Results of this study were presented at the ACVIM Forum, Anaheim, CA, 2010.
Corresponding author: T.L. Williams, Department of Veterinary Clinical Sciences, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield AL9 7TA; e-mail: email@example.com.
Background: Iatrogenic hypothyroidism can occur after treatment of hyperthyroidism, and is correlated with a reduced glomerular filtration rate in humans and dogs.
Hypothesis: Cats with iatrogenic hypothyroidism after treatment for hyperthyroidism will have a greater incidence of azotemia than euthyroid cats.
Animals: Eighty client owned cats with hyperthyroidism.
Methods: Two retrospective studies. (1) Longitudinal study of 12 hyperthyroid cats treated with radioiodine (documented as euthyroid after treatment), to assess changes in plasma thyroid stimulating hormone (TSH) concentration over a 6-month follow-up period, (2) Cross-sectional study of 75 hyperthyroid cats (documented as euthyroid) 6 months after commencement of treatment for hyperthyroidism to identify the relationship between thyroid status and the development of azotemia. Kaplan-Meier survival analysis was performed to identify relationships between thyroid and renal status and survival.
Results: Plasma TSH concentrations were not suppressed in 7 of 8 cats with hypothyroidism 3 months after radioiodine treatment. The proportion of cats with azotemia was significantly (P= .028) greater in the hypothyroid (16 of 28) than the euthyroid group (14 of 47). Twenty-eight of 41 cats (68%) with plasma TT4 concentration below the laboratory reference range had an increased plasma TSH concentration. Hypothyroid cats that developed azotemia within the follow-up period had significantly (P= .018) shorter survival times (median survival time 456 days, range 231–1589 days) than those that remained nonazotemic (median survival time 905 days, range 316–1869 days).
Conclusions and Clinical Importance: Iatrogenic hypothyroidism appears to contribute to the development of azotemia after treatment of hyperthyroidism, and reduced survival time in azotemic cats.
Hyperthyroidism in human patients is associated with an increased renal blood flow and glomerular filtration rate (GFR), and hypothyroidism is associated with a decrease in GFR.1 Increased GFR occurs in hyperthyroxinemic cats2 and subnormal GFR (<2mL/kg/min) occurs in hypothyroid dogs.3 Treatment of hyperthyroidism and restoration of euthyroidism in cats results in a decrease in GFR,4,5 which can lead to the development of azotemia if underlying chronic kidney disease (CKD)6 is present. And 17–49% of cats develop azotemia within 6 months of treatment of hyperthyroidism.4,5,7–10 These cats could represent a population of hyperthyroid cats with pre-existing CKD that were nonazotemic because of hyperfiltration and loss of muscle mass associated with the thyrotoxic state. Alternatively, antithyroid treatment could lead to iatrogenic hypothyroidism, and hypothyroidism has been correlated with reduced GFR.1 Hypothyroidism could therefore contribute to the development of azotemia if mild (IRIS Stage I or IIa)6 CKD is present. There is a lower incidence of azotemia after treatment of hyperthyroid cats with antithyroid medication (17%)10 compared with cats treated with radioiodine and bilateral thyroidectomy (33–49%).4,5,7–9 Azotemia might not develop as frequently in cats treated with antithyroid medication because of poor control of hyperthyroidism. GFR might not normalize sufficiently for azotemia to occur, despite underlying CKD. Alternatively, the lower incidence of azotemia after treatment may be because of the decreased incidence of iatrogenic hypothyroidism in cats treated with antithyroid medication. In support of this hypothesis, increased TSH concentrations (>21 mU/L) occur in 100% of cats treated by bilateral thyroidectomy, 75% of cats that received radioiodine treatment, and 35% of cats treated with methimazole.a
Diagnosis of iatrogenic hypothyroidism in cats with CKD is complicated because of suppression of total thyroxine (TT4) concentrations by nonthyroidal illness (euthyroid-sick syndrome).11 Thyroid stimulating hormone (TSH) concentrations are increased in human patients with CKD and primary hypothyroidism12; therefore increases in TSH enable iatrogenic hypothyroidism and euthyroid-sick syndrome to be differentiated, at least in humans.
