What is hepatic steatosis?

What is Hepatic Steatosis?

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

Core Definition and Histologic Characteristics

Hepatic steatosis represents the histologic hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) and is characterized by the accumulation of lipid droplets in the cytoplasm of liver cells. 3, 4

The condition manifests in two distinct histologic patterns:

• Macrovescicular steatosis involves large lipid droplets that displace the hepatocyte nucleus and occupy the entire cytoplasm, characteristically associated with metabolic dysfunction, alcohol consumption, obesity, and diabetes 4, 1
• Microvescicular steatosis consists of tiny lipid droplets measuring less than 1 mm that create a foamy cytoplasmic appearance, typically associated with drug toxicity, acute fatty liver of pregnancy, and Reye syndrome 3, 4

Pathophysiologic Mechanisms

The accumulation of hepatic triglycerides results from multiple interconnected metabolic derangements 1:

• Enhanced influx of free fatty acids from adipose tissue lipolysis and chylomicrons from intestinal absorption directly to the liver 3, 4, 1
• Increased de novo lipogenesis through activation of sterol regulatory element binding protein 1c (SREBP1c) 3, 2
• Suppression of fatty acid oxidation via decreased mitochondrial β-oxidation and suppression of peroxisome proliferator-activated receptor α (PPARα) 3, 4
• Reduced hepatic clearance through decreased very-low-density lipoprotein (VLDL) secretion 3, 2
• Insulin resistance serves as the central metabolic driver linking adipose tissue dysfunction to hepatic fat accumulation 1

In alcoholic steatosis specifically, alcohol oxidation increases NADH synthesis, which drives triglyceride and fatty acid production while simultaneously suppressing mitochondrial β-oxidation, and acetaldehyde-induced mitochondrial damage causes VLDL accumulation 3, 4.

Disease Spectrum and Clinical Significance

Hepatic steatosis exists along a clinical spectrum with vastly different prognostic implications 4, 1:

Simple Steatosis (NAFL)

• Represents 70-75% of all MASLD cases and is defined as ≥5% hepatic steatosis without evidence of hepatocellular injury or ballooning 4, 1
• Most patients remain asymptomatic and exhibit very slow or absent histological progression with minimal risk of advancing to cirrhosis 4, 1

Steatohepatitis (NASH/MASH)

• Occurs in 25-30% of MASLD cases and represents a critical pathophysiologic transition characterized by ≥5% hepatic steatosis plus inflammation with hepatocyte injury (ballooning), with or without fibrosis 4, 1
• Carries substantially higher risk of progression to cirrhosis, liver failure, and hepatocellular carcinoma 4, 1

Epidemiology and Associated Conditions

MASLD affects 20-30% of the general population, with prevalence increasing to 70% in obesity and 90% in diabetes. 5, 4

Hepatic steatosis is strongly associated with metabolic syndrome components including abdominal obesity, insulin resistance/type 2 diabetes, hypertension, and dyslipidemia 1. Beyond metabolic causes, steatosis can occur in drug toxicity, viral hepatitis (particularly HCV), cystic fibrosis, protein malnutrition, Wilson's disease, and genetic lipodystrophies 3, 6.

Clinical Presentation: A Critical Pitfall

The majority (60-80%) of patients with chronic 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.

Diagnostic Approach

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

• Ultrasound is commonly used as first-line investigation, showing increased liver echogenicity compared to renal cortex, with sensitivity of 84.8% and specificity of 93.6% for moderate to severe hepatic fat deposition 5
• Liver biopsy remains the most sensitive means of obtaining comprehensive information and is capable of identifying steatohepatitis and staging liver fibrosis, which have important prognostic implications 3
• MRI and MR spectroscopy show promise for accurate fat quantification by measuring proton density fat-fraction, which directly reflects liver fat content 6

Important caveat: Available evidence does not support the use of ultrasonography for grading of fatty liver in children, with positive predictive values of only 47-62% 3.

Clinical Implications

Hepatic steatosis should not be considered a benign feature but rather requires careful evaluation and management. 7 The presence and progression of liver fibrosis driven by hepatic inflammation is the main predictor of liver-related death across the entire spectrum of steatotic liver diseases 8. Initial evaluation should include liver biochemistries and exclusion of other liver diseases, with management focusing on lifestyle modifications, optimal management of comorbidities, and consideration of incretin-based therapies for type 2 diabetes or obesity 5.