Hepatic fibrosis is a detrimental phenomenon with progressive accumulation of types I and III collagen fibrils in the space of Disse, displacing normal matrix components (ie, type IV collagen, laminin, proteoglycans). This complex process involves many cells and is inexorably linked to initiating cell injury, inflammatory mediators, oxidative injury, and impaired sinusoidal perfusion. Thus, correct identification of initiating events and processes amplifying and progressing pathogenic mechanisms helps strategize interventional steps.
Liver biopsy is the only way to achieve a window into the considered possibilities. However, it is important to consider that initiating injury can be amplified into a self-sustaining process long after the original pathogenic insult. Many animals with chronic hepatopathies will have the extent or stage of injury refined but without a definitive explanation of causal mechanisms.
One large category of liver injury in dogs is that associated with pathological copper accumulation, which can be the major mechanism of hepatocyte damage or may be a component of a “two-hit” phenomenon making what might have been inconsequential injury into a progressive process. Notably, identification of the role of copper-associated liver injury is easily surmised on the basis of liver biopsy and specific staining of tissues to disclose the presence of cytosolic copper accumulation in hepatocytes along with liver tissue copper quantification.
Sinusoidal capillarization is a phenomenon associated with liver fibrosis that is catastrophic to LSEC function and sinusoidal perfusion. This process de-differentiates LSEC to a more typical capillary structure (ie, loss of dynamic fenestration with development of a vascular basement membrane more typical of systemic capillaries.
This pathological change disturbs transhepatic perfusion essential to ultrafiltrate formation and hepatocyte function, as well as numerous beneficial attributes of LSECs. Importantly, it disrupts stellate cell quiescence fostered by differentiated LSECs that thwart sinusoidal vasoconstriction and fibrogenesis. Thus, these changes are conscriptions for development of deleterious sinusoidal hypertension.
Morphologically, stellate cells have elongate contractile cytoplasmic processes that encircle sinusoids. Upon activation, stellate cells acquire a myofibroblastic phenotype with expression of alpha-smooth muscle actin (alpha-SMA), a metamorphosis that coordinates with contractile properties and fibrogenesis.
