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Thursday, April 2, 2020
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What millennials want from their vets

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A recent survey revealed key elements that millennials want in a veterinary visit, and how to ensure they remain loyal to a clinic.

Millennials might get a bad rap, but 75% have companion animals, and many make veterinary care a top priority. An independent survey released by Weave revealed what millennials want from their veterinary clinic experiences, what makes them move on from a clinic, and what helps them maintain loyalty. Here are some key findings:

92%of millennials are as concerned about their animals’ health as their own.

Only15%will always answer their phones even if they don’t know who’s calling, but 81% would definitely answer if they saw it was their veterinarians.

81%want their vets to automatically recognize them when they call; 72% say they have had to wait while their vets look up their accounts.

Millennials also like their veterinarians to be tech savvy. “They have grown up with technology, and expect that tech to enhance all experiences throughout their lives, including purchases like veterinary care for their animals,” says Brandon Rodman, CEO at Weave. “They require tailored services…. You can’t provide personalization without the right technology.” getweave.com

Mitochondria: the energy of life

The mitochondria is the powerhouse of the cell. But why is it unique and how can you protect the mitrochondria in small animals?

Mitochondria are fascinating and critically important “powerhouse” organelles inside cells. They use oxygen to make energy in the form of ATP. Mitochondria are unique in that their ancestors are bacteria that were ingested into cells to form a beneficial host/bacteria relationship (termed endosymbiosis) over 1.45 billion years ago. Thus, each of our cells has two different sets of DNA — one in the host cell nucleus, and the second in mitochondria (MtDNA). However, only maternal MtDNA is inherited.

During normal metabolism, mitochondria generate harmful reactive oxygen species (ROS) that must be neutralized and balanced by antioxidants to prevent cellular damage. In fact, mitochondria can inflict self-injury as they are the main intracellular generators of ROS as well as the main target of ROS attack. An imbalance of ROS and antioxidants can cause mitochondrial dysfunction, leading to inflammation and chronic illness. When antioxidant defenses are inadequate to neutralize ROS, cell damage and/or cell death results, initiating inflammation. Neutralization of ROS occurs by a variety of antioxidant systems, including the glutathione redox system, ascorbic acid, tocopherals, retinoids, catalase and superoxide dismutase.

Mitochondrial disease is a group of disorders characterized by dysfunctional energy production (ATP) along the mitochondrial electron transport chain. Most disease processes have some degree of mitochondrial dysfunction. Mitochondrial damage can occur from either too little or too much energy production. Because cells of the eye, brain and muscles require a lot of energy, they have particularly high densities of mitochondria. When mitochondria are not healthy, these tissues are often the first to show signs of poor function. Mitochondrial dysfunction can have primary (genetic) or secondary (e.g. age-related, infectious) causes. Aging tissues undergo oxidative stress because their mitochondria often fail to produce sufficient ATP. Since eyes are continually bombarded with oxidative stressors (UV light and oxygen), and mitochondria both generate and can be damaged by oxidative stress, it makes sense that chronic exposure to oxidative stress causes instability and cumulative damage of mitochondrial DNA.

Glaucoma causes chronic hypoperfusion of the optic nerve. Because the optic nerve contains abundant mitochondria, this makes it vulnerable to damage from glaucoma. Cancer is also associated with mitochondrial dysfunction. Mitochondria play important roles in carcinogenesis by altering energy metabolism, resisting apoptosis, increasing ROS production, and altering mtDNA. Uveal melanoma is the most common primary intraocular tumor in dogs, cats and humans. Novel therapies for this cancer are directed at inhibiting tumor-specific mitochondrial function, and hold promise as a new way to treat ocular cancers.

Supplements that reduce mitochondrial dysfunction help maintain healthy glutathione levels and include vitamins C and E (in the form of mixed tocopherals), alpha lipoic acid, coenzyme Q10, folate, vitamins B6 and B12, green tea extract, turmeric, Omega-3 fatty acids and zinc.

Providing a variety of antioxidants to dogs and cats may better protect the powerhouse of their cells from constant attack and self-combustion by ROS. The foundation of health is protection and enhancement of the energy of life.

Obesity linked to gene mutation

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The Morris Animal Foundation Golden Retriever Lifetime Study, is leading the pack with innovative research, and recently discovered genes linked to obesity.

You have probably seen more than your share of overweight canine patients. The Association for Pet Obesity Prevention estimates that 56% of dogs in the United States are overweight or obese — a huge problem for canine health.

Researchers at Cambridge University recently identified a gene mutation linked to obesity in Labrador retrievers; the same team plans to use DNA samples from dogs enrolled in the Morris Animal Foundation Golden Retriever Lifetime Study to search for a similar locus in this breed. Identifying dogs at risk for obesity can help you and your clients strategize on effective weight management. Click here to learn more.

Cryosurgery in the veterinary practice

Innovative advances in cryosurgery offer safe and effective treatment options with unlimited potential in the hands of the veterinarian.

Canine and feline dermatologic problems make up a substantial part of any small and/or mixed animal practice. Lesions ranging from small nodules to lumps and bumps are included in the daily questions clients ask practitioners during routine annual examinations and preanesthetic screenings of their animals. A large percentage of these masses can be benign proliferations of various gland tissues, or accumulations of abnormal but benign cell growths, while others are neoplastic tissues with invasive and metastatic potential. Traditionally, these masses have been excised with a scalpel and/or surgical laser, requiring the use of sedation or general anesthesia. While this has been an industry standard for many years, many patients presenting with skin lesions often have other problems, leading to safety concerns with chemical immobilization. Cryosurgery offers an attractive option for these patients, since it can be utilized with minimal or no sedation, collateral tissue damage and post-operative care.

Advances in cryosurgery

While cryosurgery is not a new modality, the tools used to deliver the required temperature change are evolving, making the target areas very precise. This enhanced precision reduces collateral tissue damage, leading to faster healing and less scarring. The capacity to achieve this precision is also what makes the biggest difference in treating smaller lesions. The specific unit I use in my practice is the CryoProbe X+, which runs at about -127°F. This specific model includes five separate tip sizes that can be used to match the lesion being treated, and can be operated with available 8g and 16g cartridges. (While treatment is often done without sedation or general anesthesia, the locations of some lesions will still require chemical immobilization to achieve desired results). Thanks to the precision of the micro-applicator tips, there is no collateral damage to healthy tissue, resulting in no discomfort to the patient. As such, treatments are very controlled and can be longer in duration if necessary. There is no required post-operative care; there is no bleeding, and sutures and cones are unnecessary, a wonderful benefit for both patients and caregivers. The following discussion identifies common lesions the author has treated with cryotherapy, but the modality’s use is certainly not limited to these.

  • Sebaceous adenomas: One of the most common skin ailments of aging and geriatric patients is the sebaceous adenoma. Also known as nodular sebaceous hyperplasia, this lesion is characterized as a benign non-haired soft tissue proliferation with an oily to crusted surface. The depth of abnormal tissue is often very superficial although the tissue can extend deep into the epidermis in some lesions. Cryosurgery is very effective for these, and one treatment is typically curative with very little follow-up required.
  • Cutaneous histiocytomas: Cryosurgery is very useful in the treatment of cutaneous histiocytomas. These benign and often solitary tumors often appear in places wheresurgical excision can be difficult. When they appear on the head, digits and ears, there is little room for excising while obtaining adequate margins without cosmetically affecting the closure. While these lesions can be deep and relatively dense, I have experienced successful outcomes with cryotherapy in completely resolving lesions as large as 1cm in diameter and ½cm in height. Larger masses may require an additional treatment or two to achieve complete resolution
  • Mast cell tumors: Mast cell tumors are often highly invasive and metastatic masses that can lead to very debilitating disease; higher grades and stages often result in diffuse systemic involvement. While cryosurgery is not my first line of choice in treating the masses that develop, it can be used as an additional modality to treat smaller nodules within the skin in areas where removal would be difficult. I have successfully treated smaller solitary Grade 1 nodules less than 1cm in diameter, with minimal to no recurrence. When treating these masses, I have found it beneficial to treat the nodule itself, along with 2mm to 4mm margins, and re-treating the same area after thawing has occurred.
  • Acral lick granulomas: Cryotherapy can also be used on chronic inflammatory lesions, such as acral lick granulomas, as an additional treatment modality. I have found it useful to intermittently freeze portions of the granulomas, along with using traditional therapies.
  • Epidermal and follicular inclusion cysts: These commonly-encountered nodular masses can respond well to cryosurgery. If possible, the author recommends either expressing or draining the lesions of any fluid or material prior to freezing with cryotherapy. This dramatically reduces the time required to freeze the area, permitting more effort to be directed at the tissue responsible for producing the material. If deep tissue nodules are being treated, or if draining of the lesions requires a scalpel or hypodermic needle, heavy sedation or general anesthesia is recommended for patient comfort.
  • Meibomian gland adenomas: For meibomian gland adenomas measuring 1mm or less, my preferred initial treatment option is cryosurgery over surgical excision. These common eyelid masses are full thickness proliferations often filled with a material that can be expressed with gentle pressure. I would suggest treating the tissue with cryotherapy from both palpebral and ocular sides to ensure all abnormal tissue is treated. There is little to no cosmetic change after healing.
    Photos courtesy of H&O Equipment, Inc., manufacturer of CryoProbe
  • Eosinophilic granuloma complex, ulcerative paradental stomatitis and oral neoplasia: Oral lesions such as eosinophilic granuloma complex, ulcerative paradental stomatitis and oral neoplasia that don’t involve bony tissue can be treated with cryotherapy when conventional medical and surgical techniques are not feasible. The lack of excess tissue for closure, despite efforts to elevate from the bone, can make it difficult to surgically close these lesions, leaving some cases to heal by second intention alone. I have used cryosurgery to debulk the main mass or lesions with promising results. I will reassess the areas on a regular basis and elect to refreeze the tissue as often as needed to suppress new growth formation.