Hyperthyroidism causes suppression of pituitary TSH secretion in cats13; however, the time taken, after a period of suppression, for pituitary thyrotroph function to recover once euthyroidism is restored in cats is unknown. Humans with Graves' disease have TSH concentrations that normalize around 120 days after the commencement of antithyroid drug treatment.14 Measurement of TSH concentrations will not be helpful for the diagnosis of iatrogenic hypothyroidism if pituitary TSH secretion is suppressed.
The purpose of the 1st study was to determine the duration of TSH suppression after restoration of euthyroidism in cats after radioiodine treatment. Radioiodine treatment is likely to lead to a gradual re-establishment of euthyroidism, if viable thyroid tissue remains, therefore allowing more reliable longitudinal study of patterns of TSH secretion. The aim of the 2nd study was to establish if iatrogenic hypothyroidism after treatment of hyperthyroidism was associated with a higher incidence of azotemia, reduced survival time or both, in a population of cats in first opinion practice that were treated either medically or surgically. In order to determine whether the diagnosis of iatrogenic hypothyroidism was of any pathophysiological significance, clinical and laboratory findings previously reported in hypothyroidism in cats and dogs were compared between hypothyroid and euthyroid cats.
To determine the duration of TSH suppression after restoration of euthyroidism in cats, serum samples from hyperthyroid cats receiving radioiodine treatment at the Queen Mother Hospital for Animals were collected at 1, 3, and 6 months after treatment, for TSH analysis.b Serum TSH concentrations were measured by the Immulite canine TSH assay (Siemens, Camberley, UK) as previously validated.13
For the 2nd study, records from 2 London-based first opinion practices (People's Dispensary for Sick Animals, Bow and the Beaumont Animals' Hospital, Camden) between January 1, 1999 and September 1, 2009 were reviewed and newly diagnosed hyperthyroid cats identified. Diagnosis of hyperthyroidism was based on a plasma TT4 above the laboratory reference range (>55 nmol/L, 4.26 μg/dL) or a failure of the TT4 concentration to suppress to <20 nmol/L after administration of 20 μg liothyronine sodium (T3) 3 times daily for 2 days, then 20 μg liothyronine sodium (T3) on day 3, given 2–4 hours before sampling. Cats that were azotemic at diagnosis or that had been previously diagnosed with azotemic CKD were excluded from the study. Baseline age and plasma creatinine concentration were recorded. Hyperthyroidism was treated by administration of antithyroid medication (carbimazole or methimazole) alone or in combination with thyroidectomy. Cats were monitored for the development of renal azotemia during the 6-month period after commencement of treatment for hyperthyroidism.
Renal azotemia was defined as a plasma creatinine concentration >177 μmol/L (2.0 mg/dL) in conjunction with inadequate urine concentrating ability (USG < 1.035), or persistent azotemia on 2 or more consecutive occasions without evidence of a prerenal cause. A plasma creatinine concentration of >2.0 mg/dL was chosen as this reflected the upper limit of the laboratory reference range.b Cats diagnosed with renal azotemia received a phosphate-restricted dietc free of charge although compliance was variable. Cats that were still hyperphosphatemic despite institution of a phosphate-restricted diet were also treated with aluminium hydroxide.d
Cats were included in the study if they had plasma TT4 concentration <40 nmol/L documented at least 6 months after commencement of treatment for hyperthyroidism (6-month posttreatment visit), and had stored heparinized plasma available from the same visit for TSH analysis. Plasma TSH concentrations were measured at the Royal Veterinary College laboratorye as described earlier.
Cats were grouped according to their thyroid function (based on plasma TSH and TT4 concentrations) and renal function. Cats were classified as hypothyroid if they had a plasma TT4 concentration below the laboratory reference range (10–55 nmol/L) and plasma TSH concentration above the reference range for serum TSH (<0.03–0.15 ng/mL).15 Cats were classified as euthyroid if their plasma TT4 concentration was within or below the reference range with TSH concentration <0.15 ng/mL. Cats of uncertain thyroid status (plasma TT4 within reference range, high plasma TSH) were excluded from the study.
