Abstract
Objectives
The objective was to compare the effect on thyroid function in healthy, adult cats fed a limited-iodine food or conventional diet for 24 months.
Methods
Cats in the limited-iodine group (n = 14) were fed a commercial, dry food containing 0.2 ppm iodine on a dry-matter basis (DMB). Cats in the conventional diet group (n = 12) were fed an identical diet except that the iodine content was 3.2 ppm on a DMB. Both groups were maintained on their respective diets for 24 months. The median age of the cats at baseline was 3.2 years (interquartile range 2.4–4.3). Diagnostic samples were obtained for measurement of serum biochemistry parameters, thyroid hormone concentrations, complete blood count and urinalysis, and thyroid ultrasound examination was performed at baseline, 6, 12, 18 and 24 months.
Results
Median serum concentrations of free and total thyroxine and thyroid-stimulating hormone were within respective reference intervals for both test groups at all sampling intervals. Median urine iodine concentrations in the limited-iodine group declined significantly (P = 0.0001) from baseline and were significantly different than conventional diet (P ⩽0.0007). Ultrasound examination revealed no significant change in median thyroid height in the limited-iodine group at any time point.
Conclusions and relevance
Normal serum thyroid hormone concentrations and results of urinalysis and routine biochemical testing confirmed that the limited-iodine food was safely fed for 2 years to healthy, adult cats. Ultrasound examination showing that cats on limited-iodine did not develop a change in thyroid gland height was a further indication of the absence of iatrogenic hypothyroidism in the limited iodine diet group. These results support the lack of obvious side effects associated with feeding a limited-iodine diet for 2 years to healthy, adult cats, a situation that may occur in multi-cat households where healthy cats have access to a limited-iodine diet being used to manage cats with feline hyperthyroidism.
Introduction
Feline hyperthyroidism is the most common endocrine disorder of cats, with a growing incidence worldwide. 1 It is estimated that 6–10% of cats in North America over the age of 10 years develop feline hyperthyroidism, with prevalence increasing as cats age.2,3 Thus, companion animal veterinarians can anticipate feline hyperthyroidism being a commonplace presentation in clinical practice. There is a growing recognition that feline hyperthyroidism is a potentially life-threatening disease that requires prompt intervention to normalize circulating thyroid hormone concentrations. 4
Curative treatment (ie, radioactive iodine, thyroidectomy) is preferred; however, many hyperthyroid cats are managed medically. In addition to pharmacotherapy, nutritional management is now available as a reversible therapeutic option for feline hyperthyroidism.4–6 Tarttelin et al have shown that serum thyroxine concentration in healthy, young cats is acutely responsive to changes in dietary iodine intake. 7 Use of a limited-iodine diet avoids the frequently observed side effects of antithyroid medications.8–10 A recent study found that cats previously treated with antithyroid drugs had improved feline hyperthyroidism clinical signs and a significant reduction in serum thyroid hormones when fed a limited-iodine food, indicating that nutritional management is a viable alternative and is not influenced by prior antithyroid drug treatment. 4
Various investigators have demonstrated that a limited-iodine food, generally defined as <0.3 ppm on a dry-matter basis (DMB),4,11 is effective in decreasing concentrations of circulating thyroid hormones by reducing intake of iodine trace amounts needed for thyroid hormone synthesis.4,5,11,12 These studies involved sizeable test populations with as many as 225 cats ranging in age from 4–21 years that were evaluated for up to 1 year while being fed a limited-iodine food. Serum total thyroxine (TT4) concentrations normalized in 75% of client-owned cats (n = 68) within 8 weeks in a European study and in 83% of cats (n = 47) within 6 months in a US study, providing a good indication of the onset-of-effect range and response rate.4,11 In studies involving client-owned cats, response rates could have been higher, but shortfalls in owner compliance and inconsistent feeding behavior by the test cats were noted.4,11
Current pet demographic data indicate that there is an average of 2.1 cats per cat-owning household in the USA. 13 Because controlling individual access to food resources can be difficult in multi-cat households, 14 normal, euthyroid cats are likely to consume limited-iodine food intended for a cat with feline hyperthyroidism. Nutritional management of feline hyperthyroidism becomes a more viable option in the home environment if healthy, as well as hyperthyroid, cats can consume a limited-iodine food on a long-term basis without adverse effects.
