Saturday, July 28, 2012

Cats and Nutrition: Some Key Nutritional Facts


I recently attended a lecture given by by Dr. Deb Zoran of Texas A&M University on the topic of "Protein: the Key to Metabolism, Health, and Management of Obesity in Cats." As you may already know, Deb wrote one of the seminal articles about feline nutrition now over a decade ago (1), and she is a world renowned expert on nutritional needs of cats and how to feed them (2-4). She is a Diplomate of the American College of Veterinary Internal Medicine (currently the President-elect) and also has a PhD in Nutrition.

In this blog post and the next, I'd like to share some of what I learned from Deb's excellent presentation. If you care for cats in your practice, this is all important to know, no matter what the clinical problem.

Feline Nutrition
Cats are obligate carnivores. This statement is news to no one, and yet we often don’t recognize the importance of that statement or feed them accordingly. While cats can use carbohydrates as a source of metabolic energy, they have no requirement for them (nor do dogs for that matter). But, more importantly, because cats evolved consuming prey (e.g., high protein, low to moderate fat, minimal carbohydrate), they are metabolically adapted for higher protein metabolism and lower carbohydrate utilization.

What does that mean metabolically and nutritionally? There are a number of specific metabolic and biochemical differences in feline physiology that are important. This is very important to consider when treating many feline endocrine disorders, especially diabetes and hyperthyroidism.

Cats and Nutrition: Some Key Nutritional Facts
  • Cats have an obligate need for protein and amino acids in their daily diet because they are unable to down regulate their urea cycle or transaminases (protein conversion to energy) as other species can in times of starvation.
  • Cats utilize protein for energy, even in the face of large amounts of carbohydrates in the diet.
  • Taurine, arginine, methionine, cysteine, and possibly carnitine requirements for cats are greater than non-carnivores.
  • Arachidonic acid is also an essential fatty acid in cats (it is not in dogs), and is found only in fats from animal tissue.
  • Cats require vitamin A and D to be present in the active form in their diet as they are unable to synthesize adequate amounts from other dietary precursors (e.g., carotenoids or vitamin D precursors in skin).
  • Cats have an increased need for many B vitamins in their diet (e.g., thiamin, pyridoxine, niacin, pantothenic acid) as they have greater metabolic needs for these vitamins and cannot synthesize or get them from other sources.
  • Salivary amylase is absent in cats, and they have greatly reduced levels of intestinal and pancreatic amylases – so carbohydrate digestion is much less efficient.
  • Cats have fewer disaccharidases and other brush border enzymes in their small intestine designed to digest and absorb starches.
  • The small intestine of cats is much shorter than that of an equally sized omnivore – longer GI tracts are necessary for handling of complex carbohydrates.
  • Cats have greatly reduced activities of hepatic enzymes (e.g., glucokinase) designed to convert a post prandial glucose load to glycogen and thus are less able to handle this glucose load.
  • There are no fructokinases in cats – they are unable to utilize fructose and other simple sugars.
My Bottom Line

What this list clearly points out that is that cats are not designed to eat carbohydrates as a source of metabolic energy. Instead, cats are metabolically adapted for higher protein metabolism and lower carbohydrate utilization. Therefore, why aren't we all recommending diets (low carb, higher protein) that better meet their needs, and feed cats what they were designed to eat?

References:
  1. Zoran DL. The carnivore connection to nutrition in cats. Journal of the American Veterinary Medical Association 2002;221:1559-1567. 
  2. Zoran DL, Buffington CAT. Effects of nutritional factors and lifestyle choice on the health and well-being of indoor catsJournal of the American Veterinary Medical Association 2011;239:596-606. 
  3. Zoran DL. The unique nutritional needs of the cat. In: Ettinger SJ, Feldman EC (eds). Textbook of Veterinary Internal Medicine, 7th edition. Saunders Elsevier, 2010;652-659. 
  4. Zoran DL. Obesity in dogs and cats: a metabolic and endocrine disorder. Veterinary Clinics of North America Small Animal Practice 2010 Mar;40:221-39. 

