Efficacy of iopanoic acid for treatment of spontaneous hyperthyroidism in cats

Abstract

Iopanoic acid is an iodine containing oral cholecystographic agent that has been used to treat hyperthyroidism in humans and has recently been evaluated in an experimental model of feline hyperthyroidism. The aim of this study was to evaluate the efficacy of iopanoic acid in cats with spontaneous hyperthyroidism. Eleven cats were included in the study. Eight were treated initially with 50 mg orally q 12 h and three were treated with 100 mg orally q 12 h. Prior to treatment (baseline) and at 2, 4, and 12 weeks of treatment, owner questionnaires, physical exams, complete blood count, biochemistry analyses, and T₃ and T₄ concentrations were evaluated. The mean serum T₃ concentration decreased with treatment at all time periods compared to baseline. Mean T₄ concentrations were increased at weeks 4 and 12 compared to baseline. Five cats had a partial response during the initial 4 weeks of therapy, but the effects were transient and no significant improvements in clinical signs or physical exam findings were noted at any time period. Results suggest that iopanoic acid may be beneficial for acute management of thyrotoxicosis in some cats, but is not suitable for long-term management.

Hyperthyroidism is the most common endocrinopathy in cats. Medical management is usually accomplished by inhibiting synthesis of thyroid hormones through the administration of methimazole. However, adverse effects necessitating discontinuation of methimazole such as self-induced excoriation, hepatotoxicity, and blood dyscrasias occur in up to 10% of cats treated. ^1–4 Alternative medical treatments for hyperthyroidism include propylthiouracil and oral cholecystographic agents. Serious side effects appear to occur more commonly in cats administered propylthiouracil than methimazole, so it is no longer recommended for use in cats. ⁵ Sodium ipodate, an oral cholecystographic agent (OCA) is effective in treatment of some cats with hyperthyroidism, but is no longer available. ^6,7 A related compound, iopanoic acid, has replaced ipodate for use in hyperthyroid humans. It has a rapid onset of action, and primarily acts by inhibiting de-iodination of thyroxine (T₄) to 3,5,3′-triiodothyronine (T₃). ⁸

In a previous study, the authors evaluated the effects of iopanoic acid in cats administered levothyroxine to induce a hyperthyroid state. ⁹ Iopanoic acid was effective in decreasing serum T₃ concentrations. However, the efficacy of iopanoic acid on relief of clinical signs of hyperthyroidism was not apparent, possibly due to the experimental model used. The purpose of the present study was to evaluate the effects of iopanoic acid in cats with spontaneous hyperthyroidism.

Materials and methods

Animals

Cats were enrolled from those presenting to the Virginia-Maryland Regional College of Veterinary Medicine (VMRCVM), Virginia Tech, Blacksburg, VA, and All Cats HealthCare Clinic (ACHC), Gainesville, FL from October 2006 to April 2009. Criteria for inclusion were an elevated serum total T₄ concentration, clinical findings consistent with hyperthyroidism (eg, vomiting, diarrhea, weight loss, tachycardia, palpable thyroid gland), and the absence of concurrent severe illnesses (eg, renal failure, neoplasia). Cats previously treated with methimazole were required to have treatment withdrawn for at least 2 weeks prior to study. The study was approved by the Virginia Tech Animal Care and Use Committee.

Treatment protocol

Cats were administered 50 mg of iopanoic acid (Island Pharmacy Services, WI, USA; Franck's Pharmacy, FL, USA) orally q 12 h for up to 12 weeks. If after 4 weeks of treatment the serum T₃ concentration was above the reference interval or signs of hyperthyroidism were still present, the dose of iopanoic acid was increased to 100 mg q 12 h. If poor control of hyperthyroidism was noted at 6 weeks, owners could elect to stop the trial. Cats that developed another illness during the trial were removed at the time the illness was found. After the first eight cats completed the study, the starting dosage of iopanoic acid was increased to 100 mg q 12 h because of the lack of clinical efficacy at the lower dose. Compliance with iopanoic acid administration was assessed by counting the number of capsules remaining at each time period.