An additional concern regarding feeding limited-iodine diets to healthy cats is the role it could play in the pathogenesis of feline hyperthyroidism. It has been suggested that dietary iodine deficiency could result in decreased serum concentrations of thyroid hormones (TT4 and total triiodothyronine [TT3]), leading to increased thyroid-1098612X17702261stimulating hormone (TSH) production, and subsequent thyroid gland hyperplasia and enlargement, 1 similar to iodine-deficient goiter found in humans. 15
The purpose of the study described in this report was to evaluate the effect on thyroid function and other physiologic parameters of feeding a limited-iodine food to healthy cats for a prolonged period. Physiologic indicators of renal function such as blood urea nitrogen (BUN) and creatinine were evaluated because normalization of TT4 concentrations to a euthyroid state or iatrogenic hypothyroidism can result in decreased glomerular filtration rate (GFR).16–18 In addition, if feeding a limited-iodine food to healthy cats contributes to development of feline hyperthyroidism, it would be expected to cause decreased serum concentrations of thyroid hormones (TT4, TT3, free thyroxine [fT4]) followed by increased TSH and thyroid enlargement over time. Because hyperthyroidism likely develops over a prolonged time, a long-term study would be needed to assess definitively the impact of feeding a low-iodine diet to healthy cats for >2 years. This is the first report of the effect of a limited-iodine food fed to healthy, non-geriatric cats for a 24 month period, simulating the conditions affecting client-owned cats in a household setting.
Materials and methods
Study design
The randomized, controlled study was approved by the Institutional Animal Care and Use Committee at Hill’s Pet Nutrition, and was conducted in accordance with all applicable Hill’s animal welfare policies and procedures.
Thirty clinically healthy, neutered or spayed domestic shorthair cats aged 2–5 years were enrolled in the study and randomly assigned by sex and age to one of two feeding groups (15 cats in each) given either a limited-iodine food or a conventional diet. All outcome parameters were compared within and between study groups at various intervals during the 24 month study. Following enrollment, baseline diagnostic samples were obtained for measurement of serum thyroid hormone concentrations, urinalysis, complete blood count (CBC) and serum chemistries.
Serum chemistry parameters were measured on a Cobas 6000 c501 instrument (Roche Diagnostics). Assays were validated by the manufacturer of the instrument. Calibrations were performed at recommended intervals per assay, with two-point quality control performed daily. CBC was performed on a Sysmex XTV-2000i (Sysmex America). Calibrations of the instrument are performed bi-annually or as needed by the instrument manufacturer. Three levels of quality control (low, normal, high) were performed daily. Urine analysis was performed as described by Wedekind et al. 19 Thyroid hormones were analyzed at the Diagnostic Center for Population and Animal Health, Michigan State University, using previously validated assays.20–22
fT4 was measured in feline serum with a commercially available radioimmunoassay originally developed by Nichols Institute Diagnostics and currently manufactured by Antech Diagnostics (fTe-ED). Assay procedures were performed as per the manufacturer’s instructions. The manufacturer reported negligible cross-reaction with other iodothyronines (0.001–0.044%) in the assay. The sensitivity of the assay, defined as the calculated concentration of fT4 at 2 SD below total specific binding (11 assay runs), was 3.6 pmol/l. For other estimates of assay performance, three pools of feline serum were made with residual serum from clinical samples. In feline serum pools with mean concentrations of 12 (low), 30 (mid-range) or 112 (high) pmol/l, the interassay percentage coeffecients of variation (%CVs) were 10.4%, 8.0% and 5.8%, respectively (seven assays). The intra-assay %CVs from the same pools were 14.4%, 9.9% and 6.9%, respectively (11–14 replicates). After incubation in dialysis cells, aliquots of dialysate from each serum pool were mixed in different combinations for assessment of assay parallelism. When aliquots of dialysate from the ‘high’ and ‘mid-range’ pools were mixed (parts high:parts mid-range) in combinations of 9:1, 4:1, 3:2, 1:1, 3:7 and 1:4, the recovery (%observed/expected) rates of measured fT4 were 92.6%, 88.4%, 94.9%, 107.6%, 91.3% and 84.5%, respectively, with an overall average recovery of 93.2%. When aliquots of the ‘high’ and ‘low’ pools were mixed in similar fashion at rates of 9:1, 3:2, 1:1 and 3:7, recovery rates were 85.3%, 102.9%, 109.9% and 117%, respectively, with an overall average recovery of 103.8%.
