Acute hepatitis can have an infectious, toxic, or undefined cause. Clinical signs may appear suddenly, with horses appearing lethargic, anorectic, and icteric. Photosensitization, diarrhea, and clotting abnormalities also may occur. Neurologic signs resulting from hepatic encephalopathy and/or hypoglycemia can be severe. Clinical signs of endotoxemia may be present, depending on the underlying cause and the ability of the Kupffer cells to remove endotoxin from the systemic circulation.
Increases in serum or plasma sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), glutamate dehydrogenase (GLDH), and aspartate aminotransferase (AST) activities indicate acute hepatocellular injury. Plasma or serum activities of gamma-glutamyl transferase (GGT) and alkaline phosphatase (AP) are increased with cholestasis secondary to hepatocyte swelling. Cholestasis results in hyperbilirubinemia, with the direct (conjugated) bilirubin fraction ranging from 15% to 35% of the total bilirubin in horses. Increased total serum bile acid concentration, decreased glucose and BUN concentrations, and prolonged coagulation times become evident as hepatic function progressively worsens, usually indicating that the disease process is becoming subacute to chronic. Anorexia may lead to hypokalemia. The CBC may reflect an inflammatory response with neutrophilia or endotoxemia with neutropenia (especially in horses), increased band neutrophils, and toxic changes.
Theiler disease is one of the most common causes of acute hepatitis in horses, after ascending cholangiohepatitis Cholangiohepatitis Tyzzer disease is caused by Clostridium piliforme (previously Bacillus piliformis) and results in acute necrotizing hepatitis, myocarditis, and colitis in foals 8–42 days old.... read more . It is primarily a disease of adult horses.
Etiology and Epidemiology of Theiler Disease in Horses
Horses with Theiler disease show clinical signs of hepatic failure 4–10 weeks after receiving a biologic of equine origin, most often tetanus antitoxin (TAT). Theiler disease may develop as a potential complication of the administration of any equine plasma or serum product that includes commercial equine plasma. Some affected horses have no prior history of exposure to such a product but may have been in contact with another horse that received one. Subclinical Theiler disease can also develop after administration of TAT. Most commonly, only one horse on the premises is affected, although outbreaks may occur, or other horses on the farm may have evidence of liver disease (increased enzyme concentrations) without clinical signs.
Occurrence of the disease in groups of adult horses during the late summer or early fall (August to November) suggests an infectious (viral) or vector-transmitted etiology. The seasonal occurrence may reflect the confounding fact that many foaling mares receive TAT in the spring of the year along with their newborn foals. Lactating mares that receive TAT at foaling seem to be more susceptible. Historically, a type III (immune complex−mediated) hypersensitivity reaction also has been proposed. However, recent research documents a viral cause for acute hepatic necrosis, with three different Theiler disease–associated viruses in the Hepacivirus genus of Flaviviridae, and increasing evidence for a causative virus in the Parvoviridae family.(1 References Acute hepatitis includes the acute or peracute onset of clinical signs of liver disease; however, it may be due to acute disease or acute exacerbations of chronic disease. The term "hepatitis"... read more )
Clinical Findings of Theiler Disease in Horses
The onset of clinical signs in Theiler disease is acute. Acute mortality may be 50%–60%, with overall mortality as high as 88% in affected horses. Horses with Theiler disease typically present with anorexia, hepatic encephalopathy, and icterus. CNS signs vary, ranging from lethargy to aggression or maniacal behavior, central blindness, and ataxia. Photosensitivity and discolored urine may occur as a result of high bilirubin concentrations. Fever is present in ~50% of cases. Weight loss (uncommon), ventral edema, jugular pulses, ileus, and acute respiratory distress have been observed in some horses with Theiler disease. These findings suggest there may be a subclinical phase before overt hepatic failure develops. Intravascular hemolysis with hemoglobinuria may occur in some terminal cases. Most cases are sporadic; however, outbreaks involving several horses have been reported. If Theiler disease is recognized in one horse, all horses on the same premises should be carefully monitored for clinical or serum biochemical signs of hepatic disease.
Plasma or serumactivities of hepatocellular and biliary enzymes are increased. GGT is frequently further increased during the first few days of illness, despite clinical improvement and eventual recovery in an affected horse. Horses with AST values of > 4,000 IU/L have a poor prognosis. AST activity decreases within 3–5 days in horses that improve, and SDH activity decreases even more rapidly. The total serum bilirubin concentration is generally higher in horses with Theiler disease than in horses with anorexia. Hyperbilirubinemia is common, with the unconjugated form being > 70% of the total. Total serum bile acid concentrations are increased. Moderate to severe acidosis, hypokalemia, polycythemia, increased plasma aromatic amino acids, and hyperammonemia may also be present.
At necropsy, icterus and varying degrees of ascites are present. The liver is usually small or normal in size; occasionally, however, it may be enlarged (peracute cases), with a mottled and bile-stained surface. Histologically, there is marked centrilobular to midzonal hepatocellular necrosis with apoptosis and mild to moderate mononuclear infiltrate. Mild to moderate bile duct proliferation may occur in some animals with more chronic disease.