Patient evaluation

Cats were evaluated before treatment (baseline) and at 2, 4, and 12 weeks of treatment. At each evaluation, the owner completed a standardized history to determine if signs attributable to hyperthyroidism (eg, vomiting, diarrhea, or changes in appetite, activity level, water consumption, urination, or breathing pattern) were present and if these variables had increased, decreased, or stayed the same since the previous evaluation or during the previous 6 months for the initial evaluation. Standardized physical examinations were completed by one of the authors or the practice owner at ACHC at each evaluation.

Sample analysis

Blood was collected at baseline and weeks 2, 4, and 12 of treatment for complete blood count (CBC), biochemistry analysis, and assay of serum concentrations of T₃ and T₄ (Antech Diagnostics, NY, USA). Biochemical analysis included blood urea nitrogen (BUN), creatinine, albumin, globulin, total protein, total bilirubin, glucose, cholesterol, calcium, phosphorus, sodium, potassium, chloride, and magnesium concentrations, and alkaline phosphatase (ALKP), alanine aminotransferase (ALT), and gammaglutamyl transferase (GGT) activities. Serum T₃ and T₄ concentrations were determined using commercially available radioimmunoassay kits (Coat-A-Count Total T₃ and Coat-A-Count Total T₄, Diagnostics Products Corporation, Los Angeles, CA) previously validated in cats. ¹⁰ In addition, urine was collected at baseline evaluation and submitted to the same laboratory for complete urinalysis.

Partial responders

Cats that had stable body weight during the first 4 weeks of treatment were classified as partial responders. Cats that lost weight during this period were classified as non-responders. Differences between groups for clinical findings, and T₃ and T₄ concentrations were compared.

Statistical analysis

Cats were separated into one of three groups for analysis: cats receiving 50 mg iopanoic acid q 12 h (50 mg group); cats receiving 100 mg iopanoic acid q 12 h (100 mg group); and cats receiving either dose (combined group). Differences between time periods within groups for CBC, biochemistry, T₃ and T₄ concentrations, body weights, and heart rates were compared using a mixed model analysis of variance (ANOVA) procedure using commercial statistical software (SAS 9.1.3, SAS Institute, Cary, NC, USA). Log transformation of data was performed as needed. Data for bilirubin concentrations was not normally distributed and differences were compared using the Friedman's χ² test for non-parametric data. Differences in changes at each time point for questionnaire data were compared using a χ² test. The level of significance was set at P<0.05.

Results

Animals

Twelve cats were enrolled in the study, but analysis was restricted to 11 cats as one in the 100 mg group was excluded due to developing an acute hepatopathy within the first 2 weeks of treatment. Median (range) age of the 11 cats was 13 years (7–20). There were six altered females and five altered males. Median time from diagnosis of hyperthyroidism to study entry was 6 months (range, 0–18). Seven cats had been previously treated with methimazole. Of these, four had reported reactions to methimazole including facial pruritus (three cats) and thrombocytopenia (one cat). Cats previously treated with methimazole had shown a positive clinical response.

Clinical findings

At baseline evaluation, owners reported weight loss in seven cats and no change in weight in four cats. Vomiting was noted in seven cats, with frequency ranging from one to three times a week. Diarrhea was noted in two cats, with frequency reported as three to four times a day and once every 3 weeks, respectively. Appetite was considered normal in eight, increased in one, and decreased in two cats. Activity level was considered normal in eight, increased in two, and decreased in one cat. Water consumption was reported to be normal in seven, increased in three, and decreased in one cat. Urine volume was considered normal in nine, increased in one, and decreased in one cat. Breathing pattern was judged normal in eight cats and increased in three cats.

During the course of treatment there were no statistically significant changes in the owner observed measures. Clinically, there was improvement in individual cats. Vomiting resolved in one cat and diarrhea resolved in both affected cats. One cat with an increased appetite at baseline had a decreased appetite at weeks 2 and 4, but increased at 12 weeks. One cat with normal activity level at baseline had decreased activity at weeks 4 and 12. Water consumption decreased in one cat. Urine volume was reported to be decreased in another.

At baseline the mean±SD body condition score (BCS) was 4.1±1.6 out of 9 with a mean body weight of 4.17±1.18 kg. Eight cats had palpable thyroid gland enlargement with six being unilateral and two bilateral. Eight cats had a heart murmur on auscultation, one cat had a gallop rhythm, and one cat had a heart murmur and a gallop rhythm. The heart murmur resolved in one cat at week 4 and a new heart murmur was ausculted in one cat at week 4.