Tuesday, July 24, 2012

Temporary Shortage of ProZinc (PZI Insulin)


As most of you probably already know, ProZinc (PZI insulin) has been on backorder for the last couple of weeks.  It turns out that the problem is a shortage of protamine, the protein which slows down the absorption of the PZI insulin and increases its duration of action.

Hopefully, this shortage will be short-lived and ProZinc will be back soon.


Sunday, July 22, 2012

Must Insulin Be Stored in the Refrigerator?

I have a newly diagnosed diabetic dog on NPH insulin, whose owner has not been refrigerating the insulin (Novolin N). I instructed him to store the open insulin vial in the refrigerator. However, the pharmacy where he purchased the insulin put a sticker on the vial that says it can be left at room temperature. The owner also claims he looked it up online and says it doesn't have to be refrigerated.

I have always been taught that insulin must remain in the refrigerator or it loses it's "potency." I did look up the FDA Patient Package Insert online, which says the following: 

All Unopened Novolin N:
  • Keep all unopened Novolin N in the refrigerator between 36° to 46°F (2° to 8°C).
  • Do not freeze. Do not use Novolin N if it has been frozen.
  • If refrigeration is not possible, the unopened vial may be kept at room temperature for up to 6 weeks (42 days), as long as it is kept at or below 77°F (25°C).
  • Keep unopened Novolin N in the carton to protect from light.
Opened Novolin N Vials:
  • Keep at room temperature below 77°F (25°C) for up to 6 weeks (42 days).
  • Keep vials away from direct heat or light.
  • Throw away an opened vial after 6 weeks (42 days) of use, even if there is insulin left in the vial.
  • Unopened vials can be used until the expiration date on the Novolin N label, if the medicine has been stored in a refrigerator.
So, is it okay for this man to leave the opened insulin at room temperature? This owner has been doing so for several weeks now but we still haven't gotten the dog regulated!

My Response:

Yes, it is fine to leave an opened NPH insulin vial at room temperature, but if left out of the refrigerator, we should discard it after 6 weeks (1-3). In extremely hot climates, it has been recommended that the vial be replaced even more frequently if left unrefrigerated (4). Storing the insulin in the fridge helps maintain insulin potency, allowing one to use that opened vial for up to 4 to 6 months. 

I don't know too many owners that would think leaving it out of the refrigerator is worth the added cost of purchasing more insulin. But that is the owner's choice.

I can think of only one downside for storing insulin in the refrigerator —injecting cold insulin can sometimes make the injection more painful. To avoid this, one can draw up the insulin and wait a couple of minutes before injection, making sure that the insulin is not too cold injected. Or one could roll the syringe between the palms of both hands for 30-60 seconds (with the needle facing upward) just prior to injecting to remove the "chill."

Reference:
  1. Insulin Storage and Syringe Safety. American Diabetes Association website. http://www.diabetes.org/living-with-diabetes/treatment-and-care/medication/insulin/insulin-storage-and-syringe.html
  2. Guide for Storage of Insulin. Wisconsin Department of Health Services. http://www.dhs.wisconsin.gov/rl_dsl/publications/GudStrgInsulin.pdf
  3. Grajower MM, Fraser CG, Holcombe JH, et al. How long should insulin be used once a vial is started? Diabetes Care 2003;26:2665-2666. 
  4. Vimalavathini R, Gitanjali B. Effect of temperature on the potency & pharmacological action of insulin. Indian Journal of Medical Research 2009;130:166-169. 
My Related Posts:

Tuesday, July 17, 2012

Flame Retardant Chemicals in House Dust Linked to Hyperthyroidism


The Feline Thyroid Gland: A Model for Endocrine Disruption by Polybrominated Diphenyl Ethers (PBDEs)?

D. A. Mensching, M. Slater, J. W. Scott, D. C. Ferguson, and V. R. Beasley

Hyperthyroidism is the most common endocrine disorder of cats and is a frequently diagnosed disease in small animal practice. However, despite the high rate of this disease in cats (over 10% of cats aged > 10 years), hyperthyroidism is a new disease that was first described in only 1979 (1,2). The sudden appearance and subsequent increase in the prevalence of this disorder has prompted numerous epidemiology studies searching for a potential underlying cause(s). Although such investigations point to a number of environmental and nutritional factors that could play a role in the pathogenesis of this disorder, the underlying causes remain unclear (3).

