What is the current step‑by‑step management algorithm for MASLD (metabolic dysfunction‑associated steatotic liver disease) and how does it differ from previous NAFLD (non‑alcoholic fatty liver disease) guidelines?

Management of MASLD: 2024 Updates and Key Differences from Previous NAFLD Guidelines

Major Nomenclature and Conceptual Shift

The most fundamental change is the replacement of NAFLD with MASLD, which now requires the presence of at least one cardiometabolic risk factor alongside hepatic steatosis, rather than simply excluding alcohol. 1 This represents a paradigm shift from a diagnosis of exclusion to one of inclusion based on metabolic dysfunction. 1

Key Definitional Changes:

• MASLD requires hepatic steatosis PLUS ≥1 cardiometabolic risk factor (obesity, type 2 diabetes, hypertension, dyslipidemia, impaired glucose metabolism). 1, 2
• MetALD is a new category for patients with MASLD who consume moderate alcohol (20–50 g/day in females, 30–60 g/day in males). 2
• MASH replaces NASH as the term for metabolic dysfunction-associated steatohepatitis. 1, 3
• Alcohol thresholds remain ≤20 g/day (females) or ≤30 g/day (males) for MASLD diagnosis. 2

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Step-by-Step Management Algorithm

Step 1: Case-Finding and Initial Risk Stratification

Target high-risk populations systematically rather than waiting for incidental findings. 1, 4

• Screen adults with type 2 diabetes, obesity (BMI >30), metabolic syndrome, or persistently elevated liver enzymes. 1, 4
• Assess for all cardiometabolic comorbidities at diagnosis: dyslipidemia, hypertension, chronic kidney disease, sleep apnea, polycystic ovary syndrome. 1
• Calculate FIB-4 score as the first-line non-invasive test; use age-adjusted cutoffs (1.3 for <65 years, 2.0 for ≥65 years as low-risk threshold; 2.67 as high-risk threshold). 4, 5

Key difference from 2016 guidelines: The 2024 guidelines mandate proactive case-finding in at-risk populations rather than opportunistic diagnosis. 1

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Step 2: Confirm Fibrosis Stage with Imaging

For patients with intermediate or high FIB-4, proceed immediately to vibration-controlled transient elastography (VCTE/FibroScan). 4, 5

• Low-risk pathway: FIB-4 <1.3 (<65 years) or <2.0 (≥65 years) AND liver stiffness measurement (LSM) <8.0 kPa → 5-year liver-related event risk 0.5%. 5
• High-risk pathway: FIB-4 >2.67 OR LSM >12.0 kPa → 5-year liver-related event risk 10.8%; these patients qualify for MASH-targeted therapy. 4, 5
• Intermediate-risk zone: LSM 8.0–12.0 kPa requires individualized assessment; consider LSM thresholds of <10 kPa (low-risk) and >15 kPa (high-risk) to reduce uncertainty. 5

Alternative imaging when FibroScan is inadequate:

• Use magnetic resonance elastography (MRE) in class III obesity (BMI >40), as it is less affected by body habitus than VCTE. 4
• Liver biopsy remains the gold standard when non-invasive tests are discordant or in morbid obesity. 4

Key difference from 2016 guidelines: The two-step FIB-4 → elastography pathway is now the standard of care, validated by large prospective cohorts showing excellent prognostic performance. 5

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Step 3: Lifestyle Intervention for ALL Patients

Prescribe specific, quantified targets rather than vague advice. 4

Weight Loss Targets:

• 7–10% body weight reduction achieves MASH resolution and fibrosis regression. 4
• 5% reduction is sufficient to reduce hepatic steatosis. 4

Dietary Pattern:

• Mediterranean diet: Emphasize vegetables, fruits, low-fat dairy, nuts, olive oil, legumes, unprocessed fish/poultry; eliminate sugar-sweetened beverages and ultra-processed foods. 4

Physical Activity:

• ≥150 minutes/week of moderate-intensity OR ≥75 minutes/week of vigorous-intensity aerobic exercise. 4

Alcohol:

• Complete avoidance is recommended, especially in advanced fibrosis or cirrhosis. 4

Key difference from 2016 guidelines: The 2024 guidelines provide precise, evidence-based weight-loss thresholds tied to histologic outcomes rather than general recommendations. 4