CBC

No clinically important abnormalities on CBC at baseline were present in eight cats. Three cats had mild (1392/μl, reference interval 0–1000/μl), moderate (2728/μl), or marked (8070/μl) eosinophilia. In the latter cat, eosinophils were decreased by 4 weeks (2366/μl), but were markedly increased again at 12 weeks (10,323/μl). There were no statistically significant changes in mean parameters on the CBC during treatment compared to baseline in the 50 mg, 100 mg, or combined groups.

Biochemistry

For all cats, there were no clinically important abnormalities in glucose, BUN, creatinine, total protein, albumin, bilirubin, cholesterol, calcium, phosphorus, sodium, potassium, chloride, globulin, triglycerides, GGT, or magnesium at baseline. There were no statistically significant differences in means of these parameters with treatment compared to baseline for the 50 mg, 100 mg, and combined groups except for creatinine. In the 100 mg and combined groups, creatinine was significantly increased at week 12 compared to baseline (Table 1).

Table 1.

Mean creatinine, ALT and ALKP concentrations by group for each time period.^*

Period	Creatinine			ALT			ALKP
	Group			Group			Group
	50 mg	100 mg	Both	50 mg	100 mg	Both	50 mg	100 mg	Both
Baseline	1.05±0.43	0.7±0.0	0.95±0.40	125.4±73.6	434±342.5	209.5±219.2	74.6±34.5	187.3±147.8	105.4±89.3
n=8	n=3	n=11	n=8 (5)	n=3 (2)	n=11 (7)	n=8 (2)	n=3 (2)	n=11 (4)
Week 2	1.13±0.34	0.73±0.06	1.02±0.34	174.9±206.2	269.3±282.3	200.6±218.2	74.1±26.7	143.3±117.7	93±65.7
n=8	n=3	n=11	n=8 (4)	n=3 (2)	n=11 (6)	n=8 (1)	n=3 (1)	n=11 (2)
Week 4	1.08±0.29	0.8±0.1	1.0±0.28	161±122.4	216±198.5	176±138.0	73±27.0	134.3±96.1	89.7±56.4
n=8	n=3	n=11	n=8 (4)	n=3 (2)	n=11 (6)	n=8 (1)	n=3 (1)	n=11 (2)
Week 12	1.18±0.58	0.95±0.07†	1.11±0.48†	114.8±84.0	83.5±23.3	105.9± 70.9	60.2± 25.7	88.5±31.8	68.3±28.3
n=5	n=2	n=7	n=5 (2)	n=2 (1)	n=7 (3)	n=5 (1)	n=2 (0)	n=7 (1)

^*Creatinine concentrations in mg/dl as mean±SD. Reference interval 0.6–2.4. All individual values were within the reference interval. ALT and ALKP concentrations in U/l as mean±SD with reference intervals of 10–100 and 6–102, respectively. Values in () represent number of individual values above reference interval.

^†Value significantly different from baseline in that group, P<0.05.

There were no statistically significant differences in mean ALT or ALKP activities with treatment compared to baseline for the 50 mg, 100 mg, and combined groups (Table 1). One cat each in the 50 mg and 100 mg groups had elevated ALT activity at baseline that returned to reference interval by 2 and 12 weeks of treatment, respectively. One cat each in the 50 mg and 100 mg groups had elevated ALKP activity at baseline that both returned to reference interval by week 2 of treatment.

Thyroid hormones

Three of eight cats in 50 mg group and all three cats in 100 mg group had increased serum T₃ concentrations prior to therapy. In all groups, the mean T₃ concentrations were significantly decreased compared to baseline at all time periods (Table 2). During therapy, all cats had T₃ concentrations within the reference interval at all time points. All cats had increased T₄ concentrations prior to therapy. In the 50 mg group, mean serum T₄ concentration was significantly increased at week 12 compared to baseline. When groups were combined, T₄ concentrations were significantly increased at weeks 4 and 12 compared to baseline. Serum T₃:T₄ ratios were significantly decreased in all groups at all times compared to baseline except for the 100 mg group at week 2.

