Non-Alcoholic Fatty Liver Disease (NAFLD / MASLD)
Summary
Non-Alcoholic Fatty Liver Disease (NAFLD), now renamed Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is the most common chronic liver disease worldwide, affecting ~25-30% of the global population. It is characterised by hepatic steatosis (fat accumulation in the liver) in the absence of significant alcohol consumption or other secondary causes. NAFLD represents a spectrum: Simple Steatosis (NAFL) → Non-Alcoholic Steatohepatitis (NASH/MASH – with inflammation and hepatocyte injury) → Fibrosis → Cirrhosis → Hepatocellular Carcinoma (HCC). Strongly associated with metabolic syndrome (Obesity, Type 2 Diabetes, Dyslipidaemia, Hypertension). Most patients are asymptomatic. Diagnosis is by imaging (USS, Fibroscan) and exclusion of other causes; biopsy is gold standard for staging but rarely needed. Management is primarily lifestyle modification (Weight loss 7-10%, Exercise) and control of metabolic comorbidities. Resmetirom is the first approved drug for MASH with fibrosis. Monitoring for fibrosis progression is essential. [1,2]
Clinical Pearls
Rename! NAFLD → MASLD (2023): NAFLD/NASH have been renamed to MASLD/MASH by global consensus to emphasise the metabolic aetiology and remove stigma.
7-10% Weight Loss is the Treatment: Lifestyle modification with sustained weight loss is the most effective intervention. Leads to histological improvement.
FIB-4 Score First: Use FIB-4 (Age, AST, ALT, Platelets) as first-line non-invasive test to stratify fibrosis risk.
CVD is the Leading Cause of Death: Patients with NAFLD/MASLD die more from cardiovascular disease than liver disease. Aggressive CVD risk management is essential.
Prevalence
- Global: ~25-30% of adults. Rising with obesity epidemic.
- Highest in: Middle East, South America, Asia.
- UK: ~30% prevalence.
Associations (Metabolic Syndrome)
| Component | Association |
|---|---|
| Obesity | Present in ~80% of NAFLD/MASLD. Central obesity most important. |
| Type 2 Diabetes Mellitus (T2DM) | ~70% of T2DM patients have NAFLD. |
| Dyslipidaemia | Elevated Triglycerides, Low HDL. |
| Hypertension | Common. |
| Insulin Resistance | Central driver. |
Disease Spectrum Progression
- Simple Steatosis (NAFL/MASL): ~80% of NAFLD. Benign prognosis.
- Steatohepatitis (NASH/MASH): ~20% of NAFLD. Inflammation + Ballooning. Risk of fibrosis progression.
- Fibrosis: ~20-30% of NASH develop advanced fibrosis (F3-F4).
- Cirrhosis: ~5-10% of NASH. Risk of HCC (~1-2%/year in cirrhosis).
"Two-Hit" / "Multiple Hit" Hypothesis
- First Hit – Lipid Accumulation: Insulin resistance → Increased hepatic fatty acid uptake and de novo lipogenesis → Hepatic steatosis.
- Second Hit(s) – Inflammation & Injury: Lipotoxicity (Free fatty acids, Oxidative stress), Mitochondrial dysfunction, ER stress, Gut microbiome dysbiosis, Adipokines → Hepatocyte injury, Inflammation (Steatohepatitis).
- Fibrosis Progression: Chronic inflammation → Hepatic stellate cell activation → Collagen deposition → Fibrosis → Cirrhosis.
- Carcinogenesis: Cirrhosis → HCC. Also HCC can occur in non-cirrhotic NASH.
