Liver Disease in Foals
Jennifer L. Davis
Liver disease in foals may be classified as primary or secondary and can be associated with infectious, parasitic, congenital, metabolic, or toxic causes. An initial diagnosis of hepatic disease is often made based on elevations in hepatic enzyme activities on biochemical analysis, but it is important to use age-specific reference ranges to interpret biochemical indicators of hepatic disease.
Several hepatic enzymes can have increased activity even in healthy neonates.1-3 Total bilirubin may be elevated as fetal hemoglobin converts to adult hemoglobin. Elevations may also result from a deficiency in liver binding and conjugating enzymes.1 ALP remains elevated for an extended time in young horses as a result of increased osteoblastic activity, with normal values as high as 3752 U/L reported.4 Increased GGT activity may be present in foals for 2 to 4 weeks after birth, whereas only slight increases of SDH are expected during the same period.1,3 Increased variability in ALP and GGT in healthy foals can make interpretation of hepatic function difficult. Serum bile acids (SBAs) are significantly greater in foals than adult horses for the first 6 weeks of life. According to one study, this is potentially due to upregulation of hepatic production, reduced excretion, differences in bile acid composition of the neonate, or enhanced intestinal or portal uptake.3 An additional finding of that study was that SBAs were not significantly different between healthy and sick foals.3 Another study noted that elevated liver enzymes were common in sick foals, and those foals with high liver enzymes were more likely to have sepsis than other diseases.4Tyzzer's Disease
Tyzzer's disease is an acute hepatitis affecting foals 7 to 42 days of age, with no known breed or sex predeliction.5-13 It has also been reported in calves, lambs, and other species.14-16 The causative organism is Clostridium piliforme (formerly Bacillus piliformis), a gram-negative, flagellated, spore-forming intracellular obligate anaerobe.17 Multiple strains can infect Equidae, and foals are susceptible to at least two distinct strains (isolate E and R1), with no evidence of cross-reactivity of antibodies between isolates.17,18
Although the exact pathogenesis is unknown, bacterial spores can be shed in the manure of carrier horses, suggesting a fecal-oral route of transmission with subsequent GI and hepatic colonization.19 Farms with multiple cases per year have been documented to feed higher protein diets compared to farms without cases, suggesting that high-protein and nitrogenous diets fed to nursing mares may increase proliferation of C.
piliforme in the gut of both mares and foals.13 Several other risk factors, including time of year, age, resident status of the mare, and heavy rainfall in the spring, have been associated with development of disease.13,20 Foals born between March and May were found to be more likely to develop disease in two different studies, and this was thought to be due to the increased number of animals present on the farm during that time. Foals from younger mares (in foals and may occur concurrently with cases of enteritis or entero- colitis.29,30 A lack of elevated hepatic enzyme activity may help differentiate intestinal hyperammonemia from hepatic causes. Prognosis in these cases is good if the underlying disease process can be treated.31Ascending infection of the umbilical vein can result in abscessation or inflammation of the liver with or without a concurrent elevation in hepatic enzyme activity. Bacteria associated with equine sepsis can frequently be cultured from the lesions. Diagnosis is dependent on ultrasonographic evidence of an enlarged umbilical vein extending into the hepatic parenchyma along with appropriate signalment and clinical signs. Treatment may be medical or surgical.
Equine Herpesvirus 1
Equine herpesvirus 1 (EHV-1) infection of a fetus late in gestation typically results in an aborted or stillborn fetus; however, it may occasionally result in the birth of a live foal with hepatic, respiratory, and/or GI disease.32 Affected foals may have severe neutropenia and lymphopenia, and icterus is a common clinical sign. Secondary septicemia is likely to develop due to immunosuppression. Surprisingly, significant elevations in serum hepatic enzyme activities are not present even though a severe multifocal necrotizing hepatitis with inclusion bodies is present at necropsy.33 Generally respiratory distress is progressive, and the animal's clinical condition rapidly declines within 5 days after birth despite aggressive and early treatment.
Treatment with interferon and oral acyclovir (8 to 16 mg/kg q8h)34 may improve survival rates.Neonatal Isoerythrolysis
Foals with severe and prolonged neonatal isoerythrolysis (NI) may develop liver failure,35 which results from a combination of chronic hepatic hypoxia and multiple blood transfusions. Foals receiving a total volume of blood products of 4 L or more were 19.5 times more likely to develop liver failure than foals receiving a lower volume.36 Multiple blood transfusions are thought to result in iron overload and subsequent iron toxicity. Deferoxamine, an iron chelator, enhances urinary iron elimination and decreases hepatic iron accumulation after blood transfusion in healthy foals.37 Administration of 1 g of deferoxamine subcutaneously (SC) q12h prior to blood administration may help prevent liver failure in those receiving multiple transfusions.
