SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacological management of hyperthyroidism
  5. Monitoring antithyroid drug treatment
  6. Antithyroid drug treatment and renal function
  7. Antithyroid drug treatment and hypothyroidism
  8. Conclusion
  9. References

Pharmacological management of feline hyperthyroidism offers a practical treatment option for many hyperthyroid cats. Two drugs have been licensed for cats in the last decade: methimazole and its pro-drug carbimazole. On the basis of current evidence and available tablet sizes, starting doses of 2·5 mg methimazole twice a day and 10 to 15 mg once a day for the sustained release formulation of carbimazole are recommended. These doses should then be titrated to effect in order to obtain circulating total thyroxine (TT4) concentrations in the lower half of the reference interval. Treated cases should be monitored for side-effects, especially during the first months of treatment. Some side-effects may require discontinuation of treatment. At each monitoring visit, clinical condition and quality of life should also be evaluated, with special attention to possible development of azotaemia, hypertension and iatrogenic hypothyroidism. When euthyroidism has been achieved, monitoring visits are recommended after 1 month, 3 months and biannually thereafter. Cats with pre-existing azotaemia have shorter survival times. However, development of mild azotaemia during the initial course of treatment, unless associated with hypothyroidism, does not appear to decrease survival time. The long-term effects of chronic medical management require further study.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacological management of hyperthyroidism
  5. Monitoring antithyroid drug treatment
  6. Antithyroid drug treatment and renal function
  7. Antithyroid drug treatment and hypothyroidism
  8. Conclusion
  9. References

Hyperthyroidism in cats is a life-threatening disease requiring prompt veterinary attention. In affected cats, euthyroidism can be achieved by pharmacological therapy, thyroidectomy, radioiodine therapy or an iodine-restricted diet. Several publications surrounding medical management exist, occasionally with conflicting opinions. As a consequence, the authors held a meeting in September 2011 (supported by Dechra Veterinary Products Limited), where guidelines relating to treatment with antithyroid drugs, subsequent monitoring, and two challenging complications, unmasking of underlying renal disease and iatrogenic hypothyroidism, were developed.

When possible, an evidence-based approach was used and individual references were assigned an evidence level (Table 1a). When appropriate, the authors aimed to reach a consensus view and an overall evidence grade (OEG) was given (Table 1b).

Table 1. Grading of level of evidence for individual references (a) and of overall level of evidence for consensus statements (b) (Adapted from Oxford Centre for Evidence-Based Medicine 2009, Elwood et al. 2010)
(a) Study typeLevel of evidence (LOE)
  1. a

    This principle is met when all patients died before the treatment became available, but some now survive on it; or when some patients died before the treatment became available, but none now die on it

Systematic review (with homogeneity) of randomised controlled clinical trials1a
Individual randomised controlled clinical trial (with narrow confidence interval)1b
All or none principlea1c
Systematic review (with homogeneity) of cohort studies2a
Individual cohort study (including low quality randomised controlled clinical trials; e.g. <80% follow-up) or well-controlled laboratory study2b
“Outcomes” Research; ecological studies2c
Systematic review (with homogeneity) of case-control studies3a
Individual case-control study or weak laboratory study3b
Case-series (and poor quality cohort and case-control studies)4
Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”5
(b) Group of studiesOverall evidence grade (OEG)
Consistent level 1 studiesA
Consistent level 2 or 3 studies or extrapolations from level 1 studiesB
Level 4 studies or extrapolations from level 2 or 3 studiesC
Level 5 evidence or troublingly inconsistent or inconclusive studies at any levelD

Pharmacological management of hyperthyroidism

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacological management of hyperthyroidism
  5. Monitoring antithyroid drug treatment
  6. Antithyroid drug treatment and renal function
  7. Antithyroid drug treatment and hypothyroidism
  8. Conclusion
  9. References

Antithyroid drugs can be used long-term as sole treatment or short-term to stabilise the patient before surgery or anaesthesia, or if radioiodine therapy is not immediately available (Mooney 2001 [5], Feldman & Nelson 2004 [5]).

Two main pharmaceutical active ingredients are available as veterinary licensed drugs in Europe: methimazole (Felimazole®; Dechra Veterinary Products) and carbimazole (Vidalta®; MSD Animal Health). Advantages and disadvantages of pharmacological management of hyperthyroidism are presented in Table 2. Some authors speculate that after several years of medical therapy, thyroid tissue may become malignant (Peterson & Broome 2012 [4]). It was agreed that this possibility warrants further investigation.

Table 2. Advantages and disadvantages of antithyroid drugs for treatment of hyperthyroid cats
AdvantagesDisadvantagesComments
Effective in most casesNot curativeBenign adenomatous hyperplasia (adenoma) is present in about 98% of hyperthyroid cats (Mooney 2001)
Not recommended in rare cases of functioning thyroid carcinoma (Mooney 2001)
Poor or no response in a small proportion of cats with thyroid adenoma (Peterson et al. 1988)
Stabilisation of the disease provided to cats while awaiting radioiodine treatment or before surgery (risk of metabolic and cardiac complications during anaesthesia reduced) (Mooney 2001)Iatrogenic hypothyroidism is possible 
Drug-induced side-effects (Tables 3 and 4)
 Good compliance required for successful treatment 
Reversibility (allows trial therapy to assess the effects of restoration of euthyroidism on renal function)Reversibility (Trepanier 2007) 
 Skin contact with the active ingredients, as skin allergies are possible with non-coated tablets and transdermal gelsSplitting of coated tablets is contraindicated
Wear gloves when applying transdermal gel
Widely available  
Cost-effective (short-term perspective) (Trepanier 2007)Less cost-effective from a long-term perspective compared to potentially curative treatments (thyroidectomy or radioiodine treatment) 

Pharmacodynamic and pharmacokinetic properties of the drugs

Methimazole acts by blocking thyroid peroxidase and thus inhibits biosynthesis of thyroid hormones (Mooney 2001 [5]). Carbimazole is rapidly and almost completely converted to an equimolar amount of methimazole after oral absorption. Taking into account the respective molecular weights, approximately 5 mg carbimazole (in tablets, licensed for use in humans) is equivalent to 3 mg methimazole (Peterson & Aucoin, 1993 [2b]). As in humans (Okuno et al. 1987 [3b]), methimazole presumably accumulates in the feline thyroid glands [OEG C].