Histological Features
| Stage | Histology |
|---|---|
| Simple Steatosis (NAFL) | >5% Hepatocyte steatosis. No significant inflammation or ballooning. |
| Steatohepatitis (NASH) | Steatosis + Lobular Inflammation + Hepatocyte Ballooning. NAS Score. |
| Fibrosis (F1-F4) | Perisinusoidal/Portal → Bridging → Cirrhosis. |
| Condition | Key Features |
|---|---|
| NAFLD / MASLD | Metabolic syndrome. No significant alcohol. Exclusion of other causes. |
| Alcoholic Liver Disease (ALD) | Significant alcohol intake (>30g/day men, >20g/day women). AST:ALT ratio often >2. |
| Drug-Induced Steatosis | Methotrexate, Amiodarone, Tamoxifen, Corticosteroids, Antiretrovirals. |
| Viral Hepatitis (B, C) | Serology positive. Chronic HCV can cause steatosis. |
| Wilson's Disease | Young age. Low Caeruloplasmin. KF Rings. |
| Haemochromatosis | High Ferritin, High Transferrin Saturation. HFE genetic testing. |
| Autoimmune Hepatitis | ANA, ASMA, Anti-LKM. High IgG. |
| Coeliac Disease | May have elevated transaminases. Anti-TTG positive. |
Symptoms
| Symptom | Notes |
|---|---|
| Asymptomatic | Most common. Incidental finding on LFTs or USS. |
| Fatigue | Non-specific. Common. |
| Right Upper Quadrant Discomfort | Hepatomegaly. |
| Symptoms of Cirrhosis (Late) | Ascites, Peripheral oedema, Jaundice, Confusion (Encephalopathy). |
Signs
| Sign | Notes |
|---|---|
| Obesity | Especially Central/Abdominal. |
| Hepatomegaly | Common. Liver may be normal size in advanced fibrosis/cirrhosis. |
| Acanthosis Nigricans | Marker of insulin resistance. |
| Signs of Cirrhosis (Late) | Spider Naevi, Palmar Erythema, Ascites, Splenomegaly, Jaundice. |
Blood Tests
| Test | Findings | Notes |
|---|---|---|
| LFTs | ALT often mildly elevated (1-3x ULN). AST:ALT ratio less than 1 (Unlike ALD). ALP often normal/mildly raised. May be normal. | Normal LFTs do NOT exclude NAFLD or even advanced fibrosis. |
| FBC | Low Platelets suggests advanced fibrosis/cirrhosis. | |
| Lipid Profile | High Triglycerides, Low HDL. | |
| HbA1c / Fasting Glucose | Screen for Diabetes. | |
| Ferritin | May be elevated (Dysmetabolic iron syndrome) – Not same as Haemochromatosis. | |
| Viral Hepatitis Serology | HBsAg, Anti-HCV – Exclude. | |
| Autoimmune Liver Screen | ANA, ASMA, Anti-LKM, IgG – If autoimmune suspected. |
Non-Invasive Fibrosis Assessment
| Test | Description | Cut-offs |
|---|---|---|
| FIB-4 Score (First-line) | Age, AST, ALT, Platelets. Calculator available. | less than 1.3 = Low Risk (Rule out advanced fibrosis). >2.67 = High Risk. Intermediate = Further testing. |
| ELF Test | Serum biomarkers (Hyaluronic acid, TIMP-1, PIIINP). | Score ≥9.8 = Advanced Fibrosis likely. |
| Fibroscan (Transient Elastography) | Liver stiffness measurement (LSM). Non-invasive. | less than 8 kPa = Low risk. >12 kPa = Advanced fibrosis. |
| NAFLD Fibrosis Score (NFS) | Calculator (Age, BMI, Diabetes, AST, ALT, Platelets, Albumin). | Similar to FIB-4. |
Imaging
| Imaging | Notes |
|---|---|
| Liver Ultrasound | "Bright" or "Echogenic" liver. Cheap, widely available. Cannot reliably stage fibrosis. |
| Fibroscan | Combines CAP (Controlled Attenuation Parameter – Steatosis) and LSM (Stiffness – Fibrosis). |
| MRI-PDFF | Gold standard for quantifying steatosis. Not routine. |
Liver Biopsy
- Gold Standard for diagnosis of NASH and staging fibrosis.
- Rarely needed in routine practice. Indicated if: Diagnosis uncertain, Need to confirm NASH for clinical trial / treatment decision, Suspected coexisting liver disease.