Pre-treatment evaluation

Photos courtesy of H&O Equipment, Inc., manufacturer of CryoProbe

Prior to cryosurgery implementation, it is imperative that current standards of care be followed, with appropriate cytological and histopathological diagnostic steps performed as indicated. If a mass is deemed malignant with metastatic potential, addressing the mass with aggressive surgical intervention, radiation and chemotherapy would be indicated based on oncologist recommendations should the patient’s owner elect to pursue that line of treatment. Once a mass has been diagnosed, the use of cryosurgery can be employed for nearly any lesion on the skin, as well as some mucus membrane tissues.

Conclusion

Veterinary practices today are filled with innovative technological advancements that assist us in effectively treating patients in an ethical and compassionate manner. While traditional surgical and medical practices will always provide the foundation for our therapies, additional modalities such as cryosurgery also have their place.

By adding a cryosurgical unit to my treatment toolbox, I have been able to offer another option for commonly-seen dermatological lesions that is quick, effective, less invasive, and requires little to no anesthesia. Cryosurgery has been readily accepted by my clientele and well tolerated by my patients, making it a great fit for my practice.

 

 

 

 

Disclosure: The work expressed in this article is from Dr. Walrath’s direct clinical experience of using CryoProbe in his private practice since 2016. He is not a paid consultant or remunerated in any way.

KetoPet Sanctuary: ketosis, cancer and canines, part 3

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KetoPet Sanctuary has tested using a ketogenic diet as therapy in dogs with cancer. Part 3 looks at practical applications of ketosis for dogs at home.

KetoPet Sanctuary (KPS) has demonstrated the utility of a canine diet that induces a state of nutritional ketosis. When strictly adhered to and monitored, a ketogenic diet (KetoDiet) has been shown to increase the efficacy of standard of care and adjunctive treatments, thus prolonging survival and quality of life in canine cancer patients. While the stringently-controlled conditions at KPS cannot be replicated in a home environment, nutritional ketosis can be achieved and monitored by committed dog owners. In combination with integrative therapies, results that align with those at KPS can often be achieved.

Empowering the dog parent

Ketosis is a nutritionally-induced metabolic state in which the body preferentially uses ketone bodies as energy. Ketosis is achieved by fasting, caloric control, and/or control of macronutrient ratios (high fat/adequate protein/low carbohydrate). In the overwhelming fight for survival during cancer, diet is an accessible tool available to all pet owners. No one can fully control the cause or outcome, but dog parents can control what they put in their pets’ mouths, which can provide them with a sense of empowerment in the care of their canines.

Nutritional ketosis and chronic disease

Modern dogs are burdened with a variety of physiological and metabolic challenges due to the dramatic difference between the nutritive profiles of rendered, high glycemic-response kibbles and any possible, accessible nutrient profile found in nature.1 High-heat processed feeds (kibble and canned) are contaminated with heavy metals,2 excessive levels of minerals,3,4 fat soluble vitamins,5 anti-nutrients,6 carbohydrate levels that inhibit ketosis,7 advanced glycation end products (AGEs)8 and pathogens.9 A shift to fresh low-carbohydrate food decreases exposure to these toxins and metabolically-damaging macronutrient ratios.

With and without additional therapies, nutritional ketosis has resulted in recovery from chronic skin issues, ear infections, odors (mouth and stool), chronic pancreatitis/hyperlipidemia, ocular discharge, chronic bladder stones, UTIs, obesity, arthritis and food allergies (as confirmed with allergy testing), as well as increased energy and mobility.

 

Dr. Barbara Royal reports an 80% success rate in many of these conditions. However, treatment plans that depend solely on a metabolic component have not been found to be significantly successful in the treatment of cancer. Rather, ketosis has been shown to improve the efficacy of standard of care and integrative oncology therapies while also providing protective benefits to healthy cells.

Dr. Royal has experienced resolution of recurring mast cell skin tumors, hemangiosarcomas, bladder cancers and osteosarcomas in cancer patients that have dramatically exceeded their expected expiration dates, as well as shrinking and stabilizing of lymphoma (perhaps the most notably responsive cancer at KPS) with nearly two years of no progression when chemo wasn’t tolerated. She has also experienced resolution of severe vaccine-induced intractable seizures (uncontrolled by general practice, critical care and neurology veterinarians) after implementing a KetoDiet.

Discussion

When properly executed and monitored, inducing metabolic ketosis and applying adjunctive integrative therapies with standard of care treatments can result in increased longevity and quality of life when compared to standard of care alone. The positive clinical responses veterinarians have seen, and the intriguing research on ketogenic diets for cancer in human literature, warrant additional investigation into this non-toxic and relatively inexpensive holistic therapy for canine cancer patients. In addition, open-minded veterinarians are trying other adjuvant metabolic therapies (see sidebar). If you are seeking to incorporate integrative therapies with the metabolic component of nutritional ketosis into your treatment plan, these are the tools to research and consider.

Ultimately, the most important factors for success are knowledge, effort and compliance. As with us, the health of our canine companions can be transformed by the food they are fed. The transition from cereal (kibble) or canned diets to fresh feeding (a KetoDiet) can initially seem daunting. In short order, however, it will become habit and seem simple. The KetoDiet can improve a dog’s health on its own, or in conjunction with other therapies, in the treatment of cancer, making the benefits wide-ranging and priceless. Additional resources on how to implement a KetoDiet for canines can be found in Parts 1 and Part 2 of this article, the KetoPet website, and the KetoPet Group and Ketogenic Dog Group on Facebook.29, 30

The authors want to acknowledge the veterinarians, dog parents and advocates who have shared the benefits of KetoDiets for many disease states. To the dog parents of our cases, thank you for sharing your stories.

References

1Bosch E, Plantinga E, Hendriks, W. “Dietary Nutrient Profiles of Wild Wolves: Insights for Optimal Dog Nutrition”. Researchgate.net, Nov. 2017.

2“Heavy Metal Regulation and Results”, KnowYourPetFood.org

3“Development of AAFCO Mineral Tolerances”.  AAFCO

4“Mineral Results”. KnowYourPetFood.org.

5“Animal & Veterinary, Resources for You, Animal Health Literacy, Vitamin D Toxicity in Dogs”. FDA.gov.

6“Phytic Acid and Results, KnowYourPetFood.org.

7“Masood W. “Ketoigenic Diet”. ncbi.nlm.nih.gov.

8Becker, K. “High Heat Processing Creates Higher Levels of Advanced Glycation End Products”. HealthyPets.Mercola.com

9“Pathogen in dry kibbles – CDC Salmonella Outbreaks, 2007, 2012”. Dry Kibble, Diamond. 2008, Mars PetCare Morbidity&Mortality Weekly.

10McLelland J. “How to Starve Cancer”. howtostarvecancer.com.

