Canine Liver Shunt Research Project

Researchers Looks For Genetic Mutations Causing Canine Liver Shunts
Liver shunts, or portosystemic vascular anomaly (PSVA), in toy and small breeds are not uncommon. Oftentimes, a condition known as microvascular dysplasia (MVD) occurs simultaneously. In dogs with PSVA, the accumulation of toxic material can potentially cause neurological problems and even death, whereas MVD is usually clinically silent.

Researchers at Cornell University College of Veterinary Medicine hope to identify the genetic mutations responsible for PSVA/MVD. The goal is to enable discovery of a genetic test that would identify carriers. Among the breeds involved in the study is Shih Tzu.

Liver shunts affect development of the portal vein that carries blood from the intestines to the liver. Affected dogs develop an abnormal blood vessel, the shunt, connecting the portal vein to the vena cava, the large vein in the abdomen that carries blood from the back legs to the heart. This causes a short-circuiting of blood to the heart, detouring circulation around the liver. As a result, the liver cannot cleanse the blood or add important nutrients needed by the body and the brain.

Microvascular dysplasia is an anomaly associated with PSVA in which abnormally miniaturized portal veins can be found in the liver itself. This condition causes microscopic shunting within the liver, but no illness.

“We believe that PSVA is a semilethal condition in which only a small number of these severely affected dogs are born,” says Sharon Center, D.V.M., DACVIM, professor of internal medicine at Cornell University College of Veterinary Medicine. “Some puppies with PSVA are resorbed in utero, many die at birth, and some are recognized as ‘fading puppies.’”

On the other hand, MVD is common and may occur alone or in combination with PSVA. “Our studies confirm that PSVA and MVD should be considered a single trait (PSVA/MVD) with variable severity,” Center says. “Expansive pedigrees of 10 dog breeds we are studying confirm that PSVA/MVD is a genetic condition and that incidence ranges from 30 percent to 80 percent in various breeds.” Center, who has studied the genetic aspects of PSVA and MVD for four years, recently received an AKC Canine Health Foundation grant to identify genetic mutations responsible for the disease. Besides Shih Tzu, other breeds in the study are Border Terrier, Cairn Terrier, Havanese, Maltese, Miniature Schnauzer, Norfolk Ter­rier, Papillon, Pug, Smooth Fox Terrier, Tibetan Spaniel, and Yorkshire Terrier.

“We suspect an autosomal dominant trait with variable penetrance as the mode of transmission,” Center says. “While we have strong linkage between the PSVA/MVD trait and single chromosomal region, our pedigree structures suggest there may be more than a single gene involved.

“It is likely that an ancient mutation preceded segregation of small-breed dogs. Breeders selecting dogs for some characteristic, such as small size, inadvertently selected genes causal for the PSVA/MVD trait.”

Center’s research team has determined that genes responsible for PSVA/MVD are located on a single chromosomal region in five breeds. They currently are trying to determine whether the same region applies to six additional breeds using pedigrees developed by parent clubs.

The research involves using micro­satellite markers to explore whether a region consistently linked to the PSVA/ MVD trait exists in all small-breed dogs with high PSVA/MVD incidence. The trait will be studied in affected dogs, their littermates, dams and sires, and granddams and grandsires, and association analyses using single nucleotide polymorphisms (SNPs) will be completed.

“Until the genetic mutation is known, breeders should not neuter all dogs with high bile acids consistent with the PSVA/MVD trait as it is possible that our genetic work will identify subsets of dogs that can be bred to capture the best breed characteristics,” says Center.

A healthy liver is critical to proper metabolism and filtering of toxins. In normal dogs, toxins are transported from the gastrointestinal system to the liver via the portal vein. Once inside the liver, the portal vein divides into many smaller veins like a tree branch, spreading throughout the liver tissue and allowing toxins to be removed before circulating in the body.

In dogs with a PSVA defect, unfiltered blood from the gastrointestinal system bypasses the liver and circulates throughout the body, exposing extrahepatic tissue to normally removed toxins, especially after a high-protein meat or fish-based meal. The accumulation of toxic material, particularly ammonia, a byproduct of protein digestion, can trigger a host of neurological signs and unusual behavior in as little as 15 to 45 minutes after a meal.

Liver shunts can be congenital, meaning present at birth, or acquired, developing later in life as a result of another illness such as hepatitis or cirrhosis. Shih Tzu, like other toy and small breeds, are more likely to develop extrahepatic shunts located outside the liver. This type of portal vein malformation is easier to correct surgically than intrahepatic shunts located inside the liver. Intrahepatic shunts are more common in large-breed dogs.

Clinical signs of a liver shunt are usually observed before an animal is 1 year old, and can sometimes be seen in puppies as they are weaned. However, some dogs with PSVA and most dogs with MVD show no signs. Thus, they are generally recognized when a veterinarian measures serum bile acid concentration during treatment for an unrelated illness or after prolonged recovery from surgery related to the liver’s inability to metabolize certain anesthetics.

Diagnosis of PSVA requires blood and urine tests. Affected dogs typically have small red blood cells, low blood urea nitrogen (BUN), low cholesterol, and mildly increased liver enzymes (AST and ALT). Bile acid testing, which Center developed in the early 1990s, is the most informative test since dogs with PSVA or MVD are unable to clear bile acids from their systemic circulation.

