Exploring the Mysteries of Liver Shunts

By Jerold S Bell, DVM, Tufts University School of Veterinary Medicine
(This article originally appeared in the “Healthy Dog” section of the April, 2005 AKC Gazette)

Five out of every 1,000 dogs in the general population are born with an inherited liver shunt. This condition, also called a porto-systemic shunt (PSS), is an abnormal blood vessel that bypasses the liver. The portal vein carries blood drainage from the gastrointestinal system. This blood contains nutrients, but also the waste products from digestion. Because of these waste products, the portal blood is kept separate from the rest of the (systemic) blood supply, and sent to the liver for processing.

A major portion of the waste product from protein digestion is ammonia. The liver metabolizes ammonia into urea, which is then sent to the systemic circulation through the vena cava (the major vein in the body). The kidneys filter the urea into the urine for disposal.

A porto-systemic shunt bypasses the liver, placing the portal blood into the vena cava instead. The high level of unprocessed blood ammonia and waste products can affect the brain, causing drooling, mental dullness, and seizures. This condition, called hepatic encephalopathy, can worsen after a high-protein meal. Because of the lifelong effect of waste products on all cells in the body, affected dogs can be stunted in size.

A liver shunt can be diagnosed by measuring elevated blood bile acid and ammonia levels. Most affected dogs showing clinical signs of hepatic encephalopathy can be diagnosed through a single (non-fasted) blood level. Pre-breeding screening for subclinically or mildly affected dogs requires paired, fasted, and post-meal values to make a diagnosis.

The type of liver shunt varies between affected dogs. The shunt may be a single large blood vessel, or may involve many small vessels. It can run along the outside of the liver, or be totally encased in the body of the liver. Large shunts can be diagnosed by an experienced ultrasonographer, or through a surgical contrast radiograph called a portogram. Some dogs have a disorder called hepatic microvascular dysplasia (HMD), in which the defective vessels connecting systemic and portal circulations are not large enough to be identified by ultrasound. Because of this, the definitive diagnosis for the condition requires blood measurements.

Treatment
The best way to treat a young dog with a liver shunt is through surgery. This is possible if the shunt is a large blood vessel, either inside or outside the liver. A surgeon narrows the shunt, so that a majority of the portal blood will now enter the liver. The shunt cannot be completely closed, or the liver – which because of the shunt is not accustomed to receive a high volume of portal blood – will swell and back up. This can cause fluid to build up in the abdomen (ascites), and cause liver failure. By narrowing the shunt, most affected dogs will go on to live normal lives.

If the liver shunt is microvascular, or if surgery is not a possibility, medical management may reverse the signs of hepatic encephalopathy. One third of affected dogs do well with medical management, living an average of seven years. Diets with high levels of crude protein should be avoided. Depending on the extent of clinical signs, dogs should be fed either a senior diet, or a special prescription diet. A medication called lactulose will bind to ammonia in the intestines. This prevents ammonia from being absorbed into the portal circulation, so it is eliminated in the stool. Certain antibiotics will also reduce the amount of ammonia producing bacteria in the intestines.

Breed Prevalence
Thirty-three breeds are significantly more likely to have a liver shunt than the general dog population. The breeds with the highest risk include: the Havanese, Yorkshire Terrier, Maltese, Dandie Dinmont Terrier, Pug, Miniature Schnauzer, Standard Schnauzer, Shih Tzu, Bernese Mountain Dog, and Bichon Frise. The majority are small-sized breeds, but the condition is also seen in large breeds, such as the Irish Wolfhound, Scottish Deerhound, and Old English Sheepdog.

Dr. Karen Tobias, a surgeon at the University of Tennessee College of Veterinary Medicine, has been performing epidemiological studies on congenital canine liver shunts. She has found that the incidence of liver shunts in Yorkshire Terriers has increased more than 11 times over the past 20 years. On average, approximately three percent of all Yorkshire Terriers have a porto-systemic shunt. The genes causing liver shunts in the breed are old and widespread, as inbreeding does not significantly increase the incidence of the disorder.

