Because of the liver's large functional reserve and ability to regenerate, hepatic injury must be considerable or chronic and recurrent to cause overt hepatic dysfunction or failure.
Active liver injury typically is associated with increased circulating liver enzyme activities.
Release of cytosolic transaminases (ALT, AST Aminotransferases Liver disease is often first suspected on the basis of increased liver enzyme activity on health screening profiles. However, abnormally increased liver enzyme activity exceeds the prevalence... read more ) acutely reflects altered cell membrane permeability. This may reflect a reversible phenomenon of membrane blebbing.
Increases in alkaline phosphatase (ALP Alkaline Phosphatase Liver disease is often first suspected on the basis of increased liver enzyme activity on health screening profiles. However, abnormally increased liver enzyme activity exceeds the prevalence... read more ) and gamma-glutamyl transferase (GGT Gamma-Glutamyl Transferase Liver disease is often first suspected on the basis of increased liver enzyme activity on health screening profiles. However, abnormally increased liver enzyme activity exceeds the prevalence... read more ) reflect gene-transcriptional responses (enzyme induction), direct injury to bile duct epithelium (cholangiocytes), or cholestasis associated with injury to biliary elements.
The liver is predisposed to secondary injury from systemic disorders because of its sentinel position between the systemic circulation and GI tract and because of an abundant population of macrophages (ie, Kupffer cells [resident hepatic macrophages]; liver sinusoidal endothelial cells [LSECs]).
Macrophage phagocytosis removes a multitude of substances (particulate debris and endotoxins). Such phagocytic activity has the potential to activate hepatic Kupffer cells and LSECs, initiating release of numerous inflammatory cytokines, leading to local tissue damage and recruitment of inflammatory infiltrates.
LSECs are vital for a spectrum of metabolic, secretory, storage, clearance, scavenging, and immunologic functions.
Because of their broad repertoire of activities, these cells play a central role in the pathogenesis of acute and chronic liver injury and development of liver fibrosis. The considerable spectrum of hepatic metabolism and detoxification escalates risk of generating injurious products or toxic adducts.
In the presence of the primed hepatic surveillance system (ie, Kupffer and LSEC populations), such injuries can be escalated or exaggerated, especially those provoked by toxins. This is particularly notable in centrilobular regions expressing cytochrome P450 enzymes, because these orchestrate a myriad of bioactivating and detoxication reactions that generate noxious metabolites and oxidative radicals. Hepatocytes in this region also are more easily injured by systemic hypoxia, being the last recipients of sinusoidal blood flow.
Accumulation of transition metals (eg, copper or iron) in centrilobular regions can also foster oxidative injury, aggravating damage incurred from unrelated insults. The propensity of dogs to accumulate copper Breed-specific Chronic Hepatitis Canine chronic hepatitis is a syndrome of chronic inflammation of the liver. Chronic hepatitis that does not focus on biliary structures is more common in dogs than cats. Certain breeds have... read more in centrilobular hepatocytes imposes high risk for a "two-hit" injury phenomenon (primary injury event augmented by copper-mediated oxidative damage).