In healthy cats, oral methimazole (Trepanier et al. 1991 [3b]) and carbimazole (Frénais et al. 2008 [2b]) are well absorbed and the pharmacokinetic parameters are not significantly altered by hyperthyroidism (Trepanier & Peterson 1991 [3b]). After single oral administration of methimazole or sustained-release carbimazole tablets, Longhofer et al. (2010) [2b]) showed that pharmacokinetic parameters were similar when differences in effective methimazole dose were taken into consideration.

When methimazole is applied transdermally, poor and variable absorption has been reported at a dose of 5 mg when administered once (Hoffman et al. 2002 [2b])). Using a dose of 10 mg in a lipophilic formulation and repeated dosing, Hill et al. (2011 [4]) obtained higher circulating methimazole concentrations in hyperthyroid cats. Differences in excipients used may explain this difference. Furthermore, the possibility of oral ingestion during grooming has to be considered [OEG D].

Starting dose of antithyroid drugs

Methimazole

In 1988, Peterson et al. [4] recommended starting with an oral daily dose of 10 to 15 mg methimazole in two or three divided doses depending on the severity of the thyrotoxicosis. Carbimazole was initially recommended at an oral dose of 5 mg three times a day, the higher dose possibly reflecting the loss of activity when converted to methimazole. These dose recommendations do not appear to be based on any prior pharmacokinetic studies in healthy or hyperthyroid cats but were probably dictated by clinical experience and available tablet size. Later, lower methimazole starting doses such as 2·5 mg twice a day (Feldman & Nelson 2004 [5]) or even 1·25 mg twice a day (Trepanier 2007 [5]) have been suggested, based in part on the assumption that cats are less severely affected now than before. Felimazole® Summary of Product Characteristics (SPC Anonymous, 2012a-b) recommends starting with 2·5 mg twice a day, irrespective of bodyweight and initial circulating TT4 concentration, based on a study showing that after 3 weeks of treatment at this dosage, 79% of cats were euthyroid (Publicly Available Assessment Report [4], Anonymous 2008). A dose of 2·5 mg twice a day is also associated with less serious side-effects than 5 mg once a day, twice a day or three times a day (Felimazole FOI [4], Anonymous 2009). The panel recommends using 2·5 mg twice a day as a starting dose [OEG C].

Considering higher methimazole starting doses, some authors recommended never using more than 5 mg/day (Feldman & Nelson 2004 [5]), while Peterson et al. (1988 [4]) suggested using 5 mg twice or three times a day in cases of extremely elevated TT4 concentrations. According to the panel, there is no evidence that a dose higher than 5 mg/day could increase the risk of unmasking renal disease [OEG D]. Actually, a starting dose of 5 mg twice a day can be used in cases of extremely elevated TT4 concentrations if renal parameters are within reference limits [OEG D]. Regarding transdermal methimazole, Hoffmann et al. (2003 [4]) obtained normalisation of TT4 concentrations using various dosing regimes (2·5 to 10 mg twice a day) in seven of eight cats. Sartor et al. (2004 [1b]) demonstrated in a randomised controlled trial involving 27 cats that two-thirds became euthyroid after 4 weeks of 2·5 mg twice a day. Lécuyer et al. (2006 [4]) used 5 mg twice a day and demonstrated improvement of clinical condition and normalisation of TT4 concentration after 28 days in all 10 cats. To the authors’ knowledge, no strict transdermal methimazole absorption has thus far been demonstrated [OEG D]. Topical preparations, when available, could be useful for uncooperative cats, and the same or a slightly higher starting dose as for the oral route should be used [OEG D].

Once a day versus twice a day dosing

Once daily administration can be an attractive option for improved owner compliance. The authors prefer twice a day dosing during treatment induction, but a once a day regimen can be considered after attaining euthyroidism [OEG B]. Indeed euthyroidism can still be reached using methimazole once daily in 71% of 17 cats but only after 4 weeks, while 87% of 15 cats were euthyroid after 2 weeks of twice a day dosing (Trepanier et al. 2003 [1b]).

Carbimazole

Using human carbimazole tablets, a starting dose of 5 mg three times a day showed a good level of achievement of biochemical euthyroidism (Mooney et al. 1992 [4], Bucknell 2000 [4]). Feldman & Nelson (2004 [5]) recommend using 2·5 mg twice a day for 7 days, then 5 mg twice a day for 3 weeks.

The sustained-release tablets for veterinary use (Vidalta®; MSD Animal Health) are registered with a starting dose of 15 mg once a day [or 10 mg once a day when TT4 concentration is mildly increased (50 to 100 nmol/L)] (Summary of Product Characteristics Anonymous, 2012c-d). In a clinical study, after 10 days of treatment at 15 mg once a day euthyroidism was achieved in 70% of 40 cats (Frénais et al. 2009 [4]) with good tolerability. On the basis of methimazole equimolar equivalence and clinical experience, a dose of 10 mg once a day would be a good starting dose in most cases [OEG D].

Dose adjustments

As most cats are euthyroid within 2 to 3 weeks of treatment with antithyroid drugs (Felimazole Publicly Available Assessment Report [4], Anonymous 2008, Frenais et al. 2009 [4]), the panel recommends monitoring TT4 after that time period [OEG C].

If the cat is still hyperthyroid, methimazole dose adjustments can be made in increments of 2·5 mg/day until euthyroidism is achieved (Feldman & Nelson 2004 [5]). In a registration study (NADA 141-292 [4], Anonymous 2009), after 20 weeks of treatment, varying maintenance doses had been selected with the majority of cats receiving 2·5 mg twice a day (34 of 58 cats) or 2·5 mg once a day (12 of 58 cats). Of 81 cats given methimazole for 30 to 1000 days, the final maintenance dosage ranged from 5 to 20 mg/day in 80 cats with a median dose of 10 mg/day (Peterson et al. 1988 [4]). When maintenance doses in excess of 10 mg/day are required, compliance should be questioned (Feldman & Nelson 2004 [5]). If TT4 concentration drops below the lower end of the reference interval, the dosage should be reduced in decrements of 2·5 mg/day [OEG D].

Regarding transdermal methimazole, only Hill et al. (2011 [4]) mentioned dose adjustments. A similar scheme as for oral methimazole can probably be used, and, in case of local skin irritation, switching to oral administration can be considered [OEG D].

For carbimazole, the dose may be adjusted, based on clinical signs and TT4 concentration, as early as after 10 days of treatment and dose increments should not be greater than 5 mg (Vidalta®’s SPC [5], Anonymous 2012c-d). In a clinical study, the dose used throughout the 53-week study was 10 mg once a day or 15 mg once a day in 11 of 18 cats (Frenais et al. 2009 [4]). Five cats required a dose of 20 mg once a day at the end of the study. One cat in the clinical study required a daily dose of less than 10 mg carbimazole. In cases such as this, dosing on alternate days could be considered [OEG D].