11“Mistletoe: The Holiday Plant is Making headlines as Alternative Cancer Treatment”. EuroMedFoundation.com.

12“Enhancing anticancer effects, decreasing risks and solving practical problems facing 3-bromopyruvate in clinical oncology: 10 years of research experience”. ncbi.nlm.nih.gov.

13“Metformin and cancer: an existing drug for cancer prevention and therapy”. ncbi.nlm.nih.gov.

14“Statin use and Cancer risk: a comprehensive review”. ncbi.nlm.nih.gov.

15“Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)”. ncbi.nlm.nih.gov.

16“Repurposing drugs in Oncology (ReDO) – Mebendazole as an anti-cancer agent”. ncbi.nlm.nih.gov.

17“Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer”. ncbi.nlm.nih.gov.

18“Dose evaluation safety study in individuals with astrocytoma taking PolyMVA and PolyMVAsurvivors.com”. ClinicalTrials.gov.

19“COX-2 inhibitors in cancer treatment and prevention, a recent development”. ncbi.nlm.nih.gov.

20“Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs”. ncbi.nlm.nih.gov.

21“Medicinal Mushrooms (PDQ)”. ncbi.nlm.nih.gov.

22“Yunnan Baiyao for Dogs: Chinese Herb for Bleeding Dog Cancers”. DogCancerBlog.com.

23“Epigallocatechin Gallate (EGCG) is the most effective cancer chemopreventative polyphenol in green tea”. ncbi.nlm.nih.gov.

24“Artemisinin and its synthetic derivatives as a possible therapy for cancer”. ncbi.nlm.nih.gov.

25“The current state and future perspective of cannabinoids in cancer biology”. ncbi.nlm.nih.gov.

26“Hyperbaric oxygen therapy and cancer – a review, and Hyperbaric oxygen therapy as adjunctive strategy in treatment of glioblastoma multiforme”. ncbi.nlm.nih.gov.

27“Anticancer effects of high-dose ascorbate on canine melanoma cell lines, and Intravenous Vitamin C for Cancer Therapy – identifying the current gaps in knowledge”. ncbi.nlm.nih.gov.

28“State of the Art Laser Surgery”. aesculight.com.

29Resources, Read Our eBook (free download), KetoPetSanctuary.com.

30Resources, Create a Ketogenic Diet (free calculator), KetoPetSanctuary.com.

Equine metabolic syndrome

Cases of equine metabolic syndrome (EMS) are on the rise, and research sponsored by Morris Animal Foundation is helping to unravel the complexities of EMS.

The term “equine metabolic syndrome” was coined in 2002. It was used to describe a disease that shared many features with metabolic syndrome in people. In horses, the syndrome is characterized by obesity (either generalized or regional), insulin resistance and a predisposition to laminitis.

The rise in EMS cases coincided with the transition of horses from working animals to companion animals with more sedentary lifestyles. But EMS is a complex disease that involves more than just lifestyle, and has both genetic and environmental components. This complexity has complicated EMS research, though new breakthroughs could provide key clues toward treating this disease.

Morris Animal Foundation is a major sponsor of EMS research around the world, and our grantees are leaders in the field. We’re excited about some recent findings from our funded grants.

Genetics play a role in EMS

A genetic explanation for this disease makes evolutionary sense and supports what we see clinically. It was beneficial for early equids to develop an efficient metabolism to survive in times of scarce resources. However, this same trend toward thriftiness can lead to obesity and insulin dysregulation.

Researchers at the University of Minnesota published findings on a correlation between height in Welsh ponies and their baseline insulin levels. They found that shorter ponies had higher baseline levels, which translates into a greater potential for EMS. 1

Data on the predisposition of certain horse breeds for developing EMS provides further evidence for a significant genetic influence. The Minnesota team also published a study that estimated the heritability of certain EMS biochemical traits in Morgan and Welsh ponies, which ranged from moderate to high heritability. The findings have implications for future research on genetic risk factors for EMS.2

And so does the environment

The University of Minnesota research team is also investigating environmental factors. Although it’s tempting to give genetics the major role in the development of EMS, some experts suggest that almost 50% of the phenotypic variability in EMS is due to environmental factors.

The Minnesota team recently reported how endocrine-disrupting chemicals could play a role in clinical disease in horses. They reported that horses living close to federal Superfund sites, where endocrine-disrupting chemicals may be concentrated, were more likely to have a history of laminitis and biochemical abnormalities related to EMS.3 Diet, exercise and season can also influence the EMS phenotype, but research has shown that these factors account for only a small part of this variation.

New research focus areas

Morris Animal Foundation has several new studies in progress that are tackling EMS from different directions.
Recently funded projects include:

  • How the gut microbiome and metabolome influence insulin levels
  • A description of the microbiome in Shetland ponies who do and don’t develop EMS
  • The effect of phenylbutazone on insulin and glucose dynamics
  • The roles of adiponectin and systemic inflammation on insulin dysregulation.

EMS is a complex disease. Through strategic funding, Morris Animal Foundation hopes to generate a path to better diagnostics, treatments and, hopefully, new
preventive strategies for this serious threat to horses. Learn more at morrisanimalfoundation.org.

References

1Norton EM, Avila F, Schultz NE, Mickelson JR, Geor RJ, McCue ME. “Evaluation of an HMGA2 variant for pleiotropic effects on height and metabolic traits in ponies”. J Vet Intern Med. 2019;1–11. https://doi.o r g /10 .1111/ j v i m .15 4 03

2Norton EM, Schultz NE, Rendahl AK, McFarlane D, Geor RJ, Mickelson JR, McCue ME. “Heritability of metabolic traits associated with equine metabolic syndrome in Welsh ponies and Morgan horses”. Equine Vet J. 2019;475-480. h t t p s : //d o i . o r g /10 .1111/e v j .13 0 53

3Durward-Akhurst SA, Schultz NE, Norton EM, Rendahl AK, Besselink H, Behnisch PA, Brouwer A, Geor RJ, Mickelson JR, McCue ME. “Associations between endocrine disrupting chemicals and equine metabolic syndrome phenotypes”. Chemosphere. 2019;652-661. https://doi.org/10.1016/j.c h e m o s p h e re. 2 018 .11.13 6

Do cats with chronic kidney disease need gastric acid suppression?

Gastrointestinal protectant use is ubiquitous in veterinary medicine. But is it always necessary? Learn more about new concepts regarding the use of gastric acid suppression in cats with chronic kidney disease.

It is a rare geriatric cat that doesn’t have some decline in renal function. Administration of gastric acid suppression has been considered an important component of treatment for chronic kidney disease. However, newer veterinary studies are calling this practice into question.

Chronic kidney disease (CKD) is one of the most common problems affecting older cats, with some estimates suggesting the disease affects at least 50% of older cats (defined as cats over 10 years of age). Other experts put the number even higher, at nearly 80% in cats over 15 years of age.

A lot of owners and veterinarians struggle to treat this complex illness. Although we’ve made great advances in helping cats with CKD live longer with a better quality of life, achieving this can require medication, diet change and fluid support. The multitude of treatments can be tough for cat owners to manage, which in turn can lead to poor compliance. Knowing which treatments are supported with strong evidence is key to a successful outcome.

In people, it’s long been recognized that chronic kidney disease can lead to gastric ulceration. However, gastric ulceration has never been firmly demonstrated in cats with CKD.

“There is a lot of dogma in veterinary medicine that comes from human medicine,” said Dr. Katie Tolbert, a Morris Animal Foundation-funded researcher and Associate Professor at Texas A&M University, in a recent interview. “We’re taught that CKD causes stomach ulcers in cats – it’s something that’s been passed down. However, when I talk to pathologists, they tell me they hardly ever see ulcers in cats with CKD.”

Dr. Tolbert took to heart what she heard from her pathology colleagues and studied acid secretion in cats with CKD and cats without the disease. She looked at a number of parameters including gastric pH and serum gastrin levels and found no differences between the two groups for either value. Dr. Tolbert concluded that, based on these results, cats with CKD might not need acid suppression. She published her results in the Journal of Veterinary Internal Medicine.

In her current Morris Animal Foundation-funded project, Dr. Tolbert is taking this observation one step further. She’s running a clinical trial where cats with CKD get omeprazole and others get a placebo for two weeks. After a two-week rest period, the groups switch. The research team is blinded to the treatment each cat is receiving. They’re collecting observational data as well on everything from activity to frequency of vomiting, since acid suppression is often given to improve appetite and decrease nausea and vomiting. Dr. Tolbert hopes that her results can add to the conversation around the use of these medications in cats with CKD.