One group of environmental chemicals that may contribute to thyroid disease in man includes the polybrominated diphenyl ethers (PBDEs), synthetic brominated compounds used as flame retardants in a variety of consumer products such as electronics, furniture, textiles, and construction materials (4-7).

In both man and experimental animals, PBDEs clearly disrupt thyroid hormone metabolism. Studies of rats and mice report that exposure to PBDEs lowers free and total T4 concentrations in a dose-dependent manner (8-10). In contrast, epidemiological studies in humans suggest that higher exposure to PBDEs reduces serum TSH values and may increase serum T4 concentrations (11-14).

Because PBDEs are known thyroid disruptors, these chemicals may play a role in the pathogenesis of thyroid tumors and hyperthyroidism in cats. In support of that hypothesis, major PBDE production began just before the time that hyperthyroidism was first recognized in 1979.

The purpose of this study by Mensching et al (15) was to investigate the role of PBDEs in the occurrence of hyperthyroidism in cats. To that end, they evaluated euthyroid and hyperthyroid cats and measured PBDEs in each cat's serum, diet (i.e, cat food), and environment (house dust).

Objectives of study
The role of polybrominated diphenyl ethers (PBDE) was investigated in the occurrence of feline hyperthyroidism (FH). We postulated that PBDE play a role in the development of FH, with ingestion of canned cat food and household dust serving as sources of exposure. Specific research objectives for this pilot project included the following:
  1. Compare PBDE burdens in serum in age- matched euthyroid versus hyperthyroid domesticated cats to determine if hyperthyroidism correlated with heavier contaminant loads.
  2. Determine the PBDE content of commercial canned cat foods and household dust to identify predominant exposure sources for domestic cats.
  3. Investigate possible disruption of the hypothalamic–pituitary–thyroid axis by examining an association between serum PBDE concentrations or environmental or nutritional PBDE exposure with thyroid function tests.
Methods
The role of polybrominated diphenyl ethers (PBDE) in FH was investigated by evaluating 15 PBDE congeners in serum from 62 client-owned (21 euthyroid, 41 hyperthyroid) and 10 feral cats. Ten samples of commercial canned cat food and 19 dust samples from homes of client-owned cats were also analyzed.

Results of study
Total serum PBDE concentrations in euthyroid cats were not significantly different from those of hyperthyroid cats. Total serum PBDE in feral cats, however, were significantly lower than in either of the groups of client-owned cats. Total serum PBDEs did not correlate with serum total T4 concentrations.

Total PBDEs in canned cat food ranged from 0.42 to 3.1 ng/g, and total PBDEs in dust from 510 to 95,000 ng/g. Total PBDEs in dust from homes of euthyroid cats ranged from 510 to 4900 ng/g. In dust from homes of hyperthyroid cats, total PBDEs concentrations were significantly higher, ranging from 1100 to 95,000 ng/g. Dust PBDEs and serum total T4 concentrations were also significantly correlated.

Conclusions of study
Estimates of PBDE exposures calculated from canned cat food and dust data suggest that domestic cats are primarily exposed through ingestion of household dust. These findings indicate further study of the role of PBDE is needed in the development of FH, which might identify the cat as a model and sentinel for humans with toxic nodular goiter.

Discussion
Over the last 30 years, PBDEs have become major global contaminants. Levels of PBDEs have been detected in human adipose tissue, serum, and breast milk samples collected in Asia, Europe, North America, Oceania, and the Arctic (6,7). Exposure occurs in particular through the diet (PBDEs are present in both food, milk, and water) and the indoor environment (particularly dust) (11).

