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Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

High EvidenceUpdated: 2025-12-24

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Red Flags

  • Decompensated Cirrhosis (Ascites, Jaundice, Encephalopathy)
  • Hematemesis (Variceal Bleed)
  • Unexplained Rapid Weight Loss (HCC Risk)
  • Abnormal Coagulation (INR > 1.2 indicates synthetic failure)
Overview

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

1. Clinical Overview

Summary

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as NAFLD, is the accumulation of excess fat (>5%) in the liver cells (steatosis) in the absence of significant alcohol intake or other specific liver diseases. It is the hepatic manifestation of the Metabolic Syndrome and is now the leading cause of chronic liver disease worldwide, affecting ~30% of the global population. While most patients have simple steatosis (benign), a subset develops Metabolic Dysfunction-Associated Steatohepatitis (MASH), characterised by inflammation and ballooning, which can progress to fibrosis, cirrhosis, and Hepatocellular Carcinoma (HCC). [1,2]

Clinical Pearls

The New Nomenclature (2023): The terminology has shifted from NAFLD to MASLD to remove the stigma of "Alcoholic" in the negative definition and to emphasize the positive inclusion of metabolic risk factors.

  • NAFLD -> MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease).
  • NASH -> MASH (Metabolic Dysfunction-Associated Steatohepatitis).

Heart vs Liver: The most common cause of death in patients with MASLD is NOT liver failure. It is Cardiovascular Disease (MI/Stroke) followed by malignancy. Management MUST prioritize cardiovascular risk reduction (Statins, BP control).

Normal LFTs are Misleading: Up to 50% of patients with MASH and advanced fibrosis have Normal ALT/AST. Do not rely on LFTs to exclude disease. Risk stratification (FIB-4) is mandatory for all at-risk patients (Diabetics/Obese).

2. Epidemiology

Demographics

  • Prevalence: 25-30% of the general population.
  • Diabetes: 70% of Type 2 Diabetics have MASLD.
  • Obesity: 90% of morbidly obese patients have steatosis.
  • Ethnicity: Higher prevalence in Hispanic and South Asian populations; lower in African-Americans (possibly due to PNPLA3 genetic variants).
  • Lean MASLD: Occurs in 10-20% of cases, often in Asian populations ("Tofi" - Thin Outside, Fat Inside).

Risk Factors (Metabolic Syndrome)

To diagnose MASLD, one needs Steatosis + at least 1 Metabolic Risk Factor:

  • Obesity (BMI >25 or >23 in Asians).
  • Type 2 Diabetes or Prediabetes.
  • Hypertension (>130/85).
  • Dyslipidaemia (Triglycerides >1.7 or HDL less than 1.0/1.3).
3. Pathophysiology

The Mechanics of Steatosis

  1. Insulin Resistance: This is the key driver. Muscle and adipose tissue become resistant to insulin, leading to unchecked lipolysis.
  2. Free Fatty Acid (FFA) Flux: Huge amounts of FFA flood the liver from adipose tissue.
  3. De Novo Lipogenesis: The liver also synthesizes new fat from excess dietary sugars (Fructose).
  4. Impaired Export: The liver cannot package VLDL fast enough to export the fat.
  5. Result: Triglyceride accumulation in hepatocytes (Steatosis).

Progression to MASH (The "Multiple Hit" Hypothesis)

Steatosis sensitises the liver to further injury ("hits"):

  1. Lipotoxicity: Specific lipids (Ceramides) are toxic to cells.
  2. Oxidative Stress: Overloaded mitochondria produce Reactive Oxygen Species (ROS).
  3. Inflammation: Cytokines (TNF-alpha, IL-6) are released, recruiting neutrophils and macrophages.
  4. Cell Death: Hepatocytes swell and die (Ballooning).
  5. Fibrosis: In response to injury, Hepatic Stellate Cells activate and lay down scar tissue (Collagen).
4. Differential Diagnosis (The "Fatty Liver")
ConditionDistinguishing Factors
Alcohol-Related Liver Disease (ALD)History of intake (>20g/day F, >30g/day M). AST:ALT ratio > 2:1.
MetALDFeatures of BOTH metabolic syndrome and moderate alcohol intake (very common overlap).
Drug Induced (DILI)Amiodarone, Methotrexate, Steroids, Tamoxifen.
Hepatitis C (Genotype 3)Viral Steatosis. Positive HCV RNA.
Wilson's DiseaseLow Caeruloplasmin. Kayser-Fleischer rings (Young patient).
Acute Fatty Liver of PregnancyObstetric emergency. Third trimester.
5. Clinical Presentation