Although gastrointestinal protectants have a wide margin of safety, they’re not without side effects. Mounting evidence demonstrates that the use of proton pump inhibitors (PPI) causes disruptions of the gut microbiome and, in people, there is a link between PPI use and an increased risk of Clostridium difficile infections. A recent paper looking at gut microbiome changes in healthy cats given omeprazole did not demonstrate dramatic changes after 60 days of use. While encouraging, these results might be different in cats with underlying disease or in cats that are given acid suppressors for even longer periods of time which is common in cats with CKD.

In addition to potential changes in the microbiome, long-term use of proton pump inhibitors can lead to gastric mucosal hypertrophy. There also is a rebound gastric acid hypersecretion that can occur after gastric acid suppression therapy is discontinued.

To provide greater clarity on when to use or not use acid suppressants and other similar medications, the American College of Veterinary Internal Medicine released a consensus statement in 2018 on the rational use of gastrointestinal protectants. The statement covers a number of clinical scenarios including renal disease in cats. The opinion of the panel was that cats with CKD should not receive prophylactic gastroprotectants if they are in International Renal Interest Society (IRIS) stages 1–3. They felt that additional studies are needed to determine if acid suppression is helpful for individuals in IRIS stage 4 renal disease.

Given the growing body of evidence that casts doubt on the routine use of gastric acid suppression in cats with CKD, withholding this medication in a cat with early stage CKD is reasonable. This especially holds true when other treatments, such as diet change, are available as a first step. If gastric acid suppression is instituted in a decompensated patient, weaning the patient off this medication when stable also is a reasonable alternative to long-term therapy.

To learn more about cats with chronic kidney disease and gastric acid suppression, listen to Morris Animal Foundation’s podcast with Dr. Tolbert discussing her studies on the control of gastric acid secretion in both dogs and cats.

Morris Animal bottom 4

Inflammation, depression and the role of detoxification

Stress linked to chronic inflammation can cause depression. Explore this connection and ways to improve your quality of life both on and off the job.

If you’re stressed and/or have been diagnosed with depression — a fairly familiar occurrence among veterinary practitioners — you may also have chronic inflammation and don’t even know it. The incidence of chronic inflammation increases with age, and there are a wide range of common causes. They include genetic factors,1 exposure to xenobiotics such as plastics and pesticides,2 an unhealthy microbiome,3 the American diet,4 metabolic disease,5 obesity,6 chronic conditions such as heart disease,7 an imbalance of Phase I and Phase II enzymes in the liver,8 poor early-life nutrition9 and vitamin D deficiency9 — but they also include stress9 and depression.11

The relationship between stress, inflammation and depression

Psychosocial stress increases inflammatory cytokines, including interleukin-6 (IL6), interferon gamma, and tumor necrosis factor alpha (TNFα). Affected people also show lower levels of beneficial interleukin-10 (IL10) than those without stress and anxiety.12

Chronic stress leads to an imbalance between the sympathetic and parasympathetic systems, marked by increased stimulation of the sympathetic system and decreased vagal tone. An increase in stress hormones influences the immune system to create a pro-inflammatory state, while decreased vagal tone leads to a pro-inflammatory state in the gut. The end result is generalized inflammation, platelet activation, loss of heart rate variability, and endothelial dysfunction. These symptoms are not only seen in people with cardiovascular disease, but also in most of those who have been diagnosed with major depressive disorders.11

Core features of major depression include an increased reactivity to negative information, a less positive reaction to rewards, a lowered ability to control thoughts, and an extreme focus on physical symptoms. Pain or fatigue can cause major emotional distress to the point where the patient has difficulty functioning in daily life activities. Increased inflammation makes these signs worse.13

Chronic inflammation is a major factor in six of the ten leading causes of death in the United States, as well as in depression (the second most common mental illness in the U.S.).11,14 In fact, there is evidence that while inflammation can cause depression, depression also causes inflammation. Increased inflammation makes depression worse, and high levels of inflammatory markers are associated with depression that is more resistant to antidepressant therapy.15

C-reactive protein (CRP) is a test for the general level of inflammation in the body, and is easily available as an addition to any blood panel. Inflammation increases with stress, and we all know that many stressful incidents occur in a veterinary practice. Incidence of chronic inflammation increases as we get older, yet CRP is not routinely included in annual blood tests – not even for seniors.

Genetic tests are available for other markers of chronic inflammation, including genes for inflammatory cytokines, especially interleukin-1 beta (IL-1β), IL-6, IL-10, monocyte chemoattractant protein-1, TNFα, CRP and phospholipase A2. Moreover, increased blood cytokines mRNA expression (especially of IL-1β) identifies patients that are less likely to respond to conventional antidepressants.1

Phase I and II liver enzymes

With long-standing inflammation, prolonged exposure to xenobiotics, persistent toxicants that are hard to eliminate — or a Phase I/Phase II liver enzyme imbalance34 — merely adding antioxidant foods and supplements might not be enough. Toxicants that are not directly eliminated through the kidneys are processed through Phase I and Phase II liver enzymes, and when the level of toxicants exceeds the capacity of the liver to process them, detoxification is necessary to eliminate them.

Phase I enzymes primarily consist of the cytochrome P450 group (CYP450), along with a few others. The role of Phase I enzymes is to take a fat-soluble substance and make it more chemically reactive, by oxidation/reduction and/or hydrolysis reactions. Because the products of Phase I actions are highly reactive, they are also highly inflammatory, but in a healthy balanced liver they immediately react with Phase II enzymes.

Phase II enzymes conjugate those molecules with hydrophilic cofactors. This results in water-soluble molecules that can be excreted through the kidneys. Phase II enzymes include UDP-glucuronosyl transferases, glutathione S-transferases, amino acid transferases, N-acetyl transferases, and N- and O- methyltransferases. The cofactors used for conjugation include glucuronic acid, sulfate, glutathione, various amino acids, an acetyl group and a methyl group.35

There are a number of ways that Phase I/Phase II imbalances can interfere with the elimination of inflammatory substances. When there is a low level of both enzymes, the liver processes waste products and toxins more slowly, and those toxic substances build up in the body. Initially, they are stored in body fat, but when fat depots are full, they remain in interstitial spaces, where they interact with cells and cause inflammation. The same effect occurs with a low level of Phase I enzymes alone, since Phase I treatment is required for Phase II reactions to occur.

When the imbalance is reversed, so that you see an excess of Phase I reactions, or lower than normal Phase II enzyme activity, a buildup of inflammatory highly-reactive electrophilic molecules occurs. This can result in local liver inflammation, or system-wide inflammation, when they are released into the bloodstream.

If there are not enough cofactors to allow full conjugation of all the inflammatory products of Phase I, the result is the same. In addition, Phase I enzyme activity can easily be increased, especially with high exposure to toxic substances. It is more difficult to increase Phase II, so the result again is an imbalance, with excess Phase I activity with respect to Phase II activity.36

A determination of Phase I/Phase II imbalances could help with cases of chronic inflammation that do not yield to dietary, herbal or nutraceutical intervention.37 Two labs that offer tests to determine Phase I/Phase II imbalance are Genova Diagnostics in Asheville, NC, and The Great Plains Laboratory in Lenexa, KS.

For optimal elimination of toxic substances, a number of principles must be followed. To safely increase this elimination, the level of substances normally processed by the liver must be decreased. This frees up more Phase I/Phase II enzymes to process toxins. It also allows toxic substances to be released from fat storage, as total blood concentration decreases.

A high amount of naturally-produced waste products will decrease the level of toxic products that can be processed. Those products will be stored elsewhere in the body — first in the fat and later, when fat depots are filled, in interstitial spaces. They are generally inflammatory, contributing to the inflammatory cascade and causing chronic inflammation.

The best way to remove inflammatory products is to decrease the amount of normal waste products present. A fast eliminates most by-products of digestion, and is part of the detoxification process.

In addition, enough conjugates must be available for Phase II enzymes to work at full capacity. The body must stay hydrated to flush the end products away as quickly as possible. Essential nutrients must be maintained so that organs and muscle are not degraded while the process is going on. Additional nutrients must be added to support microbiome health throughout the process, and to provide antioxidant capabilities. A proper detoxification protocol accomplishes all of this.

