Albumin is produced exclusively by the liver and has a half-life in healthy dogs estimated at ~8 days. Because the healthy liver is estimated to maintain albumin synthesis at 33% maximal capacity, it has a large reserve capability for albumin synthesis. Albumin functions as an essential transport molecule, maintaining normal drug-receptor interactions. In liver disease, decline in albumin concentration compromises its transport functions, increasing risk of adverse drug reactions (more free or unbound drug). Albumin’s large role in maintaining colloid osmotic pressure reflects its lower molecular weight compared with other plasma proteins and its higher intravascular concentration. In inflammatory disease or during malnutrition, albumin may increase its transcapillary escape rate, augmenting distribution into the interstitial space. This phenomenon hastens onset of hypoalbuminemia in animals with necroinflammatory liver disease, long before development of ascites. Concurrent hypoalbuminemia and development of hepatic presinusoidal, sinusoidal, or postsinusoidal portal hypertension is commonly associated with ascites in animals with chronic severe liver disease.
Albumin also functions as a scavenger of oxygen radicals and other oxidizing agents. These antioxidant effects may be compromised in necroinflammatory liver disease and fulminant hepatic failure. Any disease processes promoting an oxidative environment (eg, diabetes mellitus, renal disease, hepatic insufficiency, hyperthyroidism) can irreparably damage the albumin molecule, accelerating its turnover (synthesis and catabolism).
In many animals with liver disease, an early trend toward hypoalbuminemia often reflects systemic inflammation (negative acute phase effect). Only in severe hepatic insufficiency (eg, chronic progressive hepatitis) is synthetic failure a driving cause of hypoalbuminemia. Protein-losing nephropathy (glomerular disease) or protein-losing enteropathy must be excluded as underlying causes of hypoalbuminemia. Glomerular causes are associated with a urine protein:creatinine ratio >3 and hypercholesterolemia, whereas protein-losing enteropathy is associated with panhypoproteinemia and hypocholesterolemia.
Total bilirubin >2.5–3 mg/dL results in clinical icterus. Hyperbilirubinemia can reflect prehepatic (eg, hemolysis), hepatic (impaired uptake, intracellular transport, glucuronide conjugation, or canalicular elimination), or posthepatic/extrahepatic causes (EHBDO, biliary tree rupture). Total bilirubin concentrations vary markedly with different disease processes. Concentrations are highest in dogs with hemolytic disorders and in cats with HL and EHBDO. Bilirubinuria can be detected in healthy dogs because of their ability to conjugate bilirubin in renal tubules (low renal threshold). However, bilirubinuria in cats is always abnormal and should be investigated. Fractionation of total bilirubin into direct (conjugated) and indirect (unconjugated) moieties offers little diagnostic utility. Bilirubin covalently bound to albumin (biliprotein complexes) remains in the circulation and is not excreted in urine. Chronic retention can impart tissue jaundice in the absence of bilirubinuria long after a cholestatic disorder has resolved.
Common causes of hyperbilirubinemia include increased hemoprotein liberation (eg, hemolytic anemia, ineffective erythropoiesis, body cavity hemorrhage), bile duct occlusion, ruptured biliary tract, intrahepatic cholestasis, impaired hepatobiliary bilirubin processing, and sepsis. Jaundiced dogs and cats presenting with regenerative anemia should be tested for hemolytic disorders, including immune-mediated hemolytic anemia, Heinz body hemolysis, zinc toxicity, and erythroparasites (including hemotropic Mycoplasma [cats, dogs] and Babesia [dogs]).
There are no characteristic changes in BUN or creatinine concentrations with liver disorders except that low values are associated with portosystemic shunting and feeding of a restricted protein diet (only BUN, not creatinine) formulated to reduce signs of HE. The concentration of BUN reflects numerous variables, including hydration status, nutritional support, enteric bleeding, tissue catabolism, and the hepatic capacity to detoxify ammonia. Anorexia, feeding a low-protein diet, or hepatic insufficiency can result in low normal to subnormal concentration of BUN, whereas increased values relative to creatinine (discordant BUN:creatinine ratio) may reflect dehydration, enteric bleeding, or consumption of a high-protein diet. Compared with BUN, serum creatinine concentrations are less affected by dietary protein intake. The low BUN and low normal or low creatinine concentration often seen in animals with portosystemic shunting reflect increased water turnover that increases glomerular filtration rate (up to 2-fold), contributing to PU/PD. Reduced hepatic synthesis of creatinine also contributes to low creatinine concentrations in animals with hepatic insufficiency, considering that creatinine depends on hepatic synthesis of creatine in the transmethylation pathway.
Hypoglycemia is uncommon in acquired liver disease except end-stage cirrhosis or fulminant liver failure. The inability to store hepatic glycogen or convert glycogen to glucose is more common in neonates and juvenile small-breed dogs with congenital portosystemic shunts. Other causes of hypoglycemia, including sepsis, insulinoma, iatrogenic insulin overdose, rare glycogen storage disorders, or paraneoplastic effects of large primary hepatic neoplasia (canine hepatocellular carcinoma or adenoma) or other tumors should be considered in an animal with suspected liver disease.
All cells in the body except RBCs synthesize cholesterol for intracellular use. Cholesterol incorporated in plasma lipoproteins is synthesized only in the liver and distal small intestine. Bile provides the major excretory pathway for cholesterol. Hypocholesterolemia may reflect endocrine, metabolic, and nutritional factors as well as hepatic insufficiency and portosystemic shunting. Nonhepatic disorders associated with hypocholesterolemia include hypoadrenocorticism, maldigestion/malabsorption, pancreatic exocrine insufficiency, severe starvation, cachexia, sepsis, and hyperthyroidism (cats); hepatic causes include portosystemic shunting (congenital or acquired) and severe hepatic insufficiency (eg, end-stage cirrhosis, fulminant hepatic failure). Hypercholesterolemia is more common in ill animals and requires careful consideration of potential nonhepatic disorders, including hypothyroidism, diabetes mellitus, pancreatitis, nephrotic syndrome, hyperadrenocorticism or treatment with glucocorticoids, idiopathic dyslipidemias, and rarely a postprandial effect. Hypercholesterolemia is usually seen in EHBDO and in some animals with diffuse intrahepatic cholestasis, destructive cholangitis, and marked hepatic regeneration.