Veterinarians perform blood tests in healthy animals for many reasons, including assessing metabolic function in geriatric patients or patients in need of procedures that require anesthesia, monitoring for drug toxicity, and screening for breed-related diseases. Increases in hepatobiliary enzyme activities—alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP)—are commonly encountered on serum chemistry profiles in these animals. In a study of dogs with a variety of ailments, serum ALP and ALT activities were elevated in 32% and 47% of cases, respectively.1 In another study of both healthy and ill dogs, elevations in ALP, ALT, GGT, and AST activities were found in 39%, 17%, 19%, and 11% of cases, respectively.2
Although elevated serum hepatobiliary enzyme activities are frequently identified, they do not necessarily indicate clinically important hepatic disease. There are several reasons for this discordance. First, increased serum hepatobiliary enzyme activity can originate from nonhepatic tissues. Second, the liver's dual blood supply and large blood flow make it uniquely sensitive to injury due to systemic disorders and diseases in organ systems drained by the portal circulation, particularly the gastrointestinal tract and the pancreas. Finally, drugs can induce excess hepatobiliary enzyme production in the absence of liver damage (see boxed text titled "Drugs that affect liver enzyme interpretation").
Drugs that affect liver enzyme interpretation
This review provides general guidelines for the diagnostic approach to an asymptomatic dog with elevated liver enzyme activities so that needless tests are not performed and clinically important liver disease is not missed.
FACTORS AFFECTING HEPATOBILIARY ENZYME ACTIVITY
Three principal factors contribute to normal serum hepatobiliary enzyme activity. The first determinant is the normal concentration of that enzyme in tissues. Enzymes must be present in a high enough concentration for some spillover into the circulation to occur. The second determinant is the serum enzyme's half-life. An enzyme must have a serum half-life of sufficient duration to permit accumulation. The final determinant is intracellular localization, since enzymes must have access to the vascular compartment to be measured in serum.3 In general, cytosolic enzymes gain access to the serum easier than do enzymes that are within organelles or that are membrane-bound.3
Serum hepatobiliary enzyme activity increases because of leakage from damaged hepatobiliary cells, elution from damaged membranes, or increased synthesis.3 Serum hepatobiliary enzyme activity measurements are useful screening tests for liver damage. They have a high sensitivity (a measure of a test's ability to detect animals with hepatobiliary disease), so few patients with liver disease are missed (the false negative result rate is low). However, they have a lower specificity (a measure of a test's ability to exclude individuals without hepatobiliary disease), so some animals without liver disease will have elevations (false positive results). Thus, once an elevation in serum hepatobiliary enzyme activity is noted, confirmation of hepatobiliary disease requires performing tests with higher specificity. Such tests include hepatic function tests (measuring serum bilirubin, blood ammonia, and total serum bile acid concentrations), hepatobiliary histologic examination, or interpreting hepatobiliary enzyme activities in concert.
Increases in serum ALT activity are considered liver-specific in dogs. ALT activity can increase with severe muscle necrosis, but simultaneous evaluation of serum creatine kinase activity can rule out a muscle source.3,4 ALT is a cytosolic enzyme, and leakage occurs with damage to hepatobiliary membranes. The magnitude of serum ALT activity elevation is roughly proportional to the number of injured hepatocytes.3 Serum ALT activity may also increase because of induction of enzyme synthesis by corticosteroid use and, possibly to a lesser extent, by phenobarbital therapy.3,5 Serum ALT half-life is 2.5 days.6
Increases in serum ALT activity have the highest sensitivity (80% to 100%) for hepatic inflammation and necrosis, vacuolar hepatopathy, and primary neoplasia (hepatocellular carcinoma, cholangiocarcinoma) but have less sensitivity (50% to 60%) in cases of hepatic congestion, metastatic neoplasia, and portosystemic vascular anomalies.3
The highest tissue concentrations of AST are present in the liver, skeletal muscle, and cardiac muscle. Both cytosolic and mitochondrial liver isoenzymes have been found in people, and presumably both isoenzymes occur in dogs as well.3