Management Algorithm
SUSPECTED NAFLD / MASLD
(Metabolic Syndrome + Elevated LFTs / Fatty Liver on USS)
↓
CONFIRM DIAGNOSIS
- Rule out Significant Alcohol Intake (>30g/day M, >20g/day F)
- Exclude other causes (Viral, AIH, Drug, Wilson's, Haemochromatosis)
- LFTs, FBC, Lipids, HbA1c, Ferritin, Viral Serology
↓
ASSESS FIBROSIS RISK (Non-Invasive)
┌──────────────────────────────────────────────────────────┐
│ STEP 1: FIB-4 SCORE │
│ │
│ FIB-4 < 1.3 FIB-4 1.3 - 2.67 FIB-4 > 2.67 │
│ (Low Risk) (Intermediate) (High Risk) │
│ ↓ ↓ ↓ │
│ Repeat in Fibroscan / ELF Refer │
│ 2-3 years Test Hepatology │
│ ↓ │
│ LSM < 8 kPa LSM ≥ 8 kPa │
│ (Low Risk) or ELF ≥ 9.8 │
│ Repeat 2-3y → Refer Hepatology │
└──────────────────────────────────────────────────────────┘
↓
LIFESTYLE MODIFICATION (CORNERSTONE)
┌──────────────────────────────────────────────────────────┐
│ - WEIGHT LOSS: Target 7-10% body weight reduction. │
│ (5% improves steatosis; 7-10% improves NASH/Fibrosis) │
│ - DIET: Mediterranean Diet preferred. Reduce saturated │
│ fat, processed foods, sugar/fructose. │
│ - EXERCISE: 150-200 min/week moderate intensity. │
│ - ALCOHOL: Minimise (though "Non-Alcoholic", alcohol │
│ worsens outcome). Abstain if significant fibrosis. │
│ - AVOID HEPATOTOXIC DRUGS. │
└──────────────────────────────────────────────────────────┘
↓
MANAGE METABOLIC COMORBIDITIES
┌──────────────────────────────────────────────────────────┐
│ - DIABETES: Optimise glycaemic control. │
│ - GLP-1 Agonists (Semaglutide) – Benefits liver. │
│ - SGLT2 Inhibitors – May benefit liver + CVD. │
│ - Pioglitazone – Can improve NASH (But weight gain, │
│ Bladder Ca risk – use with caution). │
│ - DYSLIPIDAEMIA: Statins are SAFE in NAFLD (Common myth │
│ that they are contraindicated). Reduce CVD mortality. │
│ - HYPERTENSION: ACEi/ARB preferred. │
│ - OBESITY: Consider Bariatric Surgery if BMI ≥ 35 + NASH│
└──────────────────────────────────────────────────────────┘
↓
PHARMACOTHERAPY (For NASH with Significant Fibrosis ≥F2)
┌──────────────────────────────────────────────────────────┐
│ - RESMETIROM (Rezdiffra) – First FDA-approved drug for │
│ MASH with moderate-to-advanced fibrosis (F2-F3). │
│ Thyroid hormone receptor agonist. Improves fibrosis. │
│ - Vitamin E (800 IU/day) – May improve NASH histology. │
│ Non-diabetic, Biopsy-proven NASH. SE: Long-term risk? │
│ - Pioglitazone – Improves NASH. T2DM or without. │
│ SE: Weight gain, Fluid retention, Bone fracture, │
│ Bladder Ca. │
│ - GLP-1 Agonists (Semaglutide) – Emerging evidence for │
│ NASH resolution. Weight loss benefit. │
└──────────────────────────────────────────────────────────┘
↓
CIRRHOSIS MANAGEMENT (If Developed)
- HCC Surveillance (6-monthly USS +/- AFP).
- Manage Portal Hypertension (Varices, Ascites).
- Liver Transplant Assessment if Decompensated.
Weight Loss is Key
- 5% Weight Loss: Reduces steatosis.
- 7-10% Weight Loss: Improves NASH histology and may regress fibrosis.
