What is the diagnostic approach for Metabolic Associated Steatohepatitis Liver Disease (MASLD) in a patient with a history of metabolic disorders?

Diagnosing MASLD: A Structured Approach

Diagnose MASLD by demonstrating hepatic steatosis (via imaging or CAP/MRI-PDFF) plus at least one cardiometabolic risk factor, then use a sequential non-invasive testing strategy starting with FIB-4 followed by elastography to risk-stratify for advanced fibrosis. 1, 2

Step 1: Identify At-Risk Populations for Case-Finding

You should actively look for MASLD with liver fibrosis in three specific groups: 1

• Individuals with type 2 diabetes 1
• Those with abdominal obesity plus ≥1 additional metabolic risk factor (hypertension, dyslipidemia, prediabetes, insulin resistance) 1
• Patients with persistently abnormal liver enzymes (elevated ALT/AST) 1
• Incidental finding of hepatic steatosis on imaging 1

The 2024 EASL-EASD-EASO guidelines emphasize that early fibrosis detection can potentially prevent progression to cirrhosis and its complications, justifying this targeted case-finding approach rather than population-wide screening. 1

Step 2: Establish the Diagnosis of MASLD

Demonstrate Hepatic Steatosis

Use any of these modalities to detect steatosis: 2, 3

• Standard imaging: Ultrasound, CT, or MRI 2, 3
• Quantitative techniques:
  • Controlled attenuation parameter (CAP) via FibroScan (thresholds: S1 ≥248 dB/m, S2 ≥268 dB/m, S3 ≥280 dB/m) 1, 2
  • MRI-proton density fat fraction (MRI-PDFF) (thresholds: S1 ≥5%, S2 11-18%, S3 16-23%) 1, 2
• Liver biopsy: Only if performed for other clinical indications 2, 3

Confirm Metabolic Dysfunction

Document at least one of these cardiometabolic criteria: 2, 3

• Overweight/obesity (elevated waist circumference by population-specific definitions) 2
• Type 2 diabetes mellitus 2, 3
• Evidence of metabolic dysregulation defined as ≥2 of: 2, 3
  • Elevated blood pressure (>130/85 mmHg or on treatment) 2
  • Elevated fasting triglycerides 2
  • Low HDL cholesterol 2
  • Prediabetes or insulin resistance 2

Critical distinction: Unlike the old NAFLD terminology, MASLD does not require excluding concurrent alcohol consumption or other liver diseases unless they meet criteria for alcohol-associated liver disease or viral hepatitis. 3

Step 3: Risk-Stratify for Advanced Fibrosis Using Sequential Non-Invasive Testing

The multi-step approach is superior to standard liver enzymes (ALT/AST) alone for detecting fibrosis. 1

First-Line: FIB-4 Score

Calculate FIB-4 as your initial blood-based fibrosis assessment: 1

• FIB-4 <1.3 (age ≤65 years) or **<2.0** (age >65 years): Low risk for advanced fibrosis 1, 2

  • Intensify management of metabolic comorbidities 1
  • Reassess FIB-4 in ≤1 year initially, then every 1-3 years 1

• FIB-4 1.3-2.67 (indeterminate zone): Proceed to second-line testing 1, 2

• FIB-4 >2.67: High risk for advanced fibrosis 1, 2

  • Proceed immediately to hepatology referral or second-line testing 1

Second-Line: Liver Elastography

If FIB-4 is indeterminate or elevated, use vibration-controlled transient elastography (VCTE) or alternative imaging: 1

• VCTE <8.0 kPa: Rules out advanced fibrosis 1, 4

  • Continue intensified comorbidity management 1
  • Reassess with non-invasive tools every 1-3 years 1

• VCTE ≥8.0 kPa: Suggests advanced fibrosis 1, 4

  • Refer to hepatology for diagnostic work-up and management plan for liver-related outcomes 1
  • Intensify comorbidity management in multidisciplinary team 1

Alternative second-line tests include: 1

• Magnetic resonance elastography (MRE) 1, 3
• Shear wave elastography (SWE) 1
• Enhanced liver fibrosis (ELF) test (rule-out <7.7, rule-in >9.8 for F3 fibrosis) 1

Important Performance Characteristics

Blood biomarker scores and elastography should be used to exclude advanced fibrosis, while elastography is better suited to predict (rule-in) advanced fibrosis. 1 The 2024 guidelines emphasize that positive and negative predictive values depend heavily on chosen cut-offs and disease prevalence in your population. 1

Critical Caveats for Elastography

Several factors falsely elevate liver stiffness measurements: 4

• Acute hepatic inflammation 4
• Hepatic congestion 4
• Recent alcohol consumption 4
• Obesity (reduces exam quality and accuracy) 4

Step 4: Role of Liver Biopsy

In most cases, liver biopsy is not required for clinical management of MASLD. 1 However, biopsy remains the gold standard and is still required for: 1

• Definitive diagnosis of steatohepatitis (MASH) 1
• Ruling out alternative causes of liver disease 1
• Assessing microscopic features like ballooning or lobular inflammation that non-invasive methods cannot detect 1

Step 5: Assess Comorbidities and Cardiovascular Risk

At initial diagnosis and regular follow-up intervals, perform comprehensive metabolic assessment: 1, 3

• Type 2 diabetes screening (consider HOMA-IR or oral glucose tolerance test if diabetes not yet diagnosed) 1
• Lipid panel 3
• Blood pressure measurement 3
• Renal function 1, 3
• Obstructive sleep apnea screening 1, 3
• Polycystic ovary syndrome assessment 1, 3
• 10-year cardiovascular risk calculation 3

Cardiovascular disease is the leading cause of mortality in MASLD patients, making this assessment critical. 5

Optional: Genetic Testing in Specialized Settings

Consider genetic risk profiling only in specialized centers for personalized risk stratification: 1

• PNPLA3 p.I148M variant or polygenic risk scores may help stratify disease progression risk 1
• Refer individuals with strong family history of severe disease in first-degree relatives or early severe presentation (especially with normal body weight) for next-generation sequencing to evaluate treatable genetic causes 1

This remains investigational and should be evaluated in larger prospective studies before routine clinical use. 1

Key Pitfalls to Avoid

• Don't rely on ALT/AST alone – they have poor diagnostic accuracy compared to FIB-4 and elastography 1
• Don't skip the sequential approach – starting with FIB-4 then proceeding to elastography is the most cost-effective strategy 4
• Don't forget age-adjusted FIB-4 thresholds – use 2.0 (not 1.3) as the lower cut-off for patients >65 years 1
• Don't order liver biopsy routinely – reserve it for cases where non-invasive tests are inconclusive or alternative diagnoses need exclusion 1
• Don't neglect extrahepatic screening – encourage participation in cancer screening programs given obesity and diabetes as risk factors for extrahepatic malignancies 1