The clinical records at diagnosis of hyperthyroidism and 6 months after treatment were reviewed, and the following biochemical and physical examination data recorded: plasma TT4, cholesterol, calcium and creatinine concentrations, alanine aminotransferase and alkaline phosphatase (ALP) activities, packed cell volume (PCV), heart rate, body condition score, and body weight.
Blood and Urine Sampling and Processing
For cats included in the cross-sectional study, blood and urine samples were collected at the time of diagnosis with the informed consent of the owner. The Ethics and Welfare Committee of the RVC approved the diagnostic protocol. Jugular venous blood samples were collected and transferred to heparinized tubes. Urine samples were collected by cystocentesis. Samples were kept at 4°C before processing, which occurred within 6 hours of collection. Blood samples were placed in a centrifuge at 2016 ×g for 10 minutes to enable separation of plasma from cellular components. Heparinized plasma was submitted to an external laboratoryb for routine biochemical analysis (including TT4 concentration). Excess plasma was stored at −80°C for future analysis.
Urine samples were subjected to full in-house urinalysis including measurement of USG by refractometry, dipstick analysis, and urine sediment examination.
Once euthyroidism was achieved, cats were re-examined approximately every 8 weeks (if treated with antithyroid medication) or every 3 months if treated surgically. Blood and urine samples were repeated approximately every 3–4 months.
For cats included in the cross-sectional study, which included only those cats treated medically or surgically, survival times were calculated from the date of diagnosis of hyperthyroidism to the date of death or euthanasia. If these data were not available, the owner was contacted by telephone to request follow-up information. If the cat had died and the exact date of death was unknown, the month of death was recorded and it was assumed that the cat died on the 15th of that month for the purposes of the survival analysis. Cats were censored from the survival analysis if they were still alive at the end of the follow-up period (November 25, 2009) or if they were lost to follow up. Cats were categorized as lost to follow-up if they had not attended the clinic for 6 months and their owners were not contactable by telephone.
Statistical analyses were performed by a computerized statistical software package.f Results are reported as median (25th, 75th percentile) and statistical significance was defined as P≤ .05. For the purposes of statistical analysis, plasma TSH < 0.03 ng/mL (below limit of quantification of assay) was assigned a value of 0.02 ng/mL. The Fisher's exact test was used to compare between the hypothyroid and euthyroid groups the proportion of cats with azotemia found within these groups. The Kruskal-Wallis test was used to compare the PCV of cats divided into groups defined by thyroid status (hypothyroid versus euthyroid) and renal status (azotemic versus nonazotemic). Post hoc testing using the Mann-Whitney U-test with Bonferroni's correction was performed to identify significant differences in PCV between individual groups. The Mann-Whitney U-test or 2 sample t-test were used to compare the clinicopathologic variables (listed previously) between the hypothyroid and euthyroid groups at baseline and after 6 months of treatment.
For the survival analysis, cats were grouped according to their thyroid function alone and then further subgrouped according to their renal status so that the survival of azotemic and nonazotemic cats in the hypothyroid and euthyroid groups could be compared. Kaplan-Meier survival curves were plotted and survival times for cats in each group were compared by the log-rank test.
Time to Recovery of Thyrotroph Function
Twelve hyperthyroid cats treated with radioiodine had serum samples available at 2 or more time points in the 6-month follow-up period. All cats were documented to be euthyroid after radioiodine treatment.
Ten out of 12 cats were classified as hypothyroid 3–6 months after radioiodine treatment. Of these 10 cats, 4 out of 7 cats had increased serum TSH concentrations (>0.15 ng/mL) 1 month after treatment and 7 out of 8 cats had increased serum TSH concentrations at 3 months after treatment (Fig 1). The 2 cats that remained euthyroid had serum TSH concentrations (0.05 and 0.11 ng/mL) within the reference range at 3 months after treatment.
Cross-Sectional and Survival Study
Heparinized plasma samples were available for TSH measurement in 80 cats. In 41 cats (51.3%) plasma TT4 was below the external laboratoryb reference range (<10 nmol/L), and of these 28 (68%) had plasma TSH concentration above the reference range (>0.15 ng/mL; Table 1). The remaining 13 cats (32%) all had plasma TSH concentrations within the reference range (<0.03–0.15 ng/mL), consistent with sick-euthyroid syndrome.
