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REVIEW

Best practice for the pharmacological


management of hyperthyroid cats
with antithyroid drugs
S. Daminet*, H. S. Kooistra, F. Fracassi, P. A. Graham, A. Hibbert, A. Lloret||, C. T. Mooney**,
R. Neiger, D. Rosenberg, H. M. Syme, I. Villard|||| and G. Williams***
*Department of Medicine and Clinical Biology of Small Animals, Faculty of Veterinary Medicine, University of Ghent, 9820
Merelbeke, Belgium
Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, The Netherlands
Department of Veterinary Medical Sciences, University of Bologna, Ozzano dellEmilia (BO), Italy
NationWide Laboratories, Poulton-le-Fylde, Lancashire FY6 7LJ
The Feline Centre, Langford Veterinary Services, University of Bristol, Langford, Bristol, BS40 5DU

||Small Animal Clinic, Justus-Liebig University Giessen, 35392 Giessen, Germany


**University College Dublin Veterinary Hospital, School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4,
Ireland
Small Animal Clinic, Justus-Liebig University Giessen, 35392 Giessen, Germany
Micen Vet, Zone Creteil Europarc, 94000 Crteil, France
Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Herts AL9 7TA

||||Isavet Biosciences, 93390 Clichy sous Bois, France


***Dechra Veterinary Products Limited, Shrewsbury, Shropshire SY4 4AS

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
25 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.

Journal of Small Animal Practice (2014) 55, 413


DOI: 10.1111/jsap.12157
Accepted: 1 October 2013; Published online: 27 December 2013

Journal of Small Animal Practice

Vol 55

January 2014

2013 British Small Animal Veterinary Association

Pharmacological management of hyperthyroid cats

INTRODUCTION

PHARMACOLOGICAL MANAGEMENT
OF HYPERTHYROIDISM

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).

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 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 type

Level of evidence (LOE)

Systematic review (with homogeneity) of randomised controlled clinical trials


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

1a
1b
1c
2a
2b
2c
3a
3b
4
5
Overall evidence grade (OEG)
A
B
C
D

*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

Table 2. Advantages and disadvantages of antithyroid drugs for treatment of hyperthyroid cats
Advantages

Disadvantages

Effective in most cases

Not curative
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)

Comments
Benign adenomatous hyperplasia
(adenoma) is present in about 98% of
hyperthyroid cats (Mooney 2001)

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 gels

Widely available
Cost-effective (short-term perspective) (Trepanier
2007)

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January 2014

Splitting of coated tablets is


contraindicated
Wear gloves when applying transdermal gel

Less cost-effective from a long-term perspective


compared to potentially curative treatments
(thyroidectomy or radioiodine treatment)

2013 British Small Animal Veterinary Association

S. Daminet et al.

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 (Frnais 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].

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 (25 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 25 mg twice a day. Lcuyer 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].

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 25 mg twice a day (Feldman & Nelson 2004 [5])
or even 125 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 25 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 25 mg twice a day is also associated with less serious sideeffects than 5 mg once a day, twice a day or three times a day
(Felimazole FOI [4], Anonymous 2009). The panel recommends
using 25 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

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 25 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 (Frnais 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].

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]).

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 25 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 25 mg twice a day (34 of 58 cats) or

Journal of Small Animal Practice

Vol 55

January 2014

2013 British Small Animal Veterinary Association

Pharmacological management of hyperthyroid cats

25 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 25 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
(Vidaltas 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.

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.

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]).

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]).

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.

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 costeffective [OEG D].

MONITORING ANTITHYROID DRUG TREATMENT


Monitoring allows assessment of the response to treatment and
the detection and management of possible side-effects. Before
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January 2014

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].

2013 British Small Animal Veterinary Association

S. Daminet et al.

Table 3. Suspected adverse drug reactions to oral and transdermal methimazole


Side-effects

Dose range
(total/day)

Route of
administration

Frequency (pooled number


of cats) (references)

Time to onset after treatment start (if known)

Recommendation

Monitoring/
comments

Potentially life-threatening side-effects


Hepatopathy (icterus,
anorexia)

Monitor liver
enzymes and
liver function
1 to 2
months later

5 to 15 mg

Oral

26% (302) (Peterson et al.


1988, Trepanier et al.
2003)

15 to 60 days (Peterson
et al. 1988)

5 mg

Transdermal

4% (27) (Sartor et al. 2004)

14 days

Bleeding diathesis
(epistaxis, oral
bleeding, prolonged
PIVKA* clotting
time)

5 to 15 mg

Oral

25% (282) (Peterson et al.


1988, Randolph et al.
2000)

15 to 50 days (Peterson
et al. 1988)

Marked thrombocytopenia (usually


platelet count
<75000/L)

5 to 20 mg

Oral

28% (282) (Peterson et al.


1988, Randolph et al.
2000)

14 to 90 days (Peterson
et al. 1988)

10 mg

Transdermal

8% (13) (Lcuyer et al.


2006)

14 to 28 days

Agranulocytosis
(severe leukopenia
with a total granulocyte count <500/
L) and neutropenia

5 to 20 mg

Oral

27% (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)
Within the first 4 weeks
(Trepanier et al. 2003,
Sartor et al. 2004)

5 mg
5 to 10 mg

Transdermal

7% (27) (Sartor et al. 2004)


5% (20) (Hill et al. 2011)

Within the first 4 weeks

Unknown

Oral

4 cases reported (Shelton


et al. 1997)

60 to 120 days

5 mg twice
a day

Transdermal

1 case (Bell et al. 2012)

10 weeks

Unknown

Oral

1 case (79) (Chapman et al.


