Top Endocrine Publications of 2014: The Feline Thyroid Gland

In my fourth compilation of the canine and feline endocrine publications of 2014, I’m moving on to disorders of the feline thyroid gland. Listed below are 32 papers that deal with a variety of thyroid gland topics of issues of clinical importance in cats.

These range from from a survey of owners' perceptions and experiences after using radioiodine to treat their hyperthyroid cats (1) to the results of an online survey to determine owner experiences and opinions on the management of their cats using oral anti-thyroid medications (14); from case reports of methimazole or carbimazole-induced toxicity in cats with hyperthyroidism (3,5,19) to a number of publications involving various issues of medical treatment with methimazole (2,4,7,14,15,20); from a study of the concurrent diseases detected in hyperthyroid cats undergoing assessment for radioiodine treatment (25) to concurrent diseases and conditions in cats with renal infarcts (including hyperthyroidism (12); and finally, from studies investigating the efficacy of an iodine-restricted diet for management of cats with hyperthyroidism (9,30) to other forms of dietary management for this endocrine disease (19,24).

Finally, 2 investigations add further data concerning chronic renal disease in hyperthyroid cats (31,32), as well as the fact that iatrogenic hypothyroidism contributes to azotemia in these cats (31). A number of 2014 publications deal with the rising prevalence and/or etiopathogenesis of hyperthyroidism in cats (6,16,17,21,22,23,29). Unfortunately, further studies are needed to better define the cause(s) of this perplexing disease (download my review paper for more discussion) (23).

References:

1. Boland LA, Murray JK, Bovens CP, et al. A survey of owners' perceptions and experiences of radioiodine treatment of feline hyperthyroidism in the UK. J Feline Med Surg 2014;16:663-670. 
2. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Transdermal application of methimazole in hyperthyroid cats: a long-term follow-up study. J Feline Med Surg 2014;16:453-459. 
3. Bowlt K, Cattin I, Stewart J. Carbimazole-associated hypersensitivity vasculitis in a cat. J Small Anim Pract 2014;55:643-647. 
4. Bruyette D. Methimazole management of feline hyperthyroidism. Today's Veterinary Practice 2014;July/August:38-41.
5. Castro Lopez J, Lloret A, Ravera I, et al. Pyogranulomatous mural folliculitis in a cat treated with methimazole. J Feline Med Surg 2014;16:527-531. 
6. Chow K, Beatty JA, Barrs VR, et al. PBDEs and feline hyperthyroidism. Vet Rec 2014;175:433-434. 
7. Daminet S, Kooistra HS, Fracassi F, et al. Best practice for the pharmacological management of hyperthyroid cats with antithyroid drugs. J Small Anim Pract 2014;55:4-13. 
8. Daniel GB, Neelis DA. Thyroid scintigraphy in veterinary medicine. Semin Nucl Med 2014;44:24-34. 
9. Fritsch DA, Allen TA, Dodd DE, et al. A restricted iodine food reduces circulating thyroxine concentrations in cats with hyperthyroidism. Intern J Appl Res Vet Med 2014;12:24-32. 
10. Fryers A, Elwood C. Hypokalaemia in a hyperthyroid domestic shorthair cat with adrenal hyperplasia. J Feline Med Surg 2014;16:853-857. 
11. Galgano M, Spalla I, Callegari C, et al. Primary hypothyroidism and thyroid goiter in an adult cat. J Vet Intern Med 2014;28:682-686. 
12. Hickey MC, Jandrey K, Farrell KS, et al. Concurrent diseases and conditions in cats with renal infarcts. J Vet Intern Med 2014;28:319-323. 
13. Higgs P, Costa M, Freke A, et al. Measurement of thyroxine and cortisol in canine and feline blood samples using two immunoassay analysers. J Small Anim Pract 2014;55:153–159. http://onlinelibrary.wiley.com/doi/10.1111/jsap.12181/abstract
14. Higgs P, Murray JK, Hibbert A. Medical management and monitoring of the hyperthyroid cat: a survey of UK general practitioners. J Feline Med Surg 2014;16:788-795. 
15. Hill K, Gieseg M, Bridges J, et al. The pharmacokinetics of methimazole in a novel lipophilic formulation administered transdermally to healthy cats. N Z Vet J 2014;62:208-213. 
16. Hill KE, Shaw IC. Does exposure to thyroxine-mimics cause feline thyroid hyperplasia? Vet Rec 2014;175:228-229. 
17. Kooistra HS. Feline hyperthyroidism: a common disorder with unknown pathogenesis. Vet Rec 2014;175:456-457. 
18. Kujawa A, Olias P, Bottcher A, et al. Thyroid transcription factor-1 is a specific marker of benign but not malignant feline lung tumours. J Comp Pathol 2014;151:19-24. 
19. Laflamme D, Gunn-Moore D. Nutrition of aging cats. Vet Clin North Am Small Anim Pract 2014;44:761-774, vi. 
20. Mardell EJ. Diagnosis and management of feline hyperthyroidism. In Practice 2014;35:162-170.
21. McLean JL, Lobetti RG, Schoeman JP. Worldwide prevalence and risk factors for feline hyperthyroidism: A review. J S Afr Vet Assoc 2014;85:1097. 
22. O'Neill DG, Church DB, McGreevy PD, et al. Prevalence of disorders recorded in cats attending primary-care veterinary practices in England. Vet J 2014;202:286-291. 
23. Peterson ME. Feline hyperthyroidism: an animal model for toxic nodular goiter. J Endocrinol 2014;223:T97-T114. 
24. Peterson ME, Eirmann L. Dietary management of feline endocrine disease. Vet Clin North Am Small Anim Pract2014;44:775-788. 
25. Puig J, Cattin I, Seth M. Concurrent diseases in hyperthyroid cats undergoing assessment prior to radioiodine treatment. J Feline Med Surg 2014. 
26. Rasmussen SH, Andersen HH, Kjelgaard-Hansen M. Combined assessment of serum free and total T4 in a general clinical setting seemingly has limited potential in improving diagnostic accuracy of thyroid dysfunction in dogs and cats (Letter). Vet Clin Pathol 2014;43:1-3. 
27. Sangster JK, Panciera DL, Abbott JA, et al. Cardiac biomarkers in hyperthyroid cats. J Vet Intern Med 2014;28:465-472. 
28. Schober KE, Kent AM, Aeffner F. Tachycardia-induced cardiomyopathy in a cat. Schweiz Arch Tierheilkd 2014;156:133-139. 
29. Stephens MJ, Neill DG, Church DB, et al. Feline hyperthyroidism reported in primary-care veterinary practices in England: prevalence, associated factors and spatial distribution. Vet Rec 2014;175:458. 
30. van der Kooij M, Becvarova I, Meyer HP, et al. Effects of an iodine-restricted food on client-owned cats with hyperthyroidism. J Feline Med Surg 2014;16:491-498. 
31. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255. 
32. Williams TL, Elliott J, Syme HM. Association between urinary vascular endothelial growth factor excretion and chronic kidney disease in hyperthyroid cats. Res Vet Sci 2014;96:436-441. 