Side-effects of antithyroid drugs

Side-effects reported with the use of methimazole or carbimazole are summarised in Tables 3 and 4.

Table 3. Suspected adverse drug reactions to oral and transdermal methimazole
Side-effectsDose range (total/day)Route of administrationFrequency (pooled number of cats) (references)Time to onset after treatment start (if known)RecommendationMonitoring/comments
  1. a

    PIVKA (Proteins induced by vitamin K absence or antagonists)

Potentially life-threatening side-effects
Hepatopathy (icterus, anorexia)5 to 15 mgOral2·6% (302) (Peterson et al. 1988, Trepanier et al. 2003)15 to 60 days (Peterson et al. 1988)Discontinue treatment with antithyroid drugMonitor liver enzymes and liver function 1 to 2 months later
5 mgTransdermal4% (27) (Sartor et al. 2004)14 days
Bleeding diathesis (epistaxis, oral bleeding, prolonged PIVKA* clotting time)5 to 15 mgOral2·5% (282) (Peterson et al. 1988, Randolph et al. 2000)15 to 50 days (Peterson et al. 1988)In most cases associated with thrombocytopenia
Marked thrombocytopenia (usually platelet count <75000/μL)5 to 20 mgOral2·8% (282) (Peterson et al. 1988, Randolph et al. 2000)14 to 90 days (Peterson et al. 1988)Perform platelet counts 2 weeks later
10 mgTransdermal8% (13) (Lécuyer et al. 2006)14 to 28 days
Agranulocytosis (severe leukopenia with a total granulocyte count <500/μL) and neutropenia5 to 20 mgOral2·7% (339) (Peterson et al. 1988, Randolph et al. 2000, Trepanier et al. 2003, Sartor et al. 2004)26 to 95 days (Peterson et al. 1988)Perform CBC two weeks later
No re-challenge with antithyroid drugs
Within the first 4 weeks (Trepanier et al. 2003, Sartor et al. 2004)
5 mgTransdermal7% (27) (Sartor et al. 2004)Within the first 4 weeks
5 to 10 mg5% (20) (Hill et al. 2011)
Myasthenia gravisUnknownOral4 cases reported (Shelton et al. 1997)60 to 120 days 
5 mg twice a dayTransdermal1 case (Bell et al. 2012)10 weeks 
Anaemia (including aplastic anaemia)UnknownOral1 case (79) (Chapman et al. 2005)After 3 years of treatmentDiscontinue treatment with antithyroid drug if anaemia is severe, no re-challenge with antithyroid drugsPerform CBC 2 weeks later
2.5 to 5 mg1 case report (Weiss 2006)
Non-life-threatening side-effects
Gastro-intestinal upset or lethargy2·5 to 15 mgOralVomiting, nausea 9·3% (366) (Peterson et al. 1988, Randolph et al. 2000, Chapman et al. 2005, Niessen et al. 2007, Rutland et al. 2009)7 to 60 days (Peterson et al. 1988)Continue treatment 
1 to 78 days (Peterson et al. 1988)Lower dosage if no improvement
Discontinue treatment temporally if still no improvement
Anorexia 8.9% (361) (Peterson et al. 1988, Randolph et al. 2000, Chapman et al. 2005)
May require permanent treatment discontinuation in some cases
Within the first 4 weeks (Trepanier et al. 2003, Sartor et al. 2004)
Unspecified GI upset 23% (57) (Trepanier et al. 2003, Sartor et al. 2004)
1 to 60 days (Peterson et al. 1988)
Lethargy 10·5% (267) (Peterson et al. 1988, Niessen et al. 2007, Rutland et al. 2009)
 5 mgTransdermal3·7% (27) (Sartor et al. 2004)Within the first 4 weeks 
Generalised peripheral lymphadenopathy10 mgOral1 case report (Niessen et al. 2007)Within 2 weeks (Niessen et al. 2007)Discontinue treatment with antithyroid drug 
25% (4 healthy cats) (Rutland et al. 2009)
Antinuclear antibodies2·5 to 20 mgOral23% (318) (Peterson et al. 1988, Chapman et al. 2005)10 to 870 days (Peterson et al. 1988)Not routinely measured 
Mild haematological abnormalities (leucopenia, eosinophilia, lymphocytosis)2·5 to 25 mgOral16·4% (262) (Peterson et al. 1988)10 to 490 days (Peterson et al. 1988)Continue treatment, unless associated with clinical signs 
Positive DAT (Direct Antiglobulin Test)10 to 15 mgOral1·9% (160) (Peterson et al. 1988)45 to 60 days (Peterson et al. 1988)Continue treatment if no clinical or haematological signs of haemolytic anaemia 
Dermatological reactions (facial and/cervical excoriations, severe erythema, pruritus)5 to 15 mgOral4% (302) (Peterson et al. 1988, Trepanier et al. 2003)6 to 40 days (Peterson et al. 1988)Ideally, discontinuation of treatment is recommended 
5 to 10 mgTransdermal
8% (40) (Sartor et al. 2004, Lécuyer et al. 2006)
Within the first 4 weeks (Sartor et al. 2004)
2 to 4 weeks (Lécuyer et al. 2006)
Table 4. Suspected adverse drug reactions to oral carbimazole
 Dose range (total/day)RouteFrequency (pooled number of cats) (references)Time to onset after treatment start (if known)Recommendation/Monitoring
Non-life threatening side-effects     
Gastro-intestinal upset (vomiting, diarrhoea/soft faeces, inappetence, lethargy)5 to 25 mgOral33% (108) (Mooney et al. 1992, Bucknell 2000, Frénais et al. 2009)14 to 21 days (Mooney et al. 1992)Continue treatment
5 mg twice a dayLower dosage if no improvement
5% (20) (Hill et al. 2011)14 daysDiscontinue treatment temporally if still no improvement
May require permanent treatment discontinuation in some cases
Peripheral lymphadenopathy5 to 25 mgOral2·3% (44) (Frénais et al. 2009) Discontinue treatment with antithyroid drug
Mild haematological abnormalities (leucopenia, eosinophilia, lymphopenia, thrombocytosis, neutrophilia, lymphocytosis, leucocytosis)5 to 25 mgOral34·9% (83) (Mooney et al. 1992, Frénais et al. 2009)Within 14 days (Mooney et al. 1992)Continue treatment unless associated with clinical signs
Dermatological reactions (facial and cervical excoriations, pruritus, others)5 to 25 mgOral11·6% (69) (Bucknell 2000, Frénais et al. 2009)Within 14 days (excoriations) (Bucknell 2000)

Ideally, discontinuation of treatment is recommended.

