HOT TOPICS in FELINE MEDICINE EMERGING DIAGNOSTIC and TREATMENT OPTIONS

HOT TOPICS IN FELINE MEDICINE EMERGING DIAGNOSTIC and TREATMENT OPTIONS

Proceedings from the 2008 NAVC/WVC Conferences HOT TOPICS IN FELINE MEDICINE EMERGING DIAGNOSTIC AND TREATMENT OPTIONS

3 UPDATE ON FELINE THYROID DISORDERS Deborah S. Greco, DVM, PhD, DACVIM

8 CHRONIC RENAL INSUFFICIENCY AND ITS ASSOCIATED DISORDERS Margie Scherk, DVM, DABVP (Feline)

13 CRITICAL APPRAISAL OF INFECTIOUS DIARRHEA IN CATS Stanley L. Marks, BVSc, PhD, DACVIM (Internal Medicine, Oncology), DACVN

20 CATS WITH COLITIS: PATHOGENESIS, DIAGNOSIS, AND THERAPY Robert J. Washabau, VMD, PhD, DACVIM Update on Feline Thyroid Disorders

HYPERTHYROIDISM levels because nonthyroidal illness (chronic renal failure) can result

Clinical Aspects in spurious elevations of FT 4. Feline hyperthyroidism was first described in 1979 and 1980 by inves - tigators in New York City and Boston. 1,2 Since that time, the question Nutritional Aspects has been: Is hyperthyroidism a new disease in cats? Based on epidemi - An inability to secrete adequate amounts of thyroid hormone often ologic and hospital-acquired data, the answer appears to be yes. During leads to enlargement of the thyroid gland, a condition known as goi - a 14-year period from 1970 to 1984, hyperthyroidism was diagnosed in ter . In many places in the world, this condition is, or has been, caused an average of 1.9 cats per year; however, the incidence is now estimat - by a deficiency of iodine in the diet, which has largely been correct - ed to be as high as 2% of the feline population seen in tertiary care vet - ed through the use of iodized salt. Balanced pet foods provide suffi - erinary facilities. 3,4 Hyperthyroidism has become one of the most cient iodine but vary widely in iodine content. 6 The effects of this frequently diagnosed endocrinopathies in cats and has been reported variation have been theorized to be important in cats, but there are in North America, Europe (especially the United Kingdom), New no data to support or refute the theory. In 1992, Tartellin et al 7

Zealand, and Australia. This increase in prevalence may be due to an showed an acute inverse relationship between FT 4 and dietary iodine increase in the number of cats that survive past 10 years of age, in cats fed low- and high-iodine diets for 2 weeks. However, a subse - improved diagnostics, and increased suspicion for the disease among quent report concluded that when the cats were fed low- or high- veterinarians in practice. Dozens of studies have been published on the iodine diets for more than 5 months, no effect on serum TT 4 or FT 4 origins of feline hyperthyroidism; however, none offers a definitive levels was seen. 8 Chronic changes in dietary iodine are associated answer to the mystery behind this disease. with “adaptation” of the thyroid gland and therefore are unlikely to Hyperthyroidism is caused by adenomatous hyperplasia of the be the cause of feline hyperthyroidism. One study showed that feed - thyroid gland. Middle-aged to older cats are typically affected, and ing a low-iodine diet to cats with preexisting hyperthyroidism failed there is no breed or sex predilection, although some studies suggest to affect high circulating thyroid hormone concentrations. 3,9 a male predilection and a decreased incidence in Himalayans and Canned cat food has been implicated as a cause of feline hyperthy - Siamese. 5 roidism in multiple epidemiologic studies. 4,5,10 The suspected goitrogen Hyperthyroidism is characterized by hypermetabolism; there - is bisphenol-A-diglycidyl ether (BADGE), a substance used in making fore, polyphagia, weight loss, polydipsia, and polyuria are the most the liner of easy-open “pop-top” cans. It is suspected that this compound prominent features of the disease. Activation of the sympathetic nerv - can leach into the food and be consumed by cats. While BADGE-based ous system is also seen; hyperactivity, tachycardia, pupillary dilation, lining is generally considered safe and is used for foods for human con - and behavioral changes are characteristic of the disease in cats. sumption, cats may be more susceptible to toxic effects of BADGE Longstanding hyperthyroidism leads to hypertrophic cardiomyopa - because they have a greatly reduced ability to detoxify the compound via thy, high-output heart failure, and cachexia, which may lead to death. hepatic glucuronidation. Bisphenol A also reduces T 3 binding and caus - Feline hyperthyroidism is diagnosed through measurement of es increased TSH secretion, resulting in hyperthyroidism and goiter in 11 total tetraiodothyronine (thyroxine; TT 4); total triiodothyronine rats and some humans. Although no feline studies have been conduct - 12 (T 3) measurement does not generally contribute to a diagnosis. ed, rodent studies show a very high safety margin. It should be noted Because the disease has become more common and is more often that epidemiologic studies showing associations are not the same as recognized in its early stages, free T 4 (FT 4) concentrations have been proving cause and effect. More than 90% of cats in the United States, shown to be more diagnostic of early or “occult” hyperthyroidism. particularly older cats, consume canned commercial pet foods as their

However, FT 4 concentrations should be interpreted in light of TT 4 primary nutritional source, and relatively few develop hyperthyroidism.

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 3 Immunologic Aspects One recent report implicated brominated flame retardants The literature regarding an immunologic cause of feline hyperthy - (BFRs) as carcinogens/goitrogens possibly associated with feline roidism is contradictory. Initially, feline hyperthyroidism was thought hyperthyroidism. 29 BFRs were introduced 30 years ago, at the same to be similar to Graves’ disease in humans. 13 In fact, the clinical signs time that feline hyperthyroidism emerged. Bromide, a halide, is an of hypermetabolism associated with feline hyperthyroidism are iden - intriguing agent to implicate in feline hyperthyroidism because of tical to those of Graves’ disease. However, several studies have shown the unique composition of thyroid hormones, which contain the that unlike Graves’ disease, which is caused by autoantibodies to the halide iodide. In this recent abstract, serum levels of lipid-adjusted thyroid stimulating hormone (TSH) receptor, feline hyperthyroidism polybrominated diphenyl ethers (PBDEs) were found to be 10- to is not caused by antibodies that affect the TSH receptor. 14,15 In other 400-fold higher in cats than in humans. 29 The authors theorized that research, antibodies from hyperthyroid cats were shown to stimulate this finding is in accord with the most consistently identified risk thyroid cellular proliferation and interfere with TSH binding. 16 factor: indoor living. They also proposed that cats are at increased However, more recent reviews have indicated that an autoimmune risk because of meticulous grooming behavior and increased expo - basis for feline hyperthyroidism is unlikely and that the disease is sure to furniture and carpets. The small size of cats is also a possible more similar to toxic nodular goiter than to Graves’ disease. 17 risk factor for increased serum levels of PBDEs.

Molecular Aspects HYPOTHYROIDISM Feline hyperthyroidism is characterized by autonomous growth of Congenital Hypothyroidism thyroid follicle cells. In humans, the pathogenesis of toxic nodular Congenital hypothyroidism is a relatively common endocrine disor - goiter is an abnormality in the signal transduction of the thyroid cell. der of human infants, occurring in approximately 1 in 4,000 births. 30 The TSH receptor on the thyroid cells activates receptor-coupled In cats, congenital hypothyroidism is more common than sponta - guanosine triphosphate-binding proteins (G proteins). Uniquely, neous adult-onset hypothyroidism. 31–33 In humans, congenital thyroid cell proliferation and hormone production are both con - hypothyroidism may be caused by aplasia or hypoplasia of the thy - trolled by TSH receptor–G protein–cAMP signaling. Overexpression roid gland, thyroid ectopia, dyshormonogenesis, maternal goitrogen of stimulatory G proteins and ingestion, maternal radioactive iodine treatment, iodine deficiency underexpression of inhibitory (endemic goiter), autoimmune thyroiditis, hypopituitarism, isolated In cats, congenital G proteins have been demon - TSH deficiency, hypothalamic disease, or isolated thyrotropin- 30 hypothyroidism is strated in some humans with releasing hormone deficiency. Most cases of hypothyroidism in kit - toxic nodular goiter. 18,19 Mu- tens are the result of dysgenesis; however, Jones and colleagues more common tations of the TSH receptor reported a family of Abyssinian cats with familial dyshormonogene - that result in the receptor sis. 32 Hypothyroidism as a result of TSH resistance has also been than spontaneous remaining activated without described in a family of Japanese cats. 33 Most inherited forms of ligand (i.e., TSH) have also hypothyroidism are inherited as an autosomal recessive trait. 30 adult-onset been reported in humans with Because thyroid hormone secretion is essential for normal post - hypothyroidism. toxic nodular goiter. 20–23 natal development of the nervous and skeletal systems, congenital The same abnormalities hypothyroidism in humans is characterized by disproportionate have been investigated in hy- dwarfism, central and peripheral nervous system abnormalities, and perthyroid cats, and it appears that an activation mutation of the mental deficiency. In addition, many of the signs of adult-onset TSH receptor may be part of the pathogenesis of hyperthyroidism in hypothyroidism, such as lethargy, inappetence, constipation, der - some cats. 24 Furthermore, abnormalities of G proteins, specifically matopathy, and hypothermia, may be observed. 31–33 significantly decreased G inhibitory protein expression, have been Congenital hypothyroidism, regardless of cause, results in char - described in tissue from hyperthyroid cats. 25 acteristic historical and physical examination features. Kittens and infants have a history of large birth weight (in humans, this is the Environmental Aspects result of prolonged gestation), which is followed by aberrant and In one study, the use of cat litter was associated with an increased delayed growth. 32–34 In kittens, the first signs of abnormal growth risk of hyperthyroidism 5; however, there was no significant differ - occur as early as 3 weeks after birth, and abnormal body proportions ence between different litter brands, suggesting that the use of litter are evident by 8 weeks of age. This is similar to hypothyroid human is simply a marker of cats that are kept indoors. 17 Indoor cats are like - infants, which are normal at birth but, if hypothyroidism remains ly to live longer and hence have a higher risk of developing hyperthy - undiagnosed, exhibit characteristic signs by 6 to 8 weeks of age. 30 roidism. Exposure to pesticides and herbicides has been associated Historical findings in hypothyroid kittens, such as lethargy, mental with thyroid abnormalities in other species. 26 In particular, the use of dullness, weak nursing, delayed dental eruption, and abdominal dis - flea control products was associated with an increased risk of devel - tention, are also observed in hypothyroid children. 30 oping hyperthyroidism in cats; however, no specific product or Physical features of hypothyroid dwarfism in children include ingredient could be identified. 27,28 hypotonia, umbilical hernia, skin mottling, large anterior and poste -

4 rior fontanels, macroglossia, hoarse cry, distended abdomen, dry skin, jaundice, pallor, slow deep tendon reflex, delayed dental erup - tion, and hypothermia. 30,35–37 In kittens with congenital hypothy - roidism, hypotonia, macroglossia, distended abdomen, dry skin, delayed dental eruption, and hypothermia have been described. 31–33 In addition, because cats develop more rapidly and become weight bear - ing sooner than humans, gait abnormalities and disproportionate dwarfism are prominent features of feline congenital hypothyroidism. Midface hypoplasia, a broad nose, and a large protruding tongue are some of the sequelae of untreated hypothyroidism in humans. 38,39 Similar facial features, such as broad maxillae and macroglossia, have Figure 1. Hypothyroid kitten. been observed in affected kittens. Delayed eruption of permanent teeth is observed in untreated congenitally hypothyroid humans; 38 mild normocytic, normochromic anemia in some kittens with delayed dental eruption is characteristic of hypothyroid kittens treat - hypothyroidism. 47,48 ed after 4 months of age. In humans and cats, macroglossia and effu - T4 is essential for the proper transcription, translation, and secre - sions of the body cavities can result from myxedematous fluid tion of growth hormone by pituitary somatotrophs. 49 In humans, circu - accumulation. 40 In kittens, this effusion may be mistaken for feline lating growth hormone concentrations are very high during the first infectious peritonitis. Hypothyroid kittens often exhibit haircoat few days after birth but rapidly decrease during the subsequent few abnormalities, including retention of the kitten haircoat and thinning weeks to levels just slightly above those in adults. 30,50 of the haircoat (Figure 1). Congenitally hypothyroid rats exhibit It is vital to remember that normal kittens 5 to 6 weeks of age altered hair shaft morphology as a result of thyroid hormone defi - have serum TT 4 concentrations two to three times higher than those 39 ciency during development. of normal adult cats. Therefore, a serum TT 4 of 2.0 µg/dl, which is Thyroid hormone is crucial for proper postnatal development of normal for an adult cat, would be low in a 6-week-old kitten and the nervous system. As a result, a significant number of properly treat - indicative of thyroid dysfunction. Serum FT 4 would also be expected ed hypothyroid infants and all untreated hypothyroid infants exhibit to be higher in neonatal cats. poor coordination and speech impediments later in life. 41,42 Delayed In summary, congenital hypothyroidism is recognized by char - treatment often results in low perceptual–motor, visual–spatial, and acteristic physical examination findings (e.g., dwarfism, delayed language scores in children with congenital hypothyroidism. 42 If treat - dental eruption) and clinicopathologic and radiologic features and is ment is delayed beyond 4 to 6 months in human babies, intelligence is confirmed by thyroid function testing. irreversibly affected and mental retardation may ensue. 30 Mental retar - dation is also likely in hypothyroid kittens; however, no objective evi - Adult-Onset Hypothyroidism dence of delayed intelligence is available to assess affected animals. Spontaneous hypothyroidism secondary to lymphocytic thyroiditis Because the bulk of cerebellar development occurs after birth, Purkinje has been described in one adult cat. 51 However, the most common cell growth is also significantly affected by congenital hypothyroidism. 30 cause of adult-onset hypothyroidism in cats is radioactive iodine Skeletal abnormalities such as delayed epiphyseal maturation and therapy for hyperthyroidism. epiphyseal dysgenesis are the hallmark of congenital hypothyroidism. Clinical signs of adult-onset hypothyroidism are gradual and Delayed epiphyseal maturation is observed in the vertebral bodies and subtle in onset, with lethargy, weight gain, depression, hypothermia, long bones of affected kittens. Epiphyseal dysgenesis, which is character - and bradycardia being most commonly reported. The hypothyroid ized by a ragged epiphysis with scattered foci of calcification, is observed cat “slows down” gradually, and the owner may report gradual in both humans and cats with untreated congenital hypothyroidism. 43,44 weight gain and lethargy. Owners often report that the animal is not Normal epiphyseal development proceeds from a single center; however, hungry and may even have a reduced appetite despite weight gain. in hypothyroidism, thyroid deficiency leads to the development of mul - The owner may subject the cat to a severely calorie-restricted diet tiple epiphyseal centers, each with its own calcification progression. 43 without success. Puffy facial features associated with myxedema and Disorderly epiphyseal calcification leads to secondary arthropathies in severe apathy were reported in a hypothyroid cat. 51 children suffering from untreated congenital hypothyroidism. 43,44 Cardiovascular signs, such as bradycardia, decreased cardiac Clinicopathologic features of congenital hypothyroidism in contractility, and atherosclerosis, are uncommon presenting com - humans and dogs include hypercholesterolemia, hypercalcemia, and plaints in hypothyroid animals. Neuropathies, including bilateral or mild anemia. Hypercholesterolemia develops in both congenital and unilateral facial nerve paralysis, vestibular disease, and lower motor adult-onset hypothyroidism because of decreased hepatic metabolism neuron disorders, are occasionally seen in hypothyroid dogs but are and decreased fecal excretion of cholesterol. Hypercalcemia secondary not reported in cats. In humans, carpal tunnel syndrome is often to congenital hypothyroidism is the result of decreased renal clearance associated with hypothyroidism as a result of compression of the and increased gastrointestinal absorption of calcium. 45,46 Decreased nerves from myxedema. 49 In hypothyroid cats, myxedema results in thyroid hormone stimulation of erythropoietic precursors results in a compression of the facial nerve as it exits the skull, causing the clas -

