What is the difference between steatosis and cholestasis?

Steatosis vs. Cholestasis: Fundamental Differences

Steatosis and cholestasis are two completely distinct pathological processes: steatosis is the accumulation of fat droplets within hepatocytes, while cholestasis is an impairment of bile formation and/or bile flow. 1

Core Pathophysiological Differences

Steatosis

• Definition: Accumulation of lipid droplets (triacylglycerols) in hepatocytes, defined as intrahepatic fat comprising at least 5% of liver weight 2
• Mechanism: Results from increased fatty acid flux to the liver, increased de novo lipogenesis, and/or reduced clearance through β-oxidation or very-low-density lipoprotein secretion 2
• Cellular location: Fat accumulates inside hepatocytes themselves 1
• Types: Classified as macrovesicular (large droplets displacing the nucleus) or microvesicular (tiny droplets <1mm giving foamy appearance) 1
• Severity grading: Mild (10-30%), moderate (30-60%), or severe (>60%) based on percentage of affected hepatocytes 1

Cholestasis

• Definition: Impairment of bile formation and/or bile flow, which may be intrahepatic (functional hepatocyte defects or intrahepatic duct obstruction) or extrahepatic (bile duct obstruction distal to the liver) 1
• Mechanism: Results from defective canalicular secretion of bile or obstruction to bile flow distal to the canaliculus 3
• Cellular location: Bile accumulates in bile canaliculi, ducts, and systemically—not primarily within hepatocytes 1
• Duration: Considered chronic if lasting >6 months 1

Clinical Presentation Differences

Steatosis

• Often asymptomatic and discovered incidentally 1
• Associated with metabolic syndrome, obesity, type 2 diabetes, and dyslipidemia 2, 4
• Does not typically cause jaundice, pruritus, or fatigue as primary symptoms 4
• May progress to steatohepatitis (NASH) with inflammation and hepatocyte injury 1, 4

Cholestasis

• Presents with fatigue, pruritus, and in overt cases, jaundice 1
• Pruritus results from accumulation of bile acids in systemic circulation 3
• May cause fat-soluble vitamin malabsorption due to bile acid deficiency in intestinal lumen 3
• Can present with right upper quadrant pain and fever if associated with cholangitis 1

Biochemical Marker Differences

Steatosis

• No specific elevation of alkaline phosphatase or GGT 1
• May show mild aminotransferase elevations (ALT typically > AST in NAFLD) 4
• Bilirubin typically normal unless advanced to cirrhosis 4
• Does not cause cholestatic pattern on liver function tests 1

Cholestasis

• Early markers: Elevated serum alkaline phosphatase (AP) and γ-glutamyltranspeptidase (GGT) 1
• Advanced stages: Conjugated hyperbilirubinemia develops 1
• AP levels >1.5 times upper limit of normal (ULN) and GGT >3 times ULN warrant diagnostic workup 1
• Cholestatic pattern defined by R value ≤2, where R = (ALT/ULN)/(ALP/ULN) 5

Histological Differences

Steatosis

• Macrovesicular pattern: Large fat droplets occupying cytoplasm with peripheral nuclear displacement, typically starting in centrilobular zone 1
• Microvesicular pattern: Tiny lipid droplets giving foamy cytoplasm appearance 1
• May show hepatocyte ballooning but no bile plugs in simple steatosis 1
• Mallory-Denk bodies may be present in alcoholic steatohepatitis 1

Cholestasis

• Ductular bilirubinostasis: Bile plugs visible in bile ductules 1
• Intraparenchymal cholestasis: Bile accumulation within hepatocytes and canaliculi 1
• Periportal ductular proliferation may be present 1
• Hepatocyte injury pattern differs from steatosis—no fat droplets 1

Clinical Consequences and Complications

Steatosis

• Impairs hepatic microcirculation, decreasing resistance to ischemia-reperfusion injury 1
• Increases risk of post-hepatectomy liver failure (PHLF) to ~14% vs. 4% in non-steatotic livers 1
• Severe macrosteatosis (>60%) in donor grafts linked to unacceptable graft failure rates in transplantation 1
• Simple steatosis does not affect overall survival, but progression to NASH increases mortality 4

Cholestasis

• Significantly increases surgical morbidity (50% vs. 15%) and mortality (5-13% vs. 0-6%) compared to non-cholestatic patients 1
• Increases PHLF risk (5-17% vs. 0-3%) in hepatic resection 1
• Leads to apoptosis from retained bile acids in hepatocytes 3
• Progresses to liver fibrosis and cirrhosis if untreated, eventually requiring transplantation 6

Key Diagnostic Approach Differences

For Suspected Steatosis

• Imaging (ultrasound, CT, MRI) can detect fat accumulation but are not standardized 1
• Liver biopsy remains gold standard for definitive diagnosis and grading 1, 4
• Assess for metabolic syndrome components (obesity, diabetes, dyslipidemia) 2, 4

For Suspected Cholestasis

• First step: Abdominal ultrasonography to differentiate intra- vs. extrahepatic cholestasis by assessing for dilated ducts 1, 5
• Measure GGT to confirm hepatobiliary origin of elevated alkaline phosphatase 5
• If ultrasound negative but AP remains elevated, proceed to MRI with MRCP 5
• Thorough medication history essential—drugs taken within 6 weeks may be causative 1

Critical Clinical Pitfall

The two conditions can coexist: Alcoholic or non-alcoholic steatohepatitis can present with both steatosis and cholestatic features, including intraparenchymal cholestasis 1. In such cases, histology shows both fat droplets within hepatocytes and bile accumulation, representing overlapping pathology rather than a single disease process 1.