Tobias has found that mating two (surgically corrected) affected Yorkshire Terriers produced normal offspring – which eliminates simple autosomal recessive as the mode of inheritance. Tobias has also found that if two Cairn Terriers with microvascular shunts are bred together, they can also produce affected offspring with single, large liver shunts. This finding suggests than liver shunts can show variable expressivity, and that the single vessel and microvascular shunts may be caused by the same genes.

Genetic studies into liver shunts in Yorkshire Terriers, Cairn Terriers, Irish Wolfhounds, and Maltese have all proven a hereditary basis. It appears to be autosomal, as there is an equal ratio between affected male and female dogs. It is probable that the condition is polygenic, or controlled by more than one gene pair.

Tobias recommends testing fasting and post-feeding bile acids and blood ammonia levels on all prospective breeding stock, and to refrain from breeding dogs with elevated levels. This will eliminate phenotypically affected dogs from breeding. There is an increased risk for phenotypically normal siblings and first-degree relatives of affected dogs to be carriers of liver shunt liability genes. Therefore, breadth of pedigree normality (normal- testing littermates) is important in selecting breeding stock.

For permission to reproduce this article, please contact Dr. Bell:  jerold.bell@tufts.edu

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Managing Polygenic Disease: Canine Hip Dysplasia as an Example by Jerold S. Bell, DVM

Jerold S Bell, DVM
Cummings School of Veterinary Medicine at Tufts University, N. Grafton, MA

Polygenic disorders have been difficult for breeders to control. Examples are hip dysplasia, congenital heart defects, and epilepsy. Controlling polygenically inherited disorders involves; 1) identifying traits that more closely represent genes being selected against, 2) the standardization of nuisance factors (such as environment) that can limit your selective pressure against the genes and 3) selecting for breadth of pedigree as well as depth of pedigree.

Hip dysplasia is a classic example of a polygenically controlled hereditary disease. Due to genetically controlled defects in anatomy and/or joint laxity, affected dogs can become lame, and eventually crippled due to secondary osteoarthritis. The genetic test used to control hip dysplasia is the pelvic radiograph (x-ray).

To control polygenic disorders, they must be considered as threshold traits.  A number of genes must combine to cross a threshold producing an affected individual. Genes that combine in an additive manner are considered quantitative genes. If we theoretically state that five quantitative genes contributing to hip dysplasia can produce a dysplastic dog, then dogs receiving less than five genes from their parents would have      normal      hips. If  phenotypically normal parents produce affected offspring, both should be considered to carry a genetic load that combined to cause the disorder.

Many polygenic disorders have a major recessive or dominant trigger gene that must be present to produce an affected individual. Genes that act in a dominant or recessive manner are considered qualitative genes. If qualitative genes play a role in hip dysplasia, then it is possible that dogs with more than the threshold of quantitative genes could be phenotypically normal if they do not carry a qualitative trigger gene. They would pass on a high liability for dysplasia through their contributing high numbers of the additive genes.

A trigger gene in one breed or family may be different from the gene in others. Consequently, if a test for a trigger gene is developed in one breed or family, it may not provide useful information for all breeds or families. Molecular genetic research to identify major qualitative disease causing genes can allow better control of polygenic disorders such as hip dysplasia, epilepsy, and cataracts.

Breeders must break down hip phenotypes into traits that more directly represent the genes that control them.

One reason we have not had great progress with hip dysplasia control is that it is being treated as a single gene disease, with a test for carriers. There is no excellent hip gene, although that is what most breeders are selecting for. In polygenic disorders, the phenotype of the individual does not directly represent its genotype. Breeders must break down affected phenotypes into traits that more directly represent the genes that control them. These include clinical signs of lameness (especially during the critical period of bony ossification between six and eighteen months of age), palpable   laxity   under   anesthesia,   deep   acetabula, rounded femoral heads, the absence of remodeling, deeply seated hips on an extended leg view, and radiographic distractibility.

