CHAPTER
25  
Are Methimazole Trials Really
Necessary?
Harriet M. Syme
Hyperthyroidism and chronic kidney disease (CKD) are both
very common problems of the old cat and may occur concur-
rently in the same individual.1,2 Hyperthyroidism increases
glomerular filtration rate (GFR) and so, in some cats, the
presence of CKD is masked and only revealed once the cat
is rendered euthyroid and azotemia is documented. This has
led to the recommendation that trial treatment with methim-
azole (or carbimazole) should be routinely performed before
definitive therapy with radioactive iodine or thyroidectomy.
A few important implications result from this recommenda-
tion. First, if azotemia develops following medical treatment,
then it would be best to subsequently leave the hyperthyroid-
ism untreated (or at least undertreat it) to maximize renal
function. Second, if the patient develops azotemia, the client
should then be counseled against having definitive therapy
for their cat’s hyperthyroidism because of a poor long-term
prognosis. However, evidence suggests that both of these
conjectures are misguided, as will be outlined later.
To understand the arguments for and against doing
methimazole trials before definitive treatment for hyperthy-
roidism, it is helpful to first review the effect of thyroid
hormones on renal function and the changes that can be
anticipated following treatment of hyperthyroidism.
EFFECT OF THYROID HORMONES ON
RENAL FUNCTION
Both hyper- and hypothyroidism cause changes in renal
function, and these are usually opposite in nature. For
example, hyperthyroidism increases GFR, and hypothyroid-
ism decreases it. These changes have been demonstrated in
rodents, dogs, cats, and humans.3-5 The changes that occur in
association with thyroid disease in humans and dogs have
received relatively little attention because, in general, these
patients have adequate renal reserve and so the development
of azotemia is relatively uncommon in spite of the changing
GFR.3,6 By contrast, in elderly cats where the prevalence of
clinical and subclinical CKD is very high,7 alterations in renal
function that occur coincident with changes in thyroid status
are a source of great