2005)
1 case report (Weiss 2006)

After 3 years of treatment

Discontinue
treatment with
antithyroid drug
if anaemia is
severe, no rechallenge with
antithyroid drugs

Oral

Vomiting, nausea 93%


(366) (Peterson et al.
1988, Randolph et al.
2000, Chapman et al.
2005, Niessen et al.
2007, Rutland et al.
2009)
Anorexia 8.9% (361)
(Peterson et al. 1988,
Randolph et al. 2000,
Chapman et al. 2005)
Unspecified GI upset 23%
(57) (Trepanier et al.
2003, Sartor et al. 2004)
Lethargy 105% (267)
(Peterson et al. 1988,
Niessen et al. 2007,
Rutland et al. 2009)

7 to 60 days (Peterson
et al. 1988)

Continue
treatment
Lower dosage if
no improvement
Discontinue treatment temporally if still no
improvement
May require
permanent treatment discontinuation in some
cases

Myasthenia gravis

Anaemia (including
aplastic anaemia)

2.5 to 5 mg

In most cases
associated
with thrombocytopenia

Discontinue
treatment with
antithyroid drug
No re-challenge
with antithyroid
drugs

Perform platelet counts


2 weeks later

Perform CBC
two weeks
later

Perform CBC
2 weeks later

Non-life-threatening side-effects
Gastro-intestinal
upset or lethargy

25 to 15
mg

1 to 78 days (Peterson
et al. 1988)

Within the first 4 weeks


(Trepanier et al. 2003,
Sartor et al. 2004)
1 to 60 days (Peterson
et al. 1988)

5 mg

Transdermal

37% (27) (Sartor et al.


2004)

Within the first 4 weeks

Generalised
peripheral
lymphadenopathy

10 mg

Oral

1 case report (Niessen


et al. 2007)
25% (4 healthy cats)
(Rutland et al. 2009)

Within 2 weeks (Niessen


et al. 2007)

Discontinue
treatment with
antithyroid drug

Antinuclear antibodies

25 to 20
mg

Oral

23% (318) (Peterson et al.


1988, Chapman et al.
2005)

10 to 870 days (Peterson


et al. 1988)

Not routinely
measured

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Pharmacological management of hyperthyroid cats

Table 3. Continued
Side-effects

Dose range
(total/day)

Route of
administration

Frequency (pooled number


of cats) (references)

Time to onset after treatment start (if known)

Recommendation

Mild haematological
abnormalities (leucopenia, eosinophilia,
lymphocytosis)

25 to 25
mg

Oral

164% (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
mg

Oral

19% (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 mg

Oral

6 to 40 days (Peterson
et al. 1988)

5 to 10 mg

Transdermal

4% (302) (Peterson et al.


1988, Trepanier et al.
2003)
8% (40) (Sartor et al. 2004,
Lcuyer et al. 2006)

Ideally, discontinuation of
treatment is
recommended

Within the first 4 weeks


(Sartor et al. 2004)
2 to 4 weeks (Lcuyer
et al. 2006)

Monitoring/
comments

*PIVKA (Proteins induced by vitamin K absence or antagonists)

Table 4. Suspected adverse drug reactions to oral carbimazole


Dose range
(total/day)

Route

Frequency (pooled number of cats) (references)

Time to onset after treatment start (if known)

5 to 25 mg

Oral

33% (108) (Mooney


et al. 1992, Bucknell
2000, Frnais et al.
2009)
5% (20) (Hill et al. 2011)

14 to 21 days (Mooney
et al. 1992)

Recommendation/Monitoring

Non-life threatening side-effects


Gastro-intestinal upset (vomiting,
diarrhoea/soft faeces, inappetence, lethargy)

5 mg twice
a day

14 days

Continue treatment
Lower dosage if no improvement
Discontinue treatment temporally
if still no improvement
May require permanent treatment
discontinuation in some cases

Peripheral lymphadenopathy

5 to 25 mg

Oral

23% (44) (Frnais et al.


2009)

Mild haematological abnormalities (leucopenia, eosinophilia,


lymphopenia, thrombocytosis,
neutrophilia, lymphocytosis,
leucocytosis)

5 to 25 mg

Oral

349% (83) (Mooney


et al. 1992, Frnais
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 mg

Oral

116% (69) (Bucknell


2000, Frnais 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 mg

Oral

205% (44) (Frnais


et al. 2009)

No treatment discontinuation
required

Hepatic side-effects (increased ALT,


hepatic enlargement at palpation)

5 to 25 mg

Oral

45% (44) (Frnais et al.


2009)

Discontinue treatment with antithyroid drug

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
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Discontinue treatment with antithyroid drug

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

2013 British Small Animal Veterinary Association

S. Daminet et al.

Pre-treatment

2 to 3 weeks after the start


of anti-thyroid drugs
1 month later
3 months later
First check
(if euthyroid at previous test)* (if euthyroid at previous test)*

Every 6 months
(once 'stable')

History
Physical examination
Bodyweight and body condition score
Total T4
Complete blood count (CBC)
Full biochemistry profile
Liver profile
Renal profile
Urinalysis (USG, dipstick, sediment, culture)
Blood pressure (ideally) and/or ophthalmic examination

Recommended
Optional
If adverse event suspected or if inadequate resolution of clinical signs

*If not euthyroid then the dose of anti-thyroid drug should be adjusted and the TT4 checked every 3 weeks until the target value (TT4 concentration in lower half of reference interval) is reached

FIG 1. Monitoring of hyperthyroid cats treated with antithyroid drugs

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 overconsidered) [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
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
10

[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 preexisting 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]).

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Pharmacological management of hyperthyroid cats

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
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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 > 1035) 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
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.

2013 British Small Animal Veterinary Association

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S. Daminet et al.

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 (25 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
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
12

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.
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