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Basics ⬇

Outline

BASICS

Overview!!navigator!!

The clinical disease (acute hepatitis, Theiler disease, serum hepatitis) is characterized by fulminant hepatic failure and encephalopathy in adult horses. There appear to be 3 separate epidemiologic diseases with identical clinical, clinicopathologic, and pathologic findings:

  • Acute, often fulminant hepatitis in horses that have received equine-origin blood products approximately 4–10 weeks earlier and less severe to subclinical disease in other horses receiving the same product
  • Acute, sometimes fulminant hepatitis occurring in a horse that was in contact with a blood product-inoculated Theiler disease horse, but that did not itself receive the equine-origin blood product
  • Acute, fulminant hepatitis in horses (often broodmares on pasture in the fall) with no known equine-origin blood product administration. This last syndrome can occur as farm outbreaks

Signalment!!navigator!!

Adult horses, particularly those with a history of receiving equine-origin serum (especially tetanus antitoxin) or plasma approximately 4–10 weeks earlier. May also be horses without recent history of equine blood product administration (nonbiologic origin acute hepatitis).

Signs!!navigator!!

  • Usually sudden in onset and rapidly progressive, with death occurring 2–6 days later in some cases
  • Horses are often icteric and pass dark urine owing to the presence of bilirubin
  • Many have signs of hepatic encephalopathy including acute blindness and aimless wandering around the stall or paddock
  • Frequent yawning has been reported. Other neurologic signs may range from mild to severe depression or coma to maniacal behavior or seizures
  • Hemolysis and hemoglobinuria may be present, are poor prognostic indicators, and are thought to be the result of damage to the red blood cells passing through the damaged sinusoids, oxidative damage resulting from liver failure, or release of large amounts of copper or iron from the diseased liver
  • Some horses may have signs of photosensitivity and abdominal pain

Causes and Risk Factors!!navigator!!

  • Most commonly associated with administration of an equine-origin blood product 4–10 weeks before the onset of signs. Some epidemiologic evidence suggests that some cases may result from an infectious agent
  • Currently, there are at least 4 viruses that can establish chronic/persistent infection in horses and are being studied for their possible association with liver disease. NPHV (also called equine hepacivirus [EHCV]), TDAV, and EPgV are from the family Flaviviridae, genus Hepacivirus, which also includes the human hepatitis C virus. The fourth virus, EqPV-H, is in the family Parvoviridae, genus unclassified

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

Differential Diagnosis!!navigator!!

  • Acute onset of icterus in adult horses has multiple causes—prehepatic, hepatic, or posthepatic; serum biochemistries and CBC assist in differentiating these causes:
    • Prehepatic—red maple or wild onion toxicity, equine infectious anemia, immune-mediated hemolytic anemia poisoning
    • Hepatic—anorexia, Theiler disease, Clostridium novyi, bacterial cholangiohepatitis, hepatotoxicity
    • Posthepatic—cholelithiasis and other causes of biliary obstruction
  • Signs of HE can be very similar to those of several acute neurologic diseases—rabies, Eastern equine encephalomyelitis, Western equine encephalitis, and acute protozoal myeloencephalitis. Icterus and serum biochemical changes help in differentiating these problems
  • Hematuria, hemoglobinuria, myoglobinuria, and bilirubinuria may cause pigmenturia; urinalysis and serum biochemistries aid in differentiation. Urine from horses with hepatic failure will have green-colored bubbles (bilirubinuria) when shaken and this can serve as a useful point-of-care test to differentiate liver failure and HE from other causes of encephalopathy including encephalitides

CBC/Biochemistry/Urinalysis!!navigator!!

  • CBC—usually normal, a small number of horses may have thrombocytopenia likely associated with disseminated intravascular coagulation
  • Biochemistry—typical of acute, severe liver disease predominantly affecting hepatocellular function
  • Marked increase in aspartate aminotransferase (often nearly 2000 IU/L; >4000 IU/L seems to be associated with a poor prognosis)
  • Marked elevations in SDH and GLDH
  • Moderate increases in biliary-derived enzymes (GGT usually increased to 100–300 IU/L). GGT continues to increase during initial recovery due to bile duct hyperplasia and this should not be interpreted as a poor prognostic indicator. GGT may remain elevated, although progressively decreasing values, for ≥2 weeks after clinical recovery
  • Both conjugated and unconjugated bilirubin are increased with conjugating often constituting less than 20% of total bilirubin
  • Increased anion gap
  • Mild hyperglycemia, rarely hypoglycemia
  • Urinalysis—bilirubinuria and hemoglobinuria. The latter is a poor prognostic indicator

Other Laboratory Tests!!navigator!!

  • Prolongation of prothrombin time and partial thromboplastin time
  • Hyperlactatemia
  • Hyperammonemia
  • Elevated bile acids
  • Equine hepatitis virus PCR panel is available for research and informational purposes. Panel includes PCR testing for TDAV, NPHV, EPgV, and EqPV-H. (Note that there is no evidence for EqPeg causing liver disease in horses and testing may not be warranted.) Submit serum, fresh or formalin-fixed paraffin-embedded liver, or equine biologic products to the Cornell University Animal Health Diagnostic Center

Imaging!!navigator!!

Ultrasonography may suggest the liver is smaller and more hypoechoic than normal. May appear otherwise unremarkable.

Other Diagnostic Procedures!!navigator!!

Liver biopsy is not indicated in horses with “classic” signs of Theiler disease as histologic data will likely not change therapy.

Pathologic Findings!!navigator!!