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Step 4: Pharmacologic Management – Non-Cirrhotic MASH with F2/F3 Fibrosis

MASH-Targeted Therapy:

Resmetirom is the first and only FDA-approved agent (March 2024) specifically for non-cirrhotic MASH with moderate-to-advanced fibrosis (F2/F3). 1, 4

• Demonstrated superior histologic resolution of steatohepatitis and fibrosis regression in phase III trials with acceptable safety. 1, 4
• Eligibility: Adults with biopsy-confirmed or non-invasively confirmed F2/F3 fibrosis and active MASH. 4
• Contraindication: Decompensated cirrhosis (F4). 4

Safety monitoring:

• Measure liver enzymes at 12 weeks to detect drug-induced liver injury; transient ALT/AST elevations may occur, especially with concurrent statins. 4
• Monitor for gallbladder complications (cholelithiasis, acute cholecystitis); educate patients to report abdominal pain, nausea, vomiting, fever. 4

Statin dose adjustments during resmetirom:

• Limit rosuvastatin or simvastatin to ≤20 mg/day. 4
• Limit pravastatin or atorvastatin to ≤40 mg/day. 4

Key difference from 2016 guidelines: No MASH-specific pharmacotherapy existed in 2016; resmetirom represents the first conditionally approved disease-modifying agent. 1, 4

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Dual-Benefit Therapies for Comorbidities:

GLP-1 receptor agonists and GLP-1/GIP co-agonists are now first-line agents for patients with comorbid type 2 diabetes or obesity. 4

• Semaglutide received FDA conditional approval for MASH with moderate-to-advanced fibrosis (March 2024). 4
• Tirzepatide (GLP-1/GIP co-agonist) provides superior glycemic control and weight loss with hepatic benefit. 4
• Liraglutide and dulaglutide are alternative GLP-1 agonists. 4
• These agents can be continued alongside resmetirom; in the MAESTRO-NASH trial, ~14% of participants used tirzepatide concurrently without altering resmetirom's efficacy or tolerability. 4

SGLT2 inhibitors:

• Empagliflozin and dapagliflozin are second-line options showing moderate reductions in liver fat and ALT. 4

Metformin:

• Continue metformin in compensated cirrhosis (eGFR >30 mL/min); discontinuation increases mortality. 4
• Metformin alone does not improve MASH histology but provides cardiometabolic benefit. 4

Obesity pharmacotherapy:

• Incretin-based agents (GLP-1 agonists, tirzepatide) are strongly preferred. 4
• Non-incretin agents (orlistat, phentermine-topiramate, naltrexone-bupropion) are NOT recommended due to insufficient efficacy data. 4

Key difference from 2016 guidelines: GLP-1 agonists and SGLT2 inhibitors were not established therapies in 2016; they are now cornerstone treatments for MASLD with metabolic comorbidities. 4

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Step 5: Pharmacologic Management – Cirrhotic MASLD

No MASH-targeted pharmacotherapy is recommended for cirrhosis. 1, 4

• Metformin: Use in compensated cirrhosis if eGFR >30 mL/min; contraindicated in decompensated disease due to lactic acidosis risk. 4
• Insulin: Preferred glucose-lowering agent in decompensated cirrhosis. 4
• GLP-1 agonists and SGLT2 inhibitors: Can be used cautiously in compensated cirrhosis with close monitoring. 4

Nutritional management in cirrhosis:

• Provide high-protein diet (1.2–1.5 g/kg/day) with total calories ≥35 kcal/kg/day. 4
• Offer late-evening snack to reduce overnight fasting and preserve muscle mass in sarcopenic or decompensated patients. 4
• In compensated cirrhosis with obesity, implement moderate weight-loss plan emphasizing protein and physical activity to avoid sarcopenia. 4

Key difference from 2016 guidelines: The 2024 guidelines explicitly address cirrhosis management with specific drug adaptations and nutritional strategies, which were not detailed in 2016. 4

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Step 6: Bariatric Surgery

Bariatric surgery is indicated for non-cirrhotic MASLD patients with BMI >40 kg/m² or BMI >35 kg/m² plus comorbidities. 4

• Yields durable liver improvement, diabetes remission, and superior cardiometabolic risk reduction. 4
• In compensated cirrhosis, bariatric surgery may be considered after multidisciplinary assessment for portal hypertension. 4
• Metabolic/bariatric endoscopic procedures are NOT recommended pending further validation. 4