Q & A: Calcitriol versus Vitamin D3: What's the Difference?

What is the difference between calcitriol and vitamin D3? They both appear to be 1,25-hydroxycholecalciferol.

How about vitamin D2? It that form active at all in dogs and cats with renal failure?

My Response:

Vitamin D is a fat-soluble vitamin that exists in various forms (1). The chemical structure of vitamin D was established in the early 1930's. The main forms are vitamin D2 (ergocalciferol), found in plants, yeasts and fungi and vitamin D3 (cholecalciferol) of animal origin. Vitamin D2 and D3 are not biologically active; rather, they must be modified in the body to have any effect.

Vitamin D2 or D3 must then be first hydroxylated in the liver and then in the kidneys to become active. At this point, as biologically active 1,25-OH-cholecalciferol (also called calcitriol), this form of vitamin D can exert its endocrine effects (1).

By the early 1970's, it had become clear that calcitriol was the active form of vitamin D. It is over 1,000 times as potent as Vitamin D2 and D3 in binding to the vitamin D receptor.

The sun
Vitamin D has long been considered an essential dietary ingredient, but in several species, including humans, sheep, cattle, horses, and pigs, vitamin D3 can be formed in the skin from a cholesterol metabolite (7-dehydrocholesterol) after exposure to natural sun light.

In dogs and cats, however, this skin production of vitamin D3 does not occur (2), so they are dependent entirely on a dietary source of vitamin D.

Food
Large amounts of vitamin D are not found in adequate amounts in most foods. It’s found in fish, cod liver oil, mushrooms, liver and eggs – but usually not in substantial amounts (except in cod liver oil). Thus, getting enough vitamin D naturally from whole foods is difficult.

Both vitamin D2 and D3 have been commercially synthesized and both forms seem to be effective at maintaining blood levels of vitamin D in the body.

Use of vitamin D in renal disease
In severe renal failure, the kidneys cannot produce adequate amounts of the biologically active vitamin D, and this commonly leads to abnormalities of calcium and phosphorus metabolism (3). Oral administration of active calcitriol to animals with chronic kidney disease helps compensate for the reduced production of the active hormone (4).

It is critical to understand that administration of vitamin D2 and D3 will not work to raise active vitamin D concentrations in these animals with renal disease. Active calcitriol must be used as the form of vitamin D to treat these animals (4).

References

1. Lips P. Vitamin D physiology. Prog Biophys Mol Biol. 2006;92:4-8.
2. How KL, Hazewinkel HA, Mol JA. Dietary vitamin D dependence of cat and dog due to inadequate cutaneous synthesis of vitamin D. Gen Comp Endocrinol. 1994;96:12-18.
3. Gerber B, Hässig M, Reusch CE. Serum concentrations of 1,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol in clinically normal dogs and dogs with acute and chronic renal failure. Am J Vet Res. 2003;64:1161-1166.
4. Hostutler RA, DiBartola SP, Chew DJ, et al. Comparison of the effects of daily and intermittent-dose calcitriol on serum parathyroid hormone and ionized calcium concentrations in normal cats and cats with chronic renal failure. J Vet Intern Med. 2006;20:1307-1313. 

Hyperthyroidism & Renal Disease: Is a "Tapazole Trial" Really Necessary?

Hyperthyroidism and chronic kidney disease (CKD) are both common disorders in older cats. Therefore, it should not be surprising that both disorders frequently develop together in the same cat. The prevalence of concurrent renal disease in cats with hyperthyroidism is estimated to be approximately 30–35% (1,2).

Hyperthyroidism & the Kidney: A Love-Hate Relationship

Hyperthyroidism tends to "artificially" increase the renal blood flow (RBF) as well as the glomerular filtration rate (GFR) (1–4). When the GFR is increased in a hyperthyroid cat with underlying CKD, it can mask renal insufficiency; serum concentrations of urea nitrogen and creatinine may be normal despite mild to moderate kidney disease (1–7). Decreased muscle mass and muscle wasting, a common feature of hyperthyroidism, also contribute to the lowered serum creatinine concentration in these cats (since creatinine is derived from muscle tissue) (1,2).

Treating hyperthyroidism restores the high serum T4 concentration to normal and, in cats without CKD, also returns the high GFR back to normal values. In cats with CKD, however, the GFR will fall to the low-normal or subnormal levels expected with moderate renal dysfunction. Therefore, this decrease in GFR can result in the apparent worsening of the serum kidney function tests or the development of renal disease.

It is important to remember, however, that treating the hyperthyroidism itself does not cause the CKD in these cats. The renal disease was already present before treatment but was masked by the hyperdynamic state of the hyperthyroidism.

Physiological Interactions Between Thyroid Hormones & Renal Function

Hyperthyroidism decreases peripheral vascular resistance by dilating the arterioles of the peripheral circulation. Because of this decrease in systemic vascular resistance, the effective circulating volume decreases, stimulating the renin-angiotensin-aldosterone system. This leads to renal sodium retention with a resultant increase in blood volume. Cardiac output may increase dramatically in cats with hyperthyroidism. In addition to the decrease in systemic vascular resistance, an increase in heart rate, increases in left ventricular contractility and ejection fraction, and increase in blood volume all contribute to this increase in cardiac output (1,2).

These systemic hemodynamic factors (i.e., the increased cardiac output) combined with intrarenal vasodilation lead to increases in renal blood flow (RBF), glomerular hydrostatic pressure, and glomerular filtration rate (GFR). Thyroid hormones also influence renal tubular function including electrolyte handling.

With time, hyperthyroidism can lead to renal changes including glomerular hypertension, glomerulosclerosis, proteinuria, and hyperplasia and hypertrophy of the renal tubules (1,2).

Hyperthyroidism Itself May Contribute to Chronic Kidney Disease

Recent research provides three lines of evidence that untreated hyperthyroidism itself contributes to the development or progression of CKD in cats.

• First of all, a number of recent reports indicate that many untreated hyperthyroid cats develop proteinuria, which resolves within 4 weeks of successful treatment (8,9). This proteinuria, which reverses after treatment, could be a reflection of glomerular hypertension and hyperfiltration, changes in tubular protein handling, or a change in the structure of the glomerular barrier (1). Whatever the cause of the proteinuria, no treatment is generally needed other than treatment of the hyperthyroid state itself.
• Secondly, cats with untreated hyperthyroidism have high levels of retinol binding protein (RBP), a urinary marker for tubular dysfunction or damage (10,11). This high urinary RBP excretion may reflect tubular damage or dysfunction resulting from the thyroid-induced hypertrophy and hyperplasia of the tubular cells. After treatment, these high urinary RBP levels fall in cats without azotemia but may remain slightly high in cats with pre-existing CKD. This too suggests that hyperthyroidism can cause reversible renal dysfunction; however, the renal tubular changes may become irreversible with time as CKD progresses.
• Thirdly, many cats with untreated hyperthyroidism have high values for urinary N-acetyl-ß-D-glucosaminidase (NAG), a lysosomal glycosidase found primarily in epithelial cells of the proximal convoluted tubule (12). Like RBP, NAG is a specific marker of active proximal tubular damage. After treatment, these high urinary NAG levels decrease, again suggesting that these renal changes can be reversed, at least in cats without pre-existing CKD.