TT4 (Gammacoat; DiaSorin) and TT3 (in-house assay) were analyzed by radioimmunoassay.20,21 TSH concentrations were measured with a commercially available immunoradiometric assay for canine TSH (Canine TSH IRMA; Siemens Medical Solution Diagnostics). 22 Free T3 (fT3) was measured using a direct serum analogue-based radioimmunoassay kit (Clinical Assays Gammacoat Free T3 125I RIA Kit; DiaSorin). The manufacturer’s protocol for the assay was followed with the exception that the incubation of antibody-coated tubes containing radioligand and sample was extended to 3 h in a 37°C water bath. The assay sensitivity was determined to be 1.21 pmol/l. The intra-assay CVs were 13.7%, 13.7% and 5.6% at 2.7, 5.9 and 13.3 pmol/l, respectively, and the interassay CVs were 13.8%, 20.2% and 13.7% at 2.2, 4.2 and 11.3 pml/l, respectively.
All tests were repeated for samples obtained at 6, 12, 18 and 24 months. Daily food intake was recorded and averages were calculated. Transverse ultrasound scans of both thyroid glands were performed by the same board-certified veterinary radiologist with measurements made at the maximal dorsoventral dimension (height) at baseline and 6, 12, 18 and 24 months. Measurements were taken three times at each time point with a GE Voluson i ultrasound instrument and a 12 MHz linear probe (GE Healthcare). Body weights were determined monthly and body condition scores (BCSs) were performed at baseline and at the end of the study using a 5-point scale.
Test animals
Thirty adult cats with normal thyroid function, thyroid ultrasound evaluation and serum TT3 and T4 concentrations within the reference interval (RI) were enrolled in the study. Cats were group-housed at the sponsor’s nutritional research center, a facility that allowed ample exercise and social interaction in spacious, environmentally enriched rooms with natural light.
Test foods
Cats in the limited-iodine group were fed a commercially available, limited-iodine, dry therapeutic cat food (Hill’s Prescription Diet y/d Feline; Hill’s Pet Nutrition) containing 0.2 ppm iodine on a DMB. Cats in the conventional diet group were given a cat food produced by the same manufacturer and with the same nutrient profile as the limited-iodine food except that the iodine content was 3.2 ppm on a DMB, a level typical of dry commercially available cat foods. Composition of the two test foods is shown in Table 1. Except for the iodine level in limited iodine food, the respective test foods were formulated to meet or exceed nutrient recommendations for adult cats in accordance with the Association of American Feed Control Officials. 23
Nutrient profile per 100 kcal of limited-iodine (LI) and conventional diet (CD) test foods
Statistical analysis
All analyses were performed using SAS Statistical Software version 9.3. Medians and interquartile ranges (IQRs) were calculated for each analyte and outcome measure. Differences within and between test groups were then tested. Data were examined using a Wilcoxon test at each time point. For the BCSs the Wilcoxon two-sample exact results were used to determine statistical significance. An alpha of 0.05 was the significance level used for all tests.
Results
Test animals
Median body weights at baseline in the limited-iodine and conventional diet groups were 5.26 and 4.94 kg, respectively, a non-significant difference (P >0.05). One cat in the limited-iodine group was withdrawn from the study at 4 months owing to poor food intake and weight loss, and was later diagnosed with cardiomyopathy. Three cats in the conventional diet group were withdrawn: one because of sudden death from hypertrophic cardiomyopathy at 6 months, one for poor food intake and weight loss at 10 months, later diagnosed with kidney disease, and one with pancreatic disease at 18 months. Of the 14 cats in the limited-iodine group that completed the study, six were male and eight were female. Median age at baseline of the remaining cats in this group was 3.2 years (IQR 2.5–4.3 years). Of the 12 cats in the conventional diet group that completed the study, six were male and six were female. Median age at baseline of the remaining cats in the conventional diet group was 3.3 years (IQR 2.4–4.3 years).