We know that the environment has a role in the expression of hip dysplasia. Overnutrition and excessive environmental trauma during the critical growth periods prior to skeletal maturation will promote later dysplastic development. While limiting these environmental stresses is prudent in pet dogs, it is recommended that breeders do not overly protect or overly stress prospective breeding dog’s development. You do not want to mask the expression of dysplasia causing genes in breeding stock. Breeders should  evaluate prospective breeding dogs raised under fairly uniform conditions, which neither promote, nor overly protect against hip dysplasia.

The genetic cause of hip dysplasia between these two dogs is different.

All dogs do not have hip dysplasia due to the same gene combinations. A dog with laxity and subluxation but normal anatomy has hip dysplasia caused by different genes than a dog with no subluxation but malformed sockets. Selection against the components of the syndrome may provide better control.  If a quality dog is to be bred, but has shallow hip sockets, it should be bred to a dog with deep hip sockets. Two dogs  with  fair  hips  can  be  bred together and produce much worse hips if they share detrimental traits, or could improve on each other if they compliment each other’s good traits. You need to select for enough genes influencing normal development, to get above the threshold where dysplasia develops. Not all of these aspects will insure a genetically normal dog, but the chances increase with the more that are present.

Phenotypic Tests for Hip Dysplasia Control

The Orthopedic Foundation for Animals (OFA) has a longstanding hip dysplasia registry to attempt to control the disorder based on an extended-hip radiograph. OFA ratings are based on hip joint conformation (anatomy), joint laxity, and remodeling (arthritic changes). The Institute for Genetic Disease Control (GDC) also maintains a registry for hip dysplasia based on the extended leg view.

The PennHip method of evaluating hip status is based on a measurement of joint laxity different from that recorded on the extended leg radiograph. The PennHip method utilizes a radiograph taken while applying a uniform force on the hips of an anesthetized dog to measure the maximum distractibility of the hips. By computing a breed average of distractibility, and selecting for tighter hips than the breed average, it is believed that the incidence of hip dysplasia should decrease over time.

There are pros and cons to both the OFA and PennHip radiographic methods of hip dysplasia control. The OFA radiograph documents anatomical abnormalities (shallow sockets, early bony changes), but only natural laxity in a hip extended view. The PennHip radiograph documents maximum distractibility, but many dogs with a high distraction index do not develop hip dysplasia. It is shown that both techniques have false positive and false negative results. For both methods, radiographic findings at an early age are highly correlated to dysplasia at a later age. OFA does not give permanent certification until two years of age, but offers preliminary evaluations at any age.

While PennHip identifies maximal laxity, and OFA identifies hip conformation, neither radiographic method accounts for the breadth of pedigree. For selective pressure against hip dysplasia, these tests must be used in conjunction with knowledge of the hip status of the littermates.

Selection for Breadth vs. Depth of Pedigree

Another reason for diminished progress against hip dysplasia and other polygenic disorders is that breeders have been selecting for generations of phenotypically normal parents and grandparents (depth of pedigree). In polygenic disorders the phenotype of the full brothers and sisters more directly represent the range of genes present in the breeding individual. In other words, the breadth of the pedigree is as important, if  not  more important than the depth of the pedigree in polygenic disease control. If a dog with normal hips comes from a litter with a high incidence of hip dysplasia, you would expect it to carry a higher than normal genetic load of genes for hip dysplasia.     By     selecting     for    breadth     of phenotypically normal littermates of breeding dogs, and of parents of breeding dogs, all breeds should realize a decrease in hip dysplasia. In addition,  the offspring of breeding dogs should be monitored to see which are passing the disorder with higher frequency.

This article can be reprinted with the permission of the author: jerold.bell@tufts.edu

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Spay & Neuter Link Resources

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The Aspect of Population Size on Healthy Breeding in Dog Breeds

By Jerold S Bell DVM

Cummings School of Veterinary Medicine at Tufts University, USA jerold.bell@tufts.edu

This article originally appeared in the proceedings of the 2017 AKC Canine Health Foundation National Parent Club Canine Health Conference. It can be reprinted with written permission from the author.