Overall, these studies all suggest that that leaving a hyperthyroid cat untreated (or poorly regulated with methimazole) may be detrimental to long-term kidney function. Treating and curing hyperthyroidism may help to both reverse renal damage and preserve remaining kidney function.

Clinical Implications in Hyperthyroid Cats

Decision-making with regard to treating cats with hyperthyroidism and CKD can be difficult. Clinicians can be confronted with two different scenarios concerning hyperthyroid cats with concurrent CKD.

1. First of all, about 10% of hyperthyroid cats have known pre-existing CKD at time of diagnosis. These cats have obvious clinical and biochemical evidence of mild to moderate kidney disease, and do not present a diagnostic dilemma. However, hyperthyroid cats with pre-existing azotemia are more difficult to treat successfully, at least on a long-term basis. They have a worse prognosis than do cats that are not azotemic prior to treatment for hyperthyroidism.
2. In the second scenario, cats are initially not azotemic but develop high serum concentrations of urea nitrogen or creatinine only after they have been treated for hyperthyroidism. These cats, which represent 20% to 25% of all hyperthyroid cats, are much more of a diagnostic dilemma because one may not even suspect that they have concurrent renal disease.

1. Pre-existing Azotemia in a Newly Diagnosed Hyperthyroid Cat
In hyperthyroid cats with overt CKD, we can predict that the GFR will fall once the euthyroidism is restored. Therefore, it is generally advised to try medical management prior to a more definitive treatment in cats with concurrent hyperthyroidism and pre-existing CKD. A low starting dose (i.e., 1.25 mg orally once daily) of methimazole with gradual dose escalation is prudent when starting a cat with CKD and hyperthyroidism on medical therapy. Cats should be monitored every 2 weeks with a CBC, biochemical profile, urinalysis, and serum T4 concentration.

Because the initial decline in GFR stabilizes after a month of successful resolution of the hyperthyroidism, one can decide at that time whether or not the cat's renal function is stable or worsening.

Hyperthyroid cat with overt CKD
and hypokalemia

Concurrent management of CKD is also extremely important these cats. If the renal function remains stable after a euthyroid state is established, a more definitive treatment, such as 131-I, should be strongly considered. If, on the other hand, renal function declines dramatically after antithyroid drug treatment, especially if accompanied by marked clinical deterioration of the cat's renal failure (to IRIS Stage 3 or 4), it may be best to maintain the cat on a reversible anti-thyroid therapy, decrease the dose, or stop it all together if need be.

In some of these cats with severe CKD, maintenance of a mild hyperthyroid state may give the best short-term clinical result. However, this course of action is far from ideal, and these cats have a very guarded to poor prognosis. Except in these extreme circumstances, the validity of maintaining a cat in a mildly hyperthyroid state is questionable given that uncontrolled hyperthyroidism, in itself, appears to be damaging to renal function (1,8,10–12)

2. Non-Azotemic Before Treatment of Hyperthyroidism; Development of Post-Treatment Azotemia
Hyperthyroidism is known to increase GFR, decrease circulating creatinine concentrations, and mask underlying renal disease. About 20% to 25% of hyperthyroid cats without known CKD develop azotemia after successful treatment of hyperthyroidism, irrespective of therapeutic modality (methimazole/carbimazole, surgical thyroidectomy, or radioiodine) (1).

Predicting which hyperthyroid cats will develop overt azotemia after treatment of hyperthyroidism can be difficult to impossible. The determination of GFR is clearly the best predictor of post-treatment CKD, with a low to low-normal GFR indicating that a hyperthyroid cat is at increased risk for post-treatment azotemia. However, techniques for assessment of GFR are not widely used in practice, and even GFR determinations are not a 100% perfect predictor of CKD. Routine pre-treatment parameters such as serum urea or creatinine concentrations, and urine specific gravity are certainly useful, but they cannot consistently predict impending azotemia (13).

Should Methimazole Trials be Performed in all Hyperthyroid Cats?

For years, it has been accepted practice to perform a methimazole trial in cats in which hyperthyroidism has been newly diagnosed to evaluate the impact of a euthyroid state on renal function.  Again, determining which untreated hyperthyroid cats have clinically significant underlying CKD can sometimes be difficult. Use of methimazole or carbimazole can provide a "preview" of how the cat will be after curing hyperthyroidism. Thus, many veterinarians attempt trial therapy with methimazole or carbimazole to help test what renal function might remain after treating the hyperthyroidism. If no marked deterioration occurs, then a more permanent therapeutic option for hyperthyroidism may be recommended.

Except for advanced (IRIS Stage 3–4) CKD, the necessity of this approach in cats without pretreatment azotemia is questionable, given that treatment for the hyperthyroidism is strongly recommended whatever the outcome. In support of this reasoning, the survival of cats that do develop azotemia is not shorter than those that do not develop azotemia after treatment of hyperthyroidism. In one study, the median survival time of cats that developed azotemia (595 days) was similar to that in cats that remained non-azotemic (584 days) after treatment (14).

Preventing Hypothyroidism after Treatment for Hyperthyroidism

Whatever treatment option for hyperthyroidism is considered, it is important to avoid hypothyroidism as it may have its own detrimental effects on GFR. Hypothyroidism in both humans and dogs has been showed to reduce GFR (15,16), and it is likely that similar changes occur in cats that develop iatrogenic hypothyroidism.

In a recent study by Williams et al (17), cats with iatrogenic hypothyroidism were more likely to develop azotemia in the 6 months after treatment than cats that remained euthyroid. Hypothyroid cats with azotemia also had shorter survival times than nonazotemic cats, whereas no difference in survival between euthyroid cats with or without azotemia could be detected. This suggests that the development iatrogenic hypothyroidism contributes to the development of azotemia, at least in cats with mild underlying CKD (IRIS Stage I or II) (17,18). More importantly, the hypothyroidism may shorten survival after treatment of hyperthyroidism.

If a cat with post-treatment azotemia develops a low T4 concentration, a serum TSH level should be measured to help exclude hypothyroidism (19). The finding of a high serum TSH concentration confirms hypothyroidism. A specific assay for feline TSH is not yet available. However, the commercially available canine TSH assay cross-reacts with feline TSH enough to enable its use as a diagnostic test for hypothyroid cats (19,20).

If iatrogenic hypothyroidism is diagnosed, treatment with L-thyroxine (0.1 mg once to twice daily) is indicated (20,21). The dosage should be adjusted based on post-pill serum T4 and cTSH determinations. Most cats treated will show improvement in their azotemia as the hypothyroidism resolves and euthyroidism is restored (18).