Table 1. TSH concentrations from hyperthyroid cats after 6 months of antithyroid treatment.
Median [25th, 75th Percentile] TSH Concentration (ng/mL)
% Cats with TSH > 0.15 ng/mL
Cats were categorized into 4 groups based on plasma total thyroxine concentration and renal function (based on plasma creatinine concentrations and urine specific gravity).
TSH, thyroid stimulating hormone.
Low TT4 nonazotemic
0.71 [0.04, 2.15]
Low TT4 azotemic
0.39 [0.11, 2.90]
Normal TT4 nonazotemic
0.02 [0.02, 0.08]
Normal TT4 azotemic
0.02 [0.02, 0.06]
Twenty-eight cats were classified as hypothyroid, of which 16 (57%; 95% CI 39–75%) had developed azotemia, and 47 cats were classified as euthyroid, of which 14 (30%; 95% CI 17–43%) had developed azotemia. There were 5 cats of uncertain thyroid status with increased TSH concentration but normal plasma TT4, which were excluded from further study. There were no significant differences in age (hypothyroid group, 15 [13.5, 16.8] years, n = 28, euthyroid group, 13.6 [12, 15.9] years, n = 46; P= .063) or plasma creatinine concentrations at initial diagnosis of hyperthyroidism (hypothyroid group, 1.25 [1.04, 1.49] mg/dL, n = 26, euthyroid group, 1.27 [1.08, 1.47] mg/dL, n = 38; P= .918) between the euthyroid and hypothyroid groups. Out of the 75 cats that were included in the study, 48% of cats treated with antithyroid medication alone (n = 44), 8% of those treated by unilateral thyroidectomy (n = 25) and 67% of those treated by bilateral thyroidectomy (n = 6) were hypothyroid at the end of the 6-month study period. The proportion of cats with azotemia at the end of the 6-month study period in the euthyroid and hypothyroid groups was significantly different (P= .028).
Hypothyroid cats had significantly lower PCV (P= .004), plasma ALP activity (P < .001), and heart rate (P= .027) 6 months after treatment when compared with euthyroid cats (Table 2). Hypothyroid cats also had significantly higher plasma creatinine concentrations than euthyroid cats (P= .012).
Table 2. Selected clinicopathologic data from hypothyroid and euthyroid cats 6 months after commencement of antithyroid therapy.
Hypothyroid azotemic cats had significantly lower PCV than euthyroid nonazotemic cats (P < .001), but there were no significant differences between the other groups (Fig 2).
Fifty-one out of 75 cats (68%) died or were euthanized before the study end point, with a range of survival times of 157–2541 days. Twenty-four cats (8 hypothyroid and 16 euthyroid; 32%) were alive at the study end point and censored from the survival analysis. The range of follow-up times for censored cases was 162–2016 days. Overall, there was no significant difference between the median survival time of hypothyroid cats (625 [1279, 416] days, n = 28) and euthyroid cats (794 [1302, 413] days, n = 47). There was also no significant difference between the survival times of euthyroid cats with azotemia (728 [1416, 420] days, n = 9) and those without azotemia (794 [917, 401] days, n = 22; P= .532, Fig 3). The median survival time of hypothyroid azotemic cats (456 [841, 362] days, n = 13) was significantly shorter than that of hypothyroid nonazotemic cats (905 [1701, 625] days, n = 7; P= .018, Fig 4).
The results of the present study demonstrate that cats diagnosed with iatrogenic hypothyroidism have a greater incidence of azotemia after treatment of hyperthyroidism than those that are euthyroid after treatment. Hypothyroidism has been correlated with reduced GFR in humans1 and dogs3; however, GFR could not be measured directly because of the retrospective nature of this study. Treatment of hyperthyroidism and restoration of euthyroidism in cats leads to a reduction in GFR,4,5 as well as an increase in muscle mass and consequentially an increase in plasma creatinine concentrations.16 The present study found that the median plasma creatinine concentration after treatment of hyperthyroidism was significantly higher in cats with iatrogenic hypothyroidism than those that were defined as euthyroid. This might suggest that the decrease in GFR that occurred after treatment of hyperthyroidism was greater in the cats with iatrogenic hypothyroidism than in the cats that remained euthyroid. If mild underlying CKD (IRIS Stage I or IIa) was present in these cats, then the reduced GFR associated with iatrogenic hypothyroidism could cause azotemia.
