Introduction

Long-term steroid use has been discouraged in small animal medicine because of its many side effects.^1,2 Side effects of glucocorticoid administration in cats include polyuria, polydipsia, polyphagia, alopecia, muscle wasting, redistribution of body fat stores, hepatomegaly, thinning of the skin, and increased susceptibility to infections.¹ Glucocorticoid use has been shown to have a profound effect on endocrine function outside the hypothalamic-pituitary-adrenal axis, and prolonged use of long-term steroid therapy is attributed to the development of diabetes mellitus and hyperadrenocorticism.^2–4

Cats are reportedly more resistant to the effects of corticosteroids than canine patients, but steroid-induced hepatopathy has been described in cats receiving corticosteroid therapy.¹ A study of 14 cats by Lowe et al. in 2008 showed changes in mean WBC, neutrophil, monocyte, lymphocyte, and eosinophil counts. Serum biochemical impacts of chronic steroid treatment are unclear. Consistent increases were reported in serum concentrations of albumin, glucose, triglycerides, and cholesterol as well as varying degrees of changes in glycogen deposition, consistent with a steroid hepatopathy.¹ These cats were given oral immunosuppressive doses of steroids daily for 56 days. Another study treated four cats weekly for 4 wk with 20 mg of repositol methylprednisolone.⁴ Clinicopathologic abnormalities were inconsistent and minor.

Long-term study of nonimmunosuppressive, parenteral methylprednisolone acetate (MPA) use in cats has not been reported. We have access to a unique database in which a number of cats have received 10 mg of injectable MPA regularly for multiple years. Using this data, we looked at how clinical application of long-term methylprednisolone use affected blood parameters. We expected to see some changes in the serum biochemistry and complete blood count (CBC).

Materials and Methods

All records were taken from D.E.L.T.A. Rescue. Feline patients were selected based on the length of treatment (at least 3 yr), complete records, and the fact that they were at the time of the study still alive and housed in the facility. Every animal studied had a CBC/chemistry/T4 panel performed from the same diagnostic laboratory yearly. All blood work was sent to an outside diagnostic laboratory^a. The large national laboratory has been using the same instrumentation since before our data set was examined. The chemistry was performed on an Olympus chemistry analyzer, the CBC was performed on an Advia hematology analyzer, and the T4 was analyzed with a Microgenesis T4 assay. The reference intervals fall within the 95% confidence interval with two standard deviations.

Twenty-five cats were treated with MPA given subcutaneously for at least 3 yr. The doses the animals received ranged from 1 to 2 mg/kg depending on weight. Doses were given at 10 mg “per cat” regardless of weight. Cats included in the study population ranged in age from 4 to 14 yr old. Eleven of the cats were female, and 14 of the cats were male. Eleven cats were under 5 yr of age, and the remaining 14 over 5 yr of age. Breeds studied were domestic longhair, domestic shorthair, and domestic mediumhair. There were no purebred cats in the study. All 25 cats were treated for stomatitis and none had any pre-existing conditions. Although three of these animals with stomatitis were diagnosed with eosinophilic/plasmacytic stomatitis via biopsy and histopathologic examination, the rest of them were diagnosed solely on clinical examination. Cats had their mouths examined for stomatitis every 3 wk. A full physical exam was not typically performed. MPA administered was based on clinical symptoms. Any active lesion was treated. Using this data, we compared the pretreatment blood work with the blood work after the first, second, and third year of treatment. All blood work analyzed was sent to the same lab, ensuring continuity of the results. The age of the animal at the start of treatment was examined, and the number of MPA injections given over the 3 yr was counted. The same formulation of MPA^b was used for all treatments. All cats had been spayed or neutered prior to the start of the treatments.

The age range for animals at the beginning of treatment was from 9 mo to 11 yr. The range of the number of MPA injections given over a 3 yr period was from 24 to 68 with a mean of 39.1 and median of 38.

Results

The statistical model analysis of variance with repeated measures^c was used to ascertain if there was a difference between pretreatment blood work and 3 yr posttreatment blood work. The significance marker was P value < .05. Examined blood work included CBC/chemistry/T4 for each animal. Results are shown in Table 1. There were four statistically significant changes in the laboratory results (i.e., albumin, calcium, mean corpuscular hemoglobin, and mean corpuscular volume). However, all four values remained within the reference intervals. The means for triglycerides increased in each successive year (57–136 mg/dL) but were within the clinical normal reference interval. The means for amylase were also within the reference interval (100–1200 U/L), but in year three, there were eight cats (32%) who had values outside the reference interval. A Pearson correlation (r) and P values were performed^d and showed no correlation with regard to the number of injections of MPA given (r = 0.115, P = .618) or the age of the animals (r = 0.048, P = .837) with the high amylase. All other values showed no significant changes and were within the normal range. Two animals developed hyperthyroidism after 2 (22 MPA doses) and 3 (15 MPA doses) yr, respectively, of treatment with MPA. One cat developed diabetes mellitus 5 yr after chronic treatment with MPA.