Long-Term Renal Function in Cats that Develop Azotemia after Treatment

In most cats that develop post-treatment azotemia, the CKD is not that severe or life threatening. It is also unusual to see a jump of more than one IRIS stage after treatment (22). In other words, hyperthyroid cats with IRIS Stage I–II CKD may develop overt azotemia after treatment, but one would not expect those cats' CKD to advance to more than IRIS Stage II–III after treatment (Figure 1).

Figure 1. Box plots of serum creatine concentrations in 45 hyperthyroid cats
before and after treatment. Prior to treatment 34 of the 45 cats were not azotemic, whereas 11 cats (Green Box) had IRIS stage 2 CKD.
After treatment, 12 of the 34 nonazotemic cats progressed to stage 2 CKD (Red Box).  All 11 cats with prior azotemia remained azotemic, but the the median value was not significantly different (Green Box).
Click image above to enlarge figure.

In addition, the decline in GFR after successful treatment of a cat's hyperthyroidism is not very progressive. Rather, the fall in GFR is detectable within 1 month but then remains stable at this level for months thereafter (1,6). The rise in serum urea nitrogen and creatinine values in cats with CKD follow the decrease in GFR, so that azotemia, when it does occur, would be expect to develop within 1 month of treatment but remain relatively stable over many months (6,22).

The Bottom Line

For years, conventional wisdom has been to perform a methimazole trial in cats in which hyperthyroidism has been newly diagnosed to evaluate the impact of a euthyroid state on renal function. In most cats without overt CKD, use of a methimazole trial prior to definitive therapy is not needed.

Remember that hyperthyroidism itself has long-term deleterious effects on renal function, and survival of cats that do develop azotemia after treatment for hyperthyroidism is no shorter than for those whose renal function remains stable. For those cats that do develop azotemia after their hyperthyroid state is corrected, the renal disease is not generally severe or life-threatening and usually stabilizes within the first month of therapy.

References

1. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Veterinary Clinics of North America: Small Animal Practice 2007;37:723-743. 
2. Langston CE, Reine NJ. Hyperthyroidism and the kidney. Clinical Techniques in Small Animal Practice 2006;21:17-21. 
3. Graves TK, Olivier NB, Nachreiner RF, et al. Changes in renal function associated with treatment of hyperthyroidism in cats. American Journal of Veterinary Research 1994;55;1745-1749. 
4. Adams WH, Daniel GB, Legendre AM. Investigation of the effects of hyperthyroidism on renal function in the cat. Canadian Journal of Veterinary Research 1997;61:53-56. 
5. Becker TJ, Graves TK, Kruger JM, et al. Effects of methimazole on renal function in cats with hyperthyroidism. Journal of the American Animal Hospital Association 2000;36:215-223. 
6. Boag AK, Neiger R, Slater L, et al. Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine. Veterinary Record 2007;161:711-715. 
7. DiBartola SP, Broome MR, Stein BS, et al. Effect of treatment of hyperthyroidism on renal function in cats. Journal of the American Veterinary Medical Association 1996;208:875-878. 
8. van Hoek I, Lefebvre HP, Peremans K, et al. Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domestic Animal Endocrinology 2009;36:45-56. 
9. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. Journal of Veterinary Internal Medicine 2010;24:863-869. 
10. van Hoek I, Daminet S, Notebaert S, et al. Immunoassay of urinary retinol binding protein as a putative renal marker in cats. Journal of Immunological Methods 2008;329:208-213. 
11. van Hoek I, Meyer E, Duchateau L, et al. Retinol-binding protein in serum and urine of hyperthyroid cats before and after treatment with radioiodine. Journal of Veterinary Internal Medicine 2009;23:1031-1037. 
12. Lapointe C, Bélanger MC, Dunn M, et al. N-acetyl-beta-D-glucosaminidase index as an early biomarker for chronic kidney disease in cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2008;22:1103-1110. 
13. Riensche MR, Graves TK, Schaeffer DJ. An investigation of predictors of renal insufficiency following treatment of hyperthyroidism in cats. Journal of Feline Medicine and Surgery 2008;12:160-166. 
14. Wakeling J, Rob C, Elliott J, et al. Survival of hyperthyroid cats is not affected by post-treatment azotemia. Journal of Veterinary Internal Medicine 2006;20:1523.
15. Iglesias P, Diez JJ. Thyroid dysfunction and kidney disease. European Journal of Endocrinology 2009;160:503-515. 
16. Gommeren K, van Hoek I, Lefebvre HP, et al. Effect of thyroxine supplementation on glomerular filtration rate in hypothyroid dogs. Journal of Veterinary Internal Medicine 2009;23:844-849. 
17. 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. 
18. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Canadian Veterinary Journal 2010;51:33-34. 
19. Greco DS. Diagnosis of congenital and adult-onset hypothyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:40-44. 
20. Peterson ME: Feline hypothyroidism, In: Kirk RW (ed): Current Veterinary Therapy X. Philadelphia, WB Saunders Co., pp 1000-1001, 1989
21. Harley LS, Peterson ME, Langston CE, Nichols RL: IRIS stages of chronic kidney disease before and after treatment with radioiodine in cats with hyperthyroidism. Journal of Veterinary Internal Medicine 25: 678-679, 2011.

The Best Diet to Feed Hyperthyroid Cats

Hyperthyroidism is the most common endocrine disorder of cats, and is one of the most common medical problems seen in small animal practice. Surprisingly, despite the fact that nutritional factors and cat food likely has a role in the etiopathogenesis of this disease (1), there are only limited published recommendations about what to feed these cats.

The question, “What’s the best diet to feed my hyperthyroid cat?” is an extremely common one that I get from concerned cat owners. I’m certain that many of you get the same question.

With the recent introduction of the Hill’s y/d diet (2), the iodine deficient diet which, according to the company website “restores thyroid health,” I thought that my opinion of what diets should be fed to cats with hyperthyroidism might be of interest.

In this post, I’m not going to talk specifically about y/d or any other diet, but which types of food and nutrients hyperthyroid cats need in general. I’ll specifically address the pros and cons of y/d in my upcoming blog posts.

The Many Metabolic Problems Facing the Hyperthyroid Cat

When secreted in excess, thyroid hormones have profound metabolic effects on the whole body, and dysfunction of multiple organ systems (CNS, cardiac, gastrointestinal, hepatic, and renal) is common in hyperthyroid cats (3-5).

Weight Loss and Muscle Wasting
Weight loss, despite a normal to increased appetite, is the classic and most common signs seen in cats with hyperthyroidism (3-5). These cats lose weight because their hyperthyroidism accelerates their metabolic rate and body’s energy expenditure; they are burning up their food calories faster than they can consume their daily meals.

It’s important to realize that hyperthyroidism is a catabolic state. The progressive weight loss and muscle wasting that is so characteristic of feline disease is caused by increased protein catabolism leading to a negative nitrogen balance (6,7).

When hyperthyroid cats first lose weight, the case can usually be first noticed as a loss of muscle mass in the cat’s lumbar paravertebral area. Despite this loss of muscle mass, most mildly hyperthyroid cats retain their “belly” during the initial stages of their thyroid disease and may even have a higher than ideal body condition score.