“Bile acids are produced by the liver and secreted into bile to aid in digestion,” Center explains. “In the intestines they function rather like detergents in breaking down foods for absorption, and then are resorbed into the portal vein from the most distal portion of the small intestines.

“In normal dogs, the liver removes bile acids from the portal blood, but in dogs with PSVA, bile acids spill over into the systemic circulation, where they can be detected in high concentrations. In MVD, the microscopic shunting inside the liver causes the same shunting effect.”

Two blood samples are needed for bile acid testing — one is taken before a dog eats and the second one two hours after a meal. Dogs with shunts will almost always have high bile acid concentrations two hours after eating, and some also have high bile acid concentrations before eating. Dogs with MVD also have high bile acid concentrations.

Center recommends routine serum bile acid testing of small “terrier” type breeds to determine whether the dogs carry the trait and to avoid sudden discovery of abnormal test values later when a dog is being treated for illness. In some instances, sudden discovery of high bile acids could be interpreted as evidence of severe liver injury and result in expensive, invasive tests.

“Testing dogs early in life will protect the more commonly affected MVD dogs from inappropriate bile acid interpretation,” says Center. “We recently showed that measurement of protein C activity can help determine which dogs with high bile acids should be referred for further evaluation for a PSVA.”

Definitive determination of PSVA can only be made using specialized imaging studies. These include:
  • Colorectal scintigraphy, involving deposition of a safe isotope in the rectum and evaluation of isotope distribution via the portal vein to the liver and heart. Scintigraphy does not discern whether shunt vessels are within or outside the liver or whether the shunt is congenital or acquired.
  • Radiographic portography, which uses imaging with an iodinated dye to show blood flow in the portal vein, producing a “map” of the portal vein blood as it flows into and within the liver.
  • Abdominal ultrasound with color flow doppler is one of the least invasive imaging techniques, but also one of the most difficult to perform and interpret. Ultrasound requires an experienced ultrasonographer as shunts can be easily missed, especially if the dog is small or uncooperative.
  • Computer tomography (CT) and magnetic resonance imaging (MRI) are being used more frequently in combination with vascular contrast agents. However, they require expensive equipment and special expertise.

    Medical management of PSVA involves feeding a food to help manipulate intestinal bacteria and pH. “Most dogs with PSVA improve immediately with proper diet, and about one-third of dogs treated medically will live a relatively long life,” Center says. “Dogs that tend to do well with long-term medical management are usually older at the time of diagnosis and have more normal blood work and less severe clinical signs consistent with a lesser degree of shunting.”

    Dietary management involves feeding a prescription restricted-protein canine food that is easily digested, rich in antioxidants and vitamins, and lower in copper and iron. A veterinarian typically tries to balance a dog’s protein needs while minimizing the risk of worsening blood ammonia levels.

    “The nutritional goal is to reduce the amount of protein in the diet and to modify the type of protein ingested,” says Center. “A diet specific for liver disease, such as a specially formulated veterinary brand, is a good idea. Dogs with PSVA must not be fed red meat or fish. Rather, dairy-quality protein, tofu-based protein and, if necessary to promote appetite, white meat chicken should be fed. Vegetables, popcorn, cheese, yogurt, and even ice cream make good treats.”

    Reducing ammonia and other toxins circulating in the body is the aim of medical management. Lactu­lose, a carbohydrate digested by certain intestinal bacteria, helps to acidify the large intestine and promote defecation. This helps to eliminate ammonia and other toxins. Certain antibiotics may also be prescribed to help decrease toxin-producing bacteria in the intestines.

    Surgery provides the best chance for long life in most dogs with extrahepatic PSVA. Though the procedure is common, it is potentially dangerous as it involves application of an ameroid constrictor, a metal ring lined by a material that slowly expands and causes shunt narrowing over three to 14 days postoperatively.

    “This is a difficult surgery and best outcomes are realized in hospitals with an experienced surgical, medical and nursing staff team,” says Center. “Not all dogs are good surgical candidates, and some dogs develop many acquired shunts after application of an ameroid constrictor. Since the liver is an important site for metabolism of certain anesthetics, the combination of general anesthesia and surgery can put undue stress on an already frail animal.”

    Dietary and medical management are the first steps in offering hope to dogs diagnosed with PVSA. Surgery is another alternative and can sometimes be curative. Poten­­tially, a genetic test will be available in the near future to help breeders determine dogs that carry the genetic mutation.

    “Depending on the mode of transmission, it is possible breeders may be able to selectively breed dogs that carry the mutation,” Center says. ”Our work may help to identify subsets of dogs that can be bred to capture the best breed characteristics. I am optimistic we will identify the mutation very soon.”

    Owners of breeds highly susceptible to portosystemic vascular anomaly (PSVA), or liver shunts, and microvascular dysplasia (MVD) should be aware of common signs. These include:

  • Poor growth
  • Lethargy
  • Excessive thirst and urination
  • Diarrhea or vomiting
  • Seizures AND
  • Behavioral changes, such as confusion, circling and head pressing

  • CREDIT: Used with permission from the Purina Pro Club Shih Tzu Update newsletter, Nestle Purina PetCare.