What is liver fibrosis?

What is Liver Fibrosis

Liver fibrosis is a wound-healing response characterized by excessive accumulation of extracellular matrix proteins, particularly collagen, that occurs in response to chronic liver injury and inflammation. 1

Pathophysiological Mechanism

Liver fibrosis represents the liver's response to ongoing cellular damage, regardless of the underlying cause. 1, 2 The process begins when chronic liver injury triggers inflammation and hepatocyte damage, activating hepatic stellate cells (HSCs) which transform into myofibroblasts—the primary collagen-producing cells in the injured liver. 1, 3 These activated cells produce excessive extracellular matrix proteins, particularly collagen and alpha-smooth muscle actin. 2, 4

The fibrotic process is driven by:

• Pro-inflammatory cytokines and growth factors (particularly TGF-β1, PDGF, angiotensin II, and leptin) that promote fibrogenesis 1, 3
• Reactive oxygen species (ROS) that stimulate signaling pathways in HSCs enhancing fibrosis 1
• Portal fibroblasts and bone marrow-derived myofibroblasts that contribute to collagen production alongside HSCs 3, 4

Anatomical Progression

Fibrosis begins with deposition of fine neomatrix within the space of Disse that progressively matures and enlarges over time. 5, 6 The architectural evolution follows a predictable pattern:

• Early stage: Fibrosis occurs in specific regions, typically pericentral and perisinusoidal areas, starting in the centrilobular region (zone 3) 1, 7
• Intermediate stage: Collagen bands become more apparent and extend toward the portal tract 1, 5
• Advanced stage: Bridging fibrosis develops, connecting different liver areas (central vein to central vein, then central vein to portal tract) 1, 7
• End stage: Progression to cirrhosis occurs, characterized by regenerative nodules surrounded by fibrous tissue, with complete architectural distortion 1, 6

Common Etiologies

The major causes of liver fibrosis include:

• Viral hepatitis (hepatitis B and C) 1, 6
• Alcohol-related liver disease 1, 6
• Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) 1, 6
• Autoimmune hepatitis 1, 6
• Primary biliary cholangitis and primary sclerosing cholangitis 1, 6

Clinical Significance and Outcomes

Fibrosis stage is the strongest predictor of future outcomes and provides the greatest prognostic information in chronic liver disease. 7 The severity of fibrosis directly correlates with:

• Portal hypertension development and its complications (ascites, variceal bleeding) when fibrosis becomes advanced 1, 5
• Hepatocellular carcinoma risk, with annual incidence of 1-8% in cirrhotic patients 6
• Liver-related mortality, which increases exponentially with increasing fibrosis severity 8
• Progression to cirrhosis, which reduces median survival from >12 years (compensated) to approximately 1.8-2 years (decompensated) 6

Advanced fibrosis (stage 3-4) represents a critical threshold, defined as bridging fibrosis or cirrhosis, and serves as a meaningful surrogate for liver-related outcomes including hepatocellular carcinoma, liver decompensation, transplantation, and death. 7

Reversibility Considerations

Removing the underlying cause can lead to regression of fibrosis, such as treating viral hepatitis or stopping alcohol consumption. 1, 9 However, reversal often occurs too slowly or too infrequently to avoid life-threatening complications, particularly in advanced fibrosis. 9 The reversal of advanced fibrosis or cirrhosis is frequently impossible. 2

Diagnostic Assessment

Liver biopsy remains the gold standard for assessing liver fibrosis, though it is invasive. 1, 7 Non-invasive alternatives include:

• Serum biomarkers: FIB-4 score (most validated and recommended as first-line), APRI, NAFLD fibrosis score, Enhanced Liver Fibrosis (ELF) test 7, 1
• Imaging methods: Vibration controlled transient elastography (VCTE), shear wave elastography (SWE), magnetic resonance elastography (MRE) 7, 1

A critical pitfall: The patchy distribution of fibrosis can lead to underestimation of disease stage on biopsy, with fibrosis grade underestimated in up to 40% of cases. 7