Food intake and body weights
Food intake did not vary significantly within or between test groups during the study. Median body weights did not vary significantly within or between test groups at any time point. Final median body weights (Q1–Q3) were 5.46 kg (IQR 4.82–6.10) and 4.47 kg (IQR 4.13–5.95) in the limited-iodine and conventional diet groups, respectively (P = 0.325). The BCSs did not change significantly during the study. At baseline the median BCS was 3.0 in both groups with an IQR of 2.0–4.0 and 3.0–4.0 for conventional diet and limited-iodine diet, respectively. After 24 months the median BCSs were 3.0 and 4.0 with an IQR of 3.0–4.8 and 3.0–5.0 for conventional diet and limited-iodine diet, respectively.
Thyroid gland ultrasound evaluation
There was no significant change in the median height of the thyroid in the cats in the limited-iodine group at any test interval. There were no significant differences in gland height between the treatment groups at any time during the study (Table 2). Median thyroid height in conventional diet cats was significantly greater at 6 (P = 0.0425 [left gland]; P = 0.0420 [right gland]) and 24 months (P = 0.0149 [left gland]; P = 0.0017 [right gland]) vs baseline.
Median thyroid gland height (cm) in cats given a limited-iodine (LI) food or conventional diet (CD)
Data are median (interquartile range) unless otherwise indicated
BL = baseline; NS = non-significant at P >0.05
Serum thyroid hormone concentrations
Median serum concentrations and interquartile ranges of TT3, fT3, fT4 and TT4, and TSH are shown in Table 3.
Median and interquartile range (IQR) for total triiodothyronine (TT3), free T3 (fT3), total thyroxine (TT4), free T4 (fT4) and thyroid-stimulating hormone (TSH), in cats given a limited-iodine (LI) food or conventional diet (CD)
BL = baseline; NS = non-significant at P >0.05
Most notably, median values for each analyte varied but were within respective RIs at all sampling intervals, with the exception of TT3 and fT3. TT3 was marginally below the lower limit in the conventional diet group at 18 and 24 months. fT3 was slightly below the lower limit in the conventional diet group at 18 months and in the limited-iodine group at baseline. Median serum thyroid hormone concentrations between groups were not significantly different at any time point with four exceptions: fT3 and TT3 at 18 and 24 months. There were significant differences in some hormone concentrations within groups at various sampling intervals (Table 3). For example, median TT3 was significantly lower vs baseline in the conventional diet group at 12, 18 and 24 months, and in the limited iodine group at 12 and 18 months. Median TT4 was significantly greater in the limited iodine group at 18 and 24 months vs baseline.
Serum biochemistry and hematology
Results of serum biochemistry measurements and CBCs were unremarkable for both test groups, although some values were outside the RIs at some sampling intervals, and some were significantly different from baseline. Median values for albumin, alkaline phosphatase, BUN, total bilirubin, creatinine, glucose, hematocrit, hemoglobin, phosphorus, potassium, and total red and white blood cells for both test groups were all within normal ranges at all time points.
Urine iodine and specific gravity
Median urine iodine concentrations for the limited-iodine group declined significantly (P = 0.0001) from baseline beginning at 1 month, reflecting the effect of the low-iodine diet. Urinary iodine concentrations in the limited-iodine group remained significantly below baseline at each sampling interval for the remainder of the study. In contrast, median urine iodine concentrations in the conventional diet group changed little throughout the study, varying from baseline by <0.5 ppm, a non-significant difference. Median urine specific gravity was >1.048 and <1.052 in the limited-iodine and conventional diet groups at all sampling intervals. The differences in specific gravity values between or within test groups were not statistically significant.
Discussion
The combination of normal results for serum thyroid hormone concentrations, thyroid gland imaging, urinalysis and routine biochemistry parameters confirmed that the limited-iodine food was safely fed for 2 years to healthy, adult cats in this study. This is similar to a previous study that showed no effect on serum thyroid hormone concentrations (TT4, TT3 and fT4) when feeding a limited-iodine diet to healthy adult cats (mean age 8.1 years) for 1 year. 19 The outcome of these studies supports that a limited-iodine food can be fed to healthy adult cats for 1–2 years without obvious side effects, including iatrogenic hypothyroidism.