Like the PCBs, some of the toxic effects of PBDEs may derive from their structural similarity to thyroid hormones (see Figure 1) (6,7). The PCBs, PBDEs, and thyroid hormones all consist of two six-carbon rings decorated with halogens. Bromine attaches to the carbon rings of PBDEs, chlorine to those of PCBs, and iodine to those of thyroid hormone. In PBDEs, an atom of oxygen bridges the rings, whereas the rings of PCBs and thyroid hormones are linked by carbon-carbon bonds.
Figure 1. Chemical structure of PBDEs, PCBs, and T4.  The similarity of PBDE and PCBs to T4 may underlie chemicals' toxicity.
Because PBDEs are known thyroid disruptors, these chemicals may play a role in the pathogenesis of thyroid tumors and hyperthyroidism in cats. In one earlier study (16) designed to determine whether body burdens of PBDEs in hyperthyroid cats were greater than that of non-hyperthyroid cats, serum samples were collected from 11 hyperthyroid and 12 euthyroid house cats for PBDE measurement. The overall PBDE levels in cats were 20- to 100-fold greater than median levels in U.S. adults. However, due to high variability within each group, no association was detected between hyperthyroid cats and serum PBDE levels. In a follow-up study by the same group (17), the investigators again found that both normal and hyperthyroid cats had extremely high serum PBDE levels (approximately 50-times higher than levels in human residents living in California). PBDE congener patterns in these cats resembled patterns found in house dust, similar to findings in human patients (11). These results suggested that house dust, rather than diet, is the most likely route of exposure for PBDEs in the cats.

In this latest study from the University of Illinois, Mensching and colleagues measured serum PBDE in euthyroid, hyperthyroid, and feral cats (15).  Although no difference in serum PBDE concentrations was detected between the two groups of house cats, serum PBDE concentrations in the feral cats were significantly lower than in either of the groups of client-owned cats suggesting that the cat's home environment was the source of their exposure.

They also found significantly higher PBDEs in dust from homes of hyperthyroid cats, compares to the homes of euthyroid cats. A significant correlation was also found between dust PBDE levels and serum total T4 concentration in the cats (15). Estimates of PBDE exposures calculated from canned cat food and dust data strongly suggest that domestic cats are primarily exposed through ingestion of household dust, in agreement with the previous findings in cats (16,17)

My Bottom Line
Overall, these studies show that cats can be highly exposed to PBDEs, presumably through ingestion of household dust during their normal grooming behavior. These findings also provide provocative evidence for the possible role of PBDEs in the development of thyroid tumors and hyperthyroidism in cats. That said, additional investigation into the role of PBDEs in the development of hyperthyroidism in cats is certainly warranted. 

So it appears that house dust could be an important source of these chemicals for cats. They are likely ingesting PBDEs when they groom the dust out of their fur (a similar route is used to explain the linkage between environmental tobacco smoke and lymphoma in cats) (18). But what does this mean for cat owners? Should we all get rid of our flame-resistant furnishings, turn our indoor cats into outdoor cats, or vacuum and clean our houses more often? Only the last option seems to be a practical one for most of us.

Another issue concerns our own heath. Shouldn't we all be concerned about our own PBDE exposure?  Remember that this chemical doesn't act as a thyroid disruptor only in cats— it also affects all of us (4-7,11)!