A large number of individual dogs in a breed population allow greater choices when making breeding decisions. Multiple breed “family lines” support greater breed diversity; the genetic difference between individuals in the breed. When selecting on several different traits or disorders, a large population should allow for several choices of mates that fulfill different selection preferences. A goal of all breeds is to grow and maintain a large, diverse and healthy population.

All breeds originate from a small population of either related dogs or dogs who share a common conformational, behavioral, or working phenotype. Through selection, a breed standard is developed. Individual dogs that do not adhere to the standard or who demonstrate deleterious traits or disorders are purged from breeding. Those individuals who demonstrate and propagate desirable characteristics will have an increasing influence on the gene pool through multiple generations of descendants. Once breed characteristics are fixed in the population, it can go through an expansion stage where the population grows.

Figure 1
Figure 1

Fig. 1: Pedigree of a typical purebred dog (individual at the left). Breed founders appear at the right, and the breed goes through a purging stage, and then expansion stage.

All breeds will have several influential ancestors that appear far back in pedigrees, but pass on a high percentage of their genes to every individual in the breed. For example, all Bichons Frises share on average 17.5% of their genes with Pitou (born in 1924), which is between the contribution of a grandparent and great-grandparent. He does not appear on average until the 16th generation, but appears over 4 million times in every Bichon pedigree and 38% of his alleles have been retained in the breed population. Bearded Collie Bailie of Bothkennar was born in the 1940s, and contributes 32.6% of his genes to every modern Beardie.

This process of breed evolution causes a loss of genetic diversity through the purging of undesirable individuals and the concentration of genes of influential ancestors. All breeds are partial clones of their influential ancestors. This is an expected consequence of breed evolution and is not detrimental to the breed.

Genetic disorders can be due to ancient disease liability genes that preceded breed formation and are shared by many breeds, or by recent mutations that cause breed-specific disease. These can originate from a random mutation and be propagated through breed ancestors. Conversely, genes causing genetic disorders can be linked on a shared chromosome to a selected trait (ex., hyperuricosuria and Dalmatian spotting), or genetic disorders can be caused by direct selection for disease-causing phenotypic traits (ex., brachycephalic obstructive airway disease).

IS POPULATION SIZE DIRECTLY CORRELATED TO BREED HEALTH?

Evidence from registration figures and valid breed health surveys show that the size of a population does not determine whether the breed will suffer from higher frequencies of genetic disease. There are many large population breeds with high frequency genetic disorders, and many small population breeds that show excellent health. In a small population breed, individual mating choices and individual litters have a greater effect on the breed frequency of disease liability genes because they represent a larger percentage of the total gene pool. It is the lack of selection for genetic health in either large or small population breeds that allows the propagation of genetic disorders. Breed genetic health depends on selection against disease liability genes regardless of the size of the population.

DOES A LARGE POPULATION AUTOMATICALLY CONFER GENETIC DIVERSITY?

When analyzing entire breed population databases back to founders, every dog breed – regardless of its population size – has the same findings; high homozygosity and low effective population size (minimum number of ancestors explaining the complete genetic diversity of a population). These are necessary and expected consequences of breed formation and evolution. As a breed gene pool expands, the average recent generational relationship (inbreeding and kinship) between mates can decrease. However, the average total generational relationship between dogs back to founders does not decrease. Breeds with small populations look the same as breeds with large populations did much earlier in their evolution and development.

In both large and small population breeds, genetic diversity can be lost if breeders do not utilize dogs from the breadth of the gene pool. This is most evident in the popular sire syndrome. This can be compounded when a popular sire is replaced by a popular son, who is replaced by a popular grandson, and the entire breed truncates on a single popular sire line. This causes a loss of genetic diversity from the breadth of the gene pool that would be propagated from other quality male lines.

Another issue with popular sires is that their genetic contributions can only be evaluated after their prolific breeding period is over, and their genes have already been disseminated throughout the gene pool. Many recently identified genetic disorders that rise in frequency in a breed are caused by genes carried by popular sires. This is different from an influential ancestor, whose qualities and influence are constantly evaluated every generation. If an influential ancestor’s descendants are not producing quality, then they are not bred and the ancestor’s influence diminishes. With the popular sire syndrome a breed population may expand in numbers, but if breeding is concentrated in only a portion of the gene pool genetic diversity will diminish.