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 5 sic “tragic” facial expression. Myxedema coma is an unusual finding is a two-step process that takes 24 to 48 hours to complete and is in hypothyroid dogs and cats and manifests as stupor and coma sec - therefore expensive. The first step involves dialysis of the test sample ondary to myxedematous fluid accumulations in the brain and across a membrane that is impermeable to protein-bound T 4. The 52 severe intracerebral hyponatremia. second step subjects the dialysate to an ultrasensitive T 4 radioim -

munoassay. In human medicine, concentrations of FT 4 and free T 3 Laboratory Findings are used to differentiate between euthyroid sick syndrome and true

Clinicopathologic findings such as normocytic, normochromic anemia hypothyroidism. Theoretically, FT 4 levels are not subject to sponta - resulting from erythropoietin deficiency, decreased bone marrow activ - neous or drug-induced changes that occur with TT 4. Because of the ity, and decreased serum iron levels and iron binding capacity would be expense and time involved in ordering an equilibrium dialysis test expected in hypothyroid cats with the same frequency as in dogs (about for FT 4, I prefer to use TT 4 and eTSH concentrations as the first bat -

30%). Hypercholesterolemia (increased high-density lipoprotein) is tery of tests. If confounding results are obtained, measurement of FT 4 seen in most hypothyroid cats because of altered lipid metabolism and by dialysis may clarify the situation. binding proteins, decreased fecal excretion of cholesterol, and decreased conversion of lipids to bile acids. Increased triglyceride levels are also Endogenous TSH Concentrations seen in some hypothyroid cats. Hyponatremia, a common finding in In humans, when eTSH and TT 4 concentrations are increased and humans with hypothyroidism, is observed in hypothyroid animals as a decreased, respectively, diagnostic accuracy for primary hypothy - 52 mild decrease in serum sodium levels. Fructosamine concentrations roidism approaches 100%. As serum TT 4 and FT 4 concentrations can be affected in both hyperthyroid and hypothyroid cats as a result of decrease, intracellular T 3 also decreases, initiating a logarithmic changes in clearance and protein turnover. Hypothyroid cats exhibit increase in serum eTSH concentration. This sensitivity to intracellu - serum fructosamine concentrations in the high end of the normal lar T 3 makes eTSH the most sensitive test for the detection of early range. 53 This slowed turnover of fructosamine may lead to falsely elevat - hypothyroidism in humans. In fact, eTSH has become the gold stan - ed serum fructosamine levels in cats with concurrent diabetes mellitus. dard for the diagnosis of hypothyroidism in humans. Although there In addition, impaired glucose tolerance has been observed in hypo- is no feline-specific TSH assay, the canine immunoradiometric assay thyroid cats and humans as a result of altered lipid metabolism. 52 In my may be useful in the diagnosis of spontaneous hypothyroidism in experience, sudden onset of diabetes mellitus or exacerbation of type 2 cats. 55 The advent of the canine eTSH assay should allow discrimina - diabetes mellitus is observed in iatrogenically hypothyroid cats. tion of primary congenital hypothyroidism from secondary hypothyroidism (TSH deficiency). In my experience, cats with pri - Diagnosis mary hypothyroidism (e.g., lymphocytic thyroiditis, thyroid dysgen - Diagnosis of hypothyroidism in cats may be based on measurement esis, dyshormonogenesis) have elevated eTSH concentrations. of serum basal TT 4 concentrations, serum FT 4 concentrations, endogenous TSH (eTSH) levels, and response to therapy. Often, the Response to Therapy combination of basal TT 4 and eTSH concentrations is the most eco - In the past, veterinarians have relied heavily on the use of a trial of nomical and efficient way to diagnose hypothyroidism in cats. levothyroxine to diagnose hypothyroidism. Unfortunately, response to treatment does not necessarily mean that the cat is truly hypothyroid.

Serum Total T 4 and T 3 Concentrations This is particularly true in patients with skin and haircoat abnormali -

Measurement of serum total T 3 and TT 4 levels has been used as the ties. If results of thyroid diagnostics are equivocal and the owner wish - mainstay of diagnosis in animals; however, the specificity of these tests es to treat the animal, the veterinarian should decide on a quantitative leaves much to be desired. The specificity of a low T 4 is low because measure of response. For example, if the cat is overweight, the veteri - serum TT 4 is affected by euthyroid sick syndrome, which is character - narian should calculate the amount of weight loss that would predict a ized by a decrease in serum TT 4 and an increase in reverse T 3; tissue response (usually about 10% of the target weight). Treatment should concentrations of T 3 remain unchanged. Concurrent illnesses, such as include use of a product that has proven efficacy in veterinary patients diabetes mellitus, chronic renal failure, hepatic insufficiency, and at an adequate dose (e.g., levothyroxine 44 µg/kg/day or 22 µg/kg bid). infections, and drugs such as anesthetics, phenobarbital, primidone, diazepam, trimethoprim–sulfamethoxazole, quinidine, phenylbuta - Summary of Thyroid Panels zone, salicylates, and glucocorticoids can also decrease basal serum I use TT 4 and eTSH as first-line diagnostics to determine whether a cat

TT 4 concentrations. The more severe the illness, the lower the TT 4 has hypothyroidism. This combination of tests has been shown to have concentration. 54 the highest specificity, highest sensitivity, and lowest overall cost. If the

TT 4 level is in the low-normal range or is below normal and the TSH level

Serum Free T 4 Concentrations is high, the cat has primary hypothyroidism. If the TT 4 and eTSH levels

FT 4 is the fraction of T 4 unbound to protein and available for tissue are both low, FT 4 should be measured by equilibrium dialysis to distin - uptake. The method used to measure FT 4 is important, with equilib - guish euthyroid sick syndrome (normal FT 4) from true secondary rium dialysis being the method of choice because of its diagnostic hypothyroidism (low eTSH resulting from pituitary TSH deficiency). accuracy (approximately 90%). 54 Using this technique, measurement The diagnosis of feline hypothyroidism is made on the basis of clinical

6 signs, consistent clinicopathologic data, and serum concentrations of TT 4 gland adenomas obtained from hyperthyroid cats. Am J Vet Res 2000;61:874-879. 26. Gaitan E. Goitrogens in food and water. Annu Rev Nutr 1990;10:21-39. and eTSH; FT 4 by dialysis may be used in cases of confounding results. 27. Scarlett JM, Moise NS, Ravl J. Feline hyperthyroidism: goitrogens descriptive and case controlled study. Prev Vet Med 1988;6:295-309. REFERENCES 28. Olczak J, Jones BR, Pfeiffer DU, et al. Multivariate analysis of risk factors for feline 1. Peterson ME, Johnson JG, Andrews LK. Spontaneous hyperthyroidism in the hyperthyroidism in New Zealand. N Z Vet J 2005;53:53-58. cat. Proc ACVIM 1979:108. 29. Dye JA, Venier M, Ward CA. Brominated-flame retardants (BFRs) in cats- 2. Holzworth J, Theran P, Carpenter JL, et al. Hyperthyroidism in the cat: ten possible linkage to feline hyperthyroidism. (abstract) J Vet Intern Med cases. JAVMA 1980;176:345-353. 2007;21:595. 3. Peterson ME, Randolph JF, Mooney CT. Endocrine diseases. In: Sherding 30. LaFranchi SH. Hypothyroidism. Pediatr Clin North Am 1979;26:33-51. RG, ed. The Cat: Diseases and Clinical Management . Vol 2. 2nd ed. New York: 31. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction . Churchill Livingstone; 1994:1403-1506. 3rd ed. Philadelphia: WB Saunders; 2004. 4. Edinboro CH, Scott-Moncrieff JC, Janovitz E, et al. Epidemiologic study of 32. Jones BR, Gruffydd-Jones TJ, Sparkes AH, et al. Preliminary studies on congen - relationship between consumption of commercial canned food and risk of ital hypothyroidism in a family of Abyssinian cats. Vet Rec 1992;131:145-148. hyperthyroidism in cats. JAVMA 2004;224:879-886. 33. Tanase H, Kudo K, Horikoshi H, et al. Inherited primary hypothyroidism 5. Kass PH, Peterson ME, Levy J, et al. Evaluation of environmental, nutritional with thyrotrophin resistance in Japanese cats. J Endocrinol 1991;129:245-251. and host factors for feline hyperthyroidism. J Vet Intern Med 1999;13:323-329. 34. Kenny FM, Klein AH, Augustin AV, et al. Sporadic cretinism. In: Fisher DA, 6. Johnson LA, Ford HC, Tartellin MF. Iodine content of commercially-pre - Burrow GN, eds. Perinatal Thyroid Physiology and Disease . New York: Raven pared cat foods. N Z Vet J 1992;40:18-20. Press; 1975:73-78. 7. Tartellin MF, Johnson LA, Cooke RR. Serum free thyroxine levels respond 35. Fisher DA. Medical management of suspected cases of congenital hypothy - inversely to levels of dietary iodine in the domestic cat. N Z Vet J 1992:40:66-68. roidism. In: Burrow GN, ed. Neonatal Thyroid Screening. New York: Raven 8. Kyle AH, Tartellin MF, Cooke RR, et al. Serum free thyroxine levels in cats main - Press; 1980:237-244. tained on diets relatively high and low in iodine. N Z Vet J 1994;42:101-103. 36. Loevy HT, Aduss H, Rosenthal IM. Tooth eruption and craniofacial develop - 9. Mooney CT. Pathogenesis of hyperthyroidism. J Vet Med Surg 2002;4:167-169. ment in congenital hypothyroidism: report of a case. J Am Dent Assoc 1987; 10. Martin KM, Rossing MA, Ryland LM. Evaluation of dietary and environ - 115:429-431. mental risk factors for feline hyperthyroidism. JAVMA 2000;217:853-856. 37. Isreal H, Johnson GF, Fierro-Benitez R. Craniofacial malformation among 11. Moriyama K, Tagami T, Akimuzu T, et al. Thyroid hormone action is dis - endemic cretins in Ecuador. J Craniofac Genet Dev Biol 1983;3:3-10. rupted by bisphenol A as an antagonist. J Clin Endocrinol Metab 2002;87: 38. Sawin CT. Hypothyroidism. Med Clin North Am 1985;69:989-1004. 5185-5190. 39. Essman EJ. Alterations in hair shaft morphology in the cretin rat. Biol Clin 12. Poole A, van Herwijnen P, Weideli H, et al. Review of the toxicology, human Lab 1984;14:657-661. exposure and safety assessment for bisphenol A diglycidylether (BADGE). 40. Moschini L, Costa P, Marinelli E, et al. Longitudinal assessment of children with Food Addit Contam 2004;21(9):905-919. congenital hypothyroidism detected by neonatal screening. Helv Paediatr Acta 13. Kennedy RL, Thoday KL. Autoantibodies in feline hyperthyroidism. Res Vet 1986;41:415-424. Sci 1988;45:300-306. 41. Noguchi T, Sugisaki T. Hypomyelination in the cerebrum of the congenitally 14. Peterson ME, Livingston P, Brown RS. Lack of circulating thyroid stimulating hypothyroid mouse (hyt). J Neurochem 1984;42:891-893. immunoglobulins in cats with hyperthyroidism. Vet Immunol Immunopathol 42. Rovet J, Ehrlich R, Sorbara D. Intellectual outcome in children with fetal 1987;16:277-282. hypothyroidism. J Pediatr 1987;10:700-704. 15. Nguyen LQ, Arseven RK, Gerber H, et al. Cloning of the cat TSH receptor 43. Wilkins L. Epiphyseal dysgenesis associated with hypothyroidism. Am J Dis and evidence against an autoimmune etiology of feline hyperthyroidism. Child 1941;61:13-34. Endocrinology 2002;143:395-402. 44. Johansen NA. Endocrine arthropathies. Clin Rheum Dis 1985;11:297-323. 16. Brown et al. Thyroid growth immunoglobulins in feline hyperthyroidism. 45. Parfitt AM, Kleerekoper M. Clinical disorders of calcium, phosphorus, and Thyroid 1992;2:125-130. magnesium metabolism. In: Maxwell M, Kleeman CR, eds. Clinical Disorders of 17. Peterson ME, Ward C. Etiopathologic findings of hyperthyroidism in cats. Fluid and Electrolyte Metabolism. New York: McGraw-Hill; 1980:1026. Vet Clin North Am Small Anim Pract 2007, in press. 46. Tau C, Garagedian M, Farriaux JP, et al. Hypercalcemia in infants with con - 18. Derwahl M, Hamacher C, Papageorgiou G. Alterations of the stimulatory G genital hypothyroidism and its relation to vitamin D and thyroid hormones. protein (Gs)-adenylate cyclase cascade in thyroid carcinomas: evidence for J Pediatr 1986;109:808-814. up regulation of inhibitory G protein. Thyroid 1995;5(suppl 1):S-3. 47. Cline MJ, Berlin NI. Erythropoesis and red cell survival in the hypothyroid 19. Delemer B, Dib K, Patey M, et al . Modification of the amounts of G proteins dog. Am J Physiol 1963;204:415-418. and of the activity of adenyl cyclase in human benign thyroid tumours. 48. Schalm OW, Jain NC, Carroll EJ. Veterinary Hematology . 3rd ed. J Endocrinol 1992;132:477-485. Philadelphia: Lea & Febiger; 1975:89. 20. Parma J, Duprez L, Van Sande J, et al. Diversity and prevalence of somatic 49. DeGroot LJ, Larsen PR, Hennemann G. The Thyroid and Its Diseases . 6th ed. mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic New York: Churchill Livingstone; 1996:342-346. thyroid adenomas. J Clin Endocrinol Metab 1997: 82:2695-2701. 50. Wood DF, Franklyn JA, Docherty K. The effect of thyroid hormones on growth 21. Fuhrer D, Holzapfel HP, Wonerow P, et al. Somatic mutations in the thy - hormone gene expression in vivo in rats. J Endocrinol 1987;112:459-463. rotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thy - 51. Rand JS, Levine JU, Best SJ, Parker W. Spontaneous adult onset hypothy - roid nodules. J Clin Endocrinol Metab 1997;82:3885-3891. roidism in a cat. J Vet Intern Med 1993;7:272-276. 22. Holzapfel HP, Fuhrer D, Wonerow P, et al. Identification of constitutively 52. Greco DS. Endocrine emergencies. Part II. Compend Contin Educ Pract Vet activating somatic thyrotropin receptor mutations in a subset of toxic 1997;19(2):33-44. multinodular goiters. J Clin Endocrinal Metab 1997;82:4229-4233. 53. Reusch CE, Gerber B, Boretti FS. Serum fructosamine concentrations in 23. Russo D, Arturi F, Suarez HG, et al. Thyrotropin receptor gene alterations in dogs with hypothyroidism. Vet Res Commun 2002;7:531-536. thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab 1996;81:1548- 54. Mooney CT, Little CJL, Macrae AW. Effect of illness not associated with the 1551. thyroid gland on serum total and free thyroxine concentrations in cats. 24. Peeters ME, Timmermans-Sprang EP, Mol JA. Feline thyroid adenomas are JAVMA 1996;208:2004. in part associated with mutations in the G (s alpha) gene and not with poly - 55. Graham PA, Refsal KR, Nachreiner RF, et al. The measurement of feline thy - morphisms found in the thyrotropin receptor. Thyroid 2002;12:571-575. rotropin using a commercial canine immunoradiometric assay. J Vet Intern 25. Hammer KB, Holt DE, Ward CR. Altered expression of G proteins in thyroid Med 2000:14:342.

