Equine Liver Disease: More Common Than We Think?

Newly identified liver viruses in horses might be more common than we realize.
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Equine Liver Disease: More Common Than We Think?
Tomlinson emphasizes that many horses can test positive on polymerase chain reaction (PCR) tests for a liver virus, yet the pathogen isn’t actively causing disease, and the horse doesn’t show clinical signs. For this reason infections can go undetected in apparently healthy horses. | The Horse Staff

Decades ago, practitioners recognized that the practice of administering an equine-origin biologic product at vulnerable times—to avoid tetanus infection, for instance—could put equine patients at risk for developing Theiler’s disease, or equine serum hepatitis, which can lead to liver failure. For years they suspected viruses were likely at play, but little more. In recent years new information has come to light that explains why Theiler’s disease and the liver viruses that cause it result in consequential health issues. Additionally, researchers have been trying to determine how liver viruses are naturally transmitted between horses, and manufacturers of biologic products are taking additional steps to prevent inadvertent introduction of certain liver viruses.

Identifying New Hepatic Viruses

Since 2012 researchers have identified five new liver viruses in equids:

  1. Nonprimate equine hepacivirus (EqHV, aka nonprimate hepacivirus, or NPHV)
  2. Equine pegivirus-1 (EpgV-1)
  3. Equine pegivirus-2 (EpgV-2, previously known as Theiler’s-disease-associated virus, or TDAV)
  4. Equine parvovirus-hepatitis (EqPV-H)
  5. Equine hepatitis B (EqHBV, so far only identified in donkeys and zebras)

Testing for Liver Viruses

Joy Tomlinson, DVM, Dipl. ACVIM, research associate at Cornell University’s College of Veterinary Medicine, in Ithaca, New York, investigates viral liver diseases. “We don’t recommend testing for liver viruses unless there is already a diagnosis of liver disease,” she says. “This might be based on veterinary examination of a horse for lethargy, inappetence, icterus (yellow whites of the eyes and gums), and/or abnormal mentation such as persistent yawning, playing in the water bucket, ataxia (incoordination), head-pressing, compulsive walking. Bloodwork done during such an exam, or for any other reason, may also reveal abnormal liver function values.”

She emphasizes that many horses can test positive on polymerase chain reaction (PCR) tests for a liver virus, yet the pathogen isn’t actively causing disease, and the horse doesn’t show clinical signs. For this reason infections can go undetected in apparently healthy horses, and they might even be missed in horses with fever of unknown origin; equine hepacivirus and equine parvovirus, for instance, do not cause a fever, she says, so veterinarians wouldn’t test for either virus.

“There aren’t yet clear published criteria for histopathologic indicators of viral liver disease,” she adds. “This means that pathology reports don’t always pick up on possible viral disease yet.”

Hepacivirus (EqHV)

The equine hepacivirus is the closest known virus to human hepatitis C. This hepatotropic (showing an affinity for the liver) infection causes disease with a high viral load in the liver and serum. Tomlinson says EqHV causes both acute and chronic disease, but an acute infection typically doesn’t cause overt signs. Equine hepacivirus is not associated with Theiler’s disease (described below).

After a horse is exposed and becomes infected, viremia (virus in the bloodstream) occurs quickly, with the horse seroconverting (developing antibodies in the blood to the virus) six to eight weeks later—this is the point when antibodies to the virus attempt to clear the disease. At that time, a reaction within the inner tissues of the liver (lymphocytic and plasmocytic reaction in the portal area) leads to cellular necrosis.

“Disease is probably caused when the immune system kills infected cells or when chronic inflammation from persistent infection causes damage and tissue remodeling,” says Tomlinson.

Serology (blood serum) testing shows up to 80% of horses have antibodies to EqHV in their blood, indicating they’ve been exposed but have not necessarily experienced active infection. Active infection develops in 2-35% of horses. Most clear the infection spontaneously within six months, but a small proportion remain infected for years.