Rare cases responding to glucocorticoid therapy have been reported.

Others (weight loss, dyspnoea/tachypnoea, disorientation, aggressiveness, pyrexia, polydipsia)5 to 25 mgOral20·5% (44) (Frénais et al. 2009) No treatment discontinuation required
Hepatic side-effects (increased ALT, hepatic enlargement at palpation)5 to 25 mgOral4·5% (44) (Frénais et al. 2009) Discontinue treatment with antithyroid drug
Methimazole

The most severe but rare side-effects observed with methimazole are hepatopathy and marked blood dyscrasias (severe leukopenia, anaemia and/or thrombocytopenia). Gastrointestinal upset, pruritus and lethargy are frequently described with oral methimazole. A possible irritating effect on gastric mucosa (and slightly bitter taste of methimazole) may be causative. No relationship could be demonstrated between the dose of methimazole (Peterson et al. 1988 [4]) or the dosing regimen (once a day versus twice a day) (Trepanier et al. 2003 [1b]) and the occurrence, frequency or severity of side-effects. Most side-effects appear within the first 4 to 6 weeks of therapy and are less common after 2 or 3 months of treatment (Feldman & Nelson 2004 [5]).

Carbimazole

Carbimazole side-effects have been studied in a smaller number of cats but demonstrate the same pattern (Table 4) as methimazole. Because carbimazole is the pro-drug of methimazole, there is no value in switching from one drug to another if an adverse drug reaction is suspected.

As both drugs are potential human teratogens, pet owners should avoid exposure to the products when dosing cats and strictly follow SPCs or label administration precautions.

Monitoring antithyroid drug treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacological management of hyperthyroidism
  5. Monitoring antithyroid drug treatment
  6. Antithyroid drug treatment and renal function
  7. Antithyroid drug treatment and hypothyroidism
  8. Conclusion
  9. References

Monitoring allows assessment of the response to treatment and the detection and management of possible side-effects. Before starting treatment it is important to collect data that will serve as a baseline for monitoring:

  • thorough case history and physical examination (including cervical palpation and emphasis on cardiac assessment)
  • bodyweight and body condition score
  • blood pressure measurement to establish baseline and to acclimatise the cat to the procedure
  • ophthalmologic examination (fundic examination by indirect ophthalmoscopy to assess evidence of hypertensive retinopathy), especially if blood pressure measurement is not available or reveals elevated values
  • circulating TT4 concentration, as an increased value will confirm the diagnosis of hyperthyroidism, keeping in mind that non-thyroidal concurrent disease and early disease may result in non-elevated TT4 concentrations in hyperthyroid cats (Wakeling et al. 2008 [3b]).
  • complete blood cell count (CBC)
  • blood biochemistry, including a liver profile [e.g. alanine aminotransferase (ALT), alkaline phosphatase (ALKP) and aspartate aminotransferase (AST)] and renal profile: blood urea nitrogen (BUN), creatinine and phosphate as a minimum.
  • urinalysis, with: urine-specific gravity (USG), dipstick analysis and sediment examination as a minimum. Urine culture is ideal.

An agreed monitoring schedule is presented in Fig 1.

image

Figure 1. Monitoring of hyperthyroid cats treated with antithyroid drugs

Download figure to PowerPoint

TT4 monitoring

Circulating TT4 concentration should be measured 2 to 3 weeks after induction of therapy or any treatment adjustment(s) until euthyroidism is achieved, 3 months after stabilisation, and every 6 months thereafter [OEG D]. The panel supports the generally accepted, although not evidence-based statement that clinicians should aim for a TT4 concentration within the lower half of the reference interval [OEG D]. Clinical improvement combined with improvement of TT4 concentration (even if just within the reference interval) is not sufficient to obtain adequate control of the disease [OEG D]. Time of blood sampling for TT4 after methimazole administration is not important (Rutland et al. 2009 [3b]).

Haematology

Haematological abnormalities are known adverse reactions to antithyroid drugs. These can be mild and subclinical or more severe (neutropenia, agranulocytosis, thrombocytopenia, haemolytic anaemia). Intensive (i.e. every other week) CBC monitoring is not recommended as severe haematological side-effects are infrequent and unpredictable and such monitoring is not cost-effective [OEG D].

Biochemistry

Renal function should be assessed at each monitoring visit. It has been demonstrated (in radioiodine treated cats) that glomerular filtration rate (GFR) stabilises by approximately 1 month after achievement of euthyroidism (Boag et al. 2007 [4], van Hoek et al. 2008 [4], 2009 [4]) OEG [C].

Most hyperthyroid cats initially have elevated liver enzyme activity. After radioiodine therapy, liver enzyme activities (ALT, ALKP and AST) returned to within respective reference intervals within 6 weeks (Berent et al. 2007 [3b]). After 20 weeks of methimazole treatment, 80% of cats had lower ALT activity than pre-treatment values, with only 25% within the reference interval (Chapman et al. 2005 [4]). Following carbimazole therapy, Bucknell (2000 [4]) observed a decrease in ALT activity from twice normal to normal; Mooney et al. (1992 [4]) described a highly significant decline in ALT and ALKP in cats that achieved euthyroidism compared to no significant decline in those that did not, in parallel with TT4 concentrations.

Marked pre-treatment elevation of liver enzyme values may suggest liver damage, but most hyperthyroid cats, even with extremely high liver enzyme activities have normal liver function (Berent et al. 2007 [3b]). Further examination for hepatobiliary disease is, in most hyperthyroid cats, not warranted, unless liver values do not decrease during the first 2 months of therapy or the patient shows icterus or partial/total anorexia and does not have a typical presentation for a hyperthyroid cat [OEG C]. In the face of rising or static elevated liver enzyme values in a treated cat, the clinician should consider three possibilities: inadequate control of hyperthyroidism, progression or onset of primary liver disease, or antithyroid drug-induced hepatopathy (often over-considered) [OEG D].

Urinalysis

Pre-treatment urinalysis (including culture) is advised as urinary tract infections (UTI) are not uncommon in hyperthyroid cats and could be asymptomatic (Mayer-Roenne et al. 2007 [4]). Therefore, UTI in hyperthyroid cats should not be excluded based on routine urinalysis results or absence of clinical signs alone [OEG D].

Proteinuria is common in hyperthyroid cats (Mayer-Roenne et al. 2007 [4]) and is reversible within 4 weeks after treatment with radioiodine (van Hoek et al. 2009 [4]).