Treating depression and inflammation

    • Physicians are starting to use NSAIDs in addition to conventional drugs to treat depression, especially celecoxib and aspirin. They often get better results than with drugs alone.14,16,17,18 Most studies have used NSAIDs for acute depression, not chronic depression, but it is logical that anti-inflammatory agents should also be useful for chronic depression. It’s likely it would take longer to see effects in cases of long-standing depression.
    • Some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), decrease inflammation. They decrease pro-inflammatory cytokines, including TNFα, interferon (IFN) γ and IL-1, and increase anti-inflammatory cytokines such as IL-10.19,20
    • A natural way to accomplish the same effect is to change to an anti-inflammatory diet. Diets high in fruits and vegetables decrease CRP levels, and normalize factors that affect endothelial health, including soluble intercellular adhesion molecule 1, soluble vascular adhesion molecule 1, and E-selectin molecules.21 Metabolic disease, associated with the typical American diet, predicts a poor response to standard treatment for those with depression 22
    • Immune cells and gut microbiota influence the brain,23 and fiber favorably influences the gut microbiome.24 Beta-glucans, which promote normal immune function, are plentiful in whole grain foods.25 Consumption of whole grains decreases the risk of inflammatory disease.26
    • Certain herbs, vitamins and supplements also have anti-inflammatory actions27,28 and are not associated with the types of side effects seen with long-term NSAID use. However, one must be careful using these supplements, since a number of them have hermetic (biphasic) effects, where a low dose can cause one effect and a high dose may cause the opposite.8,29
    • Avoiding dietary substances such as glutamate both reduces inflammation and improves depression.30 Induced sweating, both from exercise and from saunas, can increase excretion of phthalate plasticizers.31 Exercise has beneficial effects in general, and can help decrease liver inflammation.32
    • The microbiome also plays a part in chronic inflammation. There are multiple links between gut organisms, diet and depression. Early life trauma, the effects of various drugs, especially antibiotics, as well as nutritional factors affect the microbiome. In turn, a change in gut flora composition has been shown to affect depression, positively or negatively, depending on the change. Including prebiotics can help: inulin selectively stimulates colonic bifidobacteria, which play a part in maintaining a proper balance of microbiome species.33

Detoxification and medical fasting

Detoxification is a recognized procedure in reversing chronic disease.38 It is a modified form of fasting, with added nutritional products that support Phase I/Phase II enzyme activity in the liver. In Europe, this procedure is known as “medical fasting”, an established therapeutic approach supported within clinical departments of integrative medicine.38 Research demonstrates its association with deceleration or prevention of chronic inflammatory diseases.39 Medical fasting reduces or prevents the generation of cytokines that promote oxidative stress.40 It decreases free radical generation by mitochondria, decreases oxidative damage to mitochondrial DNA,41 and increases autophagy.42 Most importantly, it eliminates persistent toxicants.43 Fasting can also help depression. Its efficacy on improving mood is well established.44 Symptoms of depression usually start improving on Day 2 of the fast, with an enhancement in alertness and mood, and a sense of tranquility.45

It is important for fasting to be done properly. There must be enough nutritional support to reduce inflammation from Phase I processes, decrease the chances of over-activating the Phase I process, and to supply enough cofactors for Phase II conjugation to proceed as thoroughly as possible. The detoxification process can be modulated using foods and nutraceuticals.

Fasting also has a dark side. It can decrease the immune system’s performance and cause atrophy in various organs.46 It causes changes in blood glucose regulation, plasma growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein-3 (IGFBP-3).47 There is a need for some protein and healthy fats during fasting48 to support the body’s daily metabolic processes, so that muscle and organ tissue will not be destroyed in order to provide the required nutrients. When fasting is excessively prolonged and suddenly ended, re-feeding syndrome has been reported,49 which can result in illness or death. Intracellular phosphate, magnesium and potassium may be low, though serum measurements of the three electrolytes are normal. With a reversal of metabolism from fat-based to carbohydrate-based, electrolytes are needed but not available, resulting in hypokalemia, hypophosphatemia and hypomagnesemia. Death from heart failure can occur. Unexplained deaths have been reported in obese individuals who were fasting.50

The best way to avoid these unpleasant effects when detoxing is to use a supplement with nutraceuticals that support Phase II conjugation, decrease the inflammatory effects of Phase I activity without stopping the wanted chemical effects, and supply necessary components to avoid tissue and organ destruction. In addition, rather than abruptly starting and stopping the fast itself, a more gradual introduction to the fast and resumption of a normal diet will avoid reactions similar to re-feeding syndrome.

Two products are available that will do this: Ultra-Clear from Metagenics in CA, and Mediclear from Thorne Research in SC. These products are accompanied by guides for their use and the proper beginning and end of the detoxification process. This approach is superior to some popular fasting methods, including the water fast. When properly conducted, a fast can decrease or eliminate toxicants that are causing inflammation and depression. With severe depression, fasting should not be done without medical supervision and appropriate supplementation. It is safer if the only object is to reduce potential chronic inflammation without any overt signs of disease, but the healthiest way is still a fast with the addition of proper products to avoid protein degradation in the body, support Phase II conjugation, decrease inflammation, and maintain proper electrolyte balance.

For more information, see Dr. Scanlan’s blog at longerhealthierlife.net.

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22Marijnissen RM, et al. “Metabolic dysregulation and late-life depression: a prospective study”. Psychol Med. 2017 Apr;47(6):1041-1052.

23Ho GT, et al. “MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation”. Mucosal Immunol. 2018 Jan;11(1):120-130. doi: 10.1038/mi.2017.31. Epub 2017 Apr 12.

24Tachon S, Zhou J, Keenan M, Martin R, Marco ML. “The intestinal microbiota in aged mice is modulated by dietary resistant starch and correlated with improvements in host responses”. FEMS Microbiol Ecol 2013, 83:299–30.

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32Pillon Barcelos R, et al. “Oxidative stress and inflammation: liver responses and adaptations to acute and regular exercise”. Free Radic Res. 2017 Feb;51(2):222-236.

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Behavioral changes resulting from microbiome restoration

The potential of Microbiome Restorative Therapy (MBRT) to positively affect behavior in companion animals. 

Evidence supporting the critical role of a well-functioning microbiome in the health of veterinary patients continues to grow. Research indicates that significant components
of the immune response originate in the gut,1-6 supporting the claim that disease conditions may arise from damage to the gut’s microbiome.7-13 Exposure to antibiotics and other medications, as well as environmental toxins and poor diets can alter the microbiome, weakening the immune system and setting the stage for gastrointestinal illness (GI) and allergies.14-18 The widespread use of hand sanitizers, bleaches, antimicrobials and chemicals such as pesticides, herbicides and preservatives, could contribute to the depleted numbers of microbes being found in human infants and pets.19-24 There is now growing evidence that such damage may be ameliorated by fecal transplantation, and this therapy, while still in its infancy, is increasingly being utilized in both human and animal medicine.25-34 Microbiome Restorative Therapy (MBRT) is a term this author coined in 2012 (as opposed to the customary term Fecal Microbiota Transplantation or FMT) to better describe what this therapy actually does — restore the microbiome.

Microbiome inoculation and rationale for MBRT

Mammalian transit through the birth canal at parturition results in microbial inoculation. This “vaginal gulp” occurs as the fetus emerges, bathed in vaginal fluid containing lactobacillus and other microbes. Recent research suggests that even prior to birth, fetuses ingest amniotic fluid, the individual’s first “meal” of microbes.35 Further microbial exposure takes place as the newborn nurses and later explores its environment. In the wild, baby animals crawl around in a dirt den while the mother regurgitates the food she has eaten to feed them or offers recently killed prey. This initial inoculation of the microbiome is the beginning of the individual’s immune system.

Individuals not receiving these microbiome inoculations as well as other healthy, normally-occurring environmental bacteria may lose immune strength due to deficient exposure.1-7 In humans, full-term C-section babies who do not get their initial inoculation from the birth canal benefit from an oral transfusion of their mother’s microbiome.36

In the case of animals, coprophagia may be a natural way for them to try to replenish their microbiomes. Giving them a healthy, balanced microbiome by transplantation can reset the gut flora and stop the coprophagia and eating of other undesirable things.37,38 Animals in the wild often eat particular plants and other substances that provide certain nutrients as well as diverse bacteria, an additional way to balance the microbiome.

