Liver injury

The hepatocellular leakage enzymes are useful in detecting injury to liver parenchymal cells. Generally, increased serum activity represents enzyme leakage from cells through damaged cell membranes.

  • ALT: Used in small animals only. Largely liver-specific, but can also increase in severe myopathies (release of muscle enzyme) and intravascular or in vitro hemolysis (cat, pig).
  • AST: Used in small and large animals. Present in liver as well as skeletal muscle and erythrocytes. Will be increased with liver or skeletal muscle injury. May be increased with intravascular hemolysis, stored samples or in vitro hemolysis (from release of AST in RBCs).
  • SDH: Liver specific in nearly all species. Used in large animals in place of ALT (which is not a good marker of liver disease in large animals).
  • GLDH: Liver specific in all species. Used in large animal panels concurrently with SDH (due to superior storage stability) and on exotic (non-mammalian) panels as a marker of liver injury.
  • LDH: Lactic dehydrogenase is seen in both liver and muscle, so like AST it is not liver specific. LDH is discussed further under Muscle.

In order to be of value, an enzyme should have:

  • High sensitivity: Present in larger amounts in the cell compared to the surrounding extracellular fluid.
  • High specificity: Ideally its presence should be limited to the cell of interest (i.e. hepatocytes). Membrane damage due to ATP depletion, toxins or other agents can result in cell necrosis or membrane blebbing. Membrane blebbing can then result in enzyme leakage with subsequent repair (reversible damage) or can result in membrane rupture and cell death.


Leakage enzymes are present in the cell in relatively high quantities and do not require an increase in protein synthesis to be found in appreciable levels in the blood. There are a number of different injurious mechanisms that can contribute to the release of these enzymes from a cell into the blood.

  • Cellular necrosis
  • Membrane damage due to ATP depletion, toxins or other agents can result in cell necrosis or membrane blebbing. The cell may repair (reversible injury) or go on to undergo death and release more enzyme.


  • Serum levels depend on both the number of cells affected and the severity of injury to individual cells but DO NOT correlate with reversibility of injury or hepatic function.
    • Acute sublethal injury can produce very high enzyme activity (e.g hypoxia), but may be largely reversible and without clinical signs of liver dysfunction.
    • End-stage liver disease may have only slight increases in serum enzyme activity due to a marked reduction in viable hepatocytes.
  • Judging the magnitude of a change in serum enzyme values can be challenging. As a rule of thumb, a 2-3 fold increase above the reference interval is generally considered mild, where as a 4-5 fold increase is moderate, and as the value reaches closer to a 10 fold increase this is considered marked.
    • Inflammatory or necrotizing disorders are generally associated with the largest increases (of the leakage enzymes).
  • Increases are not specific with regard to the nature of the injury.  As a result, it is critical to consider changes in enzyme activity over time and the half-life of the enzyme in the species of interest (half-lives differ between species).
  • Enzymes that are located within the mitochondria (e.g. GLDH) require a greater degree of cellular damage to escape into the serum than enzymes originating from the cytoplasm (e.g. ALT).

“Primary” hepatic disorders

  • Necrosis:  Due to many causes (e.g. toxins, infectious agents).
  • Inflammation: Viral, bacterial, fungal, immune-mediated etc. Inflammation can be suppurative or non-suppurative. Note that primary bile duct obstruction may result in secondary hepatocellular injury as accumulated bile acids are toxic to cells. Leakage enzyme levels in end-stage liver disease or portosystemic shunts may be normal or only mildly increased due to reduced number of cells and minimal active injury.
  • Congenital conditions: e.g. ductal plate abnormalities, microvascular dysplasia.
  • Toxic: Drugs, chemicals, plants. These can cause very high enzyme activity if associated with diffuse necrosis. Copper can accumulate in the liver of dogs due to congenital defects in copper metabolism (e.g. Bedlington terrier due to defects in copper metabolism domain containing 1 [COMMD1, Forman et al 2005]) or ATPB7 [Coronado et al 2008] genes) or excess copper in diet with a genetic breed disposition (e.g. Labrador retrievers [Dirksen et al 2017]). Labrador retrievers with copper toxicity frequently have high ALT activity (with fewer dogs having increased ALP activity). Some dogs develop acquired Fanconi syndrome (proximal tubular dysfunction) (Langlois et al 2013). There has been one report of a cat with copper toxicity due to an inherited defect in the ATPB7 gene (Asada et al 2019).
  • Neoplasia: Hepatocellular and bile duct carcinomas, metastatic neoplasia. Variable (even no) increases are possible depending on the extent of active hepatocellular injury.

Disorders with secondary hepatic effects

  • Circulatory: Heart failure, shock, severe anemia (ischemic injury), portosystemic shunts, septicemia, gastrointestinal disease in horses (displaced colon, acute colitis).
  • Metabolic: Endocrine disease (producing fatty liver, e.g. diabetes mellitus, Cushing’s disease), negative energy balance (lipidosis in cats, miniature and Shetland ponies, cattle, camelids), hyperthyroidism (presumed toxic effect of thyroid hormone on liver cells), acute pancreatitis, metastatic cancer etc.
Scroll to Top