What is the pathophysiology of liver fibrosis in schistosomiasis?

Pathophysiology of Liver Fibrosis in Schistosomiasis

Liver fibrosis in schistosomiasis results from a granulomatous immune response to parasite eggs trapped in the portal venous system, leading to chronic inflammation, extracellular matrix deposition, and progressive periportal fibrosis that can culminate in portal hypertension. 1

Egg Deposition and Granuloma Formation

• Schistosome eggs are primarily lodged in the liver and intestinal tissues after being carried through the portal venous system 2
• The eggs induce a granulomatous host immune response characterized by lymphocytes, eosinophils, and alternatively activated macrophages surrounding each egg 2
• Small focal areas of chronic inflammation and excess extracellular matrix are deposited in periovular granulomas, distributed at the periphery of the portal vein system in 90% of infected individuals 1
• A minority (approximately 10%) of infected individuals develop extensive disease with numerous granulomas along the entire extension of the portal spaces, mainly dependent on heavy worm load and subsequent production of numerous eggs 1

Cellular Mechanisms of Fibrosis

• Granuloma macrophages become activated in vivo and secrete fibronectin-like molecules that stimulate directional migration of fibroblasts to the site of injury 3
• Myofibroblasts within the granulomas express both matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase-1 (TIMP-1) genes 4
• Activated hepatic stellate cells transform into myofibroblasts and produce collagen, similar to other forms of chronic liver injury 5
• Granuloma adherent cells (95% macrophages) secrete factors that stimulate fibroblast proliferation and collagen synthesis 3

Collagen Dynamics and Matrix Remodeling

• Collagen types I, III, and IV gene expression are up-regulated at the onset of granuloma development, with type I collagen expression peaking at the chronic fibrotic stage 4
• The amount of deposited hepatic collagen increases with chronicity of infection, indicating cumulative fibrosis 4
• An imbalance in MMP:TIMP expression is associated with cumulative fibrosis, with TIMP-1 and TIMP-2 expression peaking at the chronic fibrotic stage 4
• Collagenase levels are approximately two times higher in vigorous granulomas compared to immunomodulated lesions, but decrease in chronic infections while fibrosis becomes cumulative 6

Inflammatory Mediators

• High levels of fibrogenic interleukin-13 and moderate production of transforming growth factor-beta (TGF-β) are concurrent with fibrosis development 4
• Pro-inflammatory cytokines and growth factors promote the fibrotic process through activation of hepatic stellate cells 5
• The granulomatous inflammation leads to chronic inflammation that results in liver fibrosis accompanied by hepatosplenomegaly and ascites 2

Hemodynamic Factors

• Heavy worm load creates special hemodynamic changes that contribute to extensive portal space involvement 1
• The fibrotic process can progress to portal hypertension, representing a severe form of chronic hepatopathy 1
• Fibrosis typically occurs in periportal areas, reflecting the distribution pattern of egg deposition in the portal venous system 1

Disease Progression and Reversibility

• The process involves both fibrosis formation and potential regression with antiparasitic treatment 1
• In chronic infections, collagen synthesis and degradation are both diminished, but fibrosis remains cumulative 6
• The presence of active neutral proteases within granulomas plays an important role in tissue repair and remodeling during the fibrotic process 6