References
  1. Peterson ME, Johnson JG, Andrews LK. Spontaneous hyperthyroidism in the cat. Proceedings of the American College of Veterinary Internal Medicine; 1979; Seattle, WA. ACVIM, 1979: 108.
  2. Baral R, Peterson ME: Thyroid gland disorders, In: Little, SE, ed. The cat: clinical medicine and management. Philadelphia:Elsevier Saunders, 2012:571-592.
  3. Peterson ME, Ward CR. Etiopathologic findings of hyperthyroidism in cats. Vet Clin North Am: Small Anim Prac 2007;37:633-645.
  4. Patrick L. Thyroid disruption: mechanism and clinical implications in human health. Altern Med Rev 2009;14:326-346.
  5. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev 2009;30:293-342.
  6. Costa LG, Giordano G, Tagliaferri S, et al. Polybrominated diphenyl ether (PBDE) flame retardants: environmental contamination, human body burden and potential adverse health effects. Acta Biomed 2008;79:172-183.
  7. Talsness CE. Overview of toxicological aspects of polybrominated diphenyl ethers: a flame-retardant additive in several consumer products. Environ Res 2008;108:158-167.
  8. Hallgren S, Darnerud PO. Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and chlorinated paraffins (CPs) in rats-testing interactions and mechanisms for thyroid hormone effects. Toxicology 2002;177:227-243.
  9. Zhou T, Ross DG, DeVito MJ, et al. Effects of short-term in vivo exposure to polybrominated diphenyl ethers on thyroid hormones and hepatic enzyme activities in weanling rats. Toxicol Sci 2001;61:76-82.
  10. Hallgren S, Sinjari T, Hakansson H, et al. Effects of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) on thyroid hormone and vitamin A levels in rats and mice. Arch Toxicol 2001;75:200–208.
  11. Meeker JD, Johnson PI, Camann D, et al. Polybrominated diphenyl ether (PBDE) concentrations in house dust are related to hormone levels in men. Sci Total Environ 2009;407:3425–3429.
  12. Chevrier J, Harley KG, Bradman A, et al. Polybrominated diphenyl ether (PBDE) flame retardants and thyroid hormone during pregnancy. Environ Health Perspect 2010;118:1444-1449.
  13. Bloom M, Spliethoff H, Vena J, et al. Environmental exposure to PBDEs and thyroid function among New York anglers. Environ Toxicol Pharmacol 2008;25:386–392.
  14. Dallaire R, Dewailly E, Pereg D, et al. Thyroid function and plasma concentrations of polyhalogenated compounds in Inuit adults. Environ Health Perspect 2009;117:1380–1386.
  15. Mensching DA, Slater J, Scott JW, et al. The feline thyroid gland: a model for endocrine disruption by polybrominated diphenyl ethers (PBDEs)? J Toxicol Environ Health A 2012;75:201-212.
  16. Dye JA, Venier M, Zhu L, et al. Elevated PBDE levels in pet cats: sentinels for humans? Environ Sci Technol 2007;15:6350-6356.
  17. Guo W, Park JS, Wang Y, et al. High polybrominated diphenyl ether levels in California house cats: House dust a primary source? Environ Toxicol Chem 2012;31:301-306.
  18. Bertone ER, Snyder LA, Moore AS. Environmental tobacco smoke and risk of malignant lymphoma in pet cats. Am J Epidemiol 2002;156:268-273.

Thursday, July 12, 2012

How Does Radioiodine Really Work to Treat Hyperthyroidism?

I had a general question regarding radioiodine (I-131) treatment for hyperthyroid cats. Although I have referred a number of feline patients for this treatment, I do not know that much about the details of the treatment.

Do all cats receive the same dose or do you vary the dose based upon the severity of the cat's hyperthyroidism? How does one actually administer the radioiodine dose? 

A little explanation would be appreciated. Thanks!

My Response:

Route of I-131 administration
We've been giving the radioiodine subcutaneously since 1986 (1). Prior to that, we initially tried the oral route, but that meant handling radioactive capsules (and hoping the cats wouldn't chew them) or stomach tubing the cats (and hoping the cats wouldn't vomit). In human patients, they generally put the radioiodine solution into a juice drink to cover up the "iodine taste" and the people just drink the solution. Obviously, that wouldn't work in cats.

Administering radioiodine
subcutaneously to a cat
From around 1980 to 1986 we gave all of the doses IV, which worked fine. However, that meant that two people always needed to be exposed when the dose is administered (now I generally do it by myself) and the cat needed to have a catheter placed for the injection. The IV administration worked well, but occasionally, I saw anaphylactoid reactions (rather terrifying!) upon treatment. Obviously, there is something in the solution that the cats don't like when the drug is given more than once intravenously. I have NEVER seen an anaphylactoid reaction when the radioiodine solution is given subcutaneously.

