FRANK J. MILNE STATE-OF-THE-ART LECTURE


lipids that serve to store vitamin A as retinal ester. When the liver is damaged, Kupffer cells produce tumor necrosis factor alpha, causing the stellate cells to contract individually but proliferate in num- bers. These activated cells become chemotactic, de- crease their vitamin A stores, secrete collagen (thus causing fibrosis) and eventually become senescent.8,14 Kupffer cells are specialized macrophages that


are part of the reticuloendothelial system. Kupffer cells are responsible for destroying gut-derived bac- teria, endotoxins, and other foreign substances. They also help in recycling iron from senescent or injured red blood cells and, as a result, Kupffer cells accumulate hemosiderin and this can be pronounced even in disease-free horses.15


2. Biochemical Testing for Liver Disease and Failure


Biochemical testing is imperative when attempting to diagnose liver disease or liver failure. From a clinical perspective, biochemical results can be help- ful in narrowing the differentials for the liver injury and, when evaluated over time, can help predict prognosis. Biochemical testing can also be used to identify subclinical hepatotoxin exposure, such as is seen with pyrollizidine alkaloid toxicity or drug- induced liver disease.16 Liver-specific enzymes in- clude sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), and gamma glutamyltrans- ferase (GGT), which respectively reflect predomi- nantly hepatocellular (SDH, GLDH) and biliary injury (GGT).11 Aspartate aminotransferase (AST) and alkaline phosphatase (ALP) also, respectively, reflect hepatocellular and biliary injury, but AST and ALP are not liver specific. Increased values of serum SDH, GLDH, and AST are expected with even mild hepatocyte injury. SDH is released from the cytosol of the hepatocyte and has a short half-life (hours) and repeated SDH measurements can be helpful in determining resolution or progression of hepatic insult.17 GLDH is localized in hepatic mi- tochondria and is markedly increased in the serum of most horses with acute liver disease resulting from or with necrosis of hepatocytes; sensitivity for GLDH elevations in detection of hepatic necrosis and hepatic lipidosis was 78 and 86%, respectively.18 GLDH is thought to be more stable and have a slightly longer T1


⁄2 than does SDH, although SDH is


stable for at least 24 hours when the sample is refrigerated.19 GGT is an excellent screening test for hepatic disease in the horse.20 In my experience it is rare that a horse with severe liver disease will not have elevated plasma/serum GGT. GGT often continues to elevate for several days after a hepatic insult is no longer present, presumably due to biliary hyperpla- sia. Although the greatest elevations in GGT are seen with biliary disease, there is some GGT release into plasma with hepatocellular injury.21 On rare occasion, and with severe chronic fibrosis, SDH and GLDH may return to normal range despite a fatal outcome.


68 2015  Vol. 61  AAEP PROCEEDINGS The magnitude of elevation of hepatic-derived en-


zymes may not correspond to functional abnormali- ties and should, therefore, be considered tests that measure disease and not tests that measure func- tion (the magnitude of increases in hepatic enzymes [especially GGT] should not routinely be used by itself to determine prognosis). During a 2-year farm investigation of a forage-associated hepatopa- thy in Europe, more than 70 weanlings, yearlings, and adults had elevated GGT values, some as high as 1000 IU/l (mean, 180 IU/l) and GLDH values as high 1200 IU/l, yet not a single horse has demon- strated signs of hepatic failure nor any obvious clin- ical signs (author, personal observation). The prognosis for horses with hepatic failure is best de- termined by function test abnormalities, etiology, and presence or absence of hepatic encephalopa- thy.22 Somewhat unique to the horse, hematocrit, serum iron, and percentage iron saturation are sometimes high in horses with severe liver disease and remain after rehydration. Racehorses occa- sionally have mild-to-moderate increases in GGT (50–140 IU/L) without any other biochemical evi- dence of liver disease. This phenomenon has been observed for at least 30 years and the elevation in GGT has often been temporally linked to poor per- formance.23 In some situations, multiple horses stabled together may have elevations in GGT. Pos- sible causes include drug administration causing induction of GGT, toxin exposure and disease spe- cific to the biliary tract, viral infections causing only increases in GGT at the time of sampling, and over- training with depletion of hepatic glycogen.24 GGT activity between 70 and 100 U/L has previously been associated with poor health, oxidative stress, and overtraining the horse, and further, those horses with high GGT values showed a markedly reduced incidence of increased GGT following reduction in training intensity in subsequent years.23 Further- more, GGT levels in these horses almost always return to normal within a few weeks with rest. Recent studies demonstrated that serum GGT activ- ity was correlated to cumulative training load and racing frequency25 and maladaptation to training.26 It should be noted that hepatocellular liver en-


zymes may be elevated with many systemic inflamma- tory disorders. This likely reflects inflammatory, vascular, hypoxic, and toxic insults to the liver sec- ondary to the primary disorder. Bile acids can be elevated in horses with intestinal disorders such as colic and enteritis and in equine dysautonomia where the elevations in bile acids may be due to both liver pathology and ileus. The severity of these laboratory abnormalities in horses with colic, espe- cially moderate-to-markedly-elevated bile acids, has been associated with prognosis.27 Liver function tests may only become abnormally elevated when approximately 70% or more of liver function is lost.28 These tests include conjugated (direct) and unconjugated (indirect) bilirubin, blood ammonia, bile acids, and prothrombin (PT)/partial


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