TABLE 1 Lab Work Analysis Pre- and 3 Years Post-Treatment

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Discussion

Treatment of plasma cell stomatitis-pharyngitis includes prednisone, methylprednisolone acetate, megestrol acetate, and triamcinolone.⁵ Parenteral doses of MPA for cats have been documented up to 20 mg (average 10 mg) depending on breed, size, severity of condition, and response.⁶ Label information for MPA includes directions that the dose may be repeated at weekly intervals. The cats we studied received 10 mg MPA per injection.

The physiologic and biologic effects of glucocorticoid therapy have been well documented.^2,7 Cats have been shown to be resistant to the adverse effects of exogenous corticosteroid administration.⁴ Although there have been reports of glucose intolerance, iatrogenic hyperadrenocorticism, and skin fragility, these are rare in veterinary literature.^4,8 However, cats, like humans, have been shown to develop congestive heart failure related to corticosteroid administration.^8,9

Previous studies on the effects of steroids on the CBC have varied results. In two separate studies in which cats were treated with prednisone daily for 2 wk, no effects were seen in the CBC.^10,11 In another study in which cats received three sequential, nonimmunosuppressive daily doses of dexamethasone, there was a significant increase in leukocytes.¹² Another study of 14 cats given immunosuppressive doses of prednisolone for 56 days showed increases in the mean WBC count, neutrophil count, and monocyte count and decreases in mean lymphocyte count and eosinophil count.¹

Several studies have shown the effects of glucocorticoid therapy on feline serum chemistry.^1,4,13 Two studies showed increased values in common with our study. One study found consistent increases in serum concentrations of albumin, glucose, triglycerides, and cholesterol, which correlate with our findings of increases in the albumin level (although our values remained within the reference interval).¹ Another study showed an increase in amylase, albumin, and bicarbonate after a single injection of MPA, also correlating with our finding of an increase in albumin.¹⁴ The study also correlates with our increase in amylase; we had eight cats who had values out of the reference interval by year 3.

We looked at the eight cats with high amylase and found no correlation regarding the age of the animal or the number of injections received. Although the mechanism of this is unclear, the increase in amylase merits further study. Unlike the findings in dogs, amylase is not useful in diagnosing pancreatitis in cats. However, as amylase is filtered by the renal tubules and resorbed by tubular epithelium, it has been shown to be increased in cats with disorders related to renal azotemia.²⁹ It is possible that long-term use of MPA may affect the renal tubules or epithelium. Continued monitoring of amylase over a longer period of time and correlating it to any presentation of azotemia merits further study. Although these findings are notable, it is important to remember that the triglyceride and amylase values in our study stayed within the normal reference interval.

Other studies showed various increases in the chemistry findings. One study showed an increase in albumin, total protein, total calcium, and serum glucose, with 75% of cats exhibiting hyperglycemia after a single 5 mg/kg subcutaneous injection of MPA.⁴ This again would correlate with our findings of statistically increased albumin and calcium, although both values remained within the reference interval. Glucocorticoids can increase serum glucose by promoting the conversion of proteins and lipids from the body and converting to glucose in the liver.¹⁵ One study showed that cats might be more susceptible than dogs to these effects.¹² Another study showed that dogs given 1–2 mg/kg/day of prednisolone for 3 wk did not become hyperglycemic, but that cats given similar doses of prednisolone did so after 8 days.^16,17 Interestingly, we take special note that the blood glucose and the liver values were not affected in our study, considering that previous studies have shown hyperglycemia with steroid admistration.^4,16,17 This may be related to dose and duration because most of our patients received 1–2 mg/kg of MPA every 3 wk, which is much lower than the doses the cats received in previous studies.

Marked steroid-induced suppression of blood cortisol responses to adrenocorticotropic hormone was seen in one study.⁴ Increases in alkaline phosphatase have been reported but are rare.^4,8 Increases in cholesterol are also commonly reported in cats but did not show up in our study.^2,18,19

Chronic use of long-acting steroids has been discouraged in animals because of clinical side effects, risk of developing diabetes, and liver damage.²⁰ One case report showed that a cat being treated for stomatitis with weekly MPA at 20 mg subcutaneously for four doses developed iatrogenic hyperadrenocorticism.²¹ Histopathologic changes consistent with steroid hepatopathy have been shown in several papers.^{1,4,14,22–24} Another study administered 5 mg/kg of MPA by intramuscular injection and measured hematologic and serum biochemical parameters at 3–6 days and 16–24 days post-MPA administration.²⁵ These results showed an increase in glucose concentration and a decrease in red blood cell count, hematocrit, hemoglobin, sodium, and chloride at 3–6 days.²⁵ All the abnormal variables returned to baseline at 16–24 days post-MPA administration. The doses our animals received ranged from 1 to 2 mg/kg, which is lower than the dose given in this paper. In addition, the doses were given at approximately 21 day intervals, which, according the paper above, would be given close to the time when the blood work returned to normal parameters. The body was possibly able to clear the effects MPA had on these variables by the time the next MPA dose was given, negating any cumulative effects.