Systemic blood pressure

Blood pressure measurement should be routinely performed in hyperthyroid cats. Hypertension is only occasionally present initially but may develop after several months of therapy that may or may not be related to unmasking of underlying renal disease (Feldman & Nelson 2004 [5]), (Morrow et al. 2009 [4]). Morrow et al. (2009 [4]) showed a prevalence of hypertension of 13% in a population of 303 untreated hyperthyroid cats, and an incidence of 23% when initially normotensive cats from the same population were treated medically and/or surgically for hyperthyroidism. Blood pressure should be measured at diagnosis and monitored during the first 6 months after restoration of euthyroidism and then biannually as recommended by Stepien (2011 [3a]). If present, hypertension should be treated [OEG D].

Antithyroid drug treatment and renal function

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacological management of hyperthyroidism
  5. Monitoring antithyroid drug treatment
  6. Antithyroid drug treatment and renal function
  7. Antithyroid drug treatment and hypothyroidism
  8. Conclusion
  9. References

Renal function is profoundly influenced by thyroid status. Excessive thyroid hormone concentrations lead to increased cardiac output and diminished peripheral vascular resistance, resulting in an increase in GFR, and consequently a decline in circulating creatinine concentration (van Hoek & Daminet 2009 [3a]). Subsequent normalisation of TT4 concentration induces a decline in GFR and can therefore unmask underlying renal function abnormalities, resulting in development of azotaemia. Many investigations regarding the impact of hyperthyroidism treatment on GFR have been performed after radioiodine treatment (Boag et al. 2007 [4], van Hoek et al. 2008 [4], 2009 [4]) and consistently show a decrease in GFR within 4 weeks post treatment, with little further decline thereafter. These data from radioiodine treated cats support the need for monitoring renal function 1 month after restoration of euthyroidism [OEG C]. The decrease in GFR post treatment has been documented also after methimazole treatment (Becker et al. 2000 [3b]) and after surgery (Graves et al. 1994) [3b] and is a consequence of the resolution of hyperthyroidism and is not directly related to treatment modality [OEG B].

Managing azotaemia and hyperthyroidism

Chronic kidney disease (CKD) and hyperthyroidism are both frequently encountered diseases in senior and geriatric cats. Clinicians can face two different scenarios concerning azotaemic hyperthyroid cats: firstly, the presence of pre-existing azotaemia in an untreated hyperthyroid cat; secondly, development of azotaemia after treatment of hyperthyroidism in an initially non-azotaemic cat. This distinction is essential as cats with pre-existing azotaemia have a shorter survival time than cats without pre-existing azotaemia (Milner et al. 2006 [4]). Williams et al. (2010a [4]) subsequently showed that the median survival time was 178 days for hyperthyroid cats with azotaemia or previously diagnosed CKD and 612 days for non-azotaemic hyperthyroid cats. Appropriate individual management of CKD following IRIS guidelines (International Renal Interest Society guidelines 2009) including if necessary additional treatment for renal disease (e.g. restricted protein/phosphate diet, ACE inhibitors, phosphate binders) is mandatory in both scenarios [OEG D].

Pre-existing azotaemia in a newly diagnosed hyperthyroid cat

Diagnosis and treatment of hyperthyroidism can be more complicated in this scenario. Firstly, diagnosis of hyperthyroidism can be challenging because of an associated suppression of TT4 within the reference interval, comparable to sick euthyroid syndrome (Mooney et al. 1996 [3b]), Peterson et al. 2001 [3b]). Secondly, given the further decline in GFR to be expected after resolution of the hyperthyroid state, most of the authors recommend starting an azotaemic hyperthyroid cat with reversible antithyroid therapy (trial therapy) before considering a definitive treatment. This is in order to see how the cat and the owner handle the normalisation of TT4 and concurrent renal disease [OEG D]. With IRIS stages I and II, treatment and monitoring of hyperthyroidism should be initiated as usual (Fig 1) unless clinical signs suggest worsening of kidney disease [OEG D]. If the patient shows a favourable clinical response even when euthyroidism is achieved, an irreversible treatment option can still be considered. The panel advises a more prudent approach with hyperthyroid cats with IRIS stages III and IV. The most conservative antithyroid dosage available/registered should be used initially and renal function should be frequently monitored. If the patient deteriorates clinically, antithyroid treatment should be ceased or decreased. Although the clinician should aim for euthyroidism, this may not be obtained without causing further deterioration of renal function [OEG D]. In such cases, a compromise between improved renal function but persistence of hyperthyroidism may be required to optimise quality of life.

Development of post treatment renal azotaemia

Up to 39% of hyperthyroid cats are diagnosed with CKD after radioiodine treatment (van Hoek et al. 2009 [4]). There is neither evidence to justify reducing the antithyroid drug dose in this group of patients nor data to support the fact that the more rapidly the TT4 concentration decreases after treatment the worse the effect on renal disease will be [OEG D].

In a population of 268 non-azotaemic hyperthyroid cats, 15% developed azotaemia within 240 days of diagnosis and initiation of therapy (Williams et al. 2010a [4]). This study also showed that post-treatment development of azotaemia did not decrease the survival time of hyperthyroid cats. The appearance of mild stable renal disease should not affect after treatment advice for hyperthyroidism given to clients [OEG C]. Providing TT4 and renal parameters are monitored closely, there is no reason to stop or reduce antithyroid drug treatment in azotaemic cats in order to normalise creatinine concentration. According to van Hoek et al. (2009 [4]) and Boag et al. (2007 [4]) decreased muscle mass may be a more important reason for relatively low creatinine concentrations in untreated hyperthyroid cats than an increased GFR. Therefore, increases in creatinine concentration should not be considered as a reliable short-term indicator of kidney function in treated hyperthyroid cats.

Predicting the unmasking of renal disease

Several predictors (pre-treatment) have been extensively evaluated in blood (TT4, creatinine, urea) and urine [USG, urinary protein/creatinine ratio (UPC)]. With regard to blood parameters, only weak associations have been described between the development of post-treatment renal azotaemia and pre-treatment TT4 concentrations (van Hoek et al. 2009 [4]) or urea and creatinine concentrations (Williams et al. 2010a [4]).