The effect of restoring euthyroidism on renal function and creatinine concentration was not directly assessed in the present study. GFR of dogs with hypothyroidism increases after restoration of euthyroidism, although the GFR was not normalized in most dogs.3 GFR in children with acquired hypothyroidism is significantly lower than normal children for up to 5 years after the start of thyroxine treatment and restoration of euthyroidism.17 In a further study,18 5 of 27 human hypothyroid patients had increased serum creatinine concentrations after 2 months of levothyroxine treatment. Of these 5 patients, 3 had previously been diagnosed with renal insufficiency, and it is interesting to note that 2 of these 3 patients were reported to have higher serum creatinine concentrations after levothyroxine treatment compared with values before treatment. This could suggest that there is reduced glomerular function after the period of hypothyroidism, and could indicate that hypothyroidism is associated with permanent damage to the kidney, particularly if there was underlying renal insufficiency. Iatrogenic hypothyroidism in cats could therefore exacerbate underlying renal disease, however, CKD secondary to hypothyroidism in cats is not reported.3 Further studies to assess the changes in renal function after restoration of euthyroidism in cats with iatrogenic hypothyroidism, ideally by measurement of GFR, are warranted.
Seventeen to 49% of initially nonazotemic hyperthyroid cats develop azotemia within 6 months of treatment of hyperthyroidism4,5,7–10; however, the survival of hyperthyroid cats that develop azotemia after restoration of euthyroidism is uncertain. The survival times of hyperthyroid cats that develop posttreatment azotemia are not significantly different than those that remain nonazotemic.g In contrast, hyperthyroid cats with azotemia before treatment for hyperthyroidism have significantly shorter survival times than do cats that are nonazotemic before treatment.19,20 In the present study, there was no significant difference in the survival of euthyroid cats with and without azotemia after treatment, in agreement with a previous study.g However, hypothyroid cats with azotemia after 6 months of treatment did have shorter survival times than nonazotemic hypothyroid cats. This suggests that hypothyroidism contributes to reduced survival times in azotemic cats, possibly through effects on the kidney or other organ systems.
Five cats in the present study also had high plasma TSH concentrations in conjunction with normal plasma TT4 concentrations. This finding in human medicine is consistent with subclinical hypothyroidism which has been correlated with a relative increase in all cause mortality when compared with euthyroid controls.21 Unfortunately, in the present study group sizes were too small to compare the survival times of euthyroid cats and cats with subclinical hypothyroidism.
In the present study, only cats that survived to 6 months were included in the survival analysis. It is possible that the effect of hypothyroidism on survival time might have been greater if cats had been studied at an earlier time point, especially if a significant proportion of cats did not survive to 6 months. Hyperthyroid cats treated at the same institutions over the same time period (n = 300) had a 6-month survival rate of 69% (data not shown); therefore the results of this study are applicable to the majority of hyperthyroid cats. Also, as euthyroidism was not achieved until 3 months after diagnosis in some cases, the use of an earlier time point might not have allowed long enough for thyrotroph recovery after suppression to occur, which would limit the detection of hypothyroidism by measurement of high TSH concentrations.
Dogs with experimentally induced hypothyroidism have a reduced GFR without significant increases in plasma creatinine concentration and a reduction in endogenous creatinine production of 33%.22 If iatrogenic hypothyroidism in cats results in a similar reduction in endogenous creatinine production, any decrease in GFR as a result of hypothyroidism might not be associated with a reciprocal increase in plasma creatinine concentrations and the development of azotemia. The number of cats in the present study with reduced renal function secondary to iatrogenic hypothyroidism could be higher than we have reported.