- Bariatric Surgery: Consider if BMI ≥35 with comorbidities. Leads to significant NASH improvement.
Pharmacotherapy (Limited Options – Evolving)
| Agent | Indication | Notes |
|---|---|---|
| Resmetirom (Rezdiffra) | MASH with Fibrosis F2-F3 | First approved drug. Thyroid hormone receptor agonist. |
| Vitamin E (800 IU/day) | Biopsy-proven NASH, Non-diabetic | May improve histology. Long-term safety uncertain. |
| Pioglitazone | NASH (Diabetic or Non-diabetic) | Improves NASH. Side effects limit use. |
| GLP-1 Agonists | T2DM with NAFLD | Weight loss + Potential direct liver benefit. |
| Complication | Notes |
|---|---|
| Cirrhosis | 5-10% of NASH. Portal hypertension, Liver failure. |
| Hepatocellular Carcinoma (HCC) | ~1-2%/year in cirrhosis. Can occur in non-cirrhotic NASH. |
| Cardiovascular Disease | Leading cause of death in NAFLD. Aggressive CVD risk management is critical. |
| Type 2 Diabetes | Bidirectional relationship. |
| Chronic Kidney Disease | Associated with NAFLD. |
- Simple Steatosis (NAFL): Generally benign. Low progression to cirrhosis.
- NASH: ~20-30% develop significant fibrosis over 10-20 years.
- NASH Cirrhosis: 5-year survival ~70-80% if compensated. Worse if decompensated.
- Leading Cause of Death in NAFLD: Cardiovascular Disease (Not liver disease).
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| EASL-EASD-EASO Clinical Practice Guidelines | EASL/EASD/EASO (2016, Update expected) | Lifestyle modification first. FIB-4 for risk stratification. |
| NICE NG49 | NICE (2016) | Use ELF test for fibrosis assessment. |
| Multi-Society Guidance on MASLD | AGA/AASLD/ACG (2023) | New nomenclature (MASLD). |
Name Change (2023)
- NAFLD → MASLD (Metabolic dysfunction-Associated Steatotic Liver Disease).
- NASH → MASH (Metabolic dysfunction-Associated Steatohepatitis).
- Emphasises metabolic drivers. Removes "Non-Alcoholic" (stigmatising, imprecise).
What is NAFLD / Fatty Liver?
Fatty liver disease means there is too much fat stored in your liver cells. If you don't drink much alcohol, it's called "Non-Alcoholic Fatty Liver Disease" (NAFLD). It's now also called MASLD (linked to metabolism).
Why is it important?
Most people with fatty liver have a mild form that doesn't cause problems. But in some people, the fat causes inflammation and scarring (Fibrosis). Over many years, this can lead to serious liver damage (Cirrhosis).
What causes it?
It is strongly linked to being overweight, having diabetes, high cholesterol, and high blood pressure – all part of "Metabolic Syndrome".
How is it treated?
The best treatment is weight loss (7-10% of your body weight). This can actually reverse the damage. A healthy diet (like the Mediterranean diet) and regular exercise are key. We also need to treat your diabetes, blood pressure, and cholesterol. In some cases, new medications can help.
Primary Sources
- European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. PMID: 27062661.
- Rinella ME, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023. PMID: 37364790.
Common Exam Questions
- Most Common Chronic Liver Disease: "What is the most common chronic liver disease worldwide?"
- Answer: NAFLD / MASLD.
- Non-Invasive Fibrosis Test: "What is the first-line non-invasive test for fibrosis in NAFLD?"
- Answer: FIB-4 Score.
- Weight Loss Target: "How much weight loss is needed to improve NASH histology?"
- Answer: 7-10% of body weight.
- Leading Cause of Death: "What is the leading cause of death in patients with NAFLD?"
- Answer: Cardiovascular Disease.
Viva Points
- Statins in NAFLD: Emphasise they are SAFE and indicated for CVD risk reduction.
- New Nomenclature: NAFLD → MASLD; NASH → MASH (2023).
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