Table 2.

Mean T₃ and T₄ concentrations by group for each time period.^*

Period	T3			T4			T3/T4 ratio
	Group		Group			Group
	50 mg	100 mg	Both	50 mg	100 mg	Both	50 mg	100 mg	Both
Baseline	196.1±97.6	208.0±44.0	199.3±84.1	11.4±6.9	11.9±1.1	11.5±5.8	19.3±8.3	17.9±5.5	18.9±7.4
n=8	n=3	n=11	n=8	n=3	n=11	n=8	n=3	n=11
Week 2	86.5±27.0‡	109.7±38.6†	92.8±30.4‡	13.3±6.4	15.0±2.4	13.8±5.7	7.1±2.1‡	7.5±2.5	7.2±2.1‡
n=8	n=3	n=11	n=8	n=3	n=11	n=8	n=3	n=11
Week 4	76.1±28.9‡	112.7±12.7†	86.1±30.1‡	13.0±6.1	17.5±6.8	14.2±6.3†	6.3±1.4‡	6.4±1.8†	6.3±1.5‡
n=8	n=3	n=11	n=8	n=3	n=11	n=8	n=3	n=11
Week 12	78.2±39.0‡	100.5±29.0†	84.6±35.7‡	12.7±4.2‡	17.9±8.6	14.4±5.7‡	5.2±1.6‡	5.9±1.2†	5.4±1.4‡
n=5	n=2	n=7	n=4	n=2	n=6	n=4	n=2	n=6

^*T₃ concentrations in ng/dl, reference interval 40–150, T₄ concentrations in μg/dl, reference interval 0.8–4.0, and T₃/T₄ ratios as mean±SD.

^†Denotes values significantly different from baseline at P<0.05.

^‡Denotes values significantly different from baseline at P<0.01.

Heart rate/body weight

Mean heart rates were not significantly different in any group during treatment compared to baseline (data not shown). Because not all cats completed the study, body weight analysis was divided into six groups. All cats in each of the three groups (50 mg, 100 mg, and combined) were included through week 4 (n=11). Cats that completed all 12 weeks of the study (n=7) were analyzed separately at baseline and weeks 2, 4, and 12 in each of the groups (censored groups).

Mean body weights decreased over time in all groups through week 4 and in censored groups through week 12 (Table 3). For all cats, mean body weights were significantly decreased at week 4 compared to baseline in the 50 mg and combined groups. For the censored groups, mean body weights were significantly decreased at week 12 compared to baseline in the 50 mg and the combined groups.

Table 3.

Mean body weight by group for each time period. ^*

Period	50 mg	50 mg cens§	100 mg	100 mg cens§	Both	Both cens§
Baseline	4.23±1.28	4.67±1.26	4.02±1.10	3.68±1.31	4.17±1.18	4.39±1.25
n=8	n=5	n=3	n=2	n=11	n=7
Week 2	4.15±1.26	4.60±1.20	3.96±1.00	3.60±1.10	4.09±1.15	4.32±1.18
n=8	n=5	n=3	n=2	n=11	n=7
Week 4	4.06±1.19‡	4.50±1.14	3.89±1.01	3.52±1.09	4.01±1.10†	4.22±1.14
n=8	n=5	n=3	n=2	n=11	n=7
Week 12		4.39±1.17‡		3.41±0.61		4.11±1.09‡
	n=5		n=2		n=7

^*Body weights in kg as mean±SD.

^†Denotes values significantly different from baseline at P<0.05.

^‡Denotes values significantly different from baseline at P<0.01.

^§Censored for cats not completing all 12 weeks of study.

Partial responders vs non-responders

Body weight was stable through 4 weeks of treatment in five cats (three in the 50 mg group and two in the 100 mg group) and increased at 12 weeks in one of these cats (partial responders). Two of the partial responders withdrew from the study before 12 weeks, while the other two had lost weight at 12 weeks. No other clinical findings improved in the partial responder group.