Some breeds may lack enough health and vitality from the start, and these breeds collapse and do not progress beyond the purging stage of development. Other breeds may have a robust and growing population, but due to other factors experience a population contraction and decline that could significantly eliminate the genetic diversity present in the gene pool. The recent economically induced decline and then rise in AKC registrations is not detrimental to a breed as long as it was a temporary slowing, and not a loss of breeding lines. Frozen semen is also an important hedge against the loss of diverse lines. Population contraction is a serious detriment to breed genetic diversity if it includes the loss of diverse within-breed lines. In extreme cases, a breed may require opening up its stud book to bring new genes into its gene pool. However most current dog breeds show acceptable genetic diversity and only require health conscious breeding and population expansion to maintain their gene pools.

DO OUTBREEDING PROGRAMS IMPROVE GENETIC DIVERSITY AND GENETIC HEALTH?

Conservation geneticists versed in rare and endangered species have designed species survival plans (SSPs) that call for outbreeding; mating together animals that are least related to each other. The purpose of SSPs is to prevent the homozygous expression of deleterious recessive genes. However, natural species and artificially selected breeds have completely different, and in many instances completely opposite selection pressures and desired outcomes. SSPs call for using all available individuals in breeding and only outbreeding. Dog breeding calls for selection, which requires differences between prospective mates and therefore genetic diversity between individuals.

Outbreeding homogenizes the population by removing the genetic difference between individuals in the breed and making everyone “alike”. If two unrelated parents are bred together, the offspring make the two lines related. If an offspring is then outbred to a further unrelated line, their offspring make all of the lines related. Outbreeding is a self-limiting process as there will eventually be no unrelated dogs. In order to have selective pressure for positive traits and against negative traits or disorders, there must be variation and genetic differences between individuals in the gene pool. This requires distinct family lines that are eliminated by outbreeding programs.

Thus, the basic conceptual point is, “What constitutes genetic diversity?” Is it the diversity within each dog (heterozygosity through outbreeding)? Or is it the diversity between each dog (maintaining diverse family lines)? These two concepts are diametrically opposed to each other and breeders and breed organizations must decide which is in the best interest of their breeds.

The genes causing common breed-specific genetic disorders have already been dispersed in breed gene pools. Therefore the chance of breeding two carriers together is based on the frequency of the deleterious gene(s) in the population, and not necessarily the type (outbreeding or linebreeding) of mating. Outbreeding propagates deleterious genes in the carrier state and randomizes the occurrence of genetic disease; the same as is seen with common genetic disorders in mixed-breed dogs. The only way to select against specific genetic disorders is to specifically select against the causative or liability genes through direct genetic testing or phenotypic genetic screening.

ADDITIONAL FACTORS IN SMALL POPULATION BREEDS

Small population breeds have added issues because each mating has a much greater influence on the entire gene pool. If a breed has particular hereditary disorders at a higher frequency, mates should be selected that can minimize or lower the risk of producing these disorders. A quality higher risk dog (closely related to affected) can be bred to a lower risk dog and replaced with a lower risk offspring. As this process is repeated, the carrier risk and deleterious gene frequency will diminish in the population. As most disorders are complexly inherited and have no tests for carriers, carrier risk must be based on knowledge of phenotypic pedigree depth (parents and grandparents) and breadth (littermates and littermates of parents).

Some breeders in small population breeds are afraid to breed and possibly cause more disease. However if no breeding is going on, the breed will certainly become extinct. Mates must be selected that reduce the risk of producing genetic disorders. Breeders need to do their best to select for health and quality and then see what they produce.

In small population breeds a greater number of offspring should be placed in breeding homes to expand the population. However, breeders of some small population breeds try to constrain breeding and limit it only to themselves. This is a shortsighted attitude. Breeders should recruit and mentor puppy buyers to become thoughtful breeders. As a population expands, the choices of mates increase and the average recent relatedness of mates will decrease. Decreasing average recent generational inbreeding coefficients is a natural consequence of expanding populations utilizing the breadth of their gene pools. It does not need to be artificially manipulated. Breeders all doing something a little different with their mating choices – i.e., which individuals they are selecting, the types of matings utilized, etc. – is what maintains breed genetic diversity. With health conscious breeding, there are greater choices available to produce healthier offspring.