With time, severe muscle wasting, emaciation, cachexia, and death from starvation can occur if the cat’s hyperthyroidism is left untreated (3-5). In hyperthyroidism, the cat’s body consumes its own muscle tissue to get the protein it needs to sustain its carnivorous life.

Even with treatment of hyperthyroidism, recovery of muscle mass and function may be prolonged, lasting several weeks to months. This is especially true if these cats are not provided with enough protein in their diet to rebuild and maintain their lost muscle mass.

Hyperglycemia, Glucose Intolerance, Insulin Resistance, and Overt Diabetes
Hyperthyroid cats commonly develop profound changes in glucose and insulin metabolism. Mild to moderate hyperglycemia is common in hyperthyroid cats, which is generally attributed to a “stress” reaction (3,5).

However, the actual metabolic changes are actually much more complicated: hyperthyroidism frequently causes moderate to severe “endogenous” insulin resistance, as demonstrated by high resting serum insulin concentrations and an exaggerated insulin response during an IV glucose tolerance test (8,9). This insulin resistance is associated with a decreased glucose clearance (impaired glucose tolerance), which is indicative of a prediabetic state (See Figures below).

Serum insulin concentrations in response to intravenous glucose tolerance test in 11 healthy cats, 15 cats with untreated hyperthyroidism, and 6 hyperthyroid cats after treatment (9). Notice the exaggerated insulin secretion in the untreated hyperthyroidism cats, which becomes even worse after treatment. Such high insulin concentrations is diagnostic for "endogenous" insulin resistance.

Occasionally, an untreated hyperthyroid cat will develop overt diabetes mellitus. Many of these diabetic cats will develop moderate resistance to the injected insulin, with poor diabetic control.

Surprisingly, the insulin resistance and prediabetic state so common in hyperthyroid cats does not always improve and may even worsen despite successful treatment of hyperthyroidism (9): see Figure above. This indicates that hyperthyroid cats may have long-lasting alterations of glucose tolerance and insulin secretion that cannot always be reversed by treatment. In accord with that, some of these hyperthyroid cats (not diabetic at time of diagnosis) will go on to develop overt diabetes mellitus in the months to years after treatment of hyperthyroidism.

Sarcopenia of Aging
In addition to loss of muscle mass from the catabolic effects of thyroid hormone excess, cats also tend to loss muscle mass they age, independent of their thyroid status. This phenomenon, referred to as sarcopenia of aging, is also common in elderly human beings (10-12). The term age-related sarcopenia is derived from Greek (meaning "poverty of flesh") and is characterized by a degenerative loss of skeletal muscle mass and strength, as well as increased muscle fatigability.

In adult cats, maintenance energy requirements decrease by about 3% per year up until the age of 11 years, and then actually start to increase again (13). This contributes to a tendency of senior cats to lose muscle mass if their energy needs are not met. Lean body mass of aging cats drops dramatically after 12 years of age, and by age 15, cats may have a mean lean tissue mass that is a third less than cats aged 7 years or less (13, 14). Body fat also tends to progressively decrease in cats after the age of 12 years; this combination of reduced lean mass and body fat contributes to weight loss experienced by many elderly cats.

The ability to digest protein is also compromised in many geriatric cats. After the age of 14 years, one-fifth of geriatric cats have reduced ability to digest protein (13-15). Reduced protein digestibility in geriatric cats seems to occur in parallel with reduction of lean tissue and it might predispose them to negative nitrogen balance. (16).

Although moderation of calorie intake might be suitable for some mature cats, it does not appear to match the needs of most geriatric cats. In contrast, it seems more logical to use highly digestible, energy-dense food for geriatric cats in order to prevent or slow their decline in body weight and lean body tissue (13,16,17).

Reducing protein intake in geriatric cats, at a time when lean tissue has been lost, is contraindicated. Geriatric cats seem to have nutritional requirements closer to kittens than to mature adult cat.

Diet Recommendations for Hyperthyroid Cats

High Dietary Protein
As discussed in my last post about what to feed normal cats, obligate carnivores, such as the cat, are unique in their need for large amounts of dietary protein (specifically, dispensable nitrogen) that separates them from omnivores and herbivore species (18-20). This absolute requirement for dietary protein intake in cats is critically important when formulating a diet for hyperthyroid cats, in which protein catabolism and muscle wasting is universally present.

Protein is the primary macronutrient responsible for maintenance of muscle mass. Restoring and preserving any remaining muscle tissue in cats treated for hyperthyroidism depends upon the cat consuming a diet with sufficient amounts of high-quality protein.

This recommendation for higher amounts of dietary protein does not change once euthyroidism has been restored. The dogma that all older cats should be fed reduced energy “senior” diets must be questioned based on what is now known about the increasing energy requirements and nutritional needs of older cats (12,13).

In most geriatric cats, logic dictates the use highly digestible, energy-dense food mitigate the decline in body weight and lean body tissue and to avoid protein:calorie malnutrition (12,16,17). Protein reduction for this geriatric life stage, at a time when lean tissue is being lost, is contraindicated. Geriatric cats seem to have nutritional requirements closer to kittens than to mature adult cats.

Low Dietary Carbohydrates
Since most of these cats also have subclinical diabetes —as evidenced by their mild hyperglycemia, glucose intolerance, and insulin resistance— feeding a low carbohydrate diet (<10% of total calories) also is strongly recommended (21).

Feeding a low carbohydrate diet will improve insulin sensitivity, reduce the need for exogenous insulin, and help stabilize glucose metabolism in these cats (21-23). This may prevent the development of overt diabetes and control long-term obesity in these cats after successful control of the hyperthyroidism.

Feeding Your Hyperthyroid Cat: The Bottom Line

Like normal and diabetic cats, I believe that it makes sense to feed most hyperthyroid cats a diet composition close to what they would be getting in the wild. That would be a diet composed of approximately 50-60% protein, 5-10% carbohydrates, and 30-50% fat.

Because older cats also loss lean muscle mass in association with the “sarcopenia of aging,” this diet composition needs to be continued even after one treats the cat’s hyperthyroidism and restores euthyroidism.

Check out this website (http://binkyspage.tripod.com/foodfaq.html), which gives you a breakdown of the composition of the various prescription and over-the-counter diets. It turns out that many of the over-the-counter diets have a better composition of protein and carbohydrates than you might have thought — even better than many of the more expensive prescription diets. Very few of my hyperthyroid cat patients require a prescription diet to fulfill their nutritional needs.

As I discussed in my last post, the composition of almost all dry food cat diets are much too high in carbohydrates and most are too low in protein content. That is why I believe it's best to limit the amount of dry food that is fed to cats, or even better, not feed dry food at all.

Cats with advanced renal disease (IRIS Stage 3 or 4) may need lower amounts of dietary protein to lessen uremic episodes (24). However, at least in early to mid-stage renal disease, lowering of the serum phosphate concentration is much more important in management than dietary protein restriction, and this can be easily accomplished with phosphate binders without lowering the protein content of the diet (25,26). It may seem impossible, but no studies have conclusively demonstrated that severe restriction protein alone will prevent further deterioration of kidney function in cats (27).