All five cats in the partial responder group had increased T₃ concentrations at baseline compared to 1/6 cats in the non-responder group. Mean (±SD) T₃ concentration at baseline for the partial responders, 272.4±71.7 ng/dl (reference interval 40–150 ng/dl), was significantly different from non-responders, 138.5±16.5 ng/dl (P<0.05). Mean changes in T₃ concentrations between baseline and week 4 for partial responders and non-responders were 152.8±71.6 ng/dl and 83.0±48.1 ng/dl, respectively, but were not significantly different. At baseline, mean T₄ concentration in the partial responders was 14.6±7.3 μg/dl (reference interval 0.8–4.0 μg/dl) and in the non-responders was 8.9±2.5 μg/dl. This difference was not significant.

Cats not completing study

A total of four cats, three in the 50 mg and one in the 100 mg groups, did not complete the study. One cat in the 50 mg group was suspected to have a recurrence of previously diagnosed cholangiohepatitis during the fifth week of the study and was removed. This cat had not shown improvement in clinical signs of hyperthyroidism during the treatment period. A second cat in this group left the study after 4 weeks due to a lack of clinical response despite a normal T₃ concentration. The third cat in the 50 mg group had the dosage increased to 100 mg q 12 h after 4 weeks due to lack of clinical response despite a normal serum T₃ concentration and left the study after week 6 because of persistent signs of hyperthyroidism. In the 100 mg group, the dosage was increased to 100 mg q 8 h in one cat at 4 weeks due to lack of clinical response, despite a normal T₃ concentration. Clinical signs of hyperthyroidism did not improve and it was withdrawn from the study after 6 weeks.

Adverse effects

Most cats tolerated iopanoic acid administration without adverse effects. One cat in the 50 mg group developed a decreased appetite after the dose was increased to 100 mg q 12 h. Appetite improved after stopping the medication. One cat in the 100 mg group developed significant hepatic disease within 2 weeks of starting the study. Hepatic lipidosis was diagnosed on cytology of a fine needle aspirate and the illness resolved rapidly and completely with supportive care. It is unclear if this was related to the iopanoic acid or an underlying disease process. Another cat in the 50 mg group, with a history of cholangiohepatitis, developed clinical and clinicopathologic abnormalities suggestive of cholangiohepatitis after 5 weeks of therapy. Signs resolved rapidly with supportive care.

Discussion

The results of this study are consistent with those noted previously using iopanoic acid in an experimental model of feline hyperthyroidism. ⁹ In the present study of cats with spontaneous hyperthyroidism, the mean serum T₃ concentration decreased by >50% while the serum T₄ concentration increased. The changes in thyroid hormones are due in part to the inhibitory effect of iopanoic acid on the activity of type I and II de-iodinases, the enzymes responsible for catalyzing the 5′-de-iodination of T₄ to T₃. Because approximately 80% of plasma T₃ is derived from de-iodination of T₄ in peripheral tissues, reduced activity of de-iodinases has a substantial impact on serum T₃ concentration. ¹¹ Decreased cellular uptake of T₄ would result in a similar decrease in generation of T₃. Oral cholecystographic agents, including iopanoic acid, have been shown to inhibit cellular uptake of thyroid hormones, and this mechanism likely was an additional factor decreasing serum T₃ in the present study. ^12,13

A fairly consistent finding in hyperthyroid humans administered OCAs is reduction in serum T₄ concentrations which has been postulated to result from large amounts of inorganic iodine released from OCAs causing a Wolff-Chaikoff effect and decreasing release of thyroid hormones from the thyroid gland. ⁸ A previous study in cats showed a significant reduction in T₄ concentrations with potassium iodate therapy. ¹⁴ However, cats in the present study had an increase in serum T₄ concentrations. This may suggest there was not enough iodine released to affect thyroid function either related to the dose of iopanoic acid used or differences in metabolism of OCAs between cats and humans.