Symptoms

Signs

Asymptomatic
The vast majority (80%) have no symptoms. Diagnosis is incidental (US scan or bloods).
Fatigue
Very common, independent of liver severity.
RUQ Discomfort
Mild ache due to stretching of the Glisson's capsule by hepatomegaly.
6. Investigations

Step 1: Diagnosis of Steatosis

  • Ultrasound Abdomen: First line. Shows "Bright" (hyper-echogenic) liver. Sensitivity drops if BMI >40.
  • CAP (Controlled Attenuation Parameter): Measured during FibroScan. Quantifies fat.

Step 2: Exclusion of Other Causes ("Liver Screen")

  • Viral Serology (Hep B/C), Autoimmune profile (ANA, AMA, SMA), Ferritin (Haemochromatosis), Caeruloplasmin (if less than 40).

Step 3: Fibrosis Risk Stratification (CRITICAL STEP)

Using non-invasive tests (NITs) to find the "at-risk" MASH patients.

A. FIB-4 Score:

  • Inputs: Age, ALT, AST, Platelets.
  • Calculate online.
  • < 1.30: Low Risk. (NPV 90%). Manage in Primary Care.
  • > 3.25: High Risk. Refer to Hepatology.
  • 1.30 - 3.25: Indeterminate. Need 2nd line test.

B. Second Line NITs:

  • ELF Test (Enhanced Liver Fibrosis): Blood test for serum markers (Hyaluronic Acid, PIIINP, TIMP-1). Score >9.8 indicates advanced fibrosis.
  • FibroScan (Transient Elastography): Measures Liver Stiffness Measurement (LSM in kPa).
    • < 8 kPa: Low risk (F0-F1).
    • 8-12 kPa: Indeterminate (F2).
    • > 12-15 kPa: Advanced Fibrosis / Cirrhosis (F3-F4).
7. Management

Management Algorithm

           MASLD DIAGNOSED
     (Steatosis on US + Metabolic Risk)
                ↓
      CALCULATE FIB-4 SCORE
        ┌───────┴───────┐
     LOW RISK       HIGH/INDETERMINATE
     (less than 1.30)        (&gt;1.30 or &gt;2.0 if &gt;65y)
        ↓               ↓
   PRIMARY CARE    SECOND LINE TEST
   MANAGEMENT      (ELF or FibroScan)
        ↓               ↓
                    HIGH RISK
                    (ELF &gt;9.8 / LSM &gt;8)
                        ↓
                 REFER HEPATOLOGY

1. Lifestyle Modification (The Cornerstone)

  • Weight Loss: The only intervention proven to reverse fibrosis.
    • 5-7% loss: Reduces Steatosis.
    • 7-10% loss: Reduces Inflammation (MASH).
    • >10% loss: Reverses Fibrosis.
  • Diet: Mediterranean Diet. AVOID FRUCTOSE (High Fructose Corn Syrup/sugary drinks) - it is uniquely lipogenic. Coffee (3 cups/day) is associated with reduced fibrosis.
  • Exercise: Both aerobic and resistance training reduce liver fat even without weight loss.

2. Pharmacotherapy (Specific)

  • Vitamin E (800 IU/day): Antioxidant. Benefit in non-diabetic MASH. Avoid in prostate cancer history.
  • Pioglitazone: Thiazolidinedione. Improves insulin sensitivity and histology in MASH. S/E: Weight gain, heart failure.
  • Resmetirom: (Newly FDA Approved 2024 / NICE Pending). Thyroid Hormone Receptor-beta agonist. First liver-specific drug.

3. Pharmacotherapy (Metabolic)

  • GLP-1 Analogues (Semaglutide/Liraglutide): Highly effective for weight loss. Secondary benefit on liver. Standard of care for diabetic MASH.
  • Statins: SAFE and indicated. They reduce cardiovascular mortality. Do not stop because of mild ALT elevation.