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 7 Chronic Renal Insufficiency and Its Associated Disorders

Margie Scherk, DVM, DABVP (Feline) Cats Only Veterinary Clinic Vancouver, British Columbia, Canada ©JupiterImages

Renal function declines with increasing age as a normal event. Renal mellitus, neoplasia, or osteoarthritis. These comorbid conditions insufficiency is, consequently, very common in aging cats. The term may complicate our ability to untangle a diagnosis and balance treat - chronic renal insufficiency is preferable to chronic renal failure ments for a specific patient. because this condition is progressive, rather than imminently termi - nal, and can be managed. DIAGNOSTICS Cats may live for many years after the initial detection of Following a comprehensive physical examination and consulta - decreased urine specific gravity and elevated blood urea nitrogen tion (including a fundic examination and blood pressure deter - (BUN) and serum creatinine levels, depending on the disease’s stage mination), a minimum database for cats beyond middle age (8 and cause. To grossly lump everything together as chronic renal fail - years or older) consists of a complete blood count (CBC) with ure is an oversimplification and a disservice to our patients and differential, serum chemistry profile (including baseline clients. Table 1 shows the criteria proposed by the International tetraiodothyronine [T 4]), and a complete urinalysis. Cats with Renal Interest Society in 2006 to characterize renal disease. Staging renal insufficiency classically have a urine specific gravity of less allows for better communication between practitioners and offers than 1.040, despite some degree of dehydration. Additionally, guidelines for the initiation of different therapies. To provide high- with progressive decline in function, BUN and creatinine will quality patient care, practitioners must attempt to carefully define exceed normal reference values in rehydrated patients. As renal the stage of chronic renal disease as well as identify and manage any disease progresses, there will be varying changes in urinary pro - concurrent medical conditions. tein and potassium levels as well as alterations in serum elec - trolytes (ionized calcium, phosphorus, and potassium). Anemia HISTORY also develops due to several causes. Clinical signs of renal insufficiency may include anorexia or inappe - Urine should be collected by cystocentesis. Because tence, vomiting, dehydration, weight loss, lethargy, oral ulceration, pyelonephritis is often subclinical, urine culture and sensitivity ptyalism, anemia, social apathy, and constipation. Polyuria and poly - testing should be considered in patients with dilute urine (urine dipsia are reported less commonly in cats than in dogs, perhaps specific gravity <1.020) and white blood cells or trace protein because of the secretive nature of cats. In assessing the degree of ill - without adequate red blood cells to account for the protein. The ness, it should be kept in mind that both decreased muscle mass method of urine collection (free catch vs. cystocentesis) affects (wasting) of cats with chronic renal insufficiency and concurrent the interpretation of bacterial colony counts. If the urine is col - hyperthyroidism will mask the severity of renal insufficiency by low - lected by cystocentesis, any number of bacteria is significant. For ering serum creatinine levels. Often cats with even moderate renal a free-catch urine sample, bacterial colony counts need to be insufficiency are asymptomatic. Our goal should be to correct and higher than 10,000/ml to be considered significant. Both dilute maintain physiologic parameters that will enable them to enjoy a urine and glucosuria encourage bacterial growth. Additional tests, good quality of life. such as serum fructosamine, can be recommended depending on Because these patients are older cats, they may have more than clinical concerns and diagnostic findings. one clinical condition. It is not uncommon to have a patient with chronic renal insufficiency that also suffers from pyelonephritis, car - MANAGING CHRONIC RENAL DISEASE diac disease, or hypertension associated with renal or thyroid dis - Hydration ease. Constipation is extremely common in elderly cats. There may Rehydration is a key component of treatment in cats with chronic renal be concurrent inflammatory bowel or small airway disease, diabetes disease. Rehydration is critical in perfusing tissues with oxygen and

8 Table 1 Staging Chronic Renal Disease in Cats*

I: Non-Azotemic III: Moderate Stage Renal Disease II: Mild Renal Azotemia Renal Azotemia IV: Severe Renal Azotemia

Creatinine level <1.6 mg/dl 1.6–2.8 mg/dl 2.9–5.0 mg/dl >5.0 mg/dl mg/dl (<140 mmol/L) (140–250 mmol/L) (251–440 mmol/L) (>440 mmol/L)

Clinical signs None Possible inappetence, Usually inappetence, weight Uremia, clinically ill weight loss, polyuria, loss, polyuria, polydipsia polydipsia

Progression Stable for long periods Stable for long periods May progress Fragile of time of time

Therapeutic goals Identify and treat Identify and treat specific Modify progression: Ameliorate uremic signs: specific primary kidney primary kidney disease phosphorus restriction, protein restriction, antiemetics, disease (e.g., acute (e.g., acute pyelonephritis, omega-3 fatty acids fluid therapy, pyelonephritis, pyelonephritis, nephrolithiasis) appetite stimulation, dialysis nephrolithiasis)

Proteinuria Classif ya Classif ya Classif ya Classif ya

Blood pressure Classif yb Classif yb Classif yb Classif yb

*Based on the International Renal Interest Society staging system. aProteinuria is determined by evaluating sequential urine protein:creatinine (UPC) ratios: nonproteinuric = UPC <0.2; borderline proteinuria = UPC 0.2 –0.4 (reevaluate after 2 months); proteinuria = UPC >0.4. bClassification of blood pressure (systolic): Nonhypertensive <150 mm Hg with no complications; borderline hypertensive = 150–160 mm Hg with no complications; hypertension with no complications = systolic blood pressure consistently >160 mm Hg; hypertension with extrarenal complications = clinical signs plus blood pressure >150 mm Hg.

nutrients and in scavenging waste. Rehydration also aids in acid–base Renally impaired cats with diarrhea from chronic small or large homeostasis. Because cats with renal insufficiency are usually in a state bowel disease have increased fluid losses above their maintenance of metabolic acidosis, alkalinizing fluids are the preferred fluid type. In replacement needs. The underlying cause of the diarrhea should be dehydrated patients, increased urea reabsorption due to decreased tubu - controlled as much as possible. If corticosteroids are part of therapy lar flow rates may lead to an increase in BUN—even before the glomeru - (e.g., for inflammatory bowel disease or small airway disease), lar filtration rate (GFR) is decreased—causing prerenal azotemia. This polyuria may worsen. Similarly, for cats with renal disease and dia - also causes serum BUN to appear higher than it actually is. betes mellitus, cellular water needs should be addressed. The patient should be rehydrated and blood work repeated before a prognosis is given. With an impaired ability to concentrate Inappetence, Nausea, and Vomiting urine—despite polydipsia—exogenous fluids are required. Clients Many cats with uremic gastritis show only signs of partial anorexia commonly administer subcutaneous fluids to cats at home. or nausea rather than outright vomiting. H 2-receptor antagonists are Increasing water intake can be encouraged by flavoring water and underutilized; they function by preventing gastric hydrochloric acid feeding more canned foods. Recirculating water fountains may appeal production. Famotidine (0.5 mg/kg/day PO) or ranitidine (2 to 3 to some cats. For cats with a fragile cardiovascular system, maintain - mg/kg PO q12h) may be considered. ing hydration to optimize renal function yet not overload cardiovas - Appetite stimulation may be attempted with cyproheptadine (1 cular capabilities requires fine-tuning through ongoing client mg PO q12h) or mirtazapine (3 mg PO q72h), the latter having the communication. This requires frequent reassessment of packed cell added benefit of antiemetic effects. Regardless of concurrent prob - volume (PCV), total solids, BUN, and serum creatinine along with lems, adequate calories (50 kcal/kg/day) need to be ingested. For reassessment of body weight, skin elasticity, appetite, and energy. patients not ingesting adequate calories (as evidenced by weight loss, For the most part, constipation is a clinical sign of dehydration. poor coat and muscle mass), placement of an esophagostomy or Cellular water content has priority over fecal water content; thus, pri - other large-bore feeding tube should be considered. mary treatment of constipation should address rehydration and the underlying cause of dehydration rather than stool passage (e.g ., with Hypertension laxatives). Promotility agents, laxatives, osmotic agents, and fiber- The incidence of hypertension in cats with renal insufficiency has enriched diets should be used only after the patient is rehydrated. been reported to be as high as 60%, whereas in cats with hyperthy -