CONCLUSIONS

All breeds require expanding or large, stable breeding populations. Mates should be selected that represent the breadth of genetic diversity in the gene pool. It is mate selection and not the types of matings that they are involved in (linebreeding or outbreeding) that maintains genetic diversity.

Large and small population breeds show the same population indices of; high homozygosity, low effective population size, and high relationship to influential ancestors. The difference between large and small populations is in the available choice of breeding individuals.

Health conscious selection through breed-appropriate genetic screening of prospective breeding individuals is the most important aspect of improving and maintaining the genetic health of any breed, regardless of its population size.

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Musculoskeletal Link Resourses

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Zoetis Receives USDA License for CYTOPOINT™

December 21, 2016 Source: Zoetis

  • First monoclonal antibody licensed to help control the clinical signs associated with atopic dermatitis in dogs
  • Targets and neutralizes interleukin-31 (IL-31), a key itch-inducing cytokine (protein) in canine atopic dermatitis
  • Provides convenience and long-lasting relief from itch with one injection every four to eight weeks
  • Joins Zoetis’ APOQUEL ® (oclacitinib tablet), giving the company two targeted treatment options to offer veterinarians for canine patients with atopic dermatitis

PARSIPPANY, N.J.–(BUSINESS WIRE)–Zoetis Inc. (NYSE:ZTS) today announced that the U.S. Department of Agriculture (USDA) has granted the company a license for CYTOPOINT™, the first monoclonal antibody (mAb) therapy approved to help provide sustained control of the clinical signs associated with atopic dermatitis in dogs. CYTOPOINT targets and neutralizes interleukin-31 (IL-31), a key protein involved in triggering itch in dogs. It provides fast, effective relief of itching – the hallmark sign of the allergic skin condition atopic dermatitis in dogs – and offers the sustained efficacy and convenience of one injection every four to eight weeks. CYTOPOINT helps improve the long-term quality of life for dogs suffering from atopic dermatitis and eases the related frustration and concern of their owners. It is now available to all veterinarians in the United States

“As the owner of allergic pets, I understand the frustration that my clients feel, and as a person with allergies myself, I understand what my patients feel,” said Laura Stokking, PhD, DVM, DACVD, Veterinary Specialty Hospital, San Diego, CA.* “With CYTOPOINT, in a single injection we now have an excellent opportunity to help control the itch without leading to any secondary signs that can be more difficult to manage than the itch itself.”

“CYTOPOINT results from our acquiring a deeper scientific understanding of the causes of allergic skin conditions in dogs at the molecular level and developing novel, targeted, effective treatments based on these new insights,” said Dr. Catherine Knupp, Executive Vice President and President, Research and Development at Zoetis. “Veterinarians have told us that allergic dogs and their owners have a variety of needs and we are proud to offer them two innovative solutions with CYTOPOINT and with our oral tablet therapy APOQUEL. These first-in-class medicines give veterinarians effective, safe options to customize atopic dermatitis treatment for canine patients, and I am very proud of the breakthrough treatments our Zoetis team has developed.”

APOQUEL® (oclacitinib tablet) is the first Janus kinase inhibitor approved by the U.S. Food and Drug Administration for veterinary use to provide fast and safe itch relief for dogs at least 12 months of age that have symptoms associated with allergic dermatitis triggered by food, fleas or contact allergens, as well as atopic dermatitis.

About CYTOPOINT

CYTOPOINT is a ready-to-use, sterile liquid injectable containing a mAb specifically designed to target and neutralize cytokine interleukin-31 (IL-31), a key cytokine (protein important in cell-to-cell communication) involved in triggering the itch associated with canine atopic dermatitis. It works by mimicking the activity of natural antibodies to selectively bind and neutralize IL-31, thus interrupting the itch cycle in atopic dogs.