In horses that clear the infection, hepacivirus does not appear to cause clinical disease. Researchers believe the reason most cases remain subclinical is because the liver has such a high reserve and regenerative capacity. Blood chemistry values might reveal elevated liver enzymes, although these tend to remain within normal reference ranges. In a few unusual cases, however, horses have developed severe liver disease with irreversible changes. Veterinarians can PCR test blood serum or liver tissue from these clinically affected horses to confirm infection and perform liver biopsies to help determine the cause of disease.

Some horses chronically infected with hepacivirus develop persistent, chronic hepatitis. “The only practical way to make this connection is to rule out other causes and demonstrate that infection persists beyond six months,” says Tomlinson. More research is needed to determine immediate diagnostic approaches.

Scientists have proven EqHV transmission through blood inoculation, and vets have reported vertical transmission to a foal through the uterus, but it’s unclear how the virus naturally infects adult horses. “An investigation (by Marcha Badenhorst) analyzed nucleic acids isolated from mosquitoes in Austria with no detection of EqHV RNA in the mosquito pools,” says Jessika Cavalleri, Dr.med.vet., Dipl. ECEIM, head of the clinical unit of equine internal medicine at the University of Veterinary Medicine in Vienna, Austria. “Yet, these negative results do not prove that insects don’t transmit the virus.”

Equine Parvovirus (EqPV-H)

The hepatotropic equine parvovirus-hepatitis develops a late viremia about two weeks after the horse receives a contaminated serum or biologic product. It has a strong association with Theiler’s disease; at six weeks antibody production stimulates hepatic disease as these blood proteins try to clear virus from liver cells.

As infected cells die, liver enzymes increase dramatically along with the lymphocytic/plasmocytic infiltrate in the liver’s periportal area. The sick horse develops jaundice, depression, anorexia, lethargy, high bilirubin (a waste product from clearing dead red blood cells) levels, and potentially neurologic deficits such as blindness, head-pressing, and ataxia.

While hepatitis can persist for a couple of weeks, most horses that survive five to seven days recover. EqPV-H is not likely to cause chronic liver disease, but it does remain detectable at low levels in the blood for months to years after infection. “To confirm that liver disease is caused by EqPV-H, use of repeated serum PCR can identify high levels at the initial diagnosis, which drop as the hepatitis improves,” says Tomlinson. “Liver biopsy is also important to show that the disease is caused by the virus—we can use a special type of stain, called in situ hybridization, to elucidate this.” (The veterinarian completes a liver biopsy via an incision between ribs on the right side of the standing horse.)

Results from one study of 10 horses with Theiler’s disease that hadn’t received biologic products showed nine of them were infected with equine ­parvovirus. ­Many other horses on the same farms were also infected. This suggests a possible mechanism for direct horizontal transmission from horse to horse, especially on broodmare farms. Most of these contact cases occur between May and November. With an incubation period of four to 12 weeks, it is likely that exposure occurs between March and October, which could suggest insect transmission.

In one study Tomlinson attempted to infect horses via horse flies, but to no avail, though scientists have been able to demonstrate infection using intravenous and intra-articular administration and oral and nasal inoculation. “Insect vectors remain a concern due to the seasonal nature of Theiler’s cases,” she says. “The study couldn’t prove transmission, but it also didn’t rule it out.” Other biting insects such as ticks, mosquitoes, and midges are possible vectors.

In experimental infection studies researchers have identified intermittent shedding of EqPV-H through nasal, oral, and fecal routes, particularly at the time of peak viremia and for at least 10 weeks following infection. This is another possible explanation for how horses not receiving biologic products could be infected just by being in contact with a horse carrying the virus. Scientists have not documented vertical EqPV-H transmission through the uterus to the foal.

Tomlinson describes the difficulties of implementing biosecurity practices for EqPV-H: “By the time a case of Theiler’s disease is identified, that horse has been infected and shedding for weeks,” she says. “The logistics of trying to identify other infected horses for isolation or segregation would be daunting since the incubation period from exposure to viremia can exceed 10 weeks. Then, the course of viremia can last many weeks at high viremia and months to years at low viremia. We don’t know yet if those ‘chronic’ carriers are infectious.”