Regarding urine parameters, no correlation has been demonstrated between UPC and development of azotaemia in hyperthyroid cats (Williams et al. 2010a [4]) or with IRIS stage (Harley et al. 2011 [4]). Pre-treatment USG seems to have some correlation with development of azotaemia. Although Riensche et al. (2008 [3b]) reported that cats with well-concentrated urine (USG > 1·035) before treatment can still develop renal disease, van Hoek et al. (2009 [4]) observed lower pre-treatment USG values in cats that developed post-treatment azotaemia. According to Harley et al. (2011 [4]), USG might be helpful in predicting to which IRIS stage a cat will progress after treatment (radioiodine in this case). On a population scale, baseline low USG and relatively low TT4 concentrations could be predictive of development of azotaemia (but not on an individual basis) [OEG C]. To the authors’ knowledge, in the absence of an easy way of assessing GFR, there is no single available in-clinic predictive biomarker allowing identification of cats with underlying renal disease. Trial therapy, with assessment of renal function once euthyroidism is achieved, is currently the best and prudent way to obtain this information. However, as these cats carry a similar prognosis to cats not developing post-treatment azotaemia (Wakeling et al. 2006 [4]) and are unlikely to increase more than one IRIS stage (Harley et al. 2011 [4]), the panel does not recommend routine use of a therapeutic trial in non-azotaemic hyperthyroid cats to assess effect on renal function [OEG C].

Antithyroid drug treatment and hypothyroidism

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacological management of hyperthyroidism
  5. Monitoring antithyroid drug treatment
  6. Antithyroid drug treatment and renal function
  7. Antithyroid drug treatment and hypothyroidism
  8. Conclusion
  9. References

Iatrogenic hypothyroidism is a well-recognised complication of all available treatment options for hyperthyroidism. Williams et al. (2010b [3b]) classified 28 of 75 cats (37%) as hypothyroid [defined as decreased TT4 concentration and elevated TSH concentration (using the canine assay)] 6 months after treatment start (either with antithyroid drugs alone or in combination with thyroidectomy). In addition, Gallagher et al. (2011 [4]) observed low TT4 concentrations in almost 15% of cats treated with antithyroid drugs.

Clinical signs of iatrogenic hypothyroidism can include lethargy, inappetence, weight gain and skin changes. Dermatological changes are characterised by seborrhoea sicca and a dull, dry, unkempt haircoat which is easily epilated. Alopecia of the pinnae can develop in some cats. However, a low TT4 concentration secondary to antithyroid drug treatment is not always associated with clinical signs of hypothyroidism (Peterson et al. 1988 [4], Mooney et al. 1992 [4]), which can make the diagnosis of iatrogenic hypothyroidism challenging.

Moreover, low circulating TT4 concentrations are expected in all cases of feline hypothyroidism (spontaneous, congenital and iatrogenic). However, as in dogs, TT4 concentrations can also be suppressed by non-thyroidal illnesses (NTI) and some drug therapies in cats (Peterson et al. 2001 [3b]). Therefore, a low TT4 concentration does not necessarily equate with a diagnosis of hypothyroidism. It should also be remembered that reference intervals for TT4 are rarely specifically made for geriatric populations and therefore results should always be evaluated in view of the age/status of the cat.

Unfortunately, although of higher specificity, free T4 (FT4) measured after equilibrium dialysis is also not a perfect test for diagnosing hypothyroidism in cats, as 3 to 17% of cats with NTI also have low FT4 concentrations (Mooney et al. 1996 [3b], Peterson et al. 2001 [3b]).

In dogs with hypothyroidism, an increased circulating TSH concentration confirms that the disease is primary (located within the thyroid gland). A specific assay for feline TSH measurement is not yet available, although use of the canine immunoradiometric assay in cats has been described (Wakeling et al. 2008 [3b]). Williams et al. (2010b [3b]) used the combination of a low TT4 concentration and an elevated TSH concentration (using the canine assay), to diagnose iatrogenic hypothyroidism in cats treated with antithyroid drugs alone or in combination with thyroidectomy. The combination of these two tests may therefore be useful in the diagnosis of iatrogenic hypothyroidism. If TT4 is within the reference interval, determining TSH is not necessary [OEG D]. However, definitive diagnosis of iatrogenic hypothyroidism remains challenging as appropriate cut-off values have not been determined for TSH and the suppressive effect of NTI cannot be totally eliminated. Recently, use of the recombinant human thyrotropin (rhTSH) response test has been described in cats to distinguish NTI from iatrogenic hypothyroidism following radioiodine therapy (van Hoek et al. 2010 [3b]).

While overt clinical signs of iatrogenic hypothyroidism may not be common, there are other potential implications. Williams et al. (2010b [3b]) showed that azotaemia was significantly more likely in cats with iatrogenic hypothyroidism and that the combination of iatrogenic hypothyroidism and azotaemia was associated with significantly shorter survival times in the study population (456 days for hypothyroid azotaemic cats vs. 905 days for hypothyroid non-azotaemic cats). This suggests that iatrogenic hypothyroidism can contribute to the development of azotaemia and reduced survival times after treatment of hyperthyroidism. A recent study suggests that renal function improves after restoration of euthyroidism in medically treated hyperthyroid cats with iatrogenic hypothyroidism (Williams et al. 2012 [4]).

Taking the above information into account, the practical recommendations are as follows: if TT4 concentration is substantially low (<10 nmol/L), the antithyroid drug dose should be decreased by 25 to 50%. If TT4 concentration is between 10 and 15 nmol/L, and the cat is in good clinical condition and not azotaemic, dose adjustment is not recommended [OEG D]. However, if the cat is azotaemic, the antithyroid drug dose should be reduced. If the cat is already on the minimum dose (2·5 mg once a day methimazole or 10 mg once a day carbimazole), the dose should be given every 36 or 48 hours [OEG D].

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacological management of hyperthyroidism
  5. Monitoring antithyroid drug treatment
  6. Antithyroid drug treatment and renal function
  7. Antithyroid drug treatment and hypothyroidism
  8. Conclusion
  9. References

Pharmacological treatment with methimazole or carbimazole allows efficient treatment in many hyperthyroid cats as a life-long therapy or temporarily to stabilise a patient (before anaesthesia/surgery or treatment with radioiodine). Close monitoring is important. Indeed, renal function before but also during treatment merits particular attention as CKD will be ‘unmasked’ in a significant percentage of hyperthyroid cats. Cats with an initial combination of hyperthyroidism and CKD and cats developing post-treatment renal azotaemia should be approached differently. Also, while monitoring TT4 values is essential (to detect under-treatment), over-treatment has to be avoided too as iatrogenic hypothyroidism negatively affects survival in azotaemic cats.

Acknowledgements

The authors are grateful to James Walker for his contribution to the manuscript.