Behavioral effects of MBRT

This author and her clinical colleagues have observed through years of working with MBRT that this therapy is beneficial not only for its physical healing qualities, but also for its effects on behavior, adding to the possible positive outcomes of fecal transplants in companion animals. We have witnessed in our veterinary clinic, or through client feedback, distinct behavioral and even personality changes in MBRT recipients. While we do not know why these behavioral changes occur, we posit that microbiome restoration appears to be at least partially responsible for this effect.

We have observed an added dimension of mental health and behavioral improvements within just a few hours or days of this novel treatment, and appreciate this as a significantly different consequence from the typical positive outcomes of other holistic treatments. A better understanding of the role the gut plays in emotional and psychological well-being is timely and necessary, and can inform the possibility of incorporating fecal transplants into behavioral therapeutic approaches for animals as well as humans.

A “One Health” approach

The “One Health” concept is a relevant paradigm from which to approach this issue. Published scientific and subjective accounts describe how some organ transplant recipients seem to suddenly take on emotions and characteristics unlike their own, but very similar to those of their donors.39-44 This effect has been documented in heart, lung, kidney, liver and other organ and body part transplant patients (although the most dramatic and long-lasting effects seem to occur with heart transplants)45,46

This intriguing side effect of organ transplants raises interesting questions regarding the nature and mechanisms of some kind of cellular memory that would generate such changes. Likewise, when we hear compelling subjective accounts of similar personality changes after fecal transplants in humans, this raises questions regarding the possible emotional and behavioral effects of MBRT in our animal patients. It is this author’s opinion that providing information on behavioral effects in humans as a result of fecal and organ
transplantation is an important segue to any discussion of analogous responses in other mammals who cannot explain in words what they are experiencing.

MBRT case studies

The following are brief observational accounts of behavior and personality changes in some of our patients, as well as a report from a client who experienced MBRT through her own medical team. Please note that in addition to MBRT treatments, each animal was provided with an overall integrative therapy approach that included several other holistic treatments. These combined treatment modalities appear to provide significant healing synergistic effects, so are deemed crucial in our treatment protocols. But it was only after receiving MBRT in particular that animals showed a marked change in their behaviors, usually occurring within hours to one or two days. 

1. An 11-year-old spayed calico cat, thin and fragile on physical examination, suffered from constant diarrhea for over 18 months, producing ten to 20 stools per day, following years of intermittent diarrhea treated with metronidazole. She frequently hid in the basement of her home, and was fearful of the family’s dog. Previous evaluations included extensive ultrasounds, blood work and fecal examinations.

Less than two days after MBRT, her stools were normal, and she could be found sitting confidently on the couch and playing with the dog. To have such a complete change in both her stool consistency and behavior after years of illness — and in less than 48 hours  following therapy — is very unusual, even in an animal treated with standard holistic care for inflammatory bowel disease. This cat continues to do well, has gained weight, and has had no further episodes of diarrhea.

2. An 18-month-old black Labrador had been raised and trained as an assistance animal. Unfortunately, as a puppy and even after extensive training that he otherwise responded favorably to, he was coprophagic and exhibited some anxiety. His behavior as an assistance animal was excellent, but eating his stool as soon as it dropped to the ground was unacceptable to the organization, so they sold the dog to a caring family. For over six months, his new family still could not break his habit of eating stools, and his anxiety remained. After a single MBRT treatment, his coprophagia ceased and his anxiety was no longer an issue.

3. A seven-year-old neutered Maine coon cat presented with a mangy coat from years of atopic dermatitis, previously treated with multiple courses of antibiotics, cyclosporine, antihistamines and steroids. Following MBRT from a oneyear-old Siamese male donor who had just been neutered, he not only started healing from his dermatitis but showed a much happier demeanor than before treatment. After subsequent MBRT treatments from the same donor, he started showing sexual behaviors not seen before. This case raises questions about the effects of fecal transplants from hormonally-charged donors.

4. A 35-year-old woman, a client of this author, suffered from an autoimmune disease with gut complications, and received three fecal transplants, each from a different donor, over a period of several weeks. The only identifying factors she knew about the donors were their ages and genders: an 11-year-old girl, a 25-year-old woman, and a healthy young man. With the young girl, she reported a dramatic change, feeling healthy, balanced and blissful. With the young woman, while she was physically improved, she felt no emotional changes. With the third, she reported sweating copiously with the strong body odor of a man, which she intensely disliked. She was also up all night feeling much stress, anxiety and upset. Upon inquiring, she learned that that the male donor was a bodybuilder who had just broken up with his girlfriend and was quite upset. Was the transplant responsible for these intense physical and emotional effects?

More questions than answers

At this stage in medical science, study of the microbiome creates more questions than answers. There are more than 100 trillion microbes in a healthy human being — microbes which originated about 3,000 million years ago. A large percentage of microbes are in the gut; however there are microbes in every organ system. Medical science does not currently understand the full significance of each of the microbiomes throughout the body. Is it the organ that runs the system, or the microbiome within the organ that directs the individual’s health?

What we do know from direct observation is that in the majority of our fecal transplant cases, the animals are livelier and happier and exhibit more vitality following MBRT. Researchers continue to appreciate the value of the microbiome and how it can influence neurotransmitters, serotonin growth factors, and many other aspects of cellular communication and survival.41 Research illuminating the connection between the gut and brain is finding that precursors to many enzymes and neurotransmitters are within the microbiome.35,47-49 How this brain/gut association is connected to actual behavioral outcomes following MBRT is an area for much-needed research. Through further observation as well as scientific research, we will uncover a better understanding of this primordial creation that is basic to all life.

For information on using MBRT in your practice, see IVC Journal (Fall 2014) or visit ivcjournal.com/mbrt-immune-system.

Acknowledgements: Many thanks to Carvel Tiekert, DVM, Odette Suter, DVM, PJ Broadfoot, DVM, and Deborah Moore, PhD for their critiques and comments on an earlier version of this paper. Thanks also to my clients and their beloved pets for seeing the possible benefits of these procedures, and much appreciation to my own dogs and cat for their microbiome donations to others.

____________________________________________

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Canine allergic dermatitis: a systemic approach to management

Canine allergic dermatitis is a clinical issue, best treated with integrative therapies that address local and systemic factors as well as key body systems.

Allergic dermatitis is a common and challenging problem in dogs. This article briefly describes canine allergic dermatitis and its local and systemic components, including the influential role of the small intestine, liver, adrenal glands, central nervous system, microbiota and anxiety in allergic inflammation. The importance of a complete patient evaluation will be highlighted, and the rationale for a systemic approach to management using nutritional supplements, herbs, probiotics and homeopathic medicines will be outlined.

More than a local skin issue

Allergic dermatitis has long been viewed as a disease that’s localized in the skin. It is now clear, however, that it is a complex clinical issue with local and systemic inflammatory processes influenced by secondary contributing factors.

The local reactions are an intricate and finely orchestrated interaction between the allergen and resident immune cells. These local reactions are also capable of recruiting non-resident immune cells to reinforce local immune reactions.

Unfortunately, from a clinical management perspective, the local reactions are not the complete story. Beyond the local reaction is an incredible interwoven pattern of interaction between the immune system, nervous system, endocrine system, skin and mucosal barriers with associated immune elements, and the microbiota. Each reacts to and is influenced by the other, meaning that effective integrative management must support multiple body systems simultaneously.