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 9 Table 2 Equivalent Erythropoietin and Darbepoetin Dose sa increased urine protein:creatinine ratio (>0.4) that are started on benazepril (0.25 to 0.5 mg/kg/day PO) should be rechecked within Erythropoietin (U/wk) Darbepoetin (μg/wk) 3 to 7 days and have their renal parameters, hydration, body weight, <1,500 6.25 appetite, and overall health monitored. Stable patients should be 1,500–2,499 6.25 reevaluated every 2 to 4 months. 2,500–4,999 12.5 5,000–10,999 25 Erythropoietin 11,000–17,999 40 Erythropoietin causes rapid correction of anemia by stimulating 18,000–33,999 60 marrow progenitor cells. When PCV is less than 20%, erythropoietin

aTotal weekly doses. (100 U/kg SC three times per week) should be considered until the PCV is in the low-normal range (35%); the dosage should then be reduced to 50 U/kg SC three times a week. It is important to moni - roidism, the incidence reportedly ranges from 40% to 60%. tor PCV for the first 60 to 90 days to detect development of anti-ery - Evaluation of blood pressure should be considered in all older cats thropoietin antibodies as noted by a decline in PCV rather than an and any ill cats. Cats with chronic renal insufficiency lose the normal increase (at comparable total solids). If this occurs, erythropoietin autoregulatory capacity of the glomerular arterioles. This not only treatment should be discontinued immediately. The cat may be causes systemic hypertension but may also promote progression of transfusion dependent for 2 to 4 months until anti-erythropoietin renal insufficiency through glomerular injury. antibody levels decrease. It is also important to administer iron at the Treatment of hypertension should be undertaken in cats with start of the regimen and until the cat’s appetite improves. While there systolic blood pressure consistently over 160 mm Hg. Amlodipine is a risk that anti-erythropoietin antibodies may develop, most cats is the most efficacious agent (0.625 mg PO q12–24h), as it has a will enjoy the benefits of an increased PCV. direct effect on the peripheral vasculature calcium channels. Recently, darbepoetin has been receiving attention as an alter - Angiotensin-converting enzyme (ACE) inhibitors are not as effica - native to erythropoietin, and it may be less antigenic and can be cious in decreasing systemic blood pressure. β-blockers reduce given less frequently. The dose is 0.45 μg/kg/week, but it is also pos - renin secretion and are similarly unimpressive for treating feline sible to convert the current erythropoietin dose (Table 2). hypertension. DRUG DOSE ADJUSTMENTS Metabolic Acidosis For a drug that relies on the kidneys for clearance, a loss in renal Cats with chronic renal diseases commonly have metabolic acidosis. function will proportionately decrease drug excretion. Thus, a 75% This acid–base imbalance promotes severe catabolism of endoge - loss in renal function results in a 75% loss in renal drug clearance. nous proteins, exacerbates azotemia regardless of diet, promotes Dosage adjustments can be made from estimates on the loss of renal wasting (degradation of protein), inhibits protein synthesis, causes a function. The most exact method of assessing renal function is to negative nitrogen balance, and enhances hypokalemia. Acidosis measure creatinine clearance as an estimate of GFR. should be corrected aggressively with the use of alkalinizing fluid A less precise but more practical approach is to make a dose therapy and H 2-receptor antagonists. adjustment based on serum creatinine, as follows:

Old dose Normal serum creatinine level ADDITIONAL TREATMENT OPTIONS New = × ACE Inhibitors dose Patient’s serum creatinine level A large, multi-institutional study (the BENazepril in Renal Insufficiency in Cats [BENRIC] Clinical Trial 1) assessed the effects Old interval Patient’s serum creatinine level New = × of benazepril on chronic renal insufficiency in cats. Results of this interval Normal serum creatinine level and other smaller studies 2,3 showed no significant difference in sur - vival time between benazepril and placebo administration. Remember that this type of dose adjustment estimate is more risky However, for cats with urinary protein loss (based on urine pro - in geriatric pets than in younger pets because serum creatinine is tein:creatinine ratios), benazepril treatment resulted in longer sur - affected by muscle mass. Therefore, a geriatric animal with vival times and better appetite than placebo did. Cats without decreased muscle mass and renal function may have a falsely low protein-losing glomerulonephropathy may potentially be harmed serum creatinine level. by this agent because it diverts renal blood, causing a beneficially increased renal interstitial blood flow but a potentially deleterious DIETARY RESTRICTION OR reduction in GFR. Before diagnosing a protein-losing glomeru - SUPPLEMENTATION lonephropathy, sequential urine protein:creatinine ratios should be Protein checked (two over a 2-week period) to ensure that proteinuria is Based on results in the feline remnant kidney model, dietary protein persistent rather than physiologic and transient. Cats with an restriction does not ameliorate progression of renal insufficiency in

10 Concurrent Osteoarthritis, Degenerative Joint Disease, and Other Disorders Analgesic Considerations in Older Cats using NSAIDs in patients predisposed to dehydration, with dele - Degenerative joint disorders have been recognized in 90% of terious effects on their gastric mucosal health or renal function. geriatric cats 1 and are but one category of many potentially Additionally, certain NSAIDs may negatively affect proteoglycan chronic, painful conditions that can occur in these cats. synthesis by cartilage. According to in vitro studies, some Bacterial cystitis and pyelonephritis are more common in NSAIDs, including meloxicam and carprofen, do not have this older cats, while the incidence of interstitial, sterile cystitis or negative effect when used at recommended doses. 2 inflammatory bowel disease is not different than in younger cats. The likelihood of neoplasia increases with age. NSAIDs With increasing age come certain risk factors that need to be Pharmacokinetic and safety data are lacking for long-term considered when planning analgesic protocols. Body composi - NSAID use in cats. The carprofen half-life varies from 9 to 40 tion changes in many elderly cats, with a decline in interstitial hours in cats. 3,4 As most NSAIDs have long half-lives in cats water and possibly a concurrent decrease in muscle mass. Drug when compared with other species, the frequency of adminis - dose calculations should, therefore, be made based on an esti - tration should be reduced to avoid toxicity. It is important to mate of lean body weight rather than total weight in overweight remember that individual patients respond differently to the cats. Attempts to rehydrate to optimize extracellular water com - same agent and dose; the lowest effective dose should be used. ponents, tissue perfusion, and glomerular filtration should be Long-term dosing for meloxicam should be based on lean, made. A decrease in renal clearance, as well as any impairment hydrated weight (day 1: 0.1–0.2 mg/kg SC or PO once; days 2 of hepatic function, may alter the pharmacokinetics of therapeu - to 4: 0.1 mg/kg/day PO; long-term: 0.025 mg/kg PO q48–72h). 5 tic agents. When liver disease is present, a rough rule of thumb NSAIDs must be used carefully and with renal, hepatic, and for drugs that require hepatic metabolism is to reduce their dose coagulation status in mind. While it would be ideal to avoid by 25%. For drugs requiring renal clearance, the frequency of NSAID use unless renal function is normal, you can enhance administration should be reduced or the dose used may be quality of life in patients with concurrent renal disease and restricted. Cats with chronic renal disease may suffer from ure - chronic pain by ensuring hydration and dosing conservatively. mic gastritis, just as dehydrated cats with reduced gastric blood Informing the client of possible side effects is important. flow do; in both situations, the use of NSAIDs increases the risk There will never be medical practices that are 100% risk- of gastric ulceration with or without perforation. free; good veterinary medicine aims to minimize risks and maximize quality of life for the individual patient. Making Analgesic Choices Opioids References The advantages of pure opioid agonists in older cats are their 1. Hardie EM, Roe SC, Martin FR: Radiographic evidence of degen - safety, the lack of a ceiling effect allowing dosing to effect, erative joint disease in geriatric cats: 100 cases (1994-1997). and partial to complete reversibility, if needed. In older JAVMA 2002;220:628–632. patients or those with impaired renal or hepatic function, 2. McLaughlin R: Management of chronic osteoarthritic pain. Vet Clin North Am Small Anim Pract 2000;30:933–949. additional doses of opioid prolong the analgesic effect. 3. Taylor PM, Delatour P, Landoni FM, et al: Pharmacodynamics and Opioids are suitable for use in moderate to severe acute pain enantioselective pharmacokinetics of carprofen in the cat. Res Vet or mild to severe chronic pain. Any opioid works in any Sci 1996;60:144–151. patient at any age or stage—the dose should be started low 4. Parton K, Balmer TV, Boyle J, et al: The pharmacokinetics and and titrated up until the desired effect is seen. effects of intravenously administered carprofen and salicylate on gastrointestinal mucosa and selected biochemical measurements Cats with joint pain are often older patients with concurrent in healthy cats. J Vet Pharmacol Ther 2000;23:73–79. problems. Of most concern are the possible consequences of 5. Robertson SA: Chronic pain—osteoarthritis. Proc AAFP ; 2006.

cats. 4 However, it is important to note that the remnant kidney ic renal insufficiency, dietary protein restriction may limit the kid - model does not reflect or emulate natural disease. ney’s compensatory response to injury. Protein restriction may lead The effectiveness of a therapeutic renal diet was examined in to protein malnutrition, which impairs the immunologic response cats with stages 3 and 4 chronic kidney disease by a randomized, and decreases hemoglobin production, thus promoting anemia, controlled clinical trial. 5 This study examined the benefits of feeding decreasing plasma protein levels, and promoting muscle wasting. a renal diet versus a standard feline maintenance diet. Cats were ran - Inadequate protein also decreases urinary excretion of magnesium, domly assigned to either the renal or maintenance diet but were which may result in calcium phosphate precipitation in the kidneys. managed in an identical manner with respect to other treatment Watching for evidence of protein–calorie malnutrition should interventions. Cats fed the maintenance diet had significantly more include monitoring for weight loss, hypoalbuminemia, poor hair- uremic episodes (22%) than did cats fed the renal diet (0%). A sig - coat quality, and muscle wasting. nificant reduction in renal-related mortality was observed in cats fed Dietary treatment of moderate to severe chronic renal insuffi - the renal diet. Importantly, significant adverse effects of feeding the ciency (serum creatinine >5 mg/dl, BUN >75 mg/dl in the rehydrat - renal diet were not detected in the study. 6 ed cat) is not controversial; restriction of both protein and However, in acute renal failure and in mild to moderate chron - phosphorus is required to avoid uremic complications. Benefits of

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 11 protein restriction are related to nonrenal effects (toxins affecting Calcitriol organs other than kidneys). Using protein sources of high biological The use of calcitriol is still controversial in that some researchers feel value/availability is important. Protein restriction may be especially that its use is more urgent than others. Calcitriol advocates suggest that harmful in renal patients that are inappetent because a sustained it should be started at 2.5 to 3.5 ng/kg/day PO in early renal insufficien - calorie deficit causes body proteins to be catabolized to supply calo - cy when serum creatinine is 2 to 3 mg/dl, urine specific gravity is com - ries and the nitrogenous end-products of this process will further patible with chronic renal insufficiency, and phosphorus is less than 6 accentuate uremic signs. Inappetence is an indication for avoiding mg/dl. In these patients, when parathyroid hormone (PTH) levels are protein-restricted diets. still normal, calcitriol is used to prevent PTH levels from increasing, thereby slowing progression of chronic renal insufficiency and prevent - Phosphorus ing clinical signs related to PTH toxicity. In patients with a serum cre - It is important to restrict phosphorus in moderately azotemic atinine level higher than 3 mg/dl and serum phosphorus level less than patients. Phosphorus restriction is more important than protein 6 mg/dl, the dose is 3.5 ng/kg/day PO. A baseline PTH measurement is restriction to survival in the canine remnant kidney model and has useful in these patients because the levels are commonly elevated and been shown to produce renal lesions that are less severe than those may require higher doses of calcitriol. It is imperative to have good seen in the feline remnant kidney model. The dose of intestinal client compliance—ionized calcium and PTH levels should be moni - phosphate binders cited in the literature may be too low (e.g., alu - tored carefully. The Ca × P product must be less than 60. minum hydroxide initially at 30 to 90 mg/kg/day but dosage must be individualized); the dose should be increased as needed to produce CONCLUSION serum phosphorus levels that are consistently within the normal Chronic renal insufficiency is progressive and can be treated. To pro - range. If calcium-based intestinal phosphate binders are used, serum vide high-quality care, veterinarians must carefully define the stage calcium levels should be monitored carefully and switched to or of chronic renal disease by taking a thorough history, performing a combined with aluminium-based phosphate binders if necessary. comprehensive physical examination, and running indicated labora - For these agents to be effective, they must be given with food; they tory tests. With proper hydration and management of concurrent act by binding the phosphorus in the ingested food and making it medical conditions, cats may live for many years after chronic renal unavailable for absorption. insufficiency is detected.

Potassium REFERENCES Because hypokalemia may induce a reversible, functional decline in 1. King JN, Font A, for the BENRIC Study Group: Effect of benazepril in chron - ic renal insufficiency in cats: Interim results from the Benric Clinical Trial GFR, potassium supplementation is warranted for cats with chronic [abstract]. Proc 27 th Annu Congress World Sm Anim Vet Assoc , 2002. renal insufficiency and hypokalemia, even in the absence of overt 2. Gunn-Moore D, for the BENRIC Study Group: Influence of proteinuria on st clinical signs. Polyuria results in increased urinary potassium loss as survival time in cats with chronic renal insufficiency [abstract]. Proc 21 Annu ACVIM Forum , 2003. well. Dietary acidification causes intracellular potassium to shift to 3. Gunn-Moore D, for the BENRIC Study Group: Effects of benazepril in Persian cats the extracellular space, raising serum potassium levels but not with chronic renal insufficiency [abstract]. Proc 21 st Annu ACVIM Forum , 2003. reflecting total body potassium levels. Thus, metabolic acidosis 4. Finco DR, Brown SA, Brown CA, et al: Protein and calorie effects on progres - sion of induced chronic renal failure in cats. Am J Vet Res 1998;59:575–582. results in a shift of potassium into the extracellular fluid and should 5. Ross SJ, Osborne CA, Kirk CA, et al: Clinical evaluation of dietary modification be rectified early in the management of hypokalemia. Potassium for treatment of spontaneous chronic kidney disease in cats. JAVMA 2006;229: 949–957. supplementation (potassium gluconate 2 to 4 mEq PO q12h) may be 6. Roudebush P, et al: An evidence-based review of therapies, submitted for pub - considered after acidosis is corrected. lication.