Calculation of the I-131 dose
As far as dosing goes, I dose the hyperthyroid cats differently than most treatment facilities, which use a fixed dose of 4 to 5 mCi administered to all cats, no matter how mild or severe the cat's hyperthyroidism.  I really do believe that facilities that use a fixed dose are overdosing most of the cats, and under-dosing others. Cats with thyroid carcinoma generally require much larger radioiodine doses, generally in amounts of around 30 mCi but sometimes even more (4,5).

Thyroid scintigraphy (scans) in 3 hyperthyroid cats. The cat on the far left has a very small unilateral nodule, the middle cat has small, assymetrical bilateral nodules,
and the cat on the right has larger bilateral disease. The calculated I-131 doses
that we administered to these cats ranged from 1.5 mCi to 3.5 mCi.

I currently give a range of doses from 1.5-10 mCi to cats with benign adenoma (adenomatous hyperplasia). This is based on severity of hyperthyroidism (both clinically and biochemically, ie, the T4 level), size of thyroid tumor(s) both on palpation and thyroid scintigraphy, age of the cat, and known concurrent diseases (2-5).

Goals of I-131 therapy: cure hyperthyroidism but avoid hypothyroidism
My goal of therapy is to 'cure' the hyperthyroid state without causing hypothyroidism. Everyone talks about the fact that they can cure 98% of hyperthyroid cats. Well, that's easy; anyone can order a big dose for all hyperthyroid cats and cure them, but many will become hypothyroid.

It becomes more difficult to titrate the doses because one has to think about the whole cat and it's thyroid uptake and iodine kinetics, but I do believe it's so very important. That's where this whole treatment issue becomes more tricky.

Hypothyroidism and the kidney
It's becoming increasing clear that both hyperthyroidism and hypothyroidism are bad for the kidneys (6), so the last thing we want to do is cure the hyperthyroidism but create iatrogenic hypothyroidism. And that is especially true if the owners cannot give oral medication or if the cat already has mild renal disease.

Well, this is probably much more than you ever wanted to know, but I hope it answers your questions.

Follow-up Question:

Thanks for the great explanation. Can I assume cats that receive a small dose of I-131 will be able to leave isolation earlier than cats that receive more substantial doses? Is there a required minimum stay for cats post treatment or is their stay based on their "radioactivity"?

My Response:

The NRC rules have a minimum stay of 3 to 5 days, depending if there are children or pregnant women at home. Once that minimum stay is met, then the cat's radiation "reading," measured by a survey meter at a meter from the cat's neck must be less than 0.5 milliRoentgens per hour (mR/hr).

So, if a cat is treated with 2 to 3 mCi, we can almost guarantee that the radiation levels will fall to below 0.5 mR/hr by 3 days. If a cat gets, 4 mCi or more, it may take a few more days, depending on the effective half-life of the radioiodine and the residence time of I-131 in the individual cat's thyroid tumor. And if a cat with thyroid carcinoma is treated with 30 mCi, they may have to stay in the hospital for 2 to 3 weeks.

Some cats excrete the radioiodine from their thyroid gland —and therefore their kidneys—faster than other cats. Such faster clearance is not always good — we need to have the radioiodine within the tumor for enough time to deliver the radiation dose to the cat's thyroid tumor!

References:
  1. Peterson ME, Becker DV. Radioiodine treatment of 524 cats with hyperthyroidism. Journal of the American Veterinary Medical Association 1995:207:1422-1428. 
  2. Peterson ME: Radioiodine treatment for hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:34-39.
  3. Peterson ME: Radioiodine for hyperthyroidism. In: Bonagura JD, Twedt DC (eds): Current Veterinary Therapy XIV. Philadelphia, Saunders Elsevier, 2008, pp 180-184.
  4. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110.
  5. Peterson ME, Broome MR: Radioiodine for hyperthyroidism. In: Bonagura JD, Twedt DC (eds): Current Veterinary Therapy XV. Philadelphia, Saunders Elsevier, 2012; in press.
  6. Williams T, Elliott J, Syme H. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. Journal of Veterinary Internal Medicine 2010;24:1086-1092. 

