What are the differences between Non-Alcoholic Fatty Liver Disease (NAFLD), Metabolic Associated Fatty Liver Disease (MAFLD), and Metabolic Associated Steatohepatitis with Liver Disease (MASLD)?

Differentiation Between NAFLD, MAFLD, and MASLD

MASLD (Metabolic dysfunction-associated steatotic liver disease) is the current preferred terminology that replaces NAFLD, requiring the presence of hepatic steatosis plus at least one cardiometabolic risk factor, while MAFLD was a transitional term with similar diagnostic criteria but has now been superseded by MASLD. 1

Key Definitions and Diagnostic Criteria

NAFLD (Non-Alcoholic Fatty Liver Disease)

• Traditional term defined by the presence of hepatic steatosis in the absence of significant alcohol consumption (>21 standard drinks/week for men, >14 standard drinks/week for women) 1
• Diagnosis of exclusion that required ruling out other causes of liver steatosis 1
• Includes a spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis/cirrhosis 1
• Criticized for its negative definition (based on what it is not) and potential stigmatizing language 1

MAFLD (Metabolic dysfunction-Associated Fatty Liver Disease)

• Transitional term proposed to replace NAFLD, focusing on the metabolic etiology 1
• Required hepatic steatosis plus at least one metabolic risk factor (obesity, type 2 diabetes, or metabolic dysregulation) 2
• Provided a positive diagnostic criterion rather than an exclusion-based definition 1, 3
• Has been superseded by MASLD in the most recent guidelines 1

MASLD (Metabolic dysfunction-Associated Steatotic Liver Disease)

• Current preferred terminology established in June 2023 through an international, multi-society guided Delphi process 1
• Defined as the presence of hepatic steatosis (documented by imaging or biopsy) plus at least one cardiometabolic risk factor 1
• Includes the full spectrum from simple steatosis (MASL) to steatohepatitis (MASH) and fibrosis/cirrhosis 1
• Embedded within the broader concept of steatotic liver disease (SLD) 1

Diagnostic Framework and Classification

Steatotic Liver Disease (SLD) Categories

• MASLD: Steatosis + cardiometabolic risk factor(s) + no harmful alcohol intake 1
• MetALD: MASLD with moderate alcohol intake (20-50g/day in women, 30-60g/day in men) 1
• ALD: Alcohol-related liver disease (>50g/day in women, >60g/day in men) 1
• Other causes: Drug-induced, monogenic diseases, etc. 1

Cardiometabolic Risk Factors for MASLD Diagnosis

• Type 2 diabetes 1
• Obesity (especially with additional metabolic risk factors) 1
• Metabolic dysregulation (prediabetes, atherogenic dyslipidemia, hypertension) 1

Clinical Implications and Population Overlap

Population Overlap Between Definitions

• Nearly complete overlap between NAFLD and MASLD populations (99.8% accordance in tertiary NAFLD cohorts) 1
• Only 5.3% of individuals with NAFLD in the NHANESIII database did not fulfill MASLD criteria 1
• MASLD identifies a greater number of individuals compared to MAFLD, particularly those with BMI <25 kg/m² 4, 5
• Both MASLD and MAFLD are associated with increased all-cause mortality risk, while NAFLD alone showed no such association 4

Clinical and Prognostic Considerations

• Clinical characteristics between NAFLD and MASLD are almost identical 1
• Non-invasive tests show equal accuracy and similar cut-offs for both NAFLD and MASLD definitions 1
• Long-term follow-up shows similar mortality rates, with slightly higher mortality in MASLD compared to NAFLD 1
• Advanced fibrosis is associated with increased mortality risk regardless of terminology used (NAFLD, MAFLD, or MASLD) 4

Practical Approach to Diagnosis

Diagnostic Algorithm

1. Identify hepatic steatosis through imaging or biopsy 1
2. Assess for cardiometabolic risk factors 1
3. Evaluate alcohol consumption patterns using detailed medical history and validated biomarkers 1
4. Rule out other specific etiologies of steatosis 1
5. Apply appropriate terminology based on findings 1

Common Pitfalls to Avoid

• Failing to assess alcohol consumption quantitatively and qualitatively 1
• Not considering the overlap between metabolic risk and alcohol consumption (MetALD) 1
• Overlooking the need for fibrosis assessment, which is the strongest predictor of outcomes 4
• Using outdated terminology that may stigmatize patients or fail to recognize the metabolic etiology 1

Clinical Management Implications

• Evidence generated under the NAFLD definition can be fully extrapolated to individuals with MASLD 1
• Management focuses on lifestyle modification, weight loss, and addressing metabolic comorbidities regardless of terminology 1
• New pharmacological treatments (e.g., resmetirom) are being evaluated specifically for MASH with significant fibrosis 1
• Screening strategies should target high-risk populations with cardiometabolic risk factors 1