12 Critical Appraisal of Infectious Diarrhea in Cats

Stanley L. Marks, BVSc, PhD, DACVIM (Internal Medicine, Oncology), DACVN University of California, Davis School of Veterinary Medicine

Diarrhea in cats is one of the most common maladies facing small guidelines should be followed to maximize the diagnostic yield of animal practitioners and managers of feline shelters and catteries fecal examinations: today. 1,2 A recent survey of the Association of Shelter Veterinarians identified kitten diarrhea as one of the top two concerns of veterinar - • Examine fresh fecal specimens. Fecal flotations should be per - ians treating shelter cats, second only to upper respiratory infec - formed on fresh specimens (<1 hour old) to help ensure that tions. 3 Despite the significant clinical importance of diarrhea in cats, eggs, oocysts, and larvae do not develop beyond their diagnos - there is a paucity of veterinary literature providing specific informa - tic stage. Fresh fecal specimens can be refrigerated within 1 tion on the causes and diagnosis of this malady. Antibiotics are com - hour of collection for up to 72 hours to facilitate preservation monly administered injudiciously to diarrheic cats, with resolution of eggs, oocysts, and cysts if immediate examination cannot be of clinical signs often wrongly equated with eradication of a “puta - performed. 22 Specimens fixed in formalin are suitable for con - tive” infectious pathogen. In addition, indiscriminate antibiotic ther - centration techniques, acid -fast stains, and immunoassays. apy may even alter the commensal intestinal microflora, leading to Survival of trichomonads can be extended simply by adding an exacerbation of the animal’s diarrhea or development of antibiot - saline to the fecal specimen (3 ml of 0.9% saline/2 g feces) to ic resistance. 4 prevent desiccation. 23 Although diarrhea in cats can have different etiologies, infec - • Perform direct wet smears routinely. Direct wet smears are indi - tious causes are believed to play an important role in many cases. 2,5 cated for recovery of trophozoites of Giardia and T. foetus . They Potential causes of bacteria-associated diarrhea in cats include must be done with saline and performed using fresh feces (body enteropathogens such as Salmonella spp, 6–8 Campylobacter spp, 9,10 temperature, <1 hour old). Trophozoites in older specimens will Clostridium perfringens ,11 and Clostridium difficile .12 Intestinal lose their motility and degenerate, becoming unrecognizable. The endoparasites such as Toxocara cati, Toxascaris leonina, and sensitivity of direct wet smear examination for diagnosis of tri - Ancylostoma spp are occasionally associated with diarrhea in cats, chomoniasis is relatively low in cats with spontaneous disease whereas intestinal protozoa such as Giardia spp ,13,14 Tritrichomonas (14%). 23 In addition, T. foetus can be difficult to distinguish from foetus ,15 Cryptosporidium spp, 16,17 and Isospora felis 18 are more com - nonpathogenic intestinal trichomonads (e.g., Pentatrichomonas monly incriminated. Of particular concern, several of these hominis ) and Giardia using light microscopy. enteropathogens have been clearly implicated as zoonotic agents, • Perform centrifugation fecal flotations. Fecal flotations are including Salmonella spp, Campylobacter spp, T. cati, Giardia spp, excellent for recovering common nematode ova, oocysts of proto - and Cryptosporidium spp, 19–21 underscoring the importance of accu - zoans (including Cryptosporidium spp), and Giardia cysts. The rately diagnosing these pathogens in affected cats. Enteric viruses, most important considerations for fecal flotations are the choice including feline parvovirus, rotavirus , and astrovirus , have also been of flotation solution and its specific gravity, 24 selection of standing isolated in some cases, although the pathogenicity of the latter virus - versus centrifugal flotation, 25,26 and the method used to transfer es in feline diarrhea is poorly understood. 2 the meniscus. 25 — Flotation solutions: The flotation solution must have a specif - INTESTINAL ENDOPARASITES ic gravity high enough to float most common parasite ova and The diagnosis of gastrointestinal parasites in cats is an integral com - low enough to avoid distortion of protozoal cysts. Three solu - ponent of small animal practice; however, in many instances, there is tions in common use are zinc sulfate (specific gravity: 1.18 to little uniformity in the application of diagnostic techniques and sub - 1.2), Sheather’s sugar (specific gravity: 1.27), and sodium optimal attention to proper identification of parasites. The following nitrate (specific gravity: 1.2). Sodium chloride is an unaccept -

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 13 Procedure for Centrifugation Flotation 1. Prepare a fecal emulsion using 2 to 5 g of feces and 30 ml of flotation solution. 2. Strain the emulsion through a tea strainer or cheesecloth into a 15-ml conical centrifuge tube. 3. Fill the tube with flotation medium to create a meniscus. 4. Place a coverslip on top of the tube. 5. Create a balance tube of equal weight containing another sample or water. 6. Centrifuge the tubes for 5 minutes at approximately 1,200 rpm (280 × g). 7. Carefully remove the coverslip from the tube after 10 minutes and place it on a slide. Centrifuge with free-swinging buckets showing cover - 8. Examine the slide within 10 minutes. Examine the entire slip in place on the centrifuge tube. coverslip at 10×. Use 40× to confirm identification by visualizing internal structures and measuring the organism. the tube by carefully adding more flotation medium with a If the centrifuge is a fixed-angle type, fill the centrifuge tube pipette down the side of the tube after the final spin. A with flotation medium to within 1 inch of the top of the tube. coverslip is then placed on top of the tube for 10 minutes After centrifugation, the meniscus can be raised to the top of before being transferred to a glass slide for examination.

able flotation medium, even when used with centrifugation, as mittently and are delicate. Many artifacts (e.g., grass pollen, yeast) it will not float Trichuris ova. 24 Aqueous zinc sulfate with a spe - mimic the morphology of Giardia cysts, and care must be exercised cific gravity of 1.18 to 1.2 has been widely recommended to differentiate these from Giardia . because it will float cysts, oocysts, and most helminth eggs Many veterinarians and reference laboratories use ELISA tests with minimal distortion and fecal debris. 27 It is important to that rely on detection of Giardia cyst wall protein I (GCWP 1). 31 The note that zinc sulfate at this concentration will not recover ELISA tests are advantageous because they are generally easy to per - spirurids ( Physaloptera ) and Taenia spp, whose specific gravi - form and results are easy to interpret. In addition, they do not rely on ties are 1.23 and 1.22 , respectively. 28 morphologic identification of cysts or oocysts via microscopy, thus sav - — Centrifugation versus gravitational (standing) flotation: ing technician time and potentially avoiding false-negative interpreta - Flotation with centrifugation is considerably more efficient tions. Enzyme immunoassays (EIAs) can also detect GCWP 1 in the than standing flotation, which may not detect parasite stages absence of detectable cysts. 31 A novel SNAP Giardia Test Kit (IDEXX shed in low numbers. 26,29 Quantitative comparisons have Laboratories, Inc., Westbrook, ME) for detection of GCWP 1 in canine shown that egg counts achieved using flotation with centrifu - and feline feces was recently released. This test is a rapid in-house EIA gation were 2.4 to 6.0 times higher than those obtained with that can be performed on fresh feces, previously frozen feces, or feces standing flotation. 26,30 stored at 2 °C to 7 °C for up to 7 days. The performance characteristics — Meniscus transfer: Once the flotation procedure is complete, of this test have been evaluated in cats, and the test was highly sensitive the meniscus containing the parasite stages should be trans - and specific (Table 1). 32 Of equal importance, parallel testing of fecal ferred by lifting the coverslip directly off the fluid surface after specimens with fecal centrifugation flotation and the SNAP Giardia test 10 minutes and placing it on a slide. Meniscus transfer using increased the sensitivity for detection of Giardia spp to 97.8%. 32 a loop or glass rod is the poorest method and reduces the sen - Direct immunofluorescence (DIF) is often the standard against sitivity of any flotation technique because only a small portion which other tests for Giardia are measured. A positive result is indicat - of the parasites recovered are transferred to the slide for ed by apple-green fluorescence of the cyst. Specimens sent to commer - examination. cial laboratories for DIF should be fixed in 10% buffered formalin. Meridian’s DIF combines the Giardia -specific and Cryptosporidium Giardia Species parvum –specific antibodies in one reagent, so specimens can be Giardia infections in adult cats are often subclinical or associated examined for both parasites with a single test (Figure 2). with a transient softening of the stool early in the infection; howev - Metronidazole was shown to be highly effective and safe when er, acute diarrhea tends to occur in kittens shortly after infection. given at 25 mg/kg PO q12h for 7 days to cats with experimental Feces are often malodorous and pale and may contain mucus. Giardia infections, 33 although it was less effective in dogs , with erad - The diagnosis of Giardia infection has traditionally depended ication of the organism occurring in 67% of treated dogs. No studies on microscopic identification of trophozoites or cysts in feces from have been published to date evaluating the efficacy of albendazole in affected animals (Figure 1) . However, microscopic diagnosis of cats, and use of this drug is strictly off-label. A recent trial evaluating Giardia infection can be difficult because cysts may be shed inter - the efficacy of fenbendazole in cats co-infected with Giardia and C.

14 Figure 3. Photomicrograph showing a tiny Cryptosporidium oocyst (approxi - mately 5 µm in diameter) in a feline fecal Figure 1. Giardia cysts observed on a Figure 2. DIF on a fecal specimen showing specimen following centrifugation flota - slide following centrifugation flotation large, oval-shaped Giardia cysts and tion and use of a modified Ziehl-Neelsen with zinc sulfate solution. smaller, round Cryptosporidium oocysts. acid-fast stain. parvum revealed that the drug was safe; however, it was relatively is small (mean size: 4.6 × 4.0 μ m) and therefore difficult to detect via ineffective (50%) in these cats .34 Fenbendazole is my drug of choice light microscop y39 and because fecal shedding may be intermittent. for treating Giardia -infected kittens. Although off-label, commercial Current laboratory methods for detection of Cryptosporidium oocysts anthelmintics containing a combination of praziquantel, febantel, in fecal specimens include light microscopy examination of fecal and pyrantel pamoate have been shown to be relatively safe and smears stained with Giemsa stain, modified Ziehl-Neelsen acid-fast effective in experimentally infected kittens when given at twice the stain (Figure 3) or modified Kinyoun acid-fast stain or use of an recommended dose. 35 The dose of febantel administered was 56.5 immunofluorescence detection procedure. Immunofluorescence mg/kg q12h for 5 days. Decontaminating the environment and detection procedures are more sensitive and specific than acid-fast bathing the animal to clean cysts from the coat are important strate - stains and are generally the method of choice for morphologic diag - gies in the management of infected animals to prevent reinfection . nosis of cryptosporidiosis in humans. 40 Administration of probiotics to cats infected with Giardia repre - Eradication of cryptosporidia has proven difficult, and many sents a novel alternative therapeutic modality that warrants further putatively effective drugs are either toxic or ineffective. Azithromycin investigation. A recent stud y36 documented the ability of the probiot - is used in humans for management of cryptosporidiosis and appears ic organism Enterococcus faecium SF68 (FortiFlora, Nestlé Purina, St. to be safe in dogs and cats when administered at a dosage of 7 to 10 Louis, MO) to antagonize Giardia intestinalis infection in mice. Oral mg/kg bid for 7 days; however, its efficacy is unknown. feeding of E. faecium SF68 starting 7 days before inoculation with Giardia trophozoites significantly increased the production of specif - Tritrichomonas foetus ic anti- Giardia intestinal IgA and blood IgG. This humoral response T. foetus , the primary causative agent of bovine trichomoniasis, has was mirrored at the cellular level by an increased percentage of CD4+ recently been recognized as a protozoal pathogen in cats. 41,42 Infected T cells in the Peyer’s patches and in the spleens of SF68-fed mice. The cats are generally young (Figure 4) but have ranged in age from 3 improvement of specific immune responses in probiotic-fed mice was months to 13 years (median : 9 months). The prevalence of T. foetus associated with a diminution in the number of active trophozoites in infection at an international cat show was found to be 31% (36 of 117 the small intestine as well as decreased shedding of fecal Giardia anti - cats), with 28 of 89 catteries affected. 42 Coinfection with T. foetus and gens (GSA65 protein). 36 Administration of metronidazole with Giardia was common and was documented in 12% of cats. Saccharomyces boulardii , a nonpathogenic probiotic yeast organism, Misdiagnosis of Giardia is common in cats having T. foetus infection to adults with naturally acquired Giardia infections demonstrated and may explain why cats diagnosed with apparent Giardia infection superior resolution of Giardia infection compared with adults treated do not respond to appropriate therapy. with metronidazole alone. 37 Clinical signs of T. foetus infection are characterized by chronic or recurrent large intestinal diarrhea with increased mucus, tenes - Cryptosporidium Species mus, occasional hematochezia, and increased frequency. The anus is Cryptosporidium infection of kittens and healthy or immunosup - frequently red, swollen, and painful, and fecal incontinence is not pressed cats can cause a spectrum of disease severity ranging from a uncommon. Most cats are usually bright, alert, responsive, and in nonclinical carrier state to mild, transient diarrhea; cholera-like ill - good body condition with a normal appetite. In my experience, T. ness; or prolonged, severe , life-threatening malabsorption syndrome. 38 foetus can also be cultured from the feces of asymptomatic cats, Laboratory detection of Cryptosporidium spp in naturally many of whom do not develop diarrhea. The presence of coexisting exposed cats with diarrhea is difficult, mainly because the organism enteric infections should be considered in cats with diagnosed T. foe -