Saturday, July 7, 2012

Hypothyroid-Induced Insulin Resistance in Dogs


Effect of Hypothyroidism on Insulin Sensitivity
and Glucose Intolerance in Dogs

N. Hofer-Inteeworn, D. L. Panciera, W. E. Monroe, K. E. Saker,
R. Hegstad Davies, K. R. Refsal, and J.W. Kemnitz
Journal of the American Veterinary Medical Association 2012; 240: 600-605.

Hypothyroidism has been associated with poor glycemic control in diabetic dogs is thought to be an uncommon cause of insulin resistance (1). However, diabetes mellitus was the most common concurrent disease in a retrospective study of dogs with hypothyroidism (2), and hypothyroidism was one of the most commonly diagnosed concurrent disorders in dogs with diabetes mellitus in another study (3). Together, these findings suggest that insulin resistance in dogs with hypothyroidism may be more common that generally thought.

The purpose of this study by Hofer-Inteeworn et al (4) was to evaluate whether hypothyroidism causes insulin resistance and to determine the overall effect of hypothyroidism on glucose tolerance in dogs. Additional objectives of this research study were to examine the secretion profile of hormones that are counter-regulatory to insulin (including, growth hormone and cortisol) and  to determine whether insulin resistance was associated with obesity in hypothyroid dogs.

Objective
To determine the effects of hypothyroidism on insulin sensitivity, glucose tolerance, and concentrations of hormones counter-regulatory to insulin in dogs.

Animals
8 anestrous mixed-breed bitches with experimentally induced hypothyroidism and 8 euthyroid control dogs.

Procedures
The insulin-modified frequently sampled IV glucose tolerance test and minimal model analysis were used to determine basal plasma insulin and glucose concentrations, acute insulin response to glucose, insulin sensitivity, glucose effectiveness, and disposition index.

Growth hormone response was assessed by stimulation and suppression tests. Additionally, basal serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations and urine cortisol-to-creatinine concentration ratios were measured. Finally, dual energy x-ray absorptiometry was performed to evaluate body composition.

Results
Insulin sensitivity was lower in the hypothyroid group than in the euthyroid group, whereas acute insulin response to glucose was higher. Glucose effectiveness and disposition index were not different between groups. Basal serum GH and IGF-1 concentrations, as well as abdominal fat content, were high in hypothyroid dogs, but urine cortisol-to-creatinine concentration ratios were unchanged.

Conclusions and Clinical Relevance
Hypothyroidism appeared to negatively affect glucose homeostasis by inducing insulin resistance, but overall glucose tolerance was maintained by increased insulin secretion in hypothyroid dogs. Possible factors affecting insulin sensitivity are high serum GH and IGF-1 concentrations and an increase in abdominal fat. In dogs with diseases involving impaired insulin secretion such as diabetes mellitus, concurrent hypothyroidism can have important clinical implications.

My Bottom Line:

The results of this study show that hypothyroidism does indeed cause substantial —even marked—insulin resistance, as evidenced by an almost 5-fold decrease in insulin sensitivity, compared with the insulin sensitivity in euthyroid dogs (4). The pathogenesis of insulin resistance appears to be multifactorial, with high serum GH and IGF-1 concentrations probably contributing. In addition, the role of visceral fat on glucose metabolism may also be important in the development of insulin resistance in hypothyroid dogs (5,6).

Despite the fact that many hypothyroid dogs are markedly insulin resistant, their glucose tolerance is unaffected as a consequence of an increase in insulin secretion, which leads to a normalization in circulating glucose concentration.

Although hypothyroidism alone does not generally lead to overt hyperglycemia or diabetes, knowledge of a dog's thyroid function could be key in the successful management of cases of "problem" diabetes (7).

In diabetic dogs suffering from insulin resistance, hypothyroidism should always be included in the list of differential diagnoses (7). Treatment of these dogs with L-T4 replacement may help reverse the underlying insulin resistance and thereby lead to better glycemic control of their concurrent diabetic state (1,7).

