What is the appropriate work‑up for a patient suspected of having metabolic dysfunction‑associated steatohepatitis (MASH)?

Work-Up for Suspected MASH

For patients suspected of having MASH, implement a stepwise case-finding strategy using non-invasive tests, starting with FIB-4 score followed by transient elastography, to identify clinically significant fibrosis rather than pursuing immediate liver biopsy. 1

Target Population for Work-Up

Apply case-finding strategies specifically in individuals with:

• Type 2 diabetes (highest priority population) 1
• Obesity with additional metabolic risk factors 1
• Abnormal liver enzymes (elevated ALT/AST) 1
• Radiological signs of hepatic steatosis on imaging 1
• Other cardiometabolic risk factors including hypertension, hypertriglyceridemia, or low HDL cholesterol 2

The presence of type 2 diabetes or obesity with metabolic syndrome components should trigger immediate risk stratification, as these patients have 60-80% prevalence of MASLD. 2

Initial Diagnostic Confirmation

Clinical Criteria

Establish the diagnosis of MASLD by confirming:

• Hepatic steatosis (by ultrasound or other imaging) 2
• At least one cardiometabolic risk factor (abdominal obesity, prediabetes/T2D, hypertension, elevated triglycerides, low HDL) 2
• Alcohol consumption below threshold: <140 g/week for women (<2 drinks/day), <210 g/week for men (<3 drinks/day) 2
• Exclusion of other causes: Rule out viral hepatitis C, medication-induced steatosis (corticosteroids, tamoxifen, methotrexate), iron overload, and other secondary causes 2

Stepwise Fibrosis Risk Stratification

Step 1: FIB-4 Score (First-Line)

Calculate the Fibrosis-4 (FIB-4) index using age, AST, ALT, and platelet count as the initial blood-based screening tool. 1, 2 This scoring system effectively rules out advanced fibrosis when low and identifies patients requiring further evaluation when elevated. 1

Step 2: Transient Elastography (Second-Line)

For patients with elevated FIB-4 scores, proceed to vibration-controlled transient elastography (VCTE) to measure liver stiffness and quantify fibrosis stage. 1, 2 This imaging-based approach provides non-invasive assessment of fibrosis severity, which is the primary predictor of liver-related outcomes. 1

Additional Non-Invasive Biomarkers

Consider supplementary serum biomarkers when available:

• Cytokeratin-18 (CK-18) 3
• NIS4 score 3
• FAST score (combines imaging and biomarkers) 3

These markers can enhance diagnostic accuracy for detecting MASH and evaluating fibrosis severity, though they are not yet universally standardized. 3

Advanced Imaging Techniques

When transient elastography is insufficient or unavailable, MRI-based techniques provide alternative non-invasive assessment of both steatosis and fibrosis. 3 MRI proton density fat fraction (MRI-PDFF) quantifies hepatic fat content with high accuracy, while MR elastography measures liver stiffness. 3

Role of Liver Biopsy

Liver biopsy remains the gold standard for definitive MASH diagnosis, particularly when:

• Non-invasive tests yield indeterminate results 3
• Clinical decision-making requires histological confirmation of steatohepatitis and precise fibrosis staging 3
• Enrollment in clinical trials is considered 3

However, the invasiveness and sampling limitations of biopsy have shifted clinical practice toward non-invasive algorithms for routine screening and monitoring. 3

Surveillance and Monitoring

For patients identified with significant fibrosis (stage ≥2):

• Hepatocellular carcinoma surveillance in cirrhotic patients 1
• Portal hypertension screening in advanced fibrosis/cirrhosis 1
• Serial non-invasive testing to monitor disease progression 1

Common Pitfalls to Avoid

• Do not rely solely on liver enzymes: ALT and AST can be normal in patients with significant MASH and fibrosis 1
• Do not overlook lean patients: The updated MASLD criteria capture lean phenotypes who may still have metabolic dysfunction and steatohepatitis 3
• Avoid manual FIB-4 calculation errors: Electronic health record integration improves accuracy and adherence to screening protocols 4
• Do not delay referral: Patients with FIB-4 scores suggesting advanced fibrosis should be referred to hepatology promptly for specialized management 5, 4

Risk Stratification for Treatment Eligibility

Identify patients with non-cirrhotic MASH and significant fibrosis (stage ≥2) through this work-up, as they are candidates for MASH-targeted pharmacotherapy with resmetirom (if locally approved). 1 Patients with stage 2-3 fibrosis also qualify for semaglutide under conditional FDA approval. 2