due to obesity and T2D as risk factors.

Non-Pharmacological Approaches

• Lifestyle Changes:
  • ≥5% to reduce liver fat.
  • 7-10% to improve liver inflammation.
  • ≥10% to reduce fibrosis (liver scarring).
  • Follow a Mediterranean-like diet.
  • Limit consumption of ultra-processed foods high in sugars and saturated fats.
  • Avoid sugar-sweetened beverages.
  • Coffee consumption is associated with improvements in liver damage.
• Aim for sustained weight loss:
• Improve diet and nutrition:
• There is no evidence to support the use of nutraceuticals (food supplements, herbal products, gut microbiota-modifying agents).
• Physical Activity:
  • Preferably >150 minutes per week of moderate activity or
  • 75 minutes per week of vigorous-intensity physical activity.
• Engage in regular physical activity:
• Manage Health Conditions: Maintain control over conditions such as T2D and obesity.

Clinical Outcomes and Follow-Up

• More research is needed to understand the long-term effects of weight loss on liver-related outcomes and survival.
• Clinical trials show that reducing calories (with or without exercise) improves liver markers such as enzymes, fat accumulation, and inflammation. However, evidence for the improvement of advanced fibrosis or cirrhosis is limited due to fewer participants with severe fibrosis in studies.

Treatment of MASLD: Surgical and Endoscopic Therapy

• For adults with non-cirrhotic MASLD, bariatric surgery is recommended.
• If compensated advanced liver disease or cirrhosis is present, evaluation by a specialized team is crucial. They will consider factors such as the type of surgery and any portal hypertension (pressure in the liver blood vessels).

Advanced Treatments and Procedures

• For those with obesity, bariatric surgery may improve liver health and lead to remission of T2D, especially if there is no severe liver cirrhosis.
• Endoscopic weight-loss procedures are still under study and are not currently recommended specifically for MASLD treatment.

For Those Who Need a Liver Transplant

• A multidisciplinary team should assess heart and metabolic problems to lower the risk of serious heart issues before, during, and after the transplant.
• Those with obesity and severe MASLD should focus on losing weight without causing muscle loss.
• Start with diet changes and exercise to lower BMI to below 40 kg/m², aiming for below 35 kg/m².
• Weight-loss medications can be considered if carefully assessed for risks and benefits.
• Surgical Options:
• For those with early-stage cirrhosis and no severe portal hypertension, sleeve gastrectomy might be considered.
• Bariatric surgery is not recommended for those with advanced cirrhosis and should be discussed in the context of liver transplantation.

Managing MASLD involves a combination of healthy lifestyle choices, regular medical evaluations, and, when necessary, medical treatments. A multidisciplinary approach is recommended to address MASLD effectively, as it is closely linked to other health issues, ensuring comprehensive care for both liver and overall health.

For more information or personalized advice, always consult with your doctor.