She acknowledges that other sources of infection might be possible, including veterinary equipment such as dental floats, endoscopes, or any tools that contact a horse’s blood or mucous membranes.

“Parvoviruses are hardy, and a quick rinse in chlorhexidine between horses is unlikely to adequately sterilize equipment,” she says.

A point of great significance from the research is that equine parvovirus exists in healthy horses. Up to 35% of horses worldwide are seropositive, and a similar number are PCR-positive (meaning they’re actively infected), indicating worldwide circulation of this virus.

Pegiviruses (EpgV and TDAV)

The pegiviruses are not of clinical concern in most cases. These viruses replicate in the horse’s bone marrow and are not pathogenic or hepatotoxic. “There are no recognized pathogenic effects of pegiviruses in any species,” says Tomlinson. “They might modulate the immune system overall, but that effect is uncertain. Horses do eventually clear the infection, and no liver disease is observed.”

Hepatitis B

Scientists have detected a recently identified equine hepadnavirus (hepatitis-B-associated) in donkeys and zebras worldwide. At this time, says Tomlinson, we don’t know if it infects horses.

horse in fly gear
Biting insects such as mosquitoes, ticks, and midges are possible vectors of some liver viruses; insect control methods might help prevent transmission. | iStock

Preventing Liver Viruses

Researchers have not documented confirmed cross-species transmission of any equine hepatitis virus. Increasing age seems to be a risk factor for EqPV-H infection, with higher prevalence in ages 16-31. This is likely because of the prolonged duration of infection, says Tomlinson.

Cavalleri says she wonders whether only blood contains infectious virus particles or if secretions or excretions can also be infectious. “For transmission, horses need to get in contact with infectious virus,” she explains. “This happens through different routes like mechanical transmission of blood-contaminated equipment or through biting insects. It is also possible that virus-containing secretions like nasal discharge, saliva, or feces contribute to transmission.”

In utero transmission of EqHV appears to be low and has not been demonstrated for EqPV-H. “The only way to minimize risk would be to test mares and maintain a negative herd,” says Tomlinson. “More information is needed about the clinical risk of infection for a foal, and while this is an area of active investigation, it is too early to make clear ­recommendations.”

Because scientists have confirmed horses can get liver viruses from contaminated biologic products, in the past two years manufacturers have been monitoring and purifying equine-origin biologic products to prevent Theiler’s-like disease caused by administering licensed products. The USDA requires EqPV-H testing of all donor horses and all antitoxin, antibody, serum, or plasma products of equine origin.

The USDA regulations don’t yet cover EqHV testing, but multiple companies are already screening horses for EqHV before they enter the donor herds. The USDA might implement testing regulations for EqHV in coming years based on new data about EqHV-associated chronic hepatitis.

Of greatest concern is the risk of transmission from a subclinically infected horse to one in contact with it. “Biosecurity protocols aiming to reduce spread of blood, secretions, and excretions and limiting direct horse-horse contact seem sensible when horses are shedding virus,” says Cavalleri. “However, it can be difficult to determine the time of shedding, especially considering the large proportion of subclinical infections in EqPV-H and EqHV and the unknown route of natural, horizontal transmission of virus.”

Take-Home Message

Liver viral disease research is a rapidly evolving field, says Tomlinson. Though researchers haven’t yet made specific recommendations for preventing transmission, farm owners should always practice smart biosecurity strategies and protect against blood-­feeding insect vectors.

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Written by:

Nancy S. Loving, DVM, owns Loving Equine Clinic in Boulder, Colorado, and has a special interest in managing the care of sport horses. Her book, All Horse Systems Go, is a comprehensive veterinary care and conditioning resource in full color that covers all facets of horse care. She has also authored the books Go the Distance as a resource for endurance horse owners, Conformation and Performance, and First Aid for Horse and Rider in addition to many veterinary articles for both horse owner and professional audiences.

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