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 15 Table 1 Performance Characteristics of Enzyme Immunoassays and Fecal Flotation for Diagnosis of Giardia in 344 Cats 33 Test Sensitivity (%) Speciﬁcity (%) False Negatives False Positives Flotation 85.3 99.7 51 Immunocard STAT! 72.7 99 93 XpecT Giardia/Crypto 79.4 99 73 SNAP Giardia ELISA 85.3 100 50 ProSpecT Giardia Microplate ELISA 91.2 99.4 32

tus infection. A fecal flotation and fecal ELISA or immunofluores - trophilic component. 45 The intestinal epithelium is frequently atten - cence assay for Giardia should be performed in cats infected with uated, and immunohistochemistry can be used to detect the tri - T. foetus because of the high incidence of coinfection with T. foetus chomonads on the surface epithelium and within crypts. and Giardia in cats. The following methods can be used to diagnose T. Ronidazole, a nitroimidazole that has been used for the preven - foetus infection: tion and treatment of histomoniasis in turkeys and for the treatment • Multiple direct wet preparations of diarrheic fecal specimens: of trichomoniasis in pigeons, is the drug of choice for the treatment Direct fecal smears are used to look for T. foetus trophozoites. The of T. foetus in cats. The currently recommended dosage of ronidazole sensitivity of direct fecal smear examination for diagnosis of T. is 30 mg/kg q12h for 10 days. Caution should be heeded in using foetus is relatively low in cats with spontaneous disease (14%). 43 T. ronidazole that contains various fillers, amino acids, vitamins, etc., foetus can be distinguished from Giardia based on morphology as these products have not been scrutinized in cats to date. Adverse and motility. Giardia trophozoites have a concave ventral disk and neurologic effects have been documented in cats given ronidazole at motility mimicking a falling leaf, whereas trichomonads are spin - 40 mg/kg bid, hence the recommendation for the lower dose. 46 The dle shaped, have an undulating membrane that courses the entire adverse effects (hyperesthesia, ataxia, weakness, and anorexia) can length of the body (Figure 5), and move in a more irregular and take up to 4 weeks to fully resolve after discontinuation of the drug. 46 jerky fashion. T. foetus does not have a cyst stage, underscoring Interestingly, metronidazole, another nitroimidazole with a chemical the limitations of fecal flotation for diagnosing this organism. structure very similar to that of ronidazole, has been demonstrated • Fecal cultures performed with an InPouch TF kit: A commer - to have in vitro efficacy against ronidazole in my laboratory; howev - cially available system marketed for diagnosis of T. foetus infec - er, the drug is not effective in vivo. 47 tion in cats (InPouch TF Feline, Biomed Diagnostics, White City, Long-term follow-up (clinical signs, fecal cultures, and PCR) of OR) is more sensitive (approximately 90% in my experience) than cats treated with ronidazole has revealed re-infections in a small the direct wet preparation. Approximately 0.05 g (less than a pep - number of cats. Some of these cats may have had persistent infec - percorn) of freshly voided feces can be placed in the InPouch for tions, underscoring the importance of conducting fecal culture or culture or , alternatively, a saline-moistened cotton-tipped swab PCR at the end of ronidazole administration to ensure successful can be placed in the rectum and then gently agitated in the eradication of the organism. Cats can have resolution of clinical signs InPouch for culture. The InPouch should be incubated in the dark despite showing evidence of infection on fecal culture or fecal PCR. in an upright position at 37 °C or room temperature and exam - There are no studies evaluating the natural transmission of T. ined every 48 hours for up to 10 days for motile trophozoites foetus in cats or the likelihood of transmission of the organism using a 20 × or 40 × objective. The media in the InPouch apparent - among cats in a multicat household. Transmission is most likely via ly do not support the growth of Giardia or P. hominis . the fecal –oral route or contaminated water or food. Litterboxes • Single -tube nested polymerase chain reaction (PCR) assay of should be cleaned on a consistent basis, and cages and litterboxes can DNA extracted from feces: A sensitive , specific , single-tube nest - be disinfected with quaternary ammonium compounds. The tropho - ed PCR assay for use with feline fecal specimens has been zoites are relatively labile and should be easily killed with most dis - described. 44 The PCR test is more sensitive than fecal culture and infectants. tested positive in 55% of cultures that were negative for T. foetus , To date, only a single case of human infection with T. foetus has even when feces were normal. been published in the literature. 48 The infection presented as epi - • Colonic mucosal biopsy: Colonic mucosal biopsy is not usually didymitis and meningoencephalitis following immunosuppression necessary to diagnose T. foetus infections in cats, and the procedure and peripheral blood stem cell transplantation. The paucity of docu - is typically performed when the above-mentioned diagnostic tests mented zoonotic cases might be a reflection of the poor host speci - are negative or appropriate medical therapy does not result in reso - ficity of T. foetus or the need for certain strains to exist in a severely lution of clinical signs. Histopathologic changes in colonic mucosal immunocompromised host. Nevertheless, because of the close asso - biopsy specimens from infected cats have predominantly consisted ciation between infected cats and their human companions, the of a lymphocytic and plasmacytic infiltrate with a significant neu - potential for zoonotic transmission should be considered.

16 Figure 5. Direct fecal preparation show - ing a T. foetus trophozoite. Note the Figure 6. Wright-Giemsa –stained fecal Figure 4. Bengal kitten diagnosed with T. undulating membrane coursing the preparation showing abundant hairpin- foetus infection. entire length of the body. shaped Clostridium spp endospores.

ENTEROPATHOGENIC BACTERIA Tetracycline use should be avoided due to the high incidence of Veterinarians are faced with a quandary when attempting to diagnose tetracycline resistance. 52 suspected bacteria-associated diarrhea in cats because the incidence of bacterial diarrhea is poorly documented and extremely variable and Clostridium difficile because putative infectious enteropathogens can commonly be isolat - C. difficile is a gram-positive, anaerobic, spore-forming bacillus. It ed from healthy cats. 19,21,49–51 It is plausible that cofactors are required to has been associated with diarrhea and enterocolitis in foals and adult enhance the pathogenicity of infectious agents or that species or strain horses as well as diarrhea in dogs and cats. However, C. diffi - differences account for the difference in clinical outcome. cile –associated diarrhea (CDAD) is less common in cats than in other species, and in a recent unpublished study, I documented an Clostridium perfringens incidence of 5% in diarrheic cats. Two toxins, A and B, are thought C. perfringens is an anaerobic, spore-forming, gram-positive bacillus to be primarily responsible for disease associated with the organism, that has been associated with outbreaks of acute, often severe , diar - although other toxins may also play a role. rhea in humans, horses, dogs, and cats. The elaboration of four CDAD is primarily diagnosed based on detection of toxin A or major toxins ( α, β, ι, and ε) is the basis for typing the organism into toxin B in fecal specimens via ELISA. Isolation of the organism alone five toxigenic phenotypes, A through E. C. perfringens enterotoxin is not sufficient for diagnosis because some strains are nontoxigenic . (CPE), a well-characterized virulence factor whose production is co- Metronidazole (10 mg/kg bid for approximately 7 days) is the thera - regulated with sporulation, was detected in nine of 62 diarrheic cats py of choice for cats with suspected CDAD. (14%) via fecal ELISA in my laboratory. In contrast, fecal ELISA test - ing for CPE was negative in 51 healthy cats. Cats with C. perfrin - Campylobacter Species gens –associated diarrhea frequently exhibit large-bowel diarrhea Campylobacter spp are small (0.2 to 0.5 × 0.5 to 5 µm), microaerophilic, characterized by increased frequency of bowel movements with gram-negative, curved rods that are members of the bacterial family tenesmus, fecal mucus , and hematochezia; however, clinical signs of Campylobacteraceae . Campylobacter spp that have been implicated in enteritis or enterocolitis are also commonly seen. 11 feline intestinal disease include Campylobacter jejuni, Campylobacter C. perfringens –associated diarrhea is currently diagnosed in coli, Campylobacter helveticus, and Campylobacter upsaliensis . Other cats based on detection of CPE in fecal specimens in conjunction enteric pathogens, such as parvovirus, Giardia , or Salmonella , may play with clinical signs of disease. Quantitative fecal culture and fecal a synergistic role. The isolation of Campylobacter spp from a diarrheic spore counts have been shown to be of poor diagnostic value, as the animal does not necessarily implicate Campylobacter as a cause of the organism is isolated from more than 80% of healthy cats , and there diarrhea. A recent unpublished study in my laboratory documented a is no correlation between spore counts (Figure 6) and detection of significantly higher incidence of Campylobacter spp in healthy, nondi - enterotoxin. There is one commercially available ELISA kit (Techlab arrheic cats (20%) versus diarrheic cats (11%). Inc., Blacksburg, VA) for detection of CPE in fecal specimens; how - Campylobacter -like organisms (CLOs) can be identified by ever, the performance characteristics of this assay have not been val - examining stained smears (Gram’s stain or Romanovsky-type stain) of idated in cats to date. fresh feces from the patient. The organism’s characteristic morpholo - Antibiotics that have been recommended for the treatment of gy (slender, curved rods with an “S” or seagull shape) allows it to be C. perfringens –associated diarrhea include ampicillin (22 mg/kg tid), identified relatively easily. The major limitation of direct examination metronidazole (10 mg/kg bid), and tylosin (15 mg/kg bid ). is that the procedure fails to differentiate between Campylobacter spp

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 17 or between related organisms , including Helicobacter spp and exposure, and antibiotic administration. Hematologic abnormalities Anaerobiospirillum spp. In addition, identification of CLOs is not suf - are variable and include nonregenerative anemia, lymphopenia, throm - ficient to warrant a diagnosis of Campylobacter -associated diarrhea, as bocytopenia, and neutropenia with a left shift. Toxic neutrophils are many healthy cats can harbor CLOs in their intestinal tract. found in animals with systemic disease and endotoxemia, findings sim - For optimal recovery of Campylobacter spp, feces or swabs of feces ilar to those documented with canine parvovirus. Fresh fecal speci - should be fresh or refrigerated at 4 °C and should be immediately placed mens should be placed onto one or more selective media, including into anaerobic transport medium before refrigeration. For isolation, the MacConkey agar, XLD agar, and brilliant green agar. For enrichment, use of a formulated selective medium containing antimicrobial agents selenite F, tetrathionate, or gram -negative broth is recommended. (e.g., Campy-CVA [Becton, Dickinson, and Co., Franklin Lakes, NJ], Intravenous fluid therapy is recommended depending on the which contains cefoperazone, vancomycin, and amphotericin B) gives severity of the diarrhea. Antibiotic therapy is typically indicated for better recovery than other direct-plating selective media. Micro- animals with concurrent signs of systemic infection or a history of aerophilic incubation conditions should be maintained, and the plates immunosuppression. Antibiotics reported to be effective against should be incubated at 37 °C or , when isolation of C. jejuni and C. coli Salmonella include fluoroquinolones, chloramphenicol, trimetho - is attempted, at 42 °C. Suspect colonies should be Gram’s stained and prim –sulfonamide, and amoxicillin. 1 subcultured to 5% sheep’s blood agar. Biochemical tests are then con - ducted to identify all CLOs isolated. A selective medium containing VIRAL ENTEROPATHIES cefoperazone should be used when attempting to isolate C. upsaliensis Feline viral enteritis is usually diagnosed in younger , unvaccinated because this organism is more resistant to cefoperazone than to animals. Signalment, history, clinical signs, and hematologic find - cephalothin. 53 Characterization of Campylobacter infections or mixed ings are important in ranking a viral etiology as a likely cause of an infections with Helicobacter and Campylobacter spp is best accom - animal’s diarrhea. plished using molecular structure-based diagnostics employing genus- and species-specific PCR, restriction fragment length polymorphism Feline Parvoviral Enteritis analysis, and 16S rRNA sequence analysis. Feline parvoviral enteritis (feline panleukopenia) is caused by a par - Although diarrhea produced by Campylobacter organisms is usu - vovirus distinct from CVP-2b, although this strain can infect cats ally self-limiting, the zoonotic potential of the organism often necessi - and cause disease. 56 Feline parvovirus has become an uncommon tates medical therapy. It is now recognized that Campylobacter spp are disease because of routine vaccination; however, outbreaks are occa - a leading cause of enteric disease in people and that diarrheic and non - sionally seen in unvaccinated animals, particularly feral populations diarrheic animals can serve as sources of infection for humans. 54 The and in catteries. The clinical signs are similar to those described for drugs of choice are the macrolides (e.g., erythromycin at 10 to 15 dogs with parvoviral enteritis. mg/kg tid) or quinolones (e.g., enrofloxacin at 5 mg/kg bid). However, Diagnosis is based on the history, physical examination find - due to the high rate of mutational resistance Campylobacter spp have ings, results of a hemogram (neutropenia), and fecal ELISA. The to the quinolones —a resistance that sometimes occurs while animals ELISA test used to detect canine parvovirus has been reported to are being treated —quinolones are not the drugs of choice. cross-react with feline parvovirus. Erythromycin is the drug of choice, despite the associated gastroin - Treatment is supportive and similar to that for other severe, testinal side effects. The duration of Campylobacter excretion in infect - acute infectious enteropathies. Intravenous fluid and electrolyte ed cats can be as long as 4 months , and infected animals should be therapy is indicated, with particular attention given to potassium quarantined away from children during this period. repletion. Dextrose solution (2.5% to 5%) is added to the IV fluids if the animal is hypoglycemic (e.g., septic shock). Plasma or colloids Salmonella Species (dextran 70 or hetastarch) are indicated if the serum albumin con - Salmonella are primarily motile, non–spore-forming, gram -negative centration drops below 2.0 g/dl . Antibiotics are administered to aerobic bacilli of the family Enterobacteriaceae. More than 2, 000 febrile or severely neutropenic cats. If the animal is neutropenic but described serotypes of Salmonella have been associated with human and afebrile, the administration of a first-generation cephalosporin is animal disease. Salmonella spp are one of the most common causes of reasonable. Cats in septic shock should be treated with a broad - human food-borne illness, with an estimated 1.4 million cases occurring spectrum aerobic and anaerobic antibiotic (e.g., ampicillin plus annually in the United States. 55 Clinical salmonellosis in cats is rare, amikacin). Antiemetics such as prochlorperazine, metoclopramide, although prevalences are higher in puppies and kennel populations. or dolasetron (0.5 to 1 mg/kg q12 –24h ) are indicated if the vomit - Signs of clinical salmonellosis in cats include fever, anorexia, ing is intractable. Metoclopramide is most effective when adminis - diarrhea (which may be bloody), vomiting, and weight loss. Most tered as a constant-rate infusion at a dose of 1 mg/kg/day . Gastric

