Laboratory diagnosis: Treatment and management of liver disease in the horse (Proceedings)

Biochemical testing is imperative in the diagnosis of both liver disease and liver failure. Biochemical results can be helpful in narrowing the differentials for the liver failure and, when evaluated over time, can help predict prognosis. Biochemical testing can also be used to identify hepatotoxin exposure (e.g., pyrollizidine alkaloid) (Curran 1996), or drug-induced liver disease (seen most commonly in foals). Liver specific enzymes include sorbital dehydrogenase (SDH) or glutamate dehydrogenase (GDH) and gamma glutamyltransferase (GGT) which respectively reflect hepatocellular and biliary injury. Aspartate aminotransferase (AST) and alkaline phosphatase (AP) also respectively reflect hepatocellular and biliary injury, but are not liver specific. Sorbital dehydrogenase would be expected to increase in the serum with mild hepatocyte injury. It has a short half life (T½) which can be helpful in determining resolution or progression of the hepatic insult (Bernard 1989), although rarely in severe cases of hepatic failure it may return to normal range in spite of a fatal outcome. GGT often continues to elevate for a few days (presumably due to biliary hyperplasia) after a hepatic insult is no longer present. Although GGT elevations are greatest with biliary disease, there is some release into the plasma with hepatocellular injury (Noonan 1981) and it is the single best screening test for hepatic disease in the horse. It is rare that a horse with liver disease will not have elevated plasma/serum GGT. The magnitude of elevation in hepatic-derived enzymes may not always correspond with functional abnormalities and should, therefore, be considered test of disease and not function. Magnitude of increases in hepatic enzymes (especially GGT) should not be used to determine prognosis. For example, I have successfully treated one horse with cholangiohepatitis that had a GGT value of 2500 IU/L. Prognosis is best determined by function test abnormalities, etiology of the hepatic failure, and presence of hepatic encephalopathy. HCT and serum iron are frequently high in horses with severe liver disease. Marked elevation in serum iron in the adult horse is most commonly seen with either hepatic and/or hemolytic disease. Race horses occasionally have mild increases (50-140 IU/L) in GGT without any other evidence of liver disease.

Liver function tests only become abnormal when approximately 60-70% of liver function is lost and these tests include elevations in direct and indirect bilirubin, blood ammonia, prothrombin and partial thromboplastin time, bile acids and gamma globulins (with chronic disease). An increase in direct bilirubin is a highly sensitive marker of liver failure. When the increase in direct bilirubin is 25% or more of the total bilirubin, this is suggestive of a predominant biliary disease. Septic foals and horses with intestinal ileus sometimes have elevations in direct bilirubin with minimal evidence of hepatocellular dysfunction. Treatment should focus on the sepsis and intestinal ileus in those cases. Increases in indirect bilirubin is also a sensitive test of liver failure, but lacks specificity since elevations may also occur with anorexia, hemolysis, or on a rare occasion marked elevation in an otherwise healthy horse (presumed congenital deficiency in glucuronyl transferase) (Divers 1993). There may be a decrease in BUN, fibrinogen, and albumin (with chronic disease and failure). Serum or plasma bile acids can be an early predictor of liver failure when values rise above 30 μmol/L. Mild elevations in bile acids (as high as 20 μmol/L) may be seen with anorexia. Serum triglycerides are increased in equines with hepatic lipidosis and the magnitude of the triglyceride increase may correlate with prognosis (Mogg 1995). In foals with hepatic failure, hypoglycemia is often present, while in adult horses, blood glucose is more commonly normal or increased but may be low (McGorum 1999). Plasma lactate is frequently high and bicarbonate low in horses with fulminant hepatic failure.

There is little published evidence-based medicine regarding the treatment of liver disease in the horse. Even in human medicine, most treatments of liver disease are supportive and often unsubstantiated by clinical trials. For example, pentoxifylline and acetylcysteine are frequently mentioned as treatments of liver disease, but efficacy data is limited (Sklar 2004).