Serum concentrations of TT3, TT4, fT4 and TSH are used to evaluate thyroid functional status.18,24,25 In contrast, little is known about effects of feeding limited-iodine diets on thyroid hormone concentrations in healthy cats. In a 1 year study, there were no significant effects of varying iodine intake (ranging from 0.17–8.8 ppm iodine) on TT4 or TT3 concentrations in healthy, adult cats at 6 and 12 months; fT4 was significantly lower at week 48 for cats fed the highest iodine concentration. 19 In the present study, cats fed the limited-iodine diet had median TT3, fT3,TT4, fT4 and TSH values within the RIs at all sampling intervals, consistent with a euthyroid state. In our study, TT3 concentrations were below the RI at 18 and 24 months in the conventional diet group. fT3 was slightly below the lower limit in the conventional diet group at 18 months and in the limited-iodine group at baseline. Because fT3 values remained within the RI at all points after feeding the limited-iodine diet, we did not consider this a clinically important finding in the limited-iodine group. In addition, the importance of fT3 concentrations is difficult to evaluate because published data are lacking for cats. The cause for significant reductions in TT3 concentrations vs baseline in both groups is unknown. We did not consider this clinically important because values remained within the RI at all points for the limited-iodine group and there were no other findings (clinical signs, low T4 concentrations) to support hypothyroidism in either group. The significantly increased TT4 concentrations (vs baseline) that occurred in both groups could have indicated developing hyperthyroidism; however, we consider this unlikely and not a diet effect because all values remained within RIs in both groups, there were no clinical or other laboratory findings consistent with hyperthyroidism, and there were no significant differences in TT4 concentrations between diet groups.
Subnormal thyroid hormone concentrations and abnormally increased TSH values are expected with iatrogenic hypothyroidism, 18 and were not observed in this study. This is particularly relevant in the case of cats with chronic kidney disease (CKD) because feline hyperthyroidism treatment typically reduces GFR and increases the risk of azotemia, which has been correlated with subnormal thyroid hormone concentrations in cats with CKD.16–18 Median BUN, serum creatinine concentrations and urine specific gravity within RIs at all time points further corroborated that cats in the limited-iodine group maintained normal renal function. It is nevertheless advisable that clinicians determine and monitor the renal status of cats prior to and during any treatment for feline hyperthyroidism.
Thyroid gland ultrasound evaluations of cats in the limited-iodine group showed no significant changes in gland height compared with baseline, prior test interval or gland height of conventional diet cats. Absence of imaging findings consistent with thyroid hyperplasia was a further indication of euthyroid status, but does not entirely rule out microscopic changes. 26
Median body weights and BCSs remained stable and food intake did not vary significantly in either test group during the study, further supporting the presence of normal thyroid function. The only noteworthy difference in outcome parameters between test groups was the significantly lower urine iodine concentrations in cats fed the limited iodine food, the desired effect, beginning at 1 month and persisting at all subsequent test intervals. Otherwise, physiologic parameters for both test groups were essentially comparable.
There are limitations of the current study that should be considered when evaluating results and interpreting their relevance. Muscle condition scores were not determined, and this would have been preferred for evaluating muscle mass. The study cats were healthy adult and middle-aged cats and findings should not be extrapolated to senior or geriatric cats, or those with concurrent diseases. The study duration was 2 years in length and abnormalities that develop slowly may not be detected without a longer study period. Because there is no commercially available assay for feline TSH, a canine assay was used to measure TSH concentration in our study. While the canine assay identifies feline TSH and is recommended as a useful diagnostic test for hypothyroidism in cats, it is possible that some of the feline TSH was not measured in serum samples of cats in the present study. 18
Conclusions
The results of this study did not reveal side effects associated with feeding a limited-iodine diet for 2 years to healthy, adult cats, a situation that may occur in multi-cat households where healthy cats have access to a limited-iodine diet being used to manage cats with feline hyperthyroidism.
Footnotes
Acknowledgements
The authors acknowledge the contribution of Mark Dana of Scientific Communications Services in the preparation of the manuscript, and Ilfra Raymond-Loher for the statistical analysis of the data.
Conflict of interest
Inke Paetau-Robinson, Dru Forrester and Patricia Burris are employees, and Lynda Melendez is a former employee, of Hill’s Pet Nutrition. Laura Armbrust received funding from Hill’s Pet Nutrition to perform the ultrasonography.
Funding
The study was funded by Hill’s Pet Nutrition.