Kernicterus, or bilirubin encephalopathy, is another potential complication of NI in foals. Neurologic signs, including seizures, develop secondary to the neurotoxic effects of unconjugated bilirubin on the CNS.36,38 Kernicterus is more likely to develop in foals with total bilirubin of 27 mg/dL or greater and is associated with a poor outcome.36 The use of therapeutic plasma exchange techniques to lower plasma bilirubin concentrations and prevent or treat kernicterus in foals has been performed in practice and holds promise as a successful treatment, if available.39
Drug-Induced Hepatotoxicity
Rarely, foals treated with macrolides, trimethoprim-sulfas, or histamine 2 (H2) blockers for pneumonia or diarrhea develop an increase in serum hepatic enzymes despite clinical improvement. With changes in drug treatment, serum enzymes return to normal, suggesting that these cases may have drug-induced hepatotoxicity.40 In one study of foals being treated for R. equi pneumonia, four of nine foals in the doxycycline-rifampin treatment group developed icterus and hemolytic anemia or increased liver enzymes, while no foals in the other treatment groups developed similar signs, including those receiving doxycycline alone.41 Steroid-induced hepatic lipidosis has been observed in foals receiving both prolonged and high doses of corticosteroids.
Iron Toxicity
Iron toxicity is the best documented toxic cause of hepatopathy in foals and may occur following administration of nutritional supplements or iron formulations containing ferrous fumarate.40,42 Toxicity manifests in newborn foals given iron prior to receiving colostrum; colostral-acquired glutathione or other substances may be protective against hepatotoxicity.42 When iron is given at birth and before colostrum, clinical signs typically develop 2 to 5 days later, although in rare cases signs may develop in older foals. The initial clinical signs are associated with hepatic encephalopathy and include seizures, marked depression, ataxia, aimless wandering, head pressing, and abnormal behavior. Icterus is noted in most foals at the time neurologic signs are exhibited, although some foals die so rapidly that icterus does not have time to develop. Abnormally high ammonia, total bilirubin, GGT and ALP activity, and packed cell volumes were present, as was an abnormally high ratio of aromatic to branched-chain amino acids. PTT and PT were prolonged, and some foals had high SDH activity.40 Affected foals had small livers with prominent bile duct proliferation, hepatic cell necrosis, and mild periportal fibrosis, and had histopathologic changes in the brain consistent with 4043
hepatic encephalopathy.40 43
Congenital or Inherited Diseases
Congenital portosystemic shunts (CPSS) occur infrequently in the equine and bovine patient.44 Clinical signs may not be noted until foals are 2 to 3 months old and begin ingesting large amounts of grain or grass. Encephalopathic signs and tenesmus are characteristic of the disease in calves. Waxing and waning signs of encephalopathy accompanied by elevated bile acids and ammonia levels and normal concentrations of hepatic-derived serum enzymes should arouse suspicion of CPSS in foals. Shunts may be single or multiple and may be intra- or extrahepatic. Diagnosis of CPSS can be made by computed tomography (CT) scan, positive-contrast portography, transrectal portoscintigraphy (in foals), or transabdominal ultrasound examination.
Further corroborative evidence can be gained by ultrasound-guided percutaneous transsplenic injection of agitated saline with simultaneous echocardiography to look for contrast in the right atrium and ventricle.45 Shortterm medical management can be attempted with antimicrobials (minocycline, neomycin, metronidazole), anti-inflammatory drugs, enemas, lactulose, and IV fluids. Successful surgical ligation of CPSS has been described in a foal and a calf.44-46A distinct syndrome of hepatic failure has been seen in Morgan foals.47,48 Clinical signs (depression and weight loss) appear soon after weaning. Liver enzymes and ammonia are elevated, and variable degrees of portal and bridging fibrosis with bile duct hyperplasia, karyomegaly, and cytomegaly are often seen on microscopic examination. The disease is fatal and may end with a terminal hemolytic crisis. The cause is unknown but is thought to be an inherited defect in mitochondrial transporter proteins, such as ornithine, that are required for complete urea synthesis.48
Glycogen branching enzyme deficiency is a fatal autosomal recessive disease of Quarter Horses and Paint Horses caused by a mutation of the glycogen branching enzyme 1 (GBEl) gene that drastically decreases the amount of GBE protein in homozygotes.49 Diseased foals cannot store and mobilize glycogen to maintain normal glucose homeostasis. Those that survive to parturition are often born weak, hypoglycemic, and hypothermic but improve with bottle feeding. Other clinical presentations include progressive muscle weakness, inability to rise, collapse, seizures, flexural limb deformities, respiratory failure, and sudden death. Common laboratory findings include leukopenia, intermittent hypoglycemia, and moderate elevations of serum CK, AST, and GGT activities. Genetic testing is available, but diagnosis can also be made based on liver and muscle biopsies from affected foals.There is no treatment, and all cases to date have been fatal.