Our results also differ from those of hyperthyroid cats administered ipodate, where serum T₄ concentrations were unchanged. The reduction in T₄ concentrations induced by OCAs is dose-dependent, requiring a higher dose than that which inhibits de-iodination. ¹⁵ While it is possible that a higher dose of iopanoic acid could have prevented the observed increase in serum T₄ concentrations, this seems unlikely given that the mean T₄ concentration in cats receiving 100 mg q 12 h was 35% higher than those receiving half that dose. Similar to the cats in the present study, serum T₄ concentration increases in euthyroid humans, presumably due to increased thyrotropin secretion. ¹⁶ It is possible that a similar mechanism might play a role in cats administered iopanoic acid, where impaired de-iodination of T₄ in thyrotropes could result in decreased negative feedback and increased thyrotropin secretion. Unfortunately, serum thyrotropin was not measured in the cats of this study. Other mechanisms that could contribute to the observed increase in serum T₄ are reduced transport of T₄ into cells, decreased de-iodination of T₄, and increased T₄ production due to continued growth of the adenomatous thyroid tissue. It is not clear why a similar increase in serum T₄ concentration was not noted in a previous report of ipodate administration to hyperthyroid cats despite a similar reduction in serum T₃ concentrations. ⁶

Despite the decrease in serum T₃ concentrations, clinical signs did not consistently improve or resolve. This is similar to our observations using iopanoic acid in experimentally-induced hyperthyroidism in cats. However, in the current study there was some evidence of reduction in the severity of hyperthyroidism. Five cats maintained their body weight and some had resolution of other signs such as diarrhea and vomiting during the initial 4 weeks of treatment. The variable and transient nature of the response is similar to what has been reported in some hyperthyroid humans treated with OCAs as well as in hyperthyroid cats administered ipodate. ^6,17,18 For this reason, OCAs are primarily used in conjunction with other antithyroid treatments for the rapid preparation of patients prior to surgery or in cases of acute thyrotoxicosis rather than long-term management. ⁸

It is uncertain why iopanoic acid had such poor efficacy compared to the previous study of ipodate in cats with spontaneous hyperthyroidism where 66% of cats showed a good response to treatment. ⁶ Good compliance was confirmed in all cases by pill counts at recheck visits. The decrease in T₃ concentrations into the reference interval is evidence that the iopanoic acid was absorbed and inhibited the conversion of T₄ to T₃ as expected. One major difference between this and the study of ipodate is that only 6/11 cats in the current study had increased T₃ concentrations at baseline compared to all 12 of the cats in the ipodate study. Because 5/6 cats in the present study with elevated T₃ had some response to iopanoic acid, pre-treatment increases in T₃ concentrations may be predictive of response to therapy with OCAs. The severity of hyperthyroidism in cats at the time of inclusion (mean 11.5 μg/dl) may also have resulted in poor efficacy as T₄ has thyromimetic activity and T₄ concentrations were not decreased by the iopanoic acid.

Iopanoic acid inhibits thyroid stimulating hormone (TSH)-induced secretion of T₄ from the thyroid gland at high concentrations. Because most human patients with hyperthyroidism have Graves’ disease caused by the formation of antibodies that activate the thyrotropin receptors on the thyroid gland, OCAs may be particularly effective at suppressing T₄ secretion in these patients. In comparison, feline hyperthyroidism is the result of TSH-independent, autologous thyroid function. Thus, inhibition of T₄ secretion may not occur in cats, resulting in an increase in T₄ concentrations that may perpetuate clinical signs of hyperthyroidism.

Despite careful screening of patients for concurrent illness, the presence of concurrent disease, particularly gastrointestinal disease, cannot be excluded and may have contributed to the clinical signs. One cat developed recurrence of cholangiohepatitis, but had stable weight during the 4 weeks of therapy. Another cat that left the study was suspected to have concurrent gastrointestinal disease and this may have contributed to the lack of response. Ideally, all cats would have been followed after the study to determine response to other forms of therapy. However, most were lost to follow-up or owners were inconsistent with treatment.

Another limitation was the small number of cats evaluated. Initially, 16 cats were to be evaluated in the 50 mg group. However, due to the poor clinical response seen at this dose in the initial eight cats, further cats were enrolled at the 100 mg dose. When all three cats at this dose showed no clinical improvement, the authors elected to stop the trial for ethical reasons. It is possible that evaluating a larger group of cats, particularly at the higher dose, may have shown some benefit in a small number.

In conclusion, iopanoic acid appears ineffective for long-term control of feline hyperthyroidism at the doses used in this study. However, the stability of disease in some cats during the first 2–4 weeks of therapy suggests that iopanoic acid may be suitable for short-term management prior to surgery or radioiodine therapy, particularly when methimazole is not tolerated.