Conflict of interest

None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacological management of hyperthyroidism
  5. Monitoring antithyroid drug treatment
  6. Antithyroid drug treatment and renal function
  7. Antithyroid drug treatment and hypothyroidism
  8. Conclusion
  9. References
  • Anonymous. (2009) Freedom of Information Summary. NADA 141-292. Felimazole coated tablets. May 27, 2009. US Food and Drug Administration, http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/. FOIADrugSummaries/UCM165091.pdf. Accessed November 28, 2012
  • Anonymous. (2008) Publicly Available Assessment Report for a Veterinary Medicinal Product. Felimazole 2.5 mg Coated Tablets for Cats, Veterinary Medicines Directorate http://www.vmd.defra.gov.uk/ProductInformationDatabase. Accessed November 28, 2012
  • Anonymous. (2012a) Summary of Product Characteristics. Felimazole 2.5 mg Coated Tablets for Cats (revised March 2012), Veterinary Medicines Directorate, http://www.vmd.defra.gov.uk/ProductInformationDatabase. Accessed November 28, 2012
  • Anonymous. (2012) Summary of Product Characteristics. Felimazole 5 mg Coated Tablets for Cats (revised August 2012), Veterinary Medicines Directorate, http://www.vmd.defra.gov.uk/ProductInformationDatabase. Accessed November 28, 2012
  • Anonymous. (2012b) Summary of Product Characteristics. Vidalta 10 mg Tablets for Cats (revised January 2012), Veterinary Medicines Directorate, http://www.vmd.defra.gov.uk/ProductInformationDatabase. Accessed November 28 2012.
  • Anonymous. (2012c) Summary of Product Characteristics. Vidalta 15 mg Tablets for Cats (revised January 2012), Veterinary Medicines Directorate, http://www.vmd.defra.gov.uk/ProductInformationDatabase. Accessed November 28, 2012
  • Becker, T. J., Graves, T. K., Kruger, J. M., et al. (2000) Effects of methimazole on renal function in cats with hyperthyroidism. Journal of the American Veterinary Medical Association 36, 215-223
  • Bell, E. T., Mansfield, C. S., James, F. E. (2012) Immune-mediated myasthenia gravis in a methamizole-treated cat. Journal of Small Animal Practice 53, 661-663
  • Berent, A. C., Drobatz, K. J., Ziemer, L., et al. (2007) Liver function in cats with hyperthyroidism before and after 131I therapy. Journal of Veterinary Internal Medicine 21, 1217-1223
  • Boag, A. K., Neiger, R., Slater, L., et al. (2007) Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine. Veterinary Record 161, 711-715
  • Bucknell, D.G. (2000) Feline hyperthyroidism: spectrum of clinical presentations and response to carbimazole therapy. Australian Veterinary Journal 78, 462-465
  • Chapman, E., Johnston, L. & Graham, P. (2005) Treatment of feline hyperthyroidism with 2.5 mg thiamazole (methimazole): efficacy and safety. Proceedings of 15th ECVIM-CA Congress. September 1 to 3, Glasgow, United Kingdom. pp 218-219
  • Elwood, C., Devauchelle, P., Elliott, J., et al. (2010) Emesis in dogs: a review. Journal of Small Animal Practice 51, 4-22
  • Feldman, E. C & Nelson, R. W. (2004) Feline hyperthyroidism (Thyrotoxicosis) In: Canine and Feline Endocrinology and Reproduction. 3rd edn. Eds E. C. Feldman and R. W. Nelson. Elsevier Saunders, St. Louis, MO, USA. pp 196-201
  • Frénais, R., Burgaud, S. & Horspool, L. J. I. (2008) Pharmacokinetics of controlled-release carbimazole tablets support once daily dosing in cats. Journal of Veterinary Pharmacology and Therapeutics 31, 213-219
  • Frénais, R., Rosenberg, D., Burgaud, S., et al. (2009) Clinical efficacy and safety of a once-daily formulation of carbimazole in cats with hyperthyroidism. Journal of Small Animal Practice 50, 510-515
  • Gallagher, B., Mooney, C. T. & Graham, P. A. (2011) Efficacy of two oral anti-thyroid medications used once daily: a laboratory survey. Proceedings British Small Animal Veterinary Association Congress 2011. March 31 to April 3, Birmingham, United Kingdom p. 457
  • Graves, T. K., Olivier, N. B., Nachreiner, R. F., et al. (1994) Changes in renal function associated with treatment of hyperthyroidism in cats. American Journal of Veterinary Research 55, 1745-1749
  • Harley, L. S., Peterson, M. E., Langston, C. E., et al. (2011) IRIS stages of chronic kidney disease before and after treatment with radioiodine in cats with hyperthyroidism. Proceedings of ACVIM forum. June 15 to 18, Denver, USA. pp 678-679
  • Hill, K. E., Gieseg, M. A., Kingsbury, D., et al. (2011) The efficacy and safety of a novel lipophilic formulation of methamizole for the once daily transdermal treatment of cats with hyperthyroidism. Journal of Veterinary Internal Medicine 25, 1357-1365
  • Hoffman, S. B., Yoder, A. R. & Trepanier L. A. (2002) Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats. Journal of Veterinary Pharmacology and Therapeutics 25, 189-193
  • Hoffmann, G., Marks, S. L., Taboada, J., et al. (2003) Transdermal methimazole treatment in cats with hyperthyroidism. Journal of Feline Medicine and Surgery 5, 77-82
  • International Renal Interest Society guidelines. Treatment recommendations (June 2009). http://www.iris-kidney.com/guidelines/en/index.shtml. Accessed November 28, 2012
  • Lécuyer, M., Prini, S., Dunn, M. E., et al. (2006) Clinical efficacy and safety of transdermal methimazole in the treatment of feline hyperthyroidism. Canadian Veterinary Journal 47, 131-135
  • Longhofer, S. L., Martín-Jiménez, T. & Soni-Gupta, J. (2010) Serum concentrations of methimazole in cats after a single oral dose of controlled-release carbimazole or sugar-coated methimazole (thiamazole). Veterinary Therapeutics 11(3), E1-7
  • Mayer-Roenne, B., Goldstein, R. E. & Erb, H. N. (2007) Urinary tract infections in cats with hyperthyroidism, diabetes mellitus and chronic kidney disease. Journal of Feline Medicine and Surgery 9, 124-132
  • Milner, R. J., Channell, C. D., Levy, J. K., et al. (2006) Survival times for cats with hyperthyroidism treated with iodine 131, methimazole, or both: 167 cases (1996-2003). Journal of the American Veterinary Medical Association 228, 559-563
  • Mooney, C. T. (2001) Feline hyperthyroidism: diagnostics and therapeutics. Veterinary Clinics of North America: Small Animal Practice 31, 963-983