References:
  1. Ford SL, Nelson RW, Feldman EC, et al. Insulin resistance in three dogs with hypothyroidism and diabetes mellitus. Journal of American Veterinary Medical Association 1993;202:1478–1480. 
  2. Dixon RM, Reid SW, Mooney CT. Epidemiological, clinical, haematological and biochemical characteristics of canine hypothyroidism. Veterinary Record 1999;145:481–487. 
  3. Hess RS, Saunders HM, Van Winkle TJ, et al. Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993–1998). Journal of American Veterinary Medical Association 2000;217:1166–1173.
  4. Hofer-Inteeworn N, Panciera, Monroe WE, et al. Effect of hypothyroidism on insulin sensitivity and glucose intolerance in dogs. Journal of the American Veterinary Medical Association 2012; 240:600-605.
  5. Gayet C, Bailhache E, Dumon H, et al. Insulin resistance and changes in plasma concentration of TNF-alpha, IGF-1, and NEFA in dogs during weight gain and obesity. Journal of Animal Physiology and Animal Nutrition (Berlin) 2004;88:157-165. 
  6. German AJ, Hervera M, Hunter L, et al. Improvement in insulin resistance and reduction in plasma inflammatory adipokines after weight loss in obese dogs. Domestic Animal Endocrinology 2009;37:214-226.  
  7. Peterson ME. Diagnosis and management of insulin resistance in dogs and cats with diabetes mellitus. Veterinary Clinics of North America: Small Animal Practice 1995;25:691-713. 

Sunday, July 1, 2012

Controlling Polyuria in Addison's Dogs Treated with Prednisone

I have a 3-year old, F/S Chihuahua, who was recently diagnosed with Addison's disease. She is doing great on injections of desoxycorticosterone pivalate (DOCP; Percoten V) and oral prednisone. She weighs 14 pounds (6.4 kg) so I'm administering 0.5 ml (12.5 mg) of Percoten V each month and 2.5 mg of prednisone every other day.

Recently, the owner noticed that on the days that she was giving the prednisone, the dog was leaking urine while asleep.We decreased dose of predisone to 1.25 mg twice weekly, but still leaking urine on the days given prednisone.

The dog may need a workup for urinary incontinence, but assuming that all checks out okay, she might be sensitive to the oral glucocorticoid. Any thoughts on a different steroid in place of the prednisone? Would dexamethasone work better?

My Response:

In dogs with hypoadrenocorticism (Addison's disease), the daily maintenance dose for prednisone (or prednisolone) to replace the missing glucocorticoids is approximately 0.1-0.2 mg/kg/day (1-4). Many dogs are very sensitive to the effects of chronic glucocorticoid replacement, and polyuria and polydipsia are common complaints (4).

In these dogs that show side effects related to prednisone replacement therapy, we start by lowering the daily maintenance dose down to the lower end of the recommended range (i.e., closer to 0.1 mg/kg/day). So this calculates out to be only 0.6 mg per day for your patient — about half the dose of what you are giving.

In small dogs like this, there is no way to use the standard 5-mg tablets of prednisone or prednisolone to administer the low dose needed. I'd either switch to a liquid prednisolone formulation (e.g., PediaPred) or get 1-mg prednisone tablets and then try 0.5-0.6 mg per day. Your other option would be to use cortisone acetate, but that drug is best given twice daily for replacement therapy (0.5 mg/kg, BID or around 2.5 mg BID in this dog).

For replacement therapy, we want to give a short-acting glucocorticoid (prednisone, prednisolone, or cortisone).  Because dexamethasone is a very potent long-acting steroid, use of this preparation isn't appropriate for long-term use in dogs with Addison's disease.

References:
  1. Kintzer PP, Peterson ME. Primary and secondary canine hypoadrenocorticism. Veterinary Clinics of North America Small Animal Practice 1997;27:349-57. 
  2. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. Journal of Veterinary Internal Medicine 1997;11:43-49. 
  3. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Canadian Veterinary Journal 2010;51:179-184.
  4. Peterson ME: Treatment of hypoadrenocorticism: Treatment pitfalls and issues. Proceedings of the ACVIM Regional Education Course on Endocrinology. 2010