  • The liver is almost always smaller than normal. In 13 cases of Theiler disease, liver weight in comparison with body weight was 1%. In healthy control horses, liver weight was 1.6% of body weight, suggesting a 40% decrease in hepatic size following disease
  • Histologically, affected livers show severe centrilobular or massive liver necrosis/apoptosis with portal areas less severely affected but with a mononuclear cell infiltration and slight to moderate bile duct proliferation, with or without fibrosis. Vasculitis has occasionally been reported. Alzheimer type II astrocytes are present in the brain in virtually all of the cases

Treatment ⬆ ⬇

TREATMENT

  • Goals of therapy are to treat or prevent HE, provide supportive care including IV fluids, nutritional support, and antioxidant, anti-inflammatory, and antibiotic therapies
  • Restrict activity, and avoid sunlight
  • In cases with HE, house the horse in a quiet place, preferably padded to prevent injury
  • Fluid therapy—correct deficits using hypertonic saline (7.5%, 4 mL/kg) or balanced isotonic crystalloid fluid preferably with an acetate rather than a lactate buffer at 20–30 mL/kg for the first hours with 50 g dextrose and 20 mEq KCl added to each liter. Continue at maintenance rate in patients that are not eating and drinking. Multiple B vitamins can be added to the fluids
  • Nutritional support—if the horse is still eating, a high-carbohydrate, low-protein diet is recommended. Highly palatable grass hay (fed at approximately 1.5% of body weight per day) along with small amounts of high glycemic feeds at <1.0 g/kg/day should be offered in 4–6 meals per day. The protein should be high in BCAAs. Sorghum or soaked beet pulp have high concentrations of BCAAs. Commercial BCAA pastes can be administered in patients that are not eating

Medications ⬆ ⬇

Outline

MEDICATIONS

Drug(s) of Choice!!navigator!!

  • Control of HE includes decreasing GI-derived neurotoxins (predominantly ammonia), decreasing cerebral edema, correcting glucose, electrolyte, and acid–base abnormalities, and maintaining perfusion and oxygenation to the brain and other vital organs. Ideally, all sedation should be avoided, but to prevent injury detomidine (5–10 µg/kg IV) can be used. If more long-term sedation is required, gabapentin (5–12 mg/kg PO every 12 h) or pregabalin (2–4 mg/kg PO every 12 h) could be considered. Conversely, in horses with profound coma, sarmazenil (0.04 mg/kg IV) or flumazenil (0.01–0.02 mg/kg IV) may be useful GABA receptor antagonists
  • Metronidazole (15 mg/kg PO every 12 h), Neomycin (10–20 mg/kg PO every 8 h) and/or lactulose (0.3–0.5 mL/kg PO or per rectum every 8 h) may help reduce ammonia production and absorption from the GI tract
  • Anti-inflammatory treatment—pentoxifylline (7.5 mg/kg PO or IV (compounded) every 8–12 h) to reduce systemic inflammation
  • Antimicrobial therapy—bactericidal antibiotic (e.g. ceftiofur) to prevent bacterial translocation from GI tract to blood
  • Antioxidant therapy—acetylcysteine by slow IV administration (up to 100 mg/kg) diluted in 5% dextrose. S-adenosyl methionine (10–15 mg/kg PO) to provide antioxidant effect

Contraindications/Possible Interactions!!navigator!!

  • Neomycin should not be given for more than 24–36 h; it may induce severe diarrhea
  • Avoid overly sedating horses with HE as excessive lowering of the head in the standing horse may induce cerebral edema
  • Ideally, all oral medications should be given by dose syringe rather than nasogastric tube as nasal bleeding resulting from passage of a stomach tube can result in ingestion of considerable amounts of blood protein, which would likely increase blood ammonia production
  • Because the liver metabolizes many drugs, their duration of action may be increased in acute hepatic disease

Follow-up ⬆ ⬇

Outline

FOLLOW-UP

Patient Monitoring!!navigator!!

Monitor liver enzymes and bilirubin every 2–3 days. Maintain adequate serum potassium levels to reduce hyperammonemia.

Expected Course and Prognosis!!navigator!!

  • Horses with severe HE have a poor prognosis. Horses that continue to eat for 3 days and have supportive treatments may fully recover
  • Decline in serum SDH and GLDH after 2–3 days of treatment along with concurrent improvement in clinical signs suggests a favorable prognosis
  • There are no proven long-term consequences in horses that recover

Miscellaneous ⬆ ⬇

MISCELLANEOUS

Abbreviations

  • BCAA = branched-chain amino acid
  • EPgV = equine pegivirus
  • EqPV-H = equine parvovirus
  • GI = gastrointestinal
  • GGT = γ-glutamyltransferase
  • GLDH = glutamate dehydrogenase
  • HE = hepatic encephalopathy
  • NPHV = nonprimate hepacivirus
  • PCR = polymerase chain reaction
  • SDH = sorbitol dehydrogenase (IDH)
  • TDAV = Theiler disease-associated virus

Suggested Reading ⬆ ⬇

Chandriani S, Skewes-Cox P, Zhong W, et al. Identification of a previously undescribed divergent virus from the Flaviviridae family in an outbreak of equine serum hepatitis. Proc Natl Acad Sci USA 2013;110(15):E1407–1415.

Divers TJ. The equine liver in health and disease. Proc Am Assoc Equine Pract 2015;61:81–103.

Author(s) ⬆

Authors: Kathleen R. Mullen and Thomas J. Divers

Consulting Editors: Michel Lévy and Heidi Banse

Acknowledgment: The authors and editors acknowledge the prior contribution of Christopher M. Brown.