Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
Summary
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as NAFLD (Non-Alcoholic Fatty Liver Disease), is the hepatic manifestation of metabolic syndrome. It represents a spectrum from simple steatosis (fat accumulation in the liver) to Metabolic Dysfunction-Associated Steatohepatitis (MASH, formerly NASH) with inflammation and hepatocyte injury, progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. MASLD is now the most common cause of chronic liver disease worldwide, affecting 25-30% of the population. Risk factors include obesity, type 2 diabetes, and dyslipidaemia. The cornerstone of treatment is weight loss (10% body weight can resolve steatohepatitis) and metabolic risk factor management.
Key Facts
- Definition: Hepatic steatosis with metabolic dysfunction (not primarily due to alcohol)
- Spectrum: Steatosis → MASH (inflammation) → Fibrosis → Cirrhosis → HCC
- Prevalence: 25-30% of adults; rising globally
- Key Risk Factors: Obesity, Type 2 Diabetes, Dyslipidaemia
- Assessment: FIB-4 score, FibroScan for fibrosis staging
- Treatment: Weight loss (10% for MASH resolution), metabolic management
Clinical Pearls
"NAFLD is Now MASLD": The terminology changed in 2023 to better reflect the metabolic basis of the disease.
"ALT > AST (Usually)": Unlike alcoholic liver disease (AST > ALT), MASLD typically shows ALT greater than AST.
"10% Weight Loss Resolves MASH": Studies show that 10% body weight loss can resolve steatohepatitis and even reverse fibrosis.
"HCC Without Cirrhosis": Uniquely, MASLD can cause HCC even before cirrhosis develops. Screen high-risk patients.
Prevalence
- 25-30% of adults globally
- 70-90% of patients with obesity or T2DM
- Most common cause of chronic liver disease
Demographics
- Increasing in all age groups
- Rising in children (linked to childhood obesity)
- Higher in certain ethnicities (Hispanic highest, African lowest)
Risk Factors (Metabolic)
| Factor | Prevalence in MASLD |
|---|---|
| Obesity | 75% |
| Type 2 Diabetes | 50% |
| Dyslipidaemia | 50-80% |
| Hypertension | 50% |
| Metabolic syndrome | 50-75% |
Disease Spectrum
| Stage | Features |
|---|---|
| Simple Steatosis (MASL) | Fat accumulation, no inflammation |
| Steatohepatitis (MASH) | Inflammation + Hepatocyte ballooning |
| Fibrosis | Collagen deposition, progressive scarring |
| Cirrhosis | Advanced fibrosis, nodular regeneration |
| HCC | Can occur with or without cirrhosis |
Mechanisms
- Insulin resistance → Free fatty acid flux to liver
- Lipotoxicity → Hepatocyte injury
- Oxidative stress → Inflammation
- Cytokine release → Fibroblast activation
- Fibrosis progression
"Multiple Hit Hypothesis"
- First hit: Steatosis
- Second hit: Oxidative stress, inflammation, insulin resistance
- Third hit: Genetic susceptibility (PNPLA3, TM6SF2)
Symptoms
Discovery Routes
General
- Obesity / central adiposity
- Acanthosis nigricans (insulin resistance)
Abdominal
- Hepatomegaly
- Signs of portal hypertension if advanced (ascites, splenomegaly)
Signs of Advanced Disease
- Spider naevi
- Palmar erythema
- Gynaecomastia
- Caput medusae (rare)
First-Line
| Test | Purpose |
|---|---|
| LFTs | ALT > AST typical; may be normal |
| Fasting glucose / HbA1c | Screen for diabetes |
| Lipid profile | Dyslipidaemia |
| Ultrasound liver | Identify steatosis (bright liver) |
Fibrosis Assessment
| Tool | Description |
|---|---|
| FIB-4 Score | Age, ALT, AST, Platelets; <1.3 = low risk |
| ELF Test | Serum biomarker panel |
| FibroScan (TE) | Transient elastography; measures liver stiffness |
| MRI PDFF | Most accurate for fat quantification |
Exclude Other Causes
- Alcohol history (<20g/day women, <30g/day men for MASLD diagnosis)
- Viral hepatitis serology (Hep B, Hep C)
