What is the approach and treatment algorithm for Multi-System Atrophy associated with Liver Disease (MASLD)?

MASLD Management: Approach and Treatment Algorithm

The management of MASLD requires a stepwise approach beginning with case-finding in high-risk populations, followed by non-invasive fibrosis staging, and then implementation of lifestyle interventions as first-line therapy, with pharmacological treatment reserved for those with significant fibrosis (stage ≥2) or specific metabolic comorbidities. 1

Case-Finding and Screening Strategy

Target populations for active case-finding include: 1

• Patients with type 2 diabetes (highest priority)
• Individuals with abdominal obesity plus ≥1 additional metabolic risk factor
• Patients with abnormal liver enzymes or radiological hepatic steatosis

Do not implement universal population screening—focus resources on these high-risk groups where early fibrosis detection can prevent progression to cirrhosis. 1

Diagnostic Algorithm: Stepwise Fibrosis Assessment

Step 1: Initial blood-based scoring 1

• Calculate FIB-4 (Fibrosis-4 index) as the first-line test
• FIB-4 has superior diagnostic accuracy compared to standard ALT/AST alone

Step 2: Confirmatory imaging for suspected fibrosis 1

• Use vibration-controlled transient elastography (VCTE) as second-step
• Alternative: Enhanced Liver Fibrosis (ELF) blood test if imaging unavailable
• These tests excel at excluding advanced fibrosis; elastography is better for predicting its presence

Step 3: Risk stratification for portal hypertension 1

• LSM ≤15 kPa + platelets ≥150×10⁹/L: Rules out clinically significant portal hypertension (CSPH)
• LSM ≥20 kPa and/or platelets <150×10⁹/L: Perform upper GI endoscopy to screen for varices
• LSM ≥25 kPa: Rules in CSPH (only valid in non-obese patients with BMI <30 kg/m²)

Critical caveat: Obesity confounds LSM measurements, and optimal non-invasive tests for CSPH in obese MASLD patients remain undefined. 1

First-Line Treatment: Lifestyle Modification

All MASLD patients require comprehensive lifestyle intervention: 1

Weight loss targets: 1

• Achieve 7-10% body weight reduction
• For pre-transplant candidates: reduce BMI to <40 kg/m² (ideally <35 kg/m²)

Dietary approach: 2

• Mediterranean diet pattern recommended for all patients
• Complete alcohol abstinence mandatory for advanced fibrosis/cirrhosis 1
• Discourage any alcohol consumption in moderate-to-high risk patients

Physical activity: 1

• Supervised exercise programs as part of first-line approach
• Essential component alongside dietary modification

Pharmacological Treatment Algorithm

For Non-Cirrhotic MASH with Significant Fibrosis (Stage ≥2)

Resmetirom is the first-line MASH-targeted therapy 1, 2

• Demonstrated histological effectiveness on steatohepatitis and fibrosis
• Acceptable safety and tolerability profile
• Only if locally approved and according to label indications

For MASLD with Type 2 Diabetes

GLP-1 receptor agonists (e.g., semaglutide) or dual agonists (e.g., tirzepatide): 1, 3

• Use according to diabetes indications
• Provide dual benefit for glycemic control and liver disease
• Safe in Child-Pugh class A cirrhosis

SGLT2 inhibitors: 1, 2

• Can be used in Child-Pugh class A and B cirrhosis
• Alternative or adjunctive glucose-lowering option

Pioglitazone: 2

• Consider as option for patients with diabetes and steatohepatitis

Avoid in decompensated cirrhosis: 1

• Metformin: contraindicated due to lactic acidosis risk (especially with renal impairment)
• Sulfonylureas: avoid due to hypoglycemia risk

For MASLD with Obesity (Without Diabetes)

Incretin-based therapies: 1, 2

• GLP-1 receptor agonists indicated for obesity management
• Provide weight loss and potential liver benefit

Bariatric surgery: 1, 2

• Option for obesity unresponsive to lifestyle and medical interventions
• Sleeve gastrectomy may be considered in compensated cirrhosis without CSPH
• Absolutely contraindicated in decompensated cirrhosis 1

Cardiovascular Risk Management

Statins are safe and underutilized in MASLD: 1, 4

• Use in all patients according to cardiovascular risk guidelines
• Safe in chronic liver disease including compensated cirrhosis
• Reduce cardiovascular events (the leading cause of death in MASLD)

Management of Advanced Disease

Compensated Cirrhosis

Portal hypertension surveillance: 1

• Initiate non-selective beta-blockers if CSPH present (unless contraindicated)
• Perform endoscopy for variceal screening when LSM ≥20 kPa or platelets <150×10⁹/L

Metabolic medication adjustments: 1

• GLP-1 agonists: safe in Child-Pugh A
• SGLT2 inhibitors: safe in Child-Pugh A and B
• Continue statins for cardiovascular protection

No MASH-targeted pharmacotherapy recommended at cirrhotic stage 1

Decompensated Cirrhosis and Transplant Candidates

Pre-transplant optimization: 1

• Multidisciplinary cardiovascular evaluation mandatory (MASLD patients have high CV event risk)
• Implement stepwise cardiac work-up: baseline ECG/echo → stress testing if age >50 or ≥2 CV risk factors → cardiology referral/angiography if positive
• Weight reduction without worsening sarcopenia improves peri-operative outcomes
• Dietary modification and supervised exercise as first-line (target BMI <40, ideally <35 kg/m²)

Post-transplant management: 1, 5

• High risk of MASLD recurrence, especially with multiple metabolic risk factors
• Accelerated fibrosis progression compared to general population
• Continue aggressive cardiometabolic risk factor control
• Standard lifestyle interventions remain cornerstone

Key Clinical Pitfalls to Avoid

1. Do not rely on ALT/AST alone—normal transaminases do not exclude significant fibrosis 1
2. Do not use LSM thresholds for CSPH in obese patients (BMI ≥30)—accuracy is compromised 1
3. Do not withhold statins in compensated cirrhosis—they are safe and reduce the primary cause of death 1, 4
4. Do not perform bariatric surgery in decompensated cirrhosis—absolute contraindication 1
5. Do not use metformin in decompensated cirrhosis with renal impairment—lactic acidosis risk 1
6. Do not neglect cardiovascular risk assessment—CV disease, not liver failure, is the leading cause of mortality 1, 4, 6, 7