CYTOPOINT begins working within 1 day and delivers 4 to 8 weeks of relief from the clinical signs of canine atopic dermatitis, allowing the damaged skin the chance to heal. In clinical studies submitted to the USDA and published in Veterinary Dermatology, treatment with CYTOPOINT at a minimum dose of 2 mg/kg resulted in a significantly (P≤0.05) greater percentage reduction from baseline in pruritus on days 1–49, and skin condition scores on days 7-56(1), when compared to placebo.

It is safe for dogs of any age, even those with concomitant diseases, and can be used with many common medications. Moreover, because of its specificity in targeting IL-31, it has minimal impact on normal immune responses.

The USDA granted Zoetis a conditional license for Canine Atopic Dermatitis Immunotherapeutic (now branded as CYTOPOINT) in August 2015. During the conditional licensing period, Zoetis collected valuable feedback from dermatology specialists, a small group of general practice veterinarians, and pet owners to prepare for full licensure.

About Atopic Dermatitis

Itching is among the most frequent complaints of pet owners, affecting roughly 1 in 6 dogs whose owners seek veterinary help(2). There are a number of factors that can trigger an itch reaction, such as infections, allergies and parasites—and approximately 15-20 percent of all itchy dogs will be diagnosed with atopic dermatitis(2).

CYTOPOINT is now available for veterinarians throughout the United States. It brings mAb therapy – a fast-growing area of human medicine – for the first time to veterinarians for use to treat atopic dermatitis in canine patients. For more information, visit www.cytopoint.com.

IMPORTANT SAFETY INFORMATION ABOUT APOQUEL

Do not use APOQUEL in dogs less than 12 months of age or those with serious infections. APOQUEL may increase the chances of developing serious infections, and may cause existing parasitic skin infestations or pre-existing cancers to get worse. APOQUEL has not been tested in dogs receiving some medications including some commonly used to treat skin conditions such as corticosteroids and cyclosporines. Do not use in breeding, pregnant, or lactating dogs. Most common side effects are vomiting and diarrhea. APOQUEL has been used safely with many common medications including parasiticides, antibiotics and vaccines….

About Zoetis

Zoetis is the leading animal health company, dedicated to supporting its customers and their businesses. Building on more than 60 years of experience in animal health, Zoetis discovers, develops, manufactures and markets veterinary vaccines and medicines, complemented by diagnostic products and genetic tests and supported by a range of services. Zoetis serves veterinarians, livestock producers and people who raise and care for farm and companion animals with sales of its products in more than 100 countries. In 2015, the company generated annual revenue of $4.8 billion with approximately 9,000 employees. For more information, visit www.zoetis.com.

Forward-Looking Statements : This press release contains forward-looking statements, which reflect the current views of Zoetis with respect to business plans or prospects, future operating or financial performance, future guidance, future operating models, expectations regarding newly approved products and other products and other future events. These statements are not guarantees of future performance or actions. Forward-looking statements are subject to risks and uncertainties. If one or more of these risks or uncertainties materialize, or if management’s underlying assumptions prove to be incorrect, actual results may differ materially from those contemplated by a forward-looking statement. Forward-looking statements speak only as of the date on which they are made. Zoetis expressly disclaims any obligation to update or revise any forward-looking statement, whether as a result of new information, future events or otherwise. A further list and description of risks, uncertainties and other matters can be found in our Annual Report on Form 10-K for the fiscal year ended December 31, 2015, including in the sections thereof captioned “Forward-Looking Information and Factors That May Affect Future Results” and “Item 1A. Risk Factors,” in our Quarterly Reports on Form 10-Q and in our Current Reports on Form 8-K. These filings and subsequent filings are available online at www.sec.gov , www.zoetis.com , or on request from Zoetis.

* Dr. Laura Stokking has a consulting relationship with Zoetis.

1 Data on file, Study Report No. C863R-US-12-018, Zoetis LLC.

2 Data on file, IL-31 Positioning Research. IPSOS 2014. L-31 Pricing Research. SKP. 2015, Zoetis LLC.

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General Interest Link Resources

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