The major problem that I have with some of the prescription kidney diets is that they restrict protein to the point that some cats – especially those with concurrent hyperthyroidism - will continue to catabolize their own muscle mass despite adequate control of the thyroid condition.

Once we have selected a few diets with the required composition breakdown of carbohydrates, protein, and fat, we next have to look at the ingredient list. Not all of the proteins in cat foods are equal in quality. Remember that quality meat is the best ingredient in a food and that meat by-products are a close second. Some vegetable and grains are fine, but they may supply a less bioavailable form of protein for cats and should not be the primary source of dietary protein.

Remember that when deprived of protein, carnivores will continue to break down muscle tissue to create the energy they need (18-20). By feeding only high-quality protein diets, we will help restore the cat’s muscle mass and improve strength and agility.

Let's use some common sense and not perpetuate the muscle wasting in these older cats by feeding diets that are too low in poor-quality protein.

References:

1. Peterson ME, Ward CR. Etiopathologic findings of hyperthyroidism in cats. Veterinary Clinics of North America Small Animal Practice 2007;37:633-645.
2. http://www.hillspet.com/products/pd-feline-yd-dry.html
3. Peterson ME, Kintzer PP, Cavanagh PG, Fox PR, Ferguson DC, Johnson GF, Becker DV. Feline hyperthyroidism: pretreatment clinical and laboratory evaluation of 131 cases. Journal of the American Veterinary Medical Association 1981;183:103-110.
4. Joseph RJ, Peterson ME. Review and comparison of neuromuscular and central nervous system manifestations of hyperthyroidism in cats and humans. Progress in Veterinary Neurology 1992;3:114-119.
5. Baral R, Peterson ME: Thyroid Diseases, In: Little, S. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders, in press.
6. Morrison WL, Gibson JN, Jung RT, Rennie MJ. Skeletal muscle and whole body protein turnover in thyroid disease. European Journal of Clinical Investigation 1988;18:62–68.
7. Riis AL, Jørgensen JO, Gjedde S, Nørrelund H, Jurik AG, Nair KS, Ivarsen P, Weeke J, Møller N. Whole body and forearm substrate metabolism in hyperthyroidism: evidence of increased basal muscle protein breakdown. American Journal of Physiology: Endocrinology and Metabolism 2005; 288:E1067-1073.
8. Hoenig M, Ferguson DC. Impairment of glucose tolerance in hyperthyroid cats. Journal of Endocrinology 1989;121:249-251.
9. Hoenig M, Peterson ME, Ferguson DC. Glucose tolerance and insulin secretion in spontaneously hyperthyroid cats. Research in Veterinary Science 1992;53:338-341.
10. Short KR, Nair KS. Mechanisms of sarcopenia of aging. Journal of Endocrinological Investigation 1999;22(5 Suppl):95-105. 
11. Fujita S, Volpi E. Nutrition and sarcopenia of ageing. Nutrition Research Reviews 2004;17:69-76. 
12. Wolfe RR. Sarcopenia of aging: Implications of the age-related loss of lean body mass. Proceedings of the Nestlé Purina Companion Animal Nutrition Summit: Focus on Gerontology. St. Louis, MO. 2010, pp. 12-17.
13. Little S: Evaluation of the senior cat with weight loss, In: Little, S. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders, in press.
14. Perez-Camargo G: Cat nutrition: What is new in the old? Compendium for Continuing Education for the Practicing Veterinarian 2004;26 (Suppl 2A):5-10.
15. Patil AR, Cupp C, Pérez-Camargo G. Incidence of impaired nutrient digestibility in aging cats. Nestlé Purina Nutrition Forum Proceedings. 2003;26,2(A):72.
16. Wakshlag JJ. Dietary protein consumption in the healthy aging companion animal. Proceedings of the Nestlé Purina Companion Animal Nutrition Summit: Focus on Gerontology. St. Louis, MO. 2010, pp. 32-39. 
17. Sparkes AH. Feeding old cats— An update on new nutritional therapies. Topics in Companion Animal Medicine 2011;26:37-42. 
18. MacDonald ML, Rogers QR, Morris JG. Nutrition of the domestic cat, a mammalian carnivore. Annual Review of Nutrition 1984;4:521-562.
19. Zoran DL. The carnivore connection to nutrition in cats. Journal of the American Veterinary Medical Association 2002;221:1559-1567.
20. Zoran DL, Buffington CA. Effects of nutrition choices and lifestyle changes on the well-being of cats, a carnivore that has moved indoors. Journal of the American Veterinary Medical Association 2011;239:596-606.
21. Rucinsky R, Cook A, Haley S, Nelson R, Zoran DL, Poundstone M. AAHA diabetes management guidelines for dogs and cats. Journal of the American Animal Hospital Association 2010;46:215-224.
22. Frank G, Anderson W, Pazak H, Hodgkins E, Ballam J, Laflamme D. Use of a high-protein diet in the management of feline diabetes mellitus. Veterinary Therapeutics 2001;2:238-246.
23. Rand JS, Fleeman LM, Farrow HA, Appleton DJ, Lederer R. Canine and feline diabetes mellitus: nature or nurture? The Journal of 2004;134(8 Suppl):2072S-2080S.
24. Plotnick A. Feline chronic renal failure: Long-term medical management. Compendium for Continuing Education for the Practicing Veterinarian 2007;29:342-324, 346-350.
25. Kidder AC, Chew D. Treatment options for hyperphosphatemia in feline CKD: what's out there? Journal of Feline Medicine and 2009;11:913-924.
26. Schmidt B, Spiecker-Hauser U, Murphy M. Efficacy and safety of Lantharenol on phosphorus metabolism in cats with chronic kidney disease. American College of Veterinary Internal Medicine Forum, 2008.
27. Ross SJ, Osborne CA, Kirk CA, Lowry SR, Koehler LA, Polzin DJ. Clinical evaluation of dietary modification for treatment of spontaneous chronic kidney disease in cats. Journal of the Veterinary Medical Association 2006;229:949-957.

Diagnostic Approach to PU/PD: Urine Specific Gravity

Urinalysis is a major key in determining the presence of a water balance problem and the disorder causing the polyuria and polydipsia. The most important features of urinalysis are: the SG or osmolality; the presence or absence of glucose, protein or bacteria; and the cellularity of the sample.

A urine SG less than 1.030 in dogs and 1.035 in cats suggests a concentrating defect and supports the complaint of polyuria. Persistent glycosuria is diagnostic for primary renal glycosuria or, more commonly, diabetes mellitus. Significant proteinuria in the presence of an inactive urinary sediment and dilute urine can be associated with hyperadrenocorticism, pyelonephritis, pyometra, glomerulonephritis or other glomerulopathy.

An active urine sediment (pyuria, hematuria or bacteriuria) in a sample obtained by catheterization or cystocentesis supports urinary tract infection and possible pyelonephritis. Because urine sediment examination may be misleading in an extremely dilute urine sample, a urine culture should always be done to rule out pyelonephritis, regardless of sediment examination findings.