To our knowledge, this is the first study in which active, clinical MPA administered cases have been followed for a relatively long period of time. Because of the nature of the rescue organization, follow-up with complete blood work was accessible and timely. Using this data, we were able to choose 25 cats and follow them out for 3 yr. No animals were lost through follow-up, and blood work was taken in a timely fashion. In addition, blood work was sent to the same laboratory, ensuring reliability and repeatability. The brand of MPA was also the same throughout the years. The steroid doses were similar to doses used commonly in practice, not immunosuppressive doses. The treatments were given in a clinically relevant manner, although one that historically has been frowned upon. We examined basic laboratory tests such as CBC/chem/T4 because they were readily available and universally used as a screening test for basic animal health. Certainly, the testing is limited in predicting disease. MPA effects on clinical laboratory tests may not be seen until disease has already started. Other factors that are not measured by a standard CBC/chem/T4 may be affected. We present this data with this limitation in mind.

Limitations of this study include the lack of histopathology as well as the length of time. We did not take histologic samples of the patients and thus were unable to ascertain any degree of changes to the liver. One of the cats developed diabetes mellitus after 5 yr of treatment. Because of the fact we had additional years of data for this cat, out of curiosity, we followed out the timeline and found that the cat developed diabetes mellitus after 5 yr of MPA treatment (66 doses). However, it is important to note that only after continuing to look at this cat’s health after the 3 yr of data analysis did this cat develop diabetes mellitus. It is possible that additional years of data after chronic MPA administration may show additional cases of diabetes mellitus. Additional years of data would also help ascertain if these animals are prone to developing diseases such as diabetes mellitus, hyperadrenocorticism, liver failure, etc. In addition, it would be worth comparing the blood work of cats who did not receive chronic MPA administration with that of the cats studied in this paper to see if age-related or husbandry factors alone could impact blood parameters. Two other cats in the study developed hyperthyroidism after 2 yr (22 doses of MPA) and 3 yr (15 doses of MPA), respectively (Table 2). Within the current cat population of 465 at the rescue facility, the cases of cats with hyperthyroidism is 17% of the population, diabetes mellitus 3%, and cats with both conditions 1%. It is important to note that the population at D.E.L.T.A. Rescue is not representative of a normal population. The rescue adopts many older, abandoned animals, which could skew the data set. Previous studies have shown that hyperthyroidism diagnosis has increased recently worldwide, varying widely between 2.6 and 11.9%.²⁶ The two cases that developed hyperthyroidism in our data set represent a prevalence of 8%, which is lower than the prevalence at the facility. The one case that developed diabetes mellitus after 5 yr represents a prevalence of 3% compared with the overall population prevalence of 3%. A recent study showed a prevalence of 0.58% in a population of primary care facilities.²⁷ As the cat did not develop diabetes during the 3 yr timeframe we were examining, this development does not impact the current data set. We were unable to determine if the development of hyperthyroidism was related to the chronic MPA administration or independent of it, but this deserves further evaluation.

TABLE 2 Standard Deviation of Pres and 3 Years Post-Treatment

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Another limitation was the lack of a sufficient number of cases required in order to place the animals in cohorts organized by age, sex, and weight as well as the possibility that we missed the short-term effects on the blood work by performing it annually instead of more frequently. It would be valuable to follow the blood work out another few years to see if the triglyceride, amylase, and monocyte values continue to increase.

Conclusion

Glucocorticoids are one of the most commonly used medications in veterinary medicine.² Applications include biologic, replacement therapy, and immunosuppression.² Oftentimes, clinicians choose dose, preparation, and frequency of administration based on clinical experience and anecdotal evidence because scientific evidence for the correct protocol is unavailable.⁷ Oft-repeated advice discourages the use of long-term steroids, not only for the clinical side effects but also for the dangers that may be associated with long-term use, such as development of diabetes mellitus, hyperadrenocorticism, and liver pathology.^7,9 Long-term steroid use has been frowned upon in animals except in cases such as Addison’s disease, immune-mediated disease, etc. Considering its history of overuse and abuse in veterinary medicine, careful use of steroids is certainly warranted. Cats have been shown to be more resistant to the effects of glucocorticoids and usually require higher doses, likely because cats have fewer, less sensitive cellular glucocorticoid receptors.²⁸ Although long-term steroid use can cause clinical as well as biological side effects, this paper concentrated on the changes in common laboratory values over a period of 3 yr. CBC/chemistry alone cannot fully ascertain the effect of long-term corticosteroids on the body’s systems. Other parameters such as hepatic pathology, heart failure, endocrine system, and blood pressure still need to be closely studied, and we continue to advocate judicious use of corticosteroids in all species. Additional testing and continued follow-up on these cats may prove enlightening.