Key difference from 2016 guidelines: Bariatric surgery is now more strongly endorsed with specific BMI thresholds and consideration even in compensated cirrhosis. 4

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Step 7: Surveillance and Monitoring

Hepatocellular Carcinoma (HCC) Surveillance:

• Cirrhotic MASLD (F4): Mandatory HCC surveillance per current guidelines (ultrasound ± AFP every 6 months). 1
• Advanced fibrosis (F3): HCC surveillance may be considered based on individual risk assessment. 1
• F0–F2 fibrosis: HCC surveillance is NOT recommended. 1
• In obese patients with cirrhosis, combine AFP measurement with ultrasound due to poor ultrasound sensitivity; consider MRI if ultrasound visualization is persistently inadequate. 1

Portal Hypertension Surveillance:

• Regular assessment for varices and decompensation in cirrhotic patients. 1, 4

Fibrosis Progression Monitoring:

• Repeat FIB-4 and elastography at tailored intervals (e.g., annually in F2/F3, every 2–3 years in F0/F1). 1, 5
• Non-invasive tests have limited ability to assess treatment response; they primarily track fibrosis progression. 1, 4
• Liver biopsy may be reserved for select cases requiring precise histologic information. 4

Key difference from 2016 guidelines: The 2024 guidelines provide risk-stratified HCC surveillance recommendations and acknowledge the limitations of non-invasive tests for monitoring treatment response. 1

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Step 8: Multidisciplinary Care

Implement a multidisciplinary team (hepatology, endocrinology, nutrition, cardiology, surgery) to address the intertwined liver disease, diabetes, obesity, and cardiovascular risk. 4

• MASLD is associated with increased cardiovascular events, chronic kidney disease, and extrahepatic malignancies. 1, 6
• Conventional cardiovascular risk scores may underestimate risk in MASLD-CKD populations. 6
• Encourage participation in extrahepatic cancer screening based on obesity and type 2 diabetes as risk factors. 1

Key difference from 2016 guidelines: The 2024 guidelines explicitly mandate multidisciplinary care and recognize MASLD as a systemic disease requiring integrated management. 4

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Common Pitfalls to Avoid

• Do NOT impose aggressive caloric restriction in sarcopenic or decompensated cirrhosis; it worsens muscle loss. 4
• Do NOT prescribe metformin in decompensated cirrhosis or eGFR <30 mL/min due to lactic acidosis risk. 4
• Do NOT withhold statins solely because of liver disease; they remain safe and cardioprotective. 4
• Do NOT discontinue metformin in compensated cirrhosis with type 2 diabetes; discontinuation increases mortality. 4
• Do NOT rely solely on ultrasound to exclude cirrhosis; it cannot definitively rule out F4 disease. 4
• Do NOT use nutraceuticals; evidence of effectiveness is insufficient. 4
• Do NOT underestimate alcohol consumption; use validated questionnaires (AUDIT-C) and biomarkers rather than relying on self-report alone. 2

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Summary of Key Differences from 2016 NAFLD Guidelines

Domain	2016 NAFLD Guidelines	2024 MASLD Guidelines
Nomenclature	NAFLD/NASH (diagnosis of exclusion)	MASLD/MASH (diagnosis of inclusion requiring cardiometabolic risk factors) [1]
Risk Stratification	Opportunistic diagnosis	Proactive case-finding in high-risk populations [1]
Fibrosis Assessment	Variable approaches	Standardized two-step FIB-4 → elastography pathway [4,5]
Weight-Loss Targets	General recommendations	Specific thresholds: 5% for steatosis, 7–10% for MASH resolution [4]
MASH-Targeted Therapy	None available	Resmetirom FDA-approved for F2/F3 non-cirrhotic MASH [1,4]
Incretin Therapies	Not established	GLP-1 agonists/tirzepatide first-line for comorbid diabetes/obesity [4]
Cirrhosis Management	Limited guidance	Detailed drug adaptations, nutritional strategies, metformin continuation [4]
HCC Surveillance	General recommendations	Risk-stratified by fibrosis stage (F3 individualized, F4 mandatory) [1]
Multidisciplinary Care	Mentioned	Explicitly mandated with specific team composition [4]
Bariatric Surgery	Considered	Strongly endorsed with specific BMI thresholds, even in compensated cirrhosis [4]