If the results of the above tests are unhelpful the direction of further diagnostic work-up can often be based on the urine SG (see Table below). For example, dogs and cats with a SG greater than 1.030--1.035 without glycosuria, are probably not polyuric and need no further work-up, at least for polyuria and polydipsia.

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Differential diagnosis based on urine specific gravity (SG) determination in animals with normal results of initial tests (CBC, serum biochemical profile and urinalysis).

Urine SG of 1.001--1.007

• Atypical hyperadrenocorticism (most common; always rule out first!)
  
• Atypical leptospirosis
  
• Psychogenic polydipsia
  
• Diabetes insipidus (complete)

Urine SG of 1.008--1.029

• Atypical hyperadrenocorticism (most common!)
  
• Atypical leptospirosis
  
• Early renal disease
  
• Typical and occult pyelonephritis
  
• Hyperthyroidism (cats)
  
• Psychogenic polydipsia
  
• Diabetes insipidus (partial)

Urine SG greater than 1.030 (without glycosuria)

• probably No further work-up for polyuria and polydipsia needed.

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Urine SG less than 1.008 A urine SG consistently less than 1.008 in a middle-aged to older dog is usually associated with diabetes insipidus, psychogenic polydipsia, atypical hyperadrenocorticism or atypical leptospirosis.

In these dogs with atypical hyperadrenocorticism, polyuria and polydipsia are major clinical signs but other characteristic clinical signs are mild or absent. In addition, these dogs with atypical disease may lack the serum biochemistry abnormalities commonly associated with hyperadrenocorticism (i.e. elevated serum alkaline phosphatase activity and hypercholesterolaemia). Results of adrenal function tests in these dogs are usually consistent with mild hyperadrenocorticism.

More recently an atypical form of leptospirosis has been recognized. These dogs present with an acute onset polyuria and polydipsia, hyposthenuria or isosthenuria, but no other laboratory abnormalities. Diagnosis of leptospira infection can be confirmed by positive leptospirosis serology or use of molecular detection of leptospiral DNA by polymerase chain reaction (PCR) testing performed on urine samples.

In general, when considering polyuric dogs with a urine SG less than 1.008, hyperadrenocorticism and atypical leptospirosis should be ruled out first before testing for central diabetes insipidus and primary polydipsia. There are several reasons for making this recommendation: the latter two disorders of water metabolism are much less common than hyperadrenocorticism (see Table below); the diagnostic tests of choice to differentiate these disorders – the water deprivation test or a therapeutic trial with the AVP-analogue desmopressin – are time-consuming and expensive. Also, dogs with hyperadrenocorticism may respond to these tests in a manner similar to dogs with central diabetes insipidus, resulting in a misdiagnosis. Moreover, water deprivation testing a dog with leptospirosis would be a major contraindication because of the possibility of causing significant patient morbidity.

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Differential rule outs for polyuria and polydipsia in dogs and cats, listed from most to least common. Dogs

• Hyperadrenocorticism
  
• Diabetes mellitus
  
• Chronic renal failure
  
• Pyelonephritis
  
• Pyometra
  
• Hypercalcaemia
  
• Atypical leptospirosis
  
• Psychogenic polydipsia
  
• Diabetes insipidus
  
• Liver disease
  
• Hypoadrenocorticism
  
• Acromegaly
  

Cats

• Chronic renal failure
  
• Diabetes mellitus
  
• Hyperthyroidism
  
• Hypercalcaemia
  
• Pyelonephritis
  
• Hypokalaemia
  
• Acromegaly
  
• Postobstructive diuresis
  
• Hyperadrenocorticism
  
• Hypoadrenocorticism
  
• Diabetes insipidus

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In cats, a urine SG consistently less than 1.008 is associated with either diabetes insipidus or hyperthyroidism. Obviously, hyperthyroidism should be ruled out first before initiating testing procedures for diabetes insipidus. It is also important to realize that the finding of a urine SG less than 1.008 in a cat or dog excludes mild (occult) renal disease, so precautions associated with the water deprivation test are not necessary.

Urine SG between 1.008 and 1.029

A urine SG of 1.008--1.012 or greater (but less than 1.030) can be associated with hyperadrenocorticism (dogs), hyperthyroidism (cats), or stage 1 renal insufficiency (including atypical leptospirosis) or pyelonephritis, as well as psychogenic polydipsia and partial forms of diabetes insipidus. 

Again, when considering animals with a urine SG greater than 1.008 hyperadrenocorticism and hyperthyroidism should first be ruled out. With this group of disorders, pyelonephritis and early renal insufficiency should next be ruled out before evaluating the animal for psychogenic polydipsia and diabetes insipidus with a water deprivation test. Performing a water deprivation test as a diagnostic tool in the face of unsuspected renal insufficiency or pyelonephritis could induce overt renal failure or urosepsis. To avoid this complication, a sensible approach is to do the following:

1. Perform a urine culture to help exclude pyelonephritis and associated urinary tract infection.
   
2. Consider leptospirosis serology and urine PCR testing.
   
3. Evaluate renal size and architecture by abdominal radiography or, preferably, renal ultrasonography. The ultrasonographic appearance of renal parenchymal disease (chronic renal failure) includes increased cortical echogenicity and loss of a distinct corticomedullary junction. The kidneys may appear smaller than normal and have an ill-defined or irregular border. Similar sonographic findings, in addition to a dilated renal pelvis, are characteristic of pyelonephritis.

If urine culture results are negative, leptopirosis serology and urine PCR testing are negative, and radiographic or ultrasonographic findings are equivocal, a creatinine or iohexol clearance test or renal biopsy may be indicated. In rare cases, the urine culture may be negative even if pyelonephritis is present. If clinical or ultrasonographic findings suggest occult pyelonephritis, a therapeutic trial with an appropriate antibiotic (e.g. enrofloxacin) should be instituted.

In the next post, I will talk about when water deprivation testing is needed in the workup of dogs and cats with PU/PD.

Diagnostic Approach to Polyuria and Polydipsia

Differentiating between the causes of polyuria and polydipsia (PU/PD) is relatively easy when the different disorders are manifested in their classic forms. For example, polyuria that develops after a known head trauma, continues after water restriction and decreases after AVP administration does not require additional tests to justify the diagnosis of central diabetes insipidus. A diagnosis of congenital nephrogenic diabetes insipidus is equally clear if polyuria occurs in a young animal with similarly affected litter mates that have normal screening laboratory tests (including renal function), negative urine cultures and whose polyuria fails to respond to fluid restriction or administration of AVP analogues (e.g. desmopressin).

Often, however, the clinical setting is of minimal help in making a diagnosis and it is then necessary to perform more detailed diagnostic tests. The initial information gathered should allow the inclusion or exclusion of the many common medical disorders associated with polyuria and polydipsia before a diagnostic work-up for the less common disorders of central diabetes insipidus, primary nephrogenic diabetes insipidus or psychogenic polydipsia is embarked upon.