Canine allergic dermatitis – environmental allergens and adverse food reactions

Three main allergy categories have been described: insect bite (i.e. flea) hypersensitivities, adverse cutaneous food reactions, and atopic dermatitis from environmental allergens.1 Classically, canine atopic dermatitis is defined as a pruritic allergic skin disease commonly associated with IgE to environmental allergens in genetically predisposed individuals.2 Interestingly, an atopic-like dermatitis has been described with similar clinical signs as canine atopic dermatitis; however, an IgE response to environmental allergens cannot be demonstrated,3 implying that IgE-mediated reactions are not always the central process in allergic inflammation.It is estimated that 10% to 15% of dogs are affected by dermatitis resulting from reactions to environmental allergens.1 Cutaneous manifestations of adverse food reactions are recognized as indistinguishable from the classic environmental allergic disease.3 The incidence of adverse food reactions in the dog is not completely clear, but an estimated 9% to 40% of pruritic dogs and 8% to 62% of dogs with allergic skin disease are affected.4 Approximately 30% of dogs with allergic dermatitis are affected by reactions to both environmental allergens and food.5 Since canine atopic dermatitis is a clinical diagnosis that can result from environmental allergens and adverse food reactions, both will be referred to here as canine allergic dermatitis (CAD), and their intertwined features will be outlined. Clinical signs of CAD generally include pruritus and erythema. Self-induced alopecia and excoriation are common. Secondary infections occur with microbes like Malassezia with epidermal hyperplasia, hyperpigmentation and lichenification; and Staphylococcus with crusts, papules and pustules. Affected areas include the ventral abdomen, distal extremities, axillae, and the inner pinnae, perioral, periocular and perianal regions. Otitis externa is reported in half of dogs with canine atopic dermatitis.2 The predominant lesions in atopic dermatitis dogs occur in the skin; however, other organs like the digestive and respiratory tracts can be involved.1 Breed predisposition and breed-associated cutaneous distribution patterns have been reported. Criteria for diagnosing atopic dermatitis have been developed. Accurate diagnosis and evaluation of secondary factors is essential. Ruling out ectoparasites like fleas is critical. Adverse food reactions can have cutaneous signs that mimic atopic dermatitis in addition to gastrointestinal signs.6 CAD related to environmental allergens is generally seasonal at onset; however, it can exhibit a non-seasonal pattern. The majority of dogs with a seasonal pattern have clinical signs in the spring or summer, while those with a non-seasonal pattern are often worse during a specific season. The presence of pruritus is considered an essential component of diagnosis. However, otitis externa was the initial clinical presentation in 43% of canine atopic dermatitis patients.6 The variability of presentation underscores the need for a systematic approach to patient evaluation, and consideration of the diagnostic criteria for CAD.

Allergic inflammation: the systemic web

The allergic reaction has been considered an overreaction to harmless allergens. This brings to mind images of immune cells aggressively attacking a harmless invader. The alternative image is of an immune response that is dysregulated because the mechanisms that would normally keep allergic inflammation in balance are not functioning appropriately. The coordination and control of allergic inflammation is a process involving a complex web of interactions, systems and body tissues, which means this control is not strictly a local problem at the site of allergic dermatitis (see Figure 1).

Regulation involves a series of interactive adjustments that influence each component of allergic inflammation. Some events are rapid-acting; others are delayed. When IgE with bound allergen contacts the mast cell membrane receptor FcεRI, the mast cell degranulates, releasing substances like histamine followed by synthesis and release of cytokines and chemokines. Histamine’s rapid reactions include vasodilation and increased vascular permeability. Cytokine and chemokine reactions, which occur later, include recruitment and activation of inflammatory cells at the local site as a result of increased local concentrations, and from systemic circulation. In the naïve individual, the process takes longer because the allergen has to be initially processed. Antigen processing cells like the dendritic cell (DC) take up the allergen and transport it to the regional lymph or local tissue site. When the DC presents the processed allergen peptides to naïve T cells, they become T helper 2 cells (TH2). The TH2 influence later allergic reactions by producing interleukin-4 (IL-4) and IL-13 that combine with other co-stimulatory molecules to induce B cells to produce IgE. The IgE diffuses locally and in the lymphatics for eventual systemic distribution in the bloodstream.7This simplified presentation of the local allergic inflammatory reaction, and the implication of a modest systemic effect, is inadequate for describing the sophisticated systemic influence. This complex regulation is why allergic inflammation and CAD are so difficult to manage clinically. Stated in another way, allergic dermatitis is a whole body problem (see Figure 1).The skin and mucous membranes form the first barrier against allergens. Allergens enter tissues in multiple ways — for example, through a damaged or altered surface barrier, penetration facilitated by allergen proteolytic properties, and allergen epithelial binding. Mucosal barrier damage in the intestine can result from inflammation, inadequate levels of certain nutritional factors, and dysbiosis of intestinal microbiota. This inflammation provides opportunity for allergen penetration beyond the mucosal surface, which can elicit local and systemic reactions. Note that “intestinal microbiota” refers to the living microorganisms inhabiting the gastrointestinal tract, including bacteria, viruses, fungi and protozoa,8 as opposed to the term “microbiome”, which includes microbe genomes.

Figure 1: A generalized overview of systemic processes and supportive care (in green) that can influence the development and management of canine allergic dermatitis. It is not intended to be an all-encompassing representation of the complex interactions that lead to propagation of allergic inflammation. Psychological stress is used here to denote the individual patient’s reaction to what they perceive as stressful or anxiety-provoking external (i.e. environmental conditions) and/or internal (i.e. illness, pain) issues. (CNS — central nervous system; PNS — peripheral nervous system; ANS — autonomic nervous system)

In addition to local and systemic signaling with cytokines and chemokines, an intimate interaction between the immune and nervous systems plays an important role in regulating the inflammatory response. Communication between these systems involves neurotransmitters, endocrine hormones and cytokines. The autonomic nervous system and hypothalamic-pituitary-adrenal (HPA) axis play central roles.9 There is evidence that a hyporeactive HPA axis significantly increases the susceptibility to developing chronic inflammation. The sympathetic adrenomedullary system also has significant effects on immune regulation and stress responses.10 Lymphoid tissues, including mucosal-associated lymphoid tissue, lymph nodes, spleen, liver and bone marrow are innervated by the parasympathetic nervous system through the neurotransmitter acetylcholine and the sympathetic nervous system (SNS) through norepinephrine. Neurotransmitter receptors for acetylcholine and norepinephrine are present on lymphocytes as well as serotonin, substance P and histamine. Receptors for neuroendocrine mediators like corticotropin-releasing hormone (CRH) and leptin are present in lymphoid tissue.11 Glucocorticoids are the key effector molecules of the HPA axis. Adrenocorticotropic hormone (ACTH) appears to increase pro-inflammatory cytokines that are modulated by the glucocorticoid production they stimulate. Interestingly, chronic allergic disease has been associated with higher levels of TH2 and reduced glucocorticoid levels.12 A peripheral HPA axis, distinct from the central HPA axis, has been described in the skin.

The peripheral HPA axis has similar components and a regulatory hierarchy that exists for the central HPA axis. Keratinocytes are able to produce CRH, ACTH, cortisol, neurotransmitters, neurotrophins, neuropeptides and their respective receptors. This peripheral HPA axis appears to be an important part of maintaining the epidermal barrier and modulating inflammation.12

The liver contains a large population of resident immune cells and is responsible for the production of substances involved in immune reactions, such as cytokines, chemokines and acute phase proteins. This is in addition to its metabolic, nutrient storage and detoxification functions. The hepatic immune system is exposed to a wide range of dietary, microbial and environmental molecules derived from the gut. Resident macrophages (Kupffer cells), which constitute almost a third of the non-parenchymal cells of the liver, and hepatocytes are able to recognize and remove immunogenic substances without producing inflammatory mediators. This is important because it prevents these immunogenic substances from entering the systemic circulation to elicit a wider immune reaction. Other immune cells in the liver include DC, T cells, B cells and natural killer cells. Even though the hepatic immune system has evolved to have some level of immune tolerance, there is some level of ongoing regulated inflammation that is thought to be beneficial for the liver.13

The intestinal tract provides a selective barrier for nutrient absorption and the exclusion of harmful substances and microbes. This process requires a properly-functioning mucosa and mucosal immune system. Intestinal microbiota have significant impacts on health based on their composition and interaction with the mucosal immune system. Interaction between intestinal microbes and the mucosal immune system allows for immune tolerance to microbes and harmless substances while allowing the immune system to react to pathogens. Epigenetic modifications of intestinal epithelial cells following exposure to microbial products facilitate tolerance. Intestinal DC sample intestinal microbiota and transport the bacterial-derived antigens to the mesenteric lymph nodes. This allows the immune system to be rapidly responsive if there is damage to the mucosa and leakage of microbes or microbial metabolites that overwhelm the liver immune system.14 Mucosal barrier health is essential for preventing the absorption of microbes, microbial metabolites and other immunogenic substances. By extension, a healthy mucosal barrier significantly reduces the level of inflammation.

