What is hepatic steatosis?

What is Hepatic Steatosis?

Hepatic steatosis is the abnormal accumulation of triglycerides within hepatocytes, defined histologically as intrahepatic fat comprising at least 5% of liver weight or affecting ≥5% of hepatocytes. 1, 2

Core Definition and Pathophysiology

Hepatic steatosis represents the histological hallmark of fatty liver disease, characterized by the deposition of lipid droplets in liver cells. 3 This accumulation results from an imbalance between fat acquisition (from dietary intake, adipose tissue lipolysis, and de novo lipogenesis) and fat disposal (through oxidation and export as very-low-density lipoproteins). 2

Key Metabolic Mechanisms

The development of hepatic steatosis involves multiple interconnected pathways:

• Enhanced fatty acid influx: Increased delivery of free fatty acids from adipose tissue and chylomicrons from intestinal absorption directly to the liver drives triglyceride accumulation in most patients with metabolic dysfunction. 4, 1

• Increased de novo lipogenesis: Activation of sterol regulatory element binding protein 1c (SREBP1c) amplifies lipid biosynthesis, while suppression of peroxisome proliferator-activated receptor α (PPARα) decreases lipolysis. 3, 4

• Reduced fat clearance: Impaired mitochondrial β-oxidation and decreased very-low-density lipoprotein (VLDL) secretion limit the liver's ability to eliminate accumulated fat. 3, 2

• Insulin resistance: This serves as the central metabolic driver linking adipose tissue dysfunction to hepatic fat accumulation, particularly in metabolic dysfunction-associated steatotic liver disease (MASLD). 1

Histologic Patterns

Hepatic steatosis manifests in two distinct histologic patterns with different clinical implications:

Macrovesicular Steatosis

• Large lipid droplets (>1 mm) that displace the hepatocyte nucleus and occupy the entire cytoplasm. 3, 4
• Characteristically associated with alcohol consumption, obesity, and diabetes. 3, 1
• Carries greater clinical significance for disease progression and is the predominant pattern in metabolic dysfunction. 4
• Graded as mild (10-30%), moderate (30-60%), or severe (>60%) based on the percentage of affected hepatocytes. 3

Microvesicular Steatosis

• Tiny lipid droplets (<1 mm) creating a foamy cytoplasmic appearance without nuclear displacement. 3, 4
• Associated with drug toxicity, acute fatty liver of pregnancy, and Reye syndrome. 3, 4
• Does not preclude organ function and typically has minimal clinical significance. 3, 4

Disease Spectrum and Clinical Significance

Hepatic steatosis exists along a spectrum of severity with distinct prognostic implications:

Simple Steatosis (NAFL)

• Represents 70-75% of all MASLD cases. 4, 1
• Defined as hepatic steatosis without hepatocellular injury or ballooning. 4
• Most patients remain asymptomatic and exhibit very slow or absent histological progression. 4
• Carries minimal risk of progression to cirrhosis. 1

Steatohepatitis (NASH/MASH)

• Occurs in 25-30% of MASLD cases and represents a critical pathophysiologic transition. 4, 1
• Characterized by hepatic steatosis plus inflammation with hepatocyte injury (ballooning), with or without fibrosis. 4
• Can progress to cirrhosis, liver failure, and hepatocellular carcinoma. 1

Etiologic Context

Hepatic steatosis occurs in multiple clinical contexts beyond metabolic dysfunction:

• Metabolic dysfunction-associated steatotic liver disease (MASLD): Prevalence of 20-30% in the general population, increasing to 70% in obesity and 90% in diabetes. 5
• Alcoholic liver disease: Alcohol oxidation increases NADH synthesis, driving triglyceride production while suppressing mitochondrial β-oxidation. 3, 4
• Other causes: Drug toxicity, viral hepatitis, cystic fibrosis, protein malnutrition, Wilson's disease, HIV, and genetic lipodystrophies. 3, 6

Diagnostic Considerations

The diagnosis of hepatic steatosis requires demonstration of ≥5% fat accumulation by imaging or histology, plus exclusion of secondary causes including significant alcohol consumption and steatogenic medications. 1

• Liver biopsy remains the gold standard, providing comprehensive cellular-level information and the ability to identify steatohepatitis and stage fibrosis. 3
• Ultrasound serves as first-line imaging, showing increased liver echogenicity compared to renal cortex, with sensitivity of 84.8% and specificity of 93.6% for moderate to severe hepatic fat. 5
• Advanced MRI techniques measuring proton density fat-fraction provide accurate, reproducible quantification of liver fat content. 6, 7

Clinical Presentation and Metabolic Associations

The majority (60-80%) of patients with hepatic steatosis remain completely asymptomatic because simple steatosis occurs without cellular injury or inflammation. 4, 1 This silent nature makes early detection challenging and underscores the importance of screening high-risk populations despite normal liver biochemistries. 4

Hepatic steatosis is strongly associated with metabolic syndrome components:

• Abdominal obesity
• Insulin resistance/type 2 diabetes
• Hypertension
• Dyslipidemia 1

Furthermore, fatty liver functions as a cardiometabolic risk factor that can contribute to diabetes mellitus and cardiovascular disease. 3