The liver performs numerous functions, including but not limited to lipid, carbohydrate, and protein metabolism; storage, metabolism, and activation of vitamins; storage of minerals, glycogen, and triglycerides; extramedullary hematopoiesis; and synthesis of coagulant, anticoagulant, and several acute phase proteins. It also influences immunologic responses and contributes to digestion through synthesis and enterohepatic circulation of bile acids and detoxification of many endogenous and exogenous compounds, toxins, and xenobiotics. Because the liver has a large functional reserve and the ability to regenerate, hepatic injury must be considerable or chronic and recurrent to cause overt hepatic dysfunction or failure.
Active liver injury is accompanied by increased liver enzyme activity, with cytosolic transaminases (ALT, AST) acutely reflecting altered membrane permeability or viability or the phenomenon of membrane blebbing, and membrane-affiliated enzyme induction (alkaline phosphatase [ALP], γ-glutamyl transferase [GGT]) reflecting cholestasis and increased protein transcription (enzyme induction). The liver is predisposed to secondary injury owing to its sentinel position between the systemic circulation and GI tract and because it contains the largest population of fixed macrophages (Kupffer cells) in the body. Macrophage phagocytosis can initiate release of a cascade of inflammatory cytokines, leading to local cellular damage and recruitment of inflammatory infiltrates. The considerable metabolic activity of the liver exaggerates its exposure to noxious products, particularly in the centrilobular region, where high cytochrome p450 activity produces noxious products and adducts. Hepatocytes in this region also are more easily injured by hypoxia. The accumulation of hepatic copper and/or iron can initiate and augment liver injury through oxidative mechanisms.
Clinical signs of liver injury vary depending on the type, mechanism, and chronicity of the insult. Common clinical features may include anorexia, vomiting, diarrhea, weight loss, and fever. With severe, diffuse liver injury, animals may become jaundiced and demonstrate polyuria and polydipsia (PU/PD), coagulation abnormalities, and ascites. Ascites indicates development of portal hypertension and is typically associated with formation of acquired portosystemic shunts (APSSs) and concurrent hypoalbuminemia. Hepatic encephalopathy (HE) develops in acquired liver disease only when diffuse fibrosis and APSSs have developed, in acute fulminant liver failure, or secondary to congenital portosystemic shunts (congenital malformations of the portal vein that shunt portal blood directly to the systemic circulation). Fecal color may change with complete occlusion of bile ducts (acholic or pale-colored feces) or because of increased enteric bilirubin elimination (green fecal color). Hepatomegaly is found with diffuse infiltrative or storage disorders, acute extrahepatic bile duct obstruction (EHBDO), congenital biliary cystic malformations, or passive congestion, whereas microhepatica (small liver) usually reflects portal venous hypoperfusion, diversion of enteric hepatotrophic factors normally delivered in the portal circulation, or the presence of chronic hepatic fibrosis in dogs.