In the horse, there is evidence-based data that cholangiohepatitis (CH) is predominantly caused by gram negative aerobic enteric and gram positive anaerobic organisms (Peek 2000). Therefore, initial antimicrobial therapy should be based upon antimicrobial sensitivity of these bacteria. This may require combination drug therapy such as an appropriate fluroquinolone, aminoglycoside or TMP/S, combined with penicillin or metronidazole. The proper duration of treatment is not known, but based upon information in other species, infections of the biliary system are refractory to sterilization and require long-term therapy (weeks-months). This author recommends treatment until the GGT is within normal range. Although there are no large case studies on equine choledocholiths, there is reasonable clinical evidence that these are secondary to CH; begin as "sludge" formation, and progress to one or multiple calcium bilirubinate stones. When stones form, they either prolong expected treatment and/or lower the prognosis. Single stones obstructing the common bile duct would likely require surgery. Management of > 40 cases of CH, either directly or via consultation by this author, has revealed a good prognosis for complete recovery if appropriate therapy is provided, there is minimal fibrosis, and no ultrasonographic evidence of "well formed" stones. Unfortunately, "stones" cannot be ruled out by transabdominal ultrasound since a large amount of the liver cannot be visualized. Other than fluid therapy, additional forms of therapy for CH are either symptomatic or have less clinical-based evidence to support their use. That being said, this author recommends pentoxifylline, DMSO flunixin meglumine and S-adenosylmethionine (SAMe) (5 gms P.O. SID).

Theiler's disease is a fulminant hepatic disease most commonly affecting one horse on the premise or less commonly a cluster of horses over several weeks. Treatment is entirely supportive with intravenous crystalloid therapy, added potassium and glucose the most important treatments. Orally administered (via syringe) medication (Neomycin, lactulose and probiotics) would seem to be indicated for fulminant hepatic disease in hopes of attenuating signs of hepatic encephalopathy (HE). These treatments are based upon strong mechanistic beliefs with limited clinical-based evidence in other species (Jalan 2005). Sedation may be a requirement for some horses with fulminant HE and "lowest dose possible" Detomidine/acepromazine may be used in hopes of controlling the maniacal horse yet avoiding abnormal lowering of the head or respiratory depression. Based upon a mechanistic understanding of HE and its association with increased cerebral hyperemia, efforts to maintain normal head position and respiration rate and depth seem prudent. Bacterocidal antibiotics and flunixin meglumine (0.3 mg/kg IV q 8 h) are routinely given since a systemic inflammatory response may occur with Theiler's disease or any acute hepatic disease.

Toxic plants most commonly cause a chronic and sometimes (e.g., pyrollizidine alkaloid toxicosis) progressive hepatic fibrosis. Removal of the toxic substance and administration of anti-fibrotic, anti-inflammatory, hepatoprotective drugs are indicated, although none are scientifically proven. Colchicine, except in pyrollizidine alkaloid toxicosis, pentoxifylline and SAMe are the drugs most frequently used by this author in hopes of arresting or slowing fibrosis. Nutritional support in equine hepatic failure has little evidence-based support except in hepatic lipidosis, although from a mechanistic view the frequent feeding (small amounts) of high carbohydrate, low to moderate protein with high branch chain:aromatic amino acid ratio seems appropriate. Treatment of hepatic lipidosis is predominantly enteral support, correction of predisposing disorders, and supportive care. There are numerous scientific articles on this topic and a recent review which also reveals differences in this disorder between ponies and miniature equines (Hughes 2004). There is experimental evidence that heparin would not be of benefit in these patients and could cause harm. The benefit of insulin therapy has not been documented, but its administration at appropriate dosages is recommended by this author.

We know from both clinical-based evidence and from a mechanistic understanding that horses with right dorsal colon displacement may have obstruction of bile flow causing severe jaundice. These horses should fully recover once the colon is repositioned (Gardner 2005).

References

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3. Noonan, N.E. Variations of plasma enzymes in the pony and the dog after carbon tetrachloride administration. Am J Vet Res 1981;42(4):674-678.

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8. Peek, S.F. and Divers, T.J. Medical treatment of cholangiohepatitis and cholelithiasis in mature horses: 9 cases (1991-1998). Equine Vet J 2000;32(4):301-306.

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11. Gardner, R.B., Nydam, D.V., Mohammed, H.O., Ducharme, N.G., and Divers, T.J. Serum gamma glutamyl transferase activity in horses with right or left dorsal displacements of the large colon. J Vet Intern Med 2005;19:761-764.