4. Bariatric Surgery

  • Gastric Sleeve / Bypass.
  • Most effective treatment for resolving MASH (85% resolution) and fibrosis in morbidly obese.
8. Complications
  • Cardiovascular: Major adverse cardiovascular events (MACE).
  • Decompensated Cirrhosis: Ascites, Variceal Bleed, Encephalopathy.
  • Hepatocellular Carcinoma (HCC): Can occur in NON-cirrhotic MASH (unlike other liver diseases), making screening difficult.
  • Extra-hepatic Cancers: Increased risk of Colorectal Ca (Screening important).
9. Prognosis and Outcomes
  • Simple Steatosis: Benign course. Normal life expectancy (liver-wise).
  • MASH: 20% progress to cirrhosis over 10-20 years.
  • Fibrosis Stage: The single most important predictor of mortality.
    • F0-F1: No increased mortality.
    • F3-F4: Significant increase in liver-related and all-cause mortality.
10. Evidence and Guidelines

Key Guidelines

GuidelineOrganisationKey Recommendations
MASLDEASL (2024) / AASLDUse FIB-4 as primary screen. Screening of all Diabetics recommended.
NomenclatureConsensus 2023Adoption of MASLD/MASH terms. Creation of MetALD category.

Landmark Evidence

1. LEAN Trial (Lancet)

  • Liraglutide (GLP-1) showed resolution of MASH compared to placebo.

2. PIVENS Trial (NEJM)

  • Pioglitazone and Vitamin E vs Placebo. Both improved histology in non-diabetic MASH.

3. MAESTRO-NASH (NEJM 2024)

  • Resmetirom achieved resolution of MASH and improvement in fibrosis. The first positive Phase 3 trial for a liver-specific drug.
11. Patient and Layperson Explanation

What is MASLD?

It stands for Metabolic Dysfunction-Associated Steatotic Liver Disease. It used to be called "Fatty Liver". It means there is too much fat stored in your liver cells, usually because of weight, diabetes, or metabolism.

Is it caused by alcohol?

No. That is a different condition. However, drinking alcohol on top of this makes it much worse, so we advise sticking to safe limits or stopping.

Is it dangerous?

For most people (80%), the fat just sits there and causes no problems. But for some, the fat irritates the liver causing inflammation (MASH). Over many years, this causes scarring (Fibrosis). If the scarring becomes severe (Cirrhosis), the liver can stop working.

Can I fix it?

Yes! The liver is very forgiving. If you lose 10% of your body weight, you can actually reverse the scarring and strip the fat out. There are no magic pills—weight loss and healthy diet are the cure.

12. References

Primary Sources

  1. Rinella ME, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023.
  2. EASL–EASD–EASO. Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016 (Updated 2024).
  3. Harrison SA, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019 (and NEJM 2024).
13. Examination Focus

Common Exam Questions

  1. Diagnosis: "Cut-off for fatty liver on biopsy?"
    • Answer: >5% of hepatocytes containing fat.
  2. Scoring: "Components of FIB-4?"
    • Answer: Age, ALT, AST, Platelets. (Note: BMI is NOT in FIB-4, but is in NAFLD Fibrosis Score).
  3. Pharmacology: "Benefit of Statins?"
    • Answer: Reduce CVS mortality (the main killer). Safe to use.
  4. Pathology: "Histological hallmark of MASH?"
    • Answer: Hepatocyte Ballooning + Inflammation (Steatosis alone is not MASH).

Viva Points

  • The "Fatty Liver Paradox": In advanced cirrhosis, the fat often disappears (Burned-out MASH). The liver shrinks and loses its steatosis, making the diagnosis difficult retrospectively appearing "Cryptogenic".
  • ALT: Why is it normal in advanced disease? As liver parenchyma is replaced by fibrosis, there are fewer cells to leak enzymes. AST often rises above ALT (reversal of ratio) as cirrhosis establishes.

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.

Last updated: 2025-12-24

At a Glance

EvidenceHigh
Last Updated2025-12-24

Red Flags

  • Decompensated Cirrhosis (Ascites, Jaundice, Encephalopathy)
  • Hematemesis (Variceal Bleed)
  • Unexplained Rapid Weight Loss (HCC Risk)
  • Abnormal Coagulation (INR &gt; 1.2 indicates synthetic failure)

Clinical Pearls

  • **MASLD** (Metabolic Dysfunction-Associated Steatotic Liver Disease).
  • **MASH** (Metabolic Dysfunction-Associated Steatohepatitis).

Guidelines

  • NICE Guidelines
  • BTS Guidelines
  • RCUK Guidelines