What is steatosis of the liver?

Hepatic Steatosis (Fatty Liver Disease)

Hepatic steatosis is defined as the abnormal accumulation of fat (triglycerides) within the cytoplasm of liver cells (hepatocytes) that can be visualized microscopically and is the hallmark feature of fatty liver disease. 1

Types and Classification

Hepatic steatosis can be classified based on:

1. Pattern of fat accumulation:

   • Macrovesicular steatosis: Large fat droplets that may occupy the entire cytoplasm
     • Severity: Mild (10-30%), Moderate (30-60%), Severe (>60% of hepatocytes affected)
   • Microvesicular steatosis: Tiny lipid droplets (<1mm) giving a foamy appearance to the cytoplasm 2, 1

2. Etiology:

   • Metabolic dysfunction-associated steatotic liver disease (MASLD) - formerly NAFLD
   • Alcohol-related liver disease (ALD)
   • MetALD - overlap between metabolic and alcoholic causes
   • Other causes of hepatic steatosis 1, 3

Causes and Risk Factors

Common Causes:

• Obesity (BMI >25 kg/m² or >23 kg/m² in Asian populations)
• Type 2 diabetes and insulin resistance
• Dyslipidemia (elevated triglycerides, low HDL)
• Alcohol consumption (>14 drinks/week for women, >21 drinks/week for men)
• Metabolic syndrome 1

Other Causes:

• Viral infections (particularly hepatitis C genotype 3)
• Medications (corticosteroids, tamoxifen, methotrexate, amiodarone)
• Genetic disorders (Wilson's disease, hypobetalipoproteinemia, lysosomal acid lipase deficiency)
• Nutritional disorders (rapid weight loss, malnutrition, total parenteral nutrition)
• Endocrine disorders (hypothyroidism, polycystic ovary syndrome, growth hormone deficiency)
• Pregnancy-related conditions (HELLP syndrome, acute fatty liver of pregnancy) 1

Pathophysiology

Hepatic steatosis occurs when there is an imbalance between:

• Delivery or synthesis of fatty acids in the liver
• Disposal through oxidative pathways or secretion as VLDL

The accumulation of fatty acid metabolites, rather than triglycerides themselves, appears to be responsible for hepatic lipotoxicity and liver injury. Triglycerides are relatively inert and may actually represent a protective mechanism against free fatty acid toxicity 4.

Diagnostic Evaluation

Non-invasive Assessment:

1. Imaging:

   • Ultrasound: First-line investigation with 84.8% sensitivity and 93.6% specificity for moderate-severe steatosis 1
   • MRI-based techniques: Most accurate non-invasive method
     • Proton density fat fraction (PDFF) provides standardized, accurate, and reproducible quantification of hepatic fat 5
     • Chemical shift-encoded MRI methods overcome limitations of conventional MRI 5
   • CT: Can suggest presence of steatosis but limited for quantification 5

2. Fibrosis Assessment:

   • FIB-4 index: <1.3 (low risk), 1.3-2.67 (indeterminate), >2.67 (high risk) 1
   • Vibration-controlled transient elastography (VCTE) for fibrosis assessment

Liver Biopsy:

• Gold standard for diagnosis but limited by invasiveness and sampling error
• Allows assessment of inflammation and fibrosis in addition to steatosis 2

Clinical Significance

Hepatic steatosis can progress to:

• Steatohepatitis (with inflammation)
• Fibrosis
• Cirrhosis
• Hepatocellular carcinoma

The presence and progression of liver fibrosis, driven by hepatic inflammation, is the main predictor of liver-related mortality across the spectrum of steatotic liver diseases 3.

Management Approach

Management depends on the underlying cause and severity:

1. Lifestyle modifications:

   • Weight loss (7-10% of body weight)
   • Regular physical activity
   • Mediterranean diet

2. Management of comorbidities:

   • Control of diabetes, hypertension, and dyslipidemia
   • Alcohol cessation if applicable

3. Follow-up:

   • Low fibrosis risk: Reevaluate every 1-3 years
   • Indeterminate risk with VCTE <8.0 kPa: Intensify management of comorbidities and reevaluate within 1 year
   • High fibrosis risk: Specialist referral and multidisciplinary care 1

Important Considerations for Liver Transplantation

For liver transplantation, the degree of steatosis in donor livers is important:

• Mild macrosteatosis (<30%): Suitable for transplantation
• Moderate macrosteatosis (30-60%): May be acceptable in select donor-recipient combinations
• Severe macrosteatosis (>60%): Associated with unacceptable risks of graft failure, kidney injury, biliary complications, and mortality 2

Microvesicular steatosis does not preclude the use of grafts for transplantation 2.