How are metabolic liver diseases classified?

Classification of Metabolic Liver Diseases

Metabolic liver diseases are classified into several distinct categories based on their underlying pathophysiology, clinical presentation, and specific metabolic dysfunction. These classifications help guide diagnosis, treatment, and monitoring of affected patients.

Primary Classification Categories

1. Steatotic Liver Diseases (SLD)

• Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) - Defined as hepatic steatosis plus at least one cardiometabolic risk factor 1, 2
• Metabolic Dysfunction and Alcohol-Related Liver Disease (MetALD) - Overlapping condition with both metabolic risk factors and moderate alcohol consumption (20-50g/day in women, 30-60g/day in men) 1
• Alcohol-Related Liver Disease (ALD) - Steatosis primarily due to significant alcohol consumption (>50g/day in women, >60g/day in men) 1

2. Genetic Metabolic Liver Diseases

• Wilson Disease - Autosomal recessive disorder of copper excretion 1
• α-1-Antitrypsin Deficiency - Most common inherited cause of liver disease requiring transplantation in children 1
• Hereditary Hemochromatosis - Disorder of iron metabolism 1
• Progressive Familial Intrahepatic Cholestasis (PFIC) - Collection of autosomal recessive defects of hepatocellular transport 1

3. Classification by Clinical Presentation

• Acute/Subacute Hepatocellular Necrosis - Including galactosemia, hereditary fructose intolerance, tyrosinemia type I 3
• Cholestatic Jaundice - Can indicate α-1-antitrypsin deficiency, Byler's disease, cystic fibrosis 3
• Hepatomegaly - May reveal glycogen storage diseases, cholesteryl ester storage disease 3
• Hepatosplenomegaly - Often associated with lysosomal storage diseases 3

MASLD Specific Classification

1. Histological Subtypes

• Nonalcoholic Fatty Liver (NAFL) - Presence of ≥5% hepatic steatosis without evidence of hepatocellular injury 1
• Nonalcoholic Steatohepatitis (NASH) - Presence of ≥5% hepatic steatosis with inflammation and hepatocyte injury (ballooning) 1
• NASH Cirrhosis - Cirrhosis with current or previous histological evidence of steatosis or steatohepatitis 1
• Cryptogenic Cirrhosis - Cirrhosis with no obvious etiology, often associated with metabolic risk factors 1

2. Risk Stratification by Fibrosis Stage

• Early Stage (F0-1) - Minimal risk of progression to cirrhosis 1
• Significant Fibrosis (F≥2) - Increased risk of progression 1, 4
• Advanced Fibrosis (F3-4) - Independent risk factor for liver-related and non-liver-related mortality 1

Associated Conditions and Risk Factors

1. Established Associations

• Obesity - Present in approximately 50% of MASLD cases 1, 5
• Type 2 Diabetes Mellitus - Present in approximately 20% of MASLD cases 1, 5
• Dyslipidemia - Present in approximately 70% of MASLD cases 1, 5
• Metabolic Syndrome - Present in approximately 40% of MASLD cases 1, 5

2. Emerging Associations

• Polycystic Ovary Syndrome 1
• Hypothyroidism 1
• Obstructive Sleep Apnea 1
• Hypopituitarism 1

Pathophysiological Classification

1. Mechanisms of Liver Injury

• Insulin Resistance - Central mechanism in MASLD development 1
• Lipotoxicity - Accumulation of toxic lipid species causing hepatocellular damage 6, 7
• Oxidative Stress - Contributing to hepatocyte injury and inflammation 6, 7
• Mitochondrial Dysfunction - Impaired fatty acid oxidation and energy production 6
• Genetic Factors - Influencing disease susceptibility and progression 1

2. Extrahepatic Manifestations

• Cardiovascular System - Increased risk of atherosclerotic cardiovascular disease 5
• Renal System - Association with chronic kidney disease 5
• Endocrine System - Bidirectional relationship with type 2 diabetes 5

Clinical Implications of Classification

• The classification of metabolic liver diseases guides diagnostic approaches, with non-invasive fibrosis tests recommended for risk stratification 1
• Treatment strategies differ based on disease category, with lifestyle modifications as first-line for MASLD 1, 2
• Pharmacological treatments are emerging, with resmetirom recently approved for non-cirrhotic MASH with significant fibrosis 1, 4
• Classification helps determine surveillance needs for complications like hepatocellular carcinoma 1, 5

Common Pitfalls in Classification

• Failing to quantitatively assess alcohol consumption can lead to misclassification between MASLD and ALD 1
• Not recognizing the overlap between metabolic risk factors and alcohol consumption (MetALD) 1
• Overlooking other specific etiologies of steatosis that may require different management 1, 2
• Focusing solely on liver enzymes, which may be normal despite significant disease 1