Measurement of water consumption
The first step in any suspected case of polyuria and polydipsia is to establish that the problem actually exists, preferably by a combination of history, random urine SG determinations and, if necessary, home measurement of water consumption over several days.

If the daily water intake is found to be normal or if a random urine SG determination is >1.035, additional history should be obtained to rule out other urinary tract disorders (such as urinary incontinence or dysuria) that commonly are confused with polyuria. If, however, random urine SG are consistently <1.030 in dogs and <1.035 in cats, and daily water intake is >100 ml/kg for dogs and 45 ml/kg for cats, polyuria and polydipsia are indeed present and a diagnostic work-up to determine the cause is warranted.

Minimum clinicopathological data
Once a problem of water balance is confirmed, a practical diagnostic approach is to first rule out the more common causes of polyuria and polydipsia in dogs and cats. Recommended initial diagnostic tests include:

• Complete blood cell count (CBC)
  
• Serum biochemical profile with electrolytes
  
• Serum total thyroxine (T4) determination in middle-aged to older cats

A careful evaluation of this initial database, together with the history and results of physical examination, usually provides the diagnosis immediately (e.g. overt renal failure, hyperthyroidism or diabetes mellitus) or offers clues to as to the underlying cause of the polyuria and polydipsia (see Table below). For example, dogs with hyperadrenocorticism commonly have a stress leucogram (i.e. neutrophilia, lymphopenia and eosinopenia). Over 90% of dogs with hyperadrenocorticism also have high alkaline phosphatase (ALP) activity, whereas over half have hypercholesterolaemia.

In contrast, physical examination findings and routine blood work are generally unremarkable in animals with less common causes of polyuria and polydipsia such as central diabetes insipidus, primary nephrogenic diabetes insipidus and psychogenic polydipsia. When abnormalities are present, they are usually secondary to dehydration caused by water restriction by the owner. Such abnormalities may include a slightly increased packed cell volume (PCV) or hypernatraemia.

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Initial work-up for polyuria and polydipsia in dogs and cats.

Signalment and history

• Age, breed and sex
  
• Reproductive history (intact female?)
  
• Changes in diet or environment?
  
• Overall general health (weight loss or gain, lethargy, vomiting or diarrhoea?)
  
• Appetite normal, increased or decreased?
  
• Drug administration (glucocorticoids, anticonvulsants, diuretics?)

Physical examination

• Kidneys small or misshapen? (chronic renal disease)
  
• Kidneys large? (pyelonephritis, lymphosarcoma)
  
• Hepatomegaly? (hyperadrenocorticism, diabetes mellitus)
  
• Peripheral lymphadenopathy? (lymphosarcoma with hypercalcaemia)
  
• Perianal mass? (anal sac adenocarcinoma with hypercalcaemia)
  
• Vaginal discharge? (pyometra)
  
• Alopecia? Pot belly? (hyperadrenocorticism)
  
• Thyroid mass? (hyperthyroidism)

Complete blood count (CBC), serum biochemical profile and electrolytes, serum thyroxine

• High urea or creatinine? (renal failure)
  
• Hyperglycaemia? (diabetes mellitus)
  
• High alkaline phosphatase activity (hyperadrenocorticism)
  
• Hypercholesterolaemia? (hyperadrenocorticism)
  
• Hypercalcaemia?
  
• Hypokalaemia?
  
• High thyroxine? (hyperthyroidism)

Complete urinalysis and urine culture

• Low urine specific gravity (confirms and defines polyuria)
  
• Proteinuria? (hyperadrenocorticism, pyometra, pyelonephritis, glomerulonephritis)
  
• Glucosuria +/- ketonuria? (Diabetes mellitus)
  
• Active urine sediment? (infection, pyelonephritis)
  
• Positive bacterial culture? (infection, pyelonephritis)

Abdominal radiography or ultrasonography

• Small kidneys with ill-defined renal or irregular border (renal failure)
  
• Increased cortical echogenicity, indistinct corticomedullary junction (renal failure)
  
• Dilated renal pelvis (pyelonephritis)

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Our next blog post we will continue discussing the diagnostic approach to PU/PD, concentrating on the urine's specific gravity.

What's the Differential Diagnosis of Polydipsia and Polyuria in Dogs and Cats?

There are many potential causes of polyuria and polydipsia.  Primary disorders of water balance (i.e. central diabetes insipidus, primary nephrogenic diabetes insipidus and primary polydipsia) although uncommon, should always be considered in the differential diagnosis of polyuria and polydipsia. In general, animals with these disorders have only one laboratory abnormality; a low urine specific gravity (SG) or osmolality.

In most instances the more common causes of polyuria and polydipsia (e.g. hyperadrenocorticism, chronic renal failure, pyelonephritis and pyometra) have other specific and obvious abnormalities on screening laboratory tests (complete blood cell count, serum biochemical profile and urinalysis). In some cases, however, a low urine SG is the only abnormality found in animals with these latter disorders.

The work-up for polyuria and polydipsia can be tedious, time-consuming, expensive, confusing and not without significant patient morbidity, especially in those dogs and cats with normal or near-normal screening test results. This chapter focuses on the diagnostic approach, especially the problems associated with testing, and the treatment of dogs and cats with disorders of water balance.

Differential diagnosis
The causes of polyuria and polydipsia can be divided into those that cause primary polydipsia (with secondary polyuria) and those that cause primary polyuria (with compensatory polydipsia). These are listed in the table below.

The major cause of primary polydipsia in dogs is psychogenic polydipsia. In contrast, the causes of primary polyuria are much more numerous and can be subdivided into the categories of: central diabetes insipidus; primary nephrogenic diabetes insipidus; secondary nephrogenic diabetes insipidus; and osmotic diuresis.

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DIFFERENTIAL DIAGNOSIS OF POLYDIPSIA AND POLYURIA

1. Primary polydipsia

• Psychogenic polydipsia (compulsive water drinking)
  
• Dipsogenic diabetes insipidus (thirst centre abnormality)
  
• Metabolic disorders (e.g. hyperthyroidism, hepatic failure)

2. Primary polyuria

Central diabetes insipidus (neurogenic, cranial, ADH-responsive)

• Idiopathic
  
• Trauma-induced
  
• Neoplastic
  
• Post-hypophysectomy

Primary nephrogenic diabetes insipidus (congenital or familial)

Secondary nephrogenic diabetes insipidus (acquired)

• Acromegaly
  
• Chronic renal disease
  
• Drug administration
  
• Liver disease
  
• Hyperadrenocorticism
  
• Hypercalcaemia
  
• Hyperthyroidism
  
• Hypoadrenocorticism
  
• Hypokalaemia
  
• Leptospirosis
  
• Postobstructive diuresis
  
• Pyelonephritis
  
• Pyometra

Osmotic diuresis (increased renal tubular solute load)

• Diabetes mellitus
  
• Primary renal glycosuria (e.g. Fanconi’s syndrome)
  
• Postobstructive diuresis
  
• Renal failure
  
• Leptospirosis

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In our next blog post, I will talk about my approach to working up the dog or cat with polyuria or polydipsia.