What is hepatic steatosis?

Hepatic Steatosis: Definition and Clinical Significance

Hepatic steatosis is defined as the abnormal accumulation of fat (lipids) in the liver cells (hepatocytes), which can be visualized microscopically as lipid droplets within the cytoplasm. 1 This condition represents the initial stage of a spectrum of liver diseases that can progress to more severe forms if left unaddressed.

Classification of Hepatic Steatosis

Hepatic steatosis can be classified based on:

1. Pattern of Fat Accumulation

• Macrovesicular steatosis: Characterized by large fat droplets that may occupy the entire cytoplasm

  • Associated with alcohol consumption, obesity, and diabetes
  • Severity classification:
    • Mild: 10-30% of hepatocytes affected
    • Moderate: 30-60% of hepatocytes affected
    • Severe: >60% of hepatocytes affected 2

• Microvesicular steatosis: Characterized by tiny lipid droplets (<1mm) giving a foamy appearance to the cytoplasm

  • Associated with drug toxicity, acute fatty liver in pregnancy, and Reye disease 2

2. Etiology (Underlying Cause)

• Metabolic dysfunction-associated steatotic liver disease (MASLD): Previously known as non-alcoholic fatty liver disease (NAFLD)

  • Associated with metabolic risk factors such as obesity, type 2 diabetes, insulin resistance, and metabolic syndrome 1

• Alcohol-related liver disease (ALD): Significant alcohol consumption (>14 drinks/week for women, >21 drinks/week for men) 1

• MetALD: The overlap between metabolic and alcohol-related causes 1, 3

• Medication-induced: Caused by drugs such as amiodarone, methotrexate, tamoxifen, corticosteroids, and NSAIDs 1

• Viral hepatitis: Particularly hepatitis C genotype 3 1, 3

• Genetic disorders: Associated with variants in PNPLA3, TM6SF2, MBOAT7, and GCKR genes 1

Pathophysiology

Hepatic steatosis occurs when there is an imbalance between:

1. Delivery or synthesis of fatty acids in the liver
2. Disposal through oxidative pathways or secretion into the blood as triacylglycerols in very low-density lipoprotein 4

Key mechanisms include:

• Increased lipogenesis (enhanced synthesis of fatty acids and triglycerides in hepatocytes)
• Inflammatory responses with cytokine activation and inflammatory cell infiltration 1

Clinical Significance

Hepatic steatosis has significant implications:

1. Microcirculatory impairment: Fat accumulation increases hepatocyte volume, reducing sinusoidal space by up to 50% compared to normal liver, potentially leading to partial or complete obstruction of hepatic sinusoids 5

2. Reduced tolerance to ischemia-reperfusion injury: Particularly important in liver transplantation where:

   • Mild macrosteatosis (<30%) is considered suitable for transplantation
   • Moderate macrosteatosis (30-60%) may result in acceptable outcomes in select donor-recipient combinations
   • Severe macrosteatosis (>60%) is linked with unacceptable risks of graft failure, acute kidney injury, biliary complications, and mortality 2

3. Disease progression risk: While simple steatosis may remain asymptomatic, it can progress through inflammatory stages (steatohepatitis), fibrosis, cirrhosis, and even liver cancer in some individuals 6

Clinical Caveat

It's important to note that while hepatic steatosis was once considered the ultimate effector of hepatic lipotoxicity, triacylglycerols themselves are relatively inert and do not directly induce insulin resistance or cellular injury. Rather, lipotoxic injury appears to be mediated by ongoing fatty acid enrichment in the liver and various fatty acid metabolites 4.

Understanding the specific etiology of hepatic steatosis is crucial for appropriate management, as steatotic liver disease has become the leading cause of cirrhosis in the EU and USA, affecting approximately 30% of the global population 3.