Diagnosis of Theiler Disease in Horses
History of plasma product administration in the previous 4–10 weeks
Acute elevations of plasma hepatocellular enzymes
Ultrasonographic examination documenting decreased liver size and enabling biopsy, culture and sensitivity evaluation
Diagnosis is based on history of plasma product exposure, acute onset of clinical signs, and laboratory findings suggestive of hepatic insufficiency. In some cases, the liver is shrunken and difficult to visualize ultrasonographically. A definitive diagnosis can be made only by liver biopsy or necropsy. Experimental equine viral hepatitis serum PCR assays are available. Differential diagnoses include acute pyrrolizidine toxicosis Pyrrolizidine Alkaloid Toxicosis Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more , hepatotoxicoses Hepatotoxins in Large Animals Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more , cholangiohepatitis Cholangiohepatitis Tyzzer disease is caused by Clostridium piliforme (previously Bacillus piliformis) and results in acute necrotizing hepatitis, myocarditis, and colitis in foals 8–42 days old.... read more , mycotoxicosis Mycotoxicoses Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more , cerebral disease (if CNS signs are present), and hemolytic disease (if hemolysis or coagulopathy is present).
Treatment of Theiler Disease in Horses
No specific treatment is available
Supportive care, including fluids, nutritional support, and sedation if necessary
There is no specific treatment for Theiler disease. Supportive care (intravenous fluids with glucose and potassium added) and treatment of the hepatic encephalopathy may be successful. Stressful situations, such as moving the animal or weaning a mare’s foal, may exacerbate the clinical signs of hepatic encephalopathy and should be avoided during the acute hepatic crisis. Sedation should be used only to control behavior that could lead to injury of the patient or handlers and to allow diagnostic or therapeutic procedures.
Recovery depends on the extent of hepatocellular necrosis and eventual fibrosis. Affected horses that remain stable for 3–5 days and that continue to eat may recover. Decreases in SDH concentration and prothrombin time, along with improvement in appetite, are the best positive predictive indicators of recovery. Horses with rapid progression of clinical signs, uncontrollable encephalopathy, hemorrhage, or hemolysis have a poor prognosis. For affected horses that do recover, the longterm prognosis is good. In some horses, progressive weight loss and death may occur during the months after the initial clinical signs.
Prevention of Theiler Disease in Horses
Use of tetanus antitoxin (TAT) or other plasma products is not without risk. Routine administration of TAT to periparturient mares is strongly discouraged. Use of TAT should be restricted to situations in which tetanus prophylaxis is necessitated and a history of active tetanus toxoid immunization is absent or unknown.
Acute Hepatic Necrosis in Cattle
Epidemiology and Pathogenesis of Acute Hepatic Necrosis in Cattle
Acute hepatic disease and failure in cattle most commonly results from a toxic insult. Hepatocellular necrosis with clinical and laboratory evidence of hepatic failure may develop in cattle after mastitis or metritis with clinical signs of endotoxemia. Endotoxin induces hepatocellular necrosis through both direct and indirect effects on the liver. Endotoxin can cause Kupffer cells to release lysosomal enzymes, prostaglandins, and collagenase that damage hepatocytes, or it may interact directly with the hepatocytes, causing lysosomal damage, decreased mitochondrial function, and necrosis. Endotoxin-related hepatocellular necrosis may be due in part to decreased hepatic blood flow and liver hypoxia.
Clinical Findings and Lesions of Acute Hepatic Necrosis in Cattle
Clinical signs of acute hepatic necrosis in cattle include weight loss, anorexia, and cessation of milk production. Photosensitization and mild icterus vary. Plasma or serum sorbitol dehydrogenase (SDH), gamma-glutamyl transferase (GGT), and aspartate aminotransferase (AST) activities are mildly to severely increased. Fatty liver or ketosis is not characteristic. The liver may be normal in size or mildly enlarged on ultrasonography or necropsy. Histologically, there is marked hydropic change with varying degrees of hepatic necrosis.
Diagnosis of Acute Hepatic Necrosis in Cattle
History of acute primary disease causing endotoxemia
Increases in plasma hepatobiliary enzyme activities
Diagnosis of acute hepatic necrosis is based on a history of hepatic-related clinical signs developing concurrently or after a primary disease (eg, toxic mastitis) and endotoxemia. Increases in hepatic and biliary enzymes and absence of ketosis support the diagnosis. Definitive diagnosis is based on liver biopsy and on the exclusion of other infectious, toxic, and inflammatory causes of hepatic dysfunction. Differential diagnoses include other causes of subacute or chronic liver disease (eg, hepatotoxins, hepatic lipidosis Hepatic Lipidosis ) and conditions causing weight loss and hypophagia.
Treatment of Acute Hepatic Necrosis in Cattle
Control of endotoxemia
Nutritional and fluid treatments are often successful in affected cows with acute hepatic necrosis after transient insults. Forced feeding of alfalfa meal (15% protein) and dried brewers’ grain or beet pulp with potassium chloride and normal rumen fluid is recommended. Intravenous administration of polyionic fluids with 5% dextrose, potassium chloride, and B vitamins may also be needed. Control of endotoxemia and treatment of the primary disease condition are essential.
Zehetner V, Cavalleri JV, Klang A, et al. Equine parvovirus-hepatitis screening in horses and donkeys with histopathologic liver abnormalities. Viruses. 2021;13(8):1599. doi: 10.3390/v13081599. PMID: 34452465; PMCID: PMC8402897.