Salmonella -infected cats are asymptomatic, although some animals protectants , including H 2-receptor antagonists and sucralfate , are may manifest clinical signs of sepsis. indicated if there is evidence of secondary esophagitis. Broad -spec - The traditional diagnosis of salmonellosis is made based on isola - trum anthelmintics to treat concurrent intestinal parasites should tion of the organism in conjunction with clinical signs and assessment be administered when the cat is no longer vomiting. Most cats can of potential risk factors such as hospitalization, age, environmental be gradually weaned onto a commercially available, highly

18 digestible diet; however, the presence of intractable vomiting might technique. Can J Comp Med 1980;44(2):148-157. warrant the administration of total parenteral nutrition. 31. Boone JH, Wilkins TD, Nash TE. Techlab and Alexon Giardia enzyme-linked immunosorbent assay kits detect cyst wall protein 1. J Clin Microbiol 1999;37:611-614. REFERENCES 32. Mekaru SR, Marks SL, Felley AJ, et al . Comparison of direct immunofluores - 1. Swihart EV. Chronic diarrhea in kittens: ending the neverending story. Vet cence, immunoassays, and fecal flotation for detection of Cryptosporidium Forum 1997:52. spp. and Giardia spp. in naturally exposed cats in 4 Northern California ani - 2. Wolf AM. Diarrhea in the cat. Semin Vet Med Surg (Small Anim) 1989;4:212-218. mal shelters. J Vet Intern Med 2007;21(5):959-965. 3. Hurley K. Unpublished data, 2003. 33. Scorza AV, Lappin MR. Metronidazole for the treatment of feline giardiasis. 4. Marks SL, Kather EJ. Antimicrobial susceptibilities of canine Clostridium dif - J Feline Med Surg 2004;6(3):157-160. ficile and Clostridium perfringens isolates to commonly utilized antimicrobial 34. Keith CL, Radecki SV, Lappin MR. Evaluation of fenbendazole for treatment drugs. Vet Microbiol 2003;94:39-45. of Giardia infection in cats concurrently infected with Cryptosporidium 5. Greene CE. Enteric bacterial infections . In: Greene CE, ed. Infectious Diseases parvum . Am J Vet Res 2003;64(8):1027-1029. of the Dog and Cat. 2nd ed. Philadelphia: WB Saunders ; 1998:243-245. 35. Scorza AV, Radecki SV, Lappin MR. Efficacy of a combination of febantel, 6. Foley JE, Orgad U, Hirsh DC, et al. Outbreak of fatal salmonellosis in cats fol - pyrantel, and praziquantel for the treatment of kittens experimentally infect - lowing use of a high-titer modified-live panleukopenia virus vaccine. JAVMA ed with Giardia species. J Feline Med Surg 2006;8(1):7-13. 1999;214:67-70, 43-44. 36. Benyacoub J, Pérez PF, Rochat F, et al. Enterococcus faecium SF68 enhances the 7. Dow SW, Jones RL, Henik RA, et al. Clinical features of salmonellosis in cats: immune response to Giardia intestinalis in mice. J Nutr 2005;135(5):1171-1176. six cases (1981-1986). JAVMA 1989;194:1464-1466. 37. Besirbellioglu BA, Ulcay A, Can M, Erdem H. Saccharomyces boulardii and 8. Tauni MA, Osterlund A. Outbreak of Salmonella typhimurium in cats and humans infection due to Giardia lamblia . Scand J Infect Dis 2006;38(6-7):479-481. associated with infection in wild birds. J Small Anim Pract 2000;41:339-341. 38. Current WL. Cryptosporidiosis. JAVMA 1985;187:1334-1337. 9. Fox JG, Claps M, Beaucage CM. Chronic diarrhea associated with 39. Sargent KD, Morgan UM, Elliot A, et al. Morphological and genetic charac - Campylobacter jejuni infection in a cat. JAVMA 1986;189:455-456. terization of Cryptosporidium oocysts from domestic cats. Vet Parasitol 10. Fleming MP. Association of Campylobacter jejuni with enteritis in dogs and 1998;77:221-227. cats. Vet Rec 1983;113:372-374. 40. Arrowood MJ, Sterling CR. Comparison of conventional staining methods 11. Foley J, Pedersen NC, Hirsch DC. An outbreak of Clostridium perfringens and monoclonal antibody-based methods for Cryptosporidium oocyst detec - enteritis in a cattery of Bengal cats and experimental transmission to specif - tion. J Clin Microbiol 1989;27:1490-1495. ic pathogen free cats. Feline Pract 1996;24:31-35. 41. Gookin JL, Breitschwerdt EB, Levy MG, et al. Diarrhea associated with tri - chomonosis in cats. JAVMA 1999;215(10):1450-1454. 12. Weese JS, Weese HE, Bourdeau TL, et al. Suspected Clostridium difficile -asso - ciated diarrhea in two cats. JAVMA 2001;218:1436-1439, 1421. 42. Gookin JL, Stebbins ME, Hunt E, et al. Prevalence of and risk factors for feline Tritrichomonas foetus and Giardia infection. J Clin Microbiol 13. Kirkpatrick CE, Farrell JP. Feline giardiasis: observations on natural and 2004;42(6):2707-2710. induced infections. Am J Vet Res 1984;45:2182-2188. 43. Gookin JL, Foster DM, Poore MF, et al. Use of a commercially available cul - 14. Kirkpatrick CE, Laczak JP. Giardiasis in a cattery. JAVMA 1985;187: 161-162. ture system for diagnosis of Tritrichomonas foetus infection in cats. JAVMA 15. Gookin JL, Levy MG, Law JM, et al. Experimental infection of cats with 2003;222:1376-1379. Tritrichomonas foetus . Am J Vet Res 2001;62:1690-1697. 44. Gookin JL, Birkenheuer AJ, Breitschwerdt EB, Levy MG. Single-tube nested 16. Lappin MR, Dowers K, Edsell D, et al. Cryptosporidiosis and inflammatory PCR for detection of Tritrichomonas foetus in feline feces. J Clin Microbiol bowel disease in a cat. Feline Pract 1997;25:10-13. 2002;40(11):4126-4130. 17. Current WL. Cryptosporidiosis. JAVMA 1985;187:1334-1338. 45. Yaeger MJ, Gookin JL. Histologic features associated with Tritrichomonas 18. Kirkpatrick CE, Dubey JP. Enteric coccidial infections. Isospora, Sarcocystis, foetus -induced colitis in domestic cats. Vet Pathol 2005;42(6):797-804. Cryptosporidium, Besnoitia, and Hammondia . Vet Clin North Am Small Anim 46. Rosado TW, Specht A, Marks SL. Neurotoxicosis in 4 cats receiving ronida - Pract 1987;17:1405-1420. zole. J Vet Intern Med 2007;21(2):328-331. 19. Kaneuchi C, Shishido K, Shibuya M, et al. Prevalences of Campylobacter , 47. Kather EJ, Marks SL, Kass PH. Determination of the in vitro susceptibility of Yersinia , and Salmonella in cats housed in an animal protection center. feline Tritrichomonas foetus to 5 antimicrobial agents. J Vet Intern Med Nippon Juigaku Zasshi 1987;49:499-506. 2007;21(5):966-970. 20. Hill SL, Cheney JM, Taton-Allen GF, et al. Prevalence of enteric zoonotic 48. Okamoto S, Wakui M, Kobayashi H, et al. Trichomonas foetus meningoen - organisms in cats. JAVMA 2000;216:687-692. cephalitis after allogeneic peripheral blood stem cell transplantation. Bone 21. Spain CV, Scarlett JM, Wade SE, et al. Prevalence of enteric zoonotic agents Marrow Transplant 1998;21(1):89-91. in cats less than 1 year old in central New York State. J Vet Intern Med 49. Hald B, Madsen M. Healthy puppies and kittens as carriers of Campylobacter 2001;15:33-38. spp., with special reference to Campylobacter upsaliensis. J Clin Microbiol 22. Davis CE: Fresh vs preserved stool specimens for detection of parasites. 1997;35:3351-3352. JAMA 1996;275(4):326-327. 50. Johnston KL, Swift NC, Forster-van Hijfte M, et al. Comparison of the bac - 23. Gookin JL, Foster DM, Poore MF, et al. Use of a commercially available cul - terial flora of the duodenum in healthy cats and cats with signs of gastroin - ture system for diagnosis of Tritrichomonas foetus infection in cats. JAVMA testinal tract disease. JAVMA 2001;218:48-51. 2003;222:1376-1379. 51. Madewell BR, Bea JK, Kraegel SA, et al. Clostridium difficile : a survey of fecal 24. Koutz FR: A comparison of flotation solutions in the detection of parasite carriage in cats in a veterinary medical teaching hospital. J Vet Diagn Invest ova in feces. Am J Vet Res 1941;1:95-100. 1999;11:50-54. 25. Faust EC, Sawitz W, Tobie J, et al: Comparative efficiency of various tech - 52. Marks SL, Kather EJ: Antimicrobial susceptibilities of canine Clostridium dif - niques for the diagnosis of protozoa and helminths in feces. ficile and Clostridium perfringens isolates to commonly utilized antimicrobial J Parasitology 1939;25:241-262. drugs. Vet Microbiol 2003;94:39-45. 26. Alcaino HA, Baker NF: Comparison of two flotation methods for detection 53. Aspinall ST, Wareing DR, Hayward PG , et al: A comparison of a new campy - of parasite eggs in feces. JAVMA 1974;164(6):620-622. lobacter selective medium (CAT) with membrane filtration for the isolation 27. Faust EC, D’Antoni J, Odom V, et al: A critical study of clinical laboratory of thermophilic campylobacters including Campylobacter upsaliensis. J Appl techniques for the diagnosis of protozoan cysts and helminth eggs in feces. Bacteriol 1996;80:645-650. Am J Trop Med 1938;18:169-183. 54. Bruce D, Zochowski W, Fleming GA: Campylobacter infections in cats and 28. David ED, Lindquist WD: Determination of the specific gravity of certain dogs. Vet Rec 1980;107:200-201, 8-30. helminth eggs using sucrose density gradient centrifugation. J Parasitol 55. Mead PS, Slutsker L, Dietz V , et al: Food-related illness and death in the 1982;68(5):916-919. United States. Emerg Infect Dis 1999;5:607-625. 29. Egwang TG, Slocombe JO: Efficiency and sensitivity of techniques for recov - 56. Ikeda Y, Nakamura K, Miyazawa T, et al. Feline host range of canine par - ering nematode eggs from bovine feces. Can J Comp Med 1981;45(3):243-248. vovirus: Recent emergence of new antigenic types in cats. Emerg Infect Dis 30. O’Grady MR, Slocombe JO: An investigation of variables in a fecal flotation 2002;8:341-346.

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 19 Cats with Colitis: Pathogenesis, Diagnosis, and Therapy

CRITERIA FOR DEFINING Immunologic Criteria FELINE COLITIS IBD has been defined immunologically by the innate and adaptive Feline colitis may be defined using clinical, pathogenetic, imaging, response of the mucosa to GI antigens. Although the precise histologic, immunologic, pathophysiologic, and/or genetic criteria. immunologic events of canine and feline IBD remain to be deter - mined, a prevailing hypothesis for the development of IBD is the loss Clinical Criteria of immunologic tolerance to the normal bacterial flora or food anti - The colitis form of inflammatory bowel disease (IBD ) has been gens, leading to abnormal T-cell immune reactivity in the gut defined clinically as a spectrum of gastrointestinal (GI) disorders of microenvironment. Genetically engineered animal models (e.g., unknown etiology associated with chronic inflammation of the interleukin [IL]-2, IL-10, and T-cell receptor knockouts) that devel - colon. A clinical diagnosis of IBD is considered only if affected cats op IBD involve alterations in T-cell development and/or function , have (1) persistent (>3 weeks ’ duration) GI signs (anorexia, diarrhea, suggesting that T-cell populations are responsible for the homeosta - hematochezia, vomiting, weight loss, feces containing mucus), (2) tic regulation of mucosal immune responses. Immunohistochemical failure to respond to symptomatic therapies (parasiticides, antibi - studies of canine and feline IBD have demonstrated an increase in otics, GI protectants) alone, (3) failure to document other causes of the T-cell population of the lamina propria, including CD3+ cells colitis by thorough diagnostic evaluation, and (4) histologic diagno - and CD4+ cells, as well as macrophages, neutrophils, and IgA-con - sis of benign colonic inflammation. Large-bowel forms of IBD have taining plasma cells. Many of the immunologic features of canine been reported in both dogs and cats, although large-bowel IBD and feline IBD can be explained as indirect consequences of mucos - appears to be more prevalent in dogs . al T-cell activation. Enterocytes are also likely involved in the immunopathogenesis of Pathogenetic Criteria IBD. Enterocytes are capable of behaving as antigen-presenting cells, Known causes of colonic diarrhea—bacterial, parasitic, or fungal and interleukins (e.g., IL-7 , IL-15) produced by enterocytes during acute infection; food sensitivity reaction; and colonic neoplasia—should inflammation activate mucosal lymphocytes. Upregulation of toll-like first be considered . Most current hypotheses on the pathogenesis of receptor 4 and toll-like receptor 2 expression contributes to the innate IBD hold that the gut has sustained reactivity to endogenous bacter - immune response of the colon. Thus, the pathogenesis and pathophysi - ial and/or food antigens. ology of IBD appear to involve the activation of a subset of CD4+ T cells within the intestinal epithelium that overproduce inflammatory Histologic Criteria cytokines with concomitant loss of a subset of CD4+ T cells and their IBD has been defined histologically by the type of inflammatory infil - associated cytokines. trate (eosinophilic, granulomatous, lymphocytic, neutrophilic, plas - macytic), associated mucosal pathology (crypt collapse, fusion, villus Pathophysiologic Criteria atrophy), distribution of the lesion (focal or generalized, superficial or Immune Responses deep), severity (mild, moderate, severe), mucosal thickness (mild, A generic inflammatory response involving cellular elements (B and moderate, severe), and topography (cecum, ascending colon, descend - T lymphocytes, plasma cells, macrophages, and dendritic cells), ing colon). Subjective interpretation of large-bowel IBD lesions has secretomotor neurons (e.g., vasoactive intestinal polypeptide , sub - made it difficult to compare tissue findings between pathologists. stance P, cholinergic neurons), cytokines and interleukins, and Subjectivity in histologic assessments has led to the development of inflammatory mediators (e.g., leukotrienes, prostanoids, reactive several IBD grading systems. oxygen metabolites, nitric oxide, 5-hydroxytryptamine [HT ], inter -