Alterations in the composition of the skin and intestinal microbiota have been linked to allergic dermatitis.15Interaction between intestinal microbes, dietary nutrients, the gut microenvironment, mucosal immune system and neuroendocrine substances have direct and indirect effects on the composition of the skin and intestinal microbiota. This can significantly influence the quality of the mucosal and dermal barriers, exposure to allergens, relative levels of allergic inflammation, development of allergic dermatitis, and response to therapy. For example, beneficial microbes directly and indirectly impact the growth and colonization of pathogens.8 This impacts inflammation, mucosal barrier function, and tolerance.16

Studies in humans demonstrate that stress is associated with increased allergic inflammation.9 Stress activates the HPA axis, SNS and sympathetic adrenomedullary system, which lead to increased CRH, ACTH and glucocorticoids. A chronically-activated HPA axis results in a dysregulatory effect on inflammation that may be due to low glucocorticoid levels from adrenal exhaustion or tissue receptor resistance. In addition, chronic elevations in ACTH may result in increases in pro-inflammatory cytokines.11,12 Chronic stress and inflammation result in changes to the dermal barrier that predispose the skin to secondary infections and increased response to allergens.

Managment of canine allergic dermatitis

Current conventional therapy for CAD involves managing acute flares and chronic skin lesions, and attempts to prevent relapses.17 Avoiding trigger allergens, controlling secondary skin infections, and reducing pruritus form the foundation of therapy. This often involves topical and oral therapies, including antimicrobials, antihistamines, shampoos and immune-suppressive drugs. Food elimination trials and hydrolyzed diets are frequently used for adverse food reactions.1 Each option has variable degrees and quality of research support for efficacy. The selection and implementation of each management component depends on careful patient assessment, severity of clinical signs, and prior history. Clinician experience plays a role in selection of the therapeutic plan.

From an integrative perspective, once a clear diagnosis has been achieved, it is critical to evaluate the patient as a whole so clear therapeutic goals and a management plan can be defined. Particular attention should be paid to historical factors like prior antimicrobial and immune-suppressive therapy, vaccination history, personality and level of anxiety, and gastrointestinal sensitivities. Identify the presence of secondary infections and ectoparasites. Observe the severity of the pruritus and the allergic dermatitis.

Realistic goals for CAD management include reducing pruritus to a tolerable level and decreasing the severity of acute flares and relapses. It is not always possible to completely resolve all pruritus and prevent acute flares. Immune-suppressive therapies and systemic antimicrobials may be necessary to initially control allergic inflammation and address secondary infections, thereby providing patient comfort or preventing self-mutilation.

Based on a broader view of allergic inflammation and the role of systemic factors, as briefly discussed here, key areas of focus for supportive therapy include the adrenal glands, liver, intestine, autonomic nervous system, immune system, intestinal microbiota, skin and mucosa (see Figure 1). All these areas should be supported at the same time instead of sequentially. Focusing on these areas will provide support for reducing the inflammatory process, improving barriers, and decreasing allergen exposure. Additional areas of support should include managing the anxiety that is not addressed through support of the adrenal glands (see Table 1).

Specific Therapies

The systemic approach to managing CAD patients described here relies on published research related to the physiological mechanisms of allergic inflammation and responses to therapy, the author’s decades of clinical experience with allergy patients and whole food nutritional supplements, and his clinical exploration of the organ and gland imbalances that influence allergic inflammation. This perspective led to his development of Canine Dermal Support™ for Standard Process Inc®.

Consistent clinical response was a critical component in product development and patient management. No controlled studies are currently available to validate this approach in its entirety.

The foundational product for this approach is Canine Dermal Support™, which is a whole food concentrate product. A discussion of the use of whole food concentrates as compared to isolated nutrients is beyond the scope of this article; however, whole food concentrates are an essential component of the systemic approach described here.

The systemic approach (see sidebar above) becomes more effective if the adrenal glands, small intestine, liver, nervous system and intestinal microbiota are supported together as the initial step. Canine Dermal Support contains a combination of whole food concentrates and herbs like Silybum marianum, Emblica officinalisand Taraxacum officinale that provide nutrients and bioactive substances for the adrenal glands, liver, small intestine, nervous and immune systems. If support from this product for targeted tissues is inadequate based on patient evaluation and clinical response, Canine Adrenal Support™, Canine Hepatic Support™ or Canine Enteric Support™ can provide additional help. Herbs like Silybum marianum, beneficial for its liver and bile support, as well as Rehmannia glutinosa for its adrenal and immune benefits, can be employed as needed.

Concern has been expressed regarding the use of supplements containing bovine origin ingredients in patients with a known or suspected adverse reaction to beef. In the author’s experience, this has not been a clinical problem when using the supplements discussed here. A number of likely reasons contribute to this observation, including the relatively small quantity of bovine origin ingredients in the recommended supplements; also, these supplements support improvement in the intestinal mucosal barrier while reducing dysregulation of the immune reactions contributing to allergic inflammation. A high quality probiotic containing a prebiotic will complement this regimen. Selecting a probiotic product should be based on clinically-demonstrated effects. Determination of probiotic efficacy can be challenging and may require changing probiotics or initiating therapies that change the microenvironment of the gut. This would include using products or herbs that increase the flow of bile, adding soluble fiber to the diet, or facilitating the reduction of high SNS tone if present.

The role that vaccination plays in promoting allergic inflammation is unclear, but clinical observations and reports of dogs with pre-existing allergies have shown increases in IgE following prophylactic vaccination. This increase was present at one and three weeks, but not eight weeks, post-vaccination.18 While the implications are not clear, it shows how allergic dogs could worsen following vaccination, and why there has been a casual observation that allergies are exacerbated four to six weeks post-vaccination. In addition, since the IgG was also shown to increase, it is possible to speculate that a low grade chronic inflammatory process could be established in susceptible individuals. The author has found consistent improvements in allergy patients by using the homeopathic rubric related to vaccinations. Commonly-used homeopathic medicines include Silicea and Thuja occidentalis; however, selection should be based on the individual patient. The selected homeopathic medicine, potency and dosing plan can be initiated at the beginning of therapy.

Anxiety and other psychological stresses should be addressed early in the management of allergies since stress can play a significant role in immune dysregulation and the stimulation of pruritus. A variety of approaches is available and should be selected for the individual patient, especially if adrenal support alone does not appreciably change the stress response pattern. These include Bach flower remedies, supplements like Min-Chex®, nutraceutical products such as Composure™, herbs or combinations selected for the individual patient, and/or medications. It is also important to consider working with a behaviorist or qualified trainer to find ways to manage stress or reduce sensitivity to stimuli. Manual therapies can be used to reduce pain and activation of SNS responses.

For patients with otitis externa problems, the approach described above is useful in addition to topical management of the ear canals. It is important to treat the infections and reduce inflammation. Anti-inflammatory ear products and washes can be helpful. Since otitis externa can be a long-term problem with occasional flares, it may require ongoing therapy.

Patients with secondary infections often benefit from antimicrobial shampoos while the systemic management plan is being instituted. Multiple shampoo treatments may be required until control is established and barrier health has improved. Ectoparasites like fleas and lice should be treated and the environment managed as appropriate.

For patients that are excessively pruritic and self-mutilating, a course of diphenhydramine, prednisone or oclacitinib may be indicated. While there is concern that the use of immune-suppressive drugs like prednisone can make later management more difficult, the patient has need for more immediate relief than can be provided with nutritional supplements alone. If immune-suppressive therapy has been ongoing and the liver and adrenal glands have been impacted, consider additional Canine Hepatic Support™ and Canine Adrenal Support™.

Clinical response to Canine Dermal Support™ and probiotics takes four to six weeks depending on the severity of the clinical condition, presence of complicating factors, and history of previous suppressive therapies. Adjustments to the support plan are made at monthly rechecks, unless needed sooner based on patient condition. Keep in mind that regardless of how the patient is managed (conventionally or integratively), pruritus is not always completely controlled and acute flares can occur. It is also interesting to note that in addition to the initial benefits of this approach, patients will continue to improve clinically over the course of a four- to five-year period when this approach is continuously used

Disclosure: The author of this publication formulated and clinically evaluated the original 16 Standard Process Veterinary Formulas™ during product development as a paid consultant for Standard Process Inc.® He is not employed by Standard Process Inc.®, derives no financial benefit and has no equity interest in either Standard Process Inc.® or Standard Process Veterinary Formulas™.

** This article is peer reviewed

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