- Autoimmune markers (ANA, SMA)
- Iron studies (haemochromatosis)
- Caeruloplasmin (Wilson's)
Liver Biopsy
- Gold standard for diagnosis of MASH and fibrosis staging
- Not routine; reserved for diagnostic uncertainty
Management Approach
┌──────────────────────────────────────────────────────────┐
│ MASLD/NAFLD MANAGEMENT │
├──────────────────────────────────────────────────────────┤
│ │
│ LIFESTYLE MODIFICATION (Cornerstone): │
│ • Weight loss: 5% for steatosis, 10% for MASH resolution│
│ • Diet: Mediterranean diet; reduce refined carbs/sugar │
│ • Exercise: 150 min/week aerobic exercise │
│ • Avoid alcohol excess │
│ • Coffee: 3+ cups/day may be protective │
│ │
│ MANAGE METABOLIC RISK FACTORS: │
│ • Tight glycaemic control (HbA1c <53) │
│ • Statin for dyslipidaemia (safe in MASLD) │
│ • Treat hypertension │
│ │
│ PHARMACOTHERAPY (Emerging/Specialist): │
│ • Pioglitazone (for MASH; some evidence) │
│ • Vitamin E 800IU/day (for non-diabetic MASH) │
│ • GLP-1 agonists (semaglutide showing promise) │
│ • Resmetirom (FDA-approved for MASH with F2-F3 fibrosis)│
│ │
│ SURVEILLANCE (Advanced fibrosis/Cirrhosis): │
│ • 6-monthly USS for HCC │
│ • Variceal screening │
│ • Liver transplant assessment if decompensated │
│ │
└──────────────────────────────────────────────────────────┘
Referral to Hepatology
- FIB-4 >1.3 or elevated FibroScan
- Uncertain diagnosis
- Advanced fibrosis/cirrhosis
Of MASLD
- Cirrhosis (10-25% of MASH over 10-20 years)
- Hepatocellular carcinoma (even pre-cirrhotic)
- Liver failure
- Cardiovascular disease (leading cause of death)
- Type 2 diabetes progression
Of Cirrhosis
- Variceal bleeding
- Ascites
- Hepatic encephalopathy
- HCC
Natural History
| Stage | Risk |
|---|---|
| Simple steatosis | Slow progression; benign in many |
| MASH | 20-25% progress to cirrhosis over 10-20 years |
| Cirrhosis | 5-year liver-related mortality 10-25% |
Leading Cause of Death
- Cardiovascular disease (not liver disease) in most MASLD patients
- Liver-related death increases with fibrosis stage
Key Guidelines
- EASL Clinical Practice Guidelines: NAFLD (2016)/MASLD (2024)
- NICE NG49: Non-Alcoholic Fatty Liver Disease (2016)
- AASLD Practice Guidance: MASLD (2023)
Key Evidence
Weight Loss
- 10% weight loss resolves MASH in majority of patients
Pharmacotherapy
- Resmetirom: FDA-approved 2024 for MASH with fibrosis
- GLP-1 agonists: Promising phase III data
What is Fatty Liver Disease?
Fatty liver disease (now called MASLD) means there's too much fat in your liver. It's very common and linked to being overweight, having diabetes, or high cholesterol.
Why Does it Matter?
In most people, it causes no harm. But in some, it causes inflammation (MASH) which can lead to scarring (fibrosis) and eventually serious liver damage (cirrhosis) or liver cancer.
How is it Found?
Usually picked up on blood tests (liver function tests) or an ultrasound showing a "bright liver."
How is it Treated?
- Losing weight: This is the most important treatment. Losing 10% of your body weight can reverse the inflammation.
- Exercise: Regular activity helps even without weight loss.
- Diet: Mediterranean-style diet, less sugar and processed food
- Managing other conditions: Controlling diabetes, cholesterol, blood pressure
What's the Outlook?
For most people, fatty liver doesn't cause serious problems. If you make lifestyle changes, you can often completely reverse it. Some people need closer monitoring if they have more advanced disease.
Primary Guidelines
- EASL. Clinical Practice Guidelines on the Management of Hepatic Steatosis. J Hepatol. 2024.
- NICE. Non-Alcoholic Fatty Liver Disease (NAFLD): Assessment and Management (NG49). 2016.
Key Studies
- Vilar-Gomez E, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(2):367-378. PMID: 25865049