20 feron [IFN ]- α, tumor necrosis factor [TNF]– γ, platelet-activating one or more subtle abnormalities. One review of canine and feline factor) is typical of canine and feline IBD . There are many similari - IBD reported several hematologic abnormalities , including mild ties between the inflammatory response of the small and large intes - anemia, basophilia, eosinopenia, eosinophilia, leukocytosis, lympho - tine, but recent immunologic studies suggest that IBD of the canine cytopenia, monocytosis, and neutrophilia with and without a left and feline colon may be more of a type 1 helper T-cell (Th1) shift . The same study reported several biochemical abnormalities , response with elaboration of IL-2, IL-12, IFN -α, and TNF- γ. including increased activities of serum alanine aminotransferase and alkaline phosphatase, hyperamylasemia, hyperglobulinemia, hyper - Motility Changes glycemia, hypoalbuminemia, hypocholesterolemia, hypokalemia, Experimental studies of the colitis form of IBD have shown that and hypoproteinemia . No consistent abnormality in the complete many of the clinical signs are related to motor abnormalities of the blood count or serum chemistry has been identified. GI tract. Inflammation impairs regulation of the colonic motility A scoring index for disease activity in canine IBD was recently patterns at several levels (i.e., enteric neurons, interstitial cells of developed that relates severity of clinical signs to serum acute-phase Cajal, circular smooth muscle cells ). protein (C-reactive protein [CRP], serum amyloid A) concentra - tions. This IBD activity index assigns levels of severity to each of sev - Genetic Criteria eral gastroenterologic signs (e.g., anorexia, diarrhea, vomiting, IBD may be defined by genetic criteria in several animal species. weight loss), and it appears to Crohn’s disease and ulcerative colitis are more common in certain be a reliable index of mucosal human genotypes, and a mutation in the nucleotide-binding inflammation in IBD. In- Complete blood oligomerization domain 2 gene ( NOD2 ) has been found in a sub - terestingly, both the activity counts, serum group of patients with Crohn’s disease. Genetic influences have not index and serum concentra - yet been identified in feline IBD, but certain breeds (e.g., Siamese tions of CRP improve with chemistries, and cats) appear to be at increased risk for the disease. successful treatment, suggest - ing that serum CRP is suitable urinalyses are CLINICAL EXAMINATION for the laboratory evaluation often normal in The clinical signs of large-bowel IBD are those of a large- of therapy in canine IBD. bowel–type diarrhea (i.e., marked increased frequency of defeca - Other acute-phase proteins mild cases of tion, reduced fecal volume per defecation, blood pigments and were less specific than CRP. mucus in feces, tenesmus ). Anorexia, vomiting, and weight loss are One important caveat that large-bowel IBD. occasionally reported in cats with severe IBD of the colon or con - should be emphasized is that current IBD of the stomach and/or small intestine. Clinical signs altered CRP is not prima facie evidence of GI inflammation. usually wax and wane. A transient response to symptomatic thera - Concurrent infections or other inflammatory conditions could cause py may occur during the initial stages of IBD. As the condition pro - an acute-phase response, including CRP, in affected patients. The gresses, diarrhea gradually increases in frequency and intensity and value of clinical scoring systems and serum biomarkers has not yet may become continuous. In some cases , the first bowel movement been established in cats. of the day may be normal or nearly normal, whereas successive bowel movements are reduced in volume and progressively more TREATMENT urgent and painful. During severe episodes, anorexia, depression, Dietary Therapy and mild fever may occur. As mentioned previously, a prevailing hypothesis for the develop - There does not appear to be any sex predilection for developing ment of IBD is the loss of immunologic tolerance to the normal IBD, but age may be a risk factor , with IBD appearing more frequent - bacterial flora or food antigens. Accordingly, dietary modification ly in middle-aged animals (mean age : approximately 6 years ; range: 6 may prove useful in the management of feline IBD. Several nutri - months to 20 years). Purebred cats appear to be at greater risk. Cats tional strategies have been proposed , including novel proteins, more often present with an upper-GI form of IBD, whereas dogs are hydrolyzed diets, and antioxidant diets. Of these strategies, some at risk for both small - and large-bowel IBD. evidence-based medicine has emerged for the use of novel protein, Physical examination is unremarkable in most cases. Thickened hydrolyzed, and fiber-supplemented diets. bowel loops may be detected during abdominal palpation if the small Food sensitivity reactions were suspected or documented in bowel is concurrently involved. Digital examination of the anorectum 49% of cats presented because of gastroenterologic problems (with or may evoke pain or reveal irregular mucosa, and blood pigments and without concurrent dermatologic problems) in a prospective study mucus may be evident on the exam glove. of adverse food reactions in cats. Beef, wheat, and corn gluten were the primary ingredients responsible for food sensitivity reactions in DIAGNOSIS that study, and most of the cats responded to the feeding of a chick - Complete blood counts, serum chemistries, and urinalyses are often en- or venison-based selected-protein diet for a minimum of 4 normal in mild cases of large-bowel IBD. Chronic cases may have weeks. The authors concluded that adverse reactions to dietary sta -

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 21 ples are common in cats with chronic GI problems and that these medicine in support of probiotic therapy in the colitis form of IBD in reactions can be successfully managed by feeding selected-protein cats is inadequately reported. diets. Further support for this concept comes from studies in which gastroenterologic or dermatologic clinical signs were significantly Antiinflammatory/Immunomodulatory Therapy improved by the feeding of novel proteins. Metronidazole Evidence is accruing that hydrolyzed diets may be useful in the Metronidazole (10 to 20 mg/kg PO two to three times a day) has been nutritional management of canine IBD. The conceptual basis of the used in the treatment of mild to moderate cases of large-bowel IBD in hydrolyzed diet is that oligopeptides are of insufficient size and both dogs and cats. This drug has been used either as a single agent or structure to induce antigen recognition or presentation. In one in conjunction with 5-aminosalicylates or glucocorticoids. preliminary study, cats with IBD showed significant improvement Metronidazole is believed to have several beneficial properties, includ - following the feeding of a ing antibacterial, antiprotozoal, and immunomodulatory effects. Side Following completion hydrolyzed diet (although they effects include anorexia, hypersalivation, and vomiting at recommend - had failed to respond to the ed doses and neurotoxicity (i.e., ataxia, head tilt, nystagmus, seizures) of drug therapy, many feeding of a novel protein ). at higher doses. Side effects usually resolve with discontinuation of Clinical improvement could therapy , but diazepam may accelerate recovery . animals are able to not be attributed solely to the maintain remission hydrolyzed nature of the pro - Glucocorticoids tein source because the test Antiinflammatory doses of prednisone or prednisolone (1 to 2 of signs with dietary diet had other modified fea - mg/kg/day PO) may be used as adjunctive therapy to dietary modi - tures (i.e., high digestibility, fication in feline and canine IBD. Prednisone and prednisolone are management alone. cornstarch rather than intact the most frequently used of the glucocorticoids because both have grains, medium-chain triglyc - short durations of action, are cost-effective, and are widely available. erides, an altered omega-6 :omega -3 ratio ). Additional studies will be Equipotent doses of dexamethasone are equally effective but may required to ascertain the efficacy of this nutritional strategy in the have more deleterious effects on brush border enzyme activity. management of IBD. Prednisone should be used for 2 to 4 weeks depending on the sever - ity of the clinical signs. Higher doses of prednisone (e.g., 2 to 4 Antibiotics mg/kg/day PO) may be needed to control severe forms of Some IBD cases are initiated by true enteric pathogens, while others eosinophilic colitis or hypereosinophilic syndrome in cats. are complicated by small intestinal bacterial overgrowth. In addi - Combination therapy with azathioprine, metronidazole, or sul - tion, some IBD cases may show short-term responsiveness to one or fasalazine may reduce the overall dosage of prednisone needed to more antibiotics (e.g., tylosin, metronidazole, oxytetracycline ). achieve remission of clinical signs. As with sulfasalazine, the dose of glucocorticoid may be reduced by 25% at 1- to 2-week intervals Probiotics while hopefully maintaining remission with dietary modification. Probiotics are living organisms with low or no pathogenicity that Because of steroid side effects and suppression of the hypothal - exert beneficial effects (e.g., stimulation of innate and acquired amic –pituitary –adrenal axis, several alternative glucocorticoids have immunity) on the health of the host. The gram-positive commensal been developed that have excellent topical (i.e., mucosal) antiinflam - lactic acid bacteria (e.g., lactobacilli) have many beneficial health matory activity but are significantly metabolized during first-pass effects, including enhanced lymphocyte proliferation, innate and hepatic metabolism. Budesonide has been used for many years as an acquired immunity, and antiinflammatory cytokine production. inhaled medication for asthma, and an enteric-coated form of the Lactobacillus rhamnosus GG, a bacterium used in the production of drug is now available for treatment of IBD in humans and animals. yogurt, is effective in preventing and treating diarrhea, recurrent There is little evidence supporting the use of this medication in Clostridium difficile infection, primary rotavirus infection, and atopic canine or feline IBD, but a dosage of 1 mg/day has been used in both dermatitis in humans. L. rhamnosus GG has been safely colonized in dogs and cats with some success in anecdotal cases. the canine GI tract, although probiotic effects in the canine intestine have not been firmly established. The probiotic organism Cyclosporine Enterococcus faecium (SF68) has been safely colonized in the canine Cyclosporine has been used in renal transplantation patients for its GI tract, and it has been shown to increase fecal IgA content and cir - inhibitory effect on T-cell function. More recently, cyclosporine has culating mature B (CD21+/major histocompatibility complex [MHC] been used in a number of immune-mediated disorders, including class II+) cells in young puppies. Anecdotal evidence suggests that immune-mediated hemolytic anemia, keratoconjunctivitis sicca, and this probiotic may be useful in the prevention or treatment of canine perianal fistula (anal furunculosis). Anecdotal reports suggest that GI disease. This organism may, however, enhance Campylobacter cyclosporine (3 to 7 mg/kg PO q12h ) may be useful in the treatment jejuni adhesion and colonization of the canine intestine, perhaps con - of some cases of refractory IBD. Evidence-based studies will be ferring carrier status on colonized dogs. The role and evidence-based needed to establish efficacy, but anecdotal experience would suggest

22 that cyclosporine may be useful in some of the more difficult or many animals are able to maintain remission of signs with dietary refractory cases of IBD. management alone. Treatment failures are uncommon and are usu - ally due to (1) incorrect diagnosis (it is especially important to rule Chlorambucil out alimentary lymphosarcoma), (2) irreversible mucosal lesions Chlorambucil (2 mg/m 2 PO every other day) has been used in place of such as fibrosis, (3) poor client compliance with appropriate azathioprine in some difficult or refractory cases of feline IBD. drug/dietary recommendations, (4) use of inappropriate drugs or nutritional therapy, and (5) presence of concurrent disease such as Behavioral Modification hepatobiliary disease. The prognosis for cure of IBD is poor, and IBD and irritable bowel syndrome very likely have underlying relapses should be anticipated. behavioral components. Abnormal personality traits and potential environmental stressors were identified in 38% of dogs in one study . RECOMMENDED READING Multiple factors were present in affected households; these factors 1. Guilford WG. The gastrointestinal tract and adverse reactions to food. In August JR (ed). Consultations in Feline Internal Medicine . Philadelphia: WB included aggression, house construction, noise sensitivity, reloca - Saunders; 2000:113-117. tion, separation anxiety, submissive urination, and travel . The role of 2. Jergens AE, Schreiner CA, Frank DE, et al. A scoring index for disease activi - behavior in the pathogenesis and therapy of feline GI disorders ty in canine inflammatory bowel disease. J Vet Intern Med 2003;17:291. 3. Ridyard AE, Nuttall TJ, Else RW, et al. Evaluation of Th1, Th2 and immuno - remains largely unexplored. suppressive cytokine mRNA expression within the colonic mucosa of dogs with idiopathic lymphocytic-plasmacytic colitis. Vet Immunol Immunopathol PROGNOSIS 2002;86: 205. 4. Washabau RJ, Holt DE. Pathophysiology of gastrointestinal disease. In Slatter Most reports indicate that the short-term prognosis for control of D (ed) Textbook of Veterinary Surgery . 3rd ed. Philadelphia: WB Saunders; IBD is good to excellent. Following completion of drug therapy, 2003:530-552.

Hot Topics in Feline Medicine, 2008 NAVC/WVC Proceedings 23 This information has not been peer reviewed and does not necessarily reflect the opinions of, nor constitute or imply endorsement or recommendation by, the Publisher. The Publisher is not responsible for any data, opinions, or statements provided herein.

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