A large proportion of cats (68%) with plasma TT4 concentrations below the laboratory reference range (<10 nmol/l) had plasma TSH concentrations above the reference range, suggesting that these cats were hypothyroid. The comparison of clinical and laboratory variables that have reported to be altered in hypothyroidism identified hypothyroid cats as having significantly lower PCV, and significantly lower plasma ALP activity and heart rate than euthyroid cats. This suggests that iatrogenic hypothyroidism can exert effects on the cardiovascular and hemopoietic systems; however, the clinical significance of these effects is unknown at this time.
Hypothyroidism in dogs and cats is associated with a normocytic normochromic anemia,23–25 and in the present study, the PCV was significantly lower in the hypothyroid group compared with the euthyroid group. However, full hematological analysis was not performed so the nature of any anemia could not be determined. As a greater proportion of hypothyroid cats were azotemic, the lower PCV could be attributed to an increased incidence of anemia of CKD; however, there was no significant difference between the PCV of azotemic and nonazotemic cats of the same thyroid function.
Plasma ALP activity was significantly lower in hypothyroid cats compared with euthyroid cats. In contrast, mild increases in ALP activity are reported in dogs with hypothyroidism.24 Some human studies have reported decreased markers of bone formation and resorption in the hypothyroid state.26,27 The decreased ALP activity observed in hypothyroid cats in the present study could reflect a state of decreased bone turnover.
The TSH reference range for normal cats15 was established using serum; however, in the current study, serum samples were not available and therefore heparinized plasma was used for TSH analysis. There is no significant difference between the measured TSH concentrations from paired heparinized plasma and serum samples. However, there is a tendency for plasma TSH concentrations to be lower than serum TSH concentrations at higher TSH concentrations.15 This could lead to an underestimation of the TSH concentrations in the present study.
The reference range used in the present study was derived from a study of 90 normal geriatric cats15 and therefore was used on the grounds that it was derived from a population that is more likely to be age matched to the cats included in the present study. An earlier study identified a reference range for serum TSH of 0.01–0.21 ng/mL, a range that is slightly higher than that used in the present study; however, that reference range was derived from samples obtained from 21 young cats.28
In the present study no attempt was made to evaluate the presence of clinical signs of hypothyroidism in cats with iatrogenic hypothyroidism. Lethargy and obesity are the most commonly reported clinical signs of feline hypothyroidism,24 although other signs such as myxedema and alopecia have also been reported in 1 hypothyroid cat.29 The present study found no significant difference in the weight or body condition score of animals defined as hypothyroid and euthyroid. There was a lack of complete body condition score data, because of the retrospective nature of the present study, and this may have limited the assessment of obesity as a sign of hypothyroidism. The other main clinical sign of hypothyroidism, lethargy, can be multifactorial and difficult to evaluate in the geriatric cat.
In conclusion, cats with iatrogenic hypothyroidism were more likely to develop azotemia in the 6 months after treatment of hyperthyroidism than cats defined as euthyroid. Hypothyroid cats with azotemia also had shorter survival times than nonazotemic cats, whereas there was no difference in the survival of euthyroid cats with and without azotemia. This suggests that iatrogenic hypothyroidism can contribute to the development of azotemia and reduced survival times after treatment of hyperthyroidism. Restoration of euthyroidism may be indicated in these cases to normalize renal function, although further studies are required to assess the changes in renal function after restoration of euthyroidism in cats with iatrogenic hypothyroidism.
aGraham P. Measurement of feline thyrotropin using a commercial canine-specific immunoradiometric assay. J Vet Intern Med 2000; 14:342 (abstract)
bIdexx Laboratories, Wetherby, UK
cRoyal Canin Renal Diet, Melton Mowbray, Leicestershire, UK
dAluminium hydroxide, 10–30 mg/kg q8–12 hours, Alucaps, Loughborough, UK
eRoyal Veterinary College Diagnostic Laboratories, North Mymms, Hatfield, UK
fSPSS 16.0 for Windows, SPSS Inc, Chicago, IL
gWakeling J, Rob C, Elliott J, et al. Survival of hyperthyroid cats is not affected by posttreatment azotaemia. J Vet Intern Med 2006; 20:1523 (abstract)