  • Mooney, C. T., Thoday, K. L. & Doxey, D. L. (1992) Carbimazole therapy of feline hyperthyroidism. Journal of Small Animal Practice 33, 228-235
  • Mooney, C. T., Little C. J. & Macrae A. W. (1996) Effect of illness not associated with the thyroid gland on serum total and free thyroxine concentrations in cats. Journal of the American Veterinary Medical Association 208, 2004-2008
  • Morrow, L. D., Adams, V. J., Elliott, J., et al. (2009) Hypertension in hyperthyroid cats: prevalence, incidence and predictors of its development. Proceedings of ACVIM forum. June 3 to 6, Montreal, Canada. p. 699
  • Niessen, S. J. M., Voyce, M. J., de Villiers, L., et al. (2007) Generalised lymphadenomegaly associated with methimazole treatment in a hyperthyroid cat. Journal of Small Animal Practice 48, 165-168
  • Okuno, A., Yano, K., Inyaku, F., et al. (1987) Pharmacokinetics of methimazole in children and adolescents with Graves’ disease. Studies on plasma and intrathyroidal concentrations. Acta Endocrinologica 115, 112-118
  • Oxford Centre for Evidence-Based Medicine. Levels of Evidence (March 2009). http://www.cebm.net/index.aspx?o=1025. Accessed November 28, 2012
  • Peterson, M. E. & Aucoin, D. P. (1993) Comparison of the disposition of carbimazole and methimazole in clinically normal cats. Research in Veterinary Science 54, 351-355
  • Peterson, M. E. & Broome, M. R. (2012) Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. Proceedings of 22nd ECVIM-CA Congress. September 6 to 8, Maastricht, The Netherlands. p. 224
  • Peterson, M. E., Kintzer, P. P. & Hurvitz, A. I. (1988) Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2, 150-157
  • Peterson, M. E., Melián C. & Nichols R. (2001) Measurement of serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with nonthyroidal disease. Journal of the American Veterinary Medical Association 218, 529-536
  • Randolph, J. F., DeMarco, J., Center, S. A., et al. (2000) Prothrombin, activated partial thromboplastin, and proteins induced by vitamin K absence or antagonists clotting times in 20 hyperthyroid cats before and after methimazole treatment. Journal of Veterinary Internal Medicine 14, 56-59
  • Riensche, M. R., Graves, T. K. & Schaeffer, D. J. (2008) An investigation of predictors of renal insufficiency following treatment of hyperthyroidism in cats. Journal of Feline Medicine and Surgery 10, 160-166
  • Rutland, B. E., Nachreiner, R. F. & Kruger, J. M. (2009) Optimal testing for thyroid hormone concentration after treatment with methimazole in healthy and hyperthyroid cats. Journal of Veterinary Internal Medicine 23, 1025-1030
  • Sartor, L. L., Trepanier, L. A., Kroll, M. M., et al. (2004) Efficacy and safety of transdermal methimazole in the treatment of cats with hyperthyroidism. Journal of Veterinary Internal Medicine 18, 651-655
  • Shelton, G. D., Joseph, R., Richter, K., et al. (1997) Acquired myasthenia gravis in hyperthyroid cats on Tapazole therapy. Journal of Veterinary Internal Medicine 11, 120
  • Stepien, R. L. (2011) Feline systemic hypertension: diagnosis and management. Journal of Feline Medicine and Surgery 13, 35-43
  • Trepanier, L. A. (2007) Pharmacologic management of feline hyperthyroidism. Veterinary Clinics of North America: Small Animal Practice 37, 775-788
  • Trepanier, L. A. & Peterson, M. E. (1991) Pharmacokinetics of methimazole in normal cats and cats with hyperthyroidism. Research in Veterinary Science 50, 69-74
  • Trepanier, L. A., Peterson, M. E. & Aucoin, D. P. (1991) Pharmacokinetics of intravenous and oral methimazole following single- and multiple-dose administration in normal cats. Journal of Veterinary Pharmacology and Therapeutics 14, 367-373
  • Trepanier, L. A., Hoffman, S. B., Kroll, M., et al. (2003) Efficacy and safety of once versus twice daily administration of methimazole in cats with hyperthyroidism. Journal of the American Veterinary Medical Association 222, 954-958
  • van Hoek, I. & Daminet, S. (2009). Interactions between thyroid and kidney function in pathological conditions of these organ systems: a review. General and Comparative Endocrinology 160, 205-215
  • van Hoek, I., Lefebvre, H. P., Kooistra, H. S., et al. (2008) Plasma clearance of exogenous creatinine, exo-iohexol, and endo-iohexol in hyperthyroid cats before and after treatment with radioiodine. Journal of Veterinary Internal Medicine 22, 879-885
  • van Hoek, I., Lefebvre, H. P., Peremans, K., et al. (2009) Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domestic Animal Endocrinology 36, 45-56
  • van Hoek, I. M., Vandermeulen, E., Peremans, K., et al. (2010) Thyroid stimulation with recombinant human thyrotropin in healthy cats, cats with non-thyroidal illness and in cats with low serum thyroxin and azotaemia after treatment of hyperthyroidism. Journal of Feline Medicine and Surgery 12, 117-121
  • Wakeling, J., Rob, C., Elliott, J, et al. (2006) Survival of hyperthyroid cats is not affected by post-treatment azotaemia. Proceedings of 16th ECVIM-CA Congress. September 14 to 16, Amsterdam, The Netherlands. p. 185
  • Wakeling, J., Moore, K., Elliott, J., et al. (2008) Diagnosis of hyperthyroidism in cats with mild chronic kidney disease. Journal of Small Animal Practice 49, 287-294
  • Weiss, D. J. (2006) Aplastic anemia in cats – clinicopathological features and associated disease conditions 1996–2004. Journal of Feline Medicine and Surgery 8, 203-206
  • Williams, T. L., Peak, K. J., Brodbelt, D., et al. (2010a) Survival and the development of azotemia after treatment of hyperthyroid cats. Journal of Veterinary Internal Medicine 24, 863-869
  • Williams, T. L., Elliott, J. & Syme, H. M. (2010b) Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. Journal of Veterinary Internal Medicine 24, 1086-1092
  • Williams, T. L., Elliott J. & Syme H. M. (2012). Restoration of euthyroidism in medically treated hyperthyroid cats with iatrogenic hypothyroidism (IH) improves renal function. . Proceedings of ACVIM forum. May 30 to June 3, New Orleans, USA. p. 753-754