What is the recommended next step in management for a 72‑year‑old woman with intermittent mild right‑upper‑quadrant pain, hepatic steatosis and mildly irregular liver contour on ultrasound, mildly elevated AST and ALT, normal INR, negative hepatitis panel, normal iron studies, and no history of alcohol use?

Management of Suspected MASLD with Possible Advanced Fibrosis

This 72-year-old woman requires immediate non-invasive fibrosis risk stratification using FIB-4 score, followed by transient elastography or Enhanced Liver Fibrosis (ELF) testing if the FIB-4 is indeterminate or elevated, and should be referred to hepatology if advanced fibrosis is confirmed. 1

Immediate Next Steps: Two-Tier Fibrosis Assessment

Step 1: Calculate FIB-4 Score

• Calculate FIB-4 immediately using age, AST, ALT, and platelet count (from the CBC you should order if not already done). 1
• FIB-4 < 2.0 (for patients >65 years): Advanced fibrosis is effectively ruled out; manage in primary care with lifestyle modification and reassess in 2–3 years. 1
• FIB-4 ≥ 2.0 (for patients >65 years): Proceed immediately to Step 2 for specialist testing. 1
• FIB-4 > 2.67: High probability of advanced fibrosis (positive predictive value 60–80%); refer to hepatology regardless of second-tier test results. 1

Step 2: Second-Line Fibrosis Testing (if FIB-4 ≥ 2.0)

• Order transient elastography (FibroScan) or Enhanced Liver Fibrosis (ELF) test to confirm or exclude advanced fibrosis. 1
• Liver stiffness ≥ 12 kPa on elastography indicates high risk for advanced fibrosis (≥F3) and mandates hepatology referral. 1, 2
• Liver stiffness ≥ 20 kPa or thrombocytopenia present: Suspect cirrhosis; refer urgently for endoscopic variceal screening and hepatocellular carcinoma surveillance. 2

Complete the Diagnostic Workup

Laboratory Tests to Order Now

• Complete blood count (to calculate FIB-4 and assess for thrombocytopenia suggesting portal hypertension). 1
• Comprehensive metabolic panel including albumin (hypoalbuminemia suggests cirrhosis). 1
• Fasting glucose or HbA1c (diabetes is the strongest predictor of advanced fibrosis in MASLD). 1
• Lipid panel (dyslipidemia is a core cardiometabolic risk factor and cardiovascular disease is the leading cause of death in MASLD). 1, 2

Assess for Competing or Overlapping Liver Diseases

• The negative acute hepatitis panel and normal iron studies are appropriate, but confirm you have tested: hepatitis B surface antigen, hepatitis C antibody with reflex PCR, anti-mitochondrial antibody, anti-smooth muscle antibody, antinuclear antibody, and serum immunoglobulins. 1
• Transferrin saturation should be checked alongside ferritin; isolated elevated ferritin without elevated transferrin saturation (>45%) reflects dysmetabolic iron overload (common in MASLD), not hemochromatosis. 1

When to Consider Liver Biopsy

Liver biopsy is indicated in this patient if: 1

• Non-invasive tests are discordant (e.g., FIB-4 suggests advanced fibrosis but elastography does not, or vice versa). 1
• There is diagnostic uncertainty regarding competing etiologies despite negative serologic workup. 1
• The patient has confirmed advanced fibrosis (≥F2) on non-invasive testing and is being considered for pharmacologic therapy or clinical trial enrollment; biopsy confirms NASH activity (inflammation and ballooning) which is required for treatment decisions. 1

Lifestyle Modification: Mandatory First-Line Therapy

Weight Loss and Diet

• Target 7–10% total body weight loss achieved gradually (<1 kg/week); this degree of weight loss improves steatohepatitis and can reverse fibrosis. 1, 2
• Prescribe a Mediterranean dietary pattern: daily vegetables, fruits, high-fiber cereals, nuts, fish or white meat, olive oil; limit simple sugars, red meat, and processed foods. 1, 2
• Complete alcohol abstinence is required; even modest intake doubles the risk of hepatic decompensation in MASLD. 2

Physical Activity

• Prescribe 150–300 minutes of moderate-intensity aerobic exercise per week (or 75–150 minutes of vigorous-intensity); exercise reduces steatosis and improves liver enzymes even without significant weight loss. 1, 2

Management of Cardiometabolic Comorbidities

If Diabetes or Prediabetes is Present

• Prefer GLP-1 receptor agonists (semaglutide, liraglutide) over other glucose-lowering agents; they improve both glycemic control and liver histology in NASH. 1, 2

If Dyslipidemia is Present

• Statins are safe and strongly recommended for all MASLD patients with dyslipidemia; they reduce hepatocellular carcinoma risk by 37% and lower the risk of hepatic decompensation. 2

Pharmacologic Therapy for NASH (Only if Biopsy-Proven)

• Pharmacologic treatment should be reserved exclusively for patients with biopsy-proven NASH and significant fibrosis (≥F2). 1, 2
• Resmetirom is the preferred agent where locally approved for non-cirrhotic NASH with ≥F2 fibrosis; it demonstrates histologic improvement in steatohepatitis and fibrosis. 1, 2
• Vitamin E 800 IU/day may be considered in non-diabetic patients with biopsy-proven NASH, though long-term safety concerns limit routine use. 1, 2
• Pioglitazone increases odds of NASH resolution (OR 3.2) and fibrosis reversal (OR ~3.1) in patients with or without diabetes, but causes modest weight gain (2.7%). 2

Surveillance Strategy if Advanced Fibrosis or Cirrhosis is Confirmed

For Advanced Fibrosis (F3)

• Repeat non-invasive fibrosis assessment every 1–3 years to monitor for progression. 1
• Optimize cardiometabolic risk factors aggressively; cardiovascular disease is the leading cause of death before cirrhosis develops. 2

For Cirrhosis (F4)

• Right upper quadrant ultrasound every 6 months for hepatocellular carcinoma surveillance; annual HCC incidence in NASH cirrhosis is 2–3%. 1, 2
• Screening endoscopy for esophageal varices at the time of cirrhosis diagnosis. 1, 2
• Refer to liver transplant center if decompensation occurs or when standard transplant criteria are met. 2

Common Pitfalls to Avoid

• Do not assume normal ALT excludes advanced fibrosis; one-quarter of patients with MASLD and advanced fibrosis have persistently normal aminotransferases. 1
• Do not use FIB-4 alone in patients >65 years without adjusting the cutoff; the standard cutoff of 1.3 has poor specificity in older adults—use 2.0 as the lower threshold instead. 1
• Do not start pharmacologic therapy without biopsy confirmation of NASH; simple steatosis (without inflammation or ballooning) has excellent prognosis and does not warrant drug treatment. 1, 2
• Do not discontinue statins out of fear of hepatotoxicity; statins are safe in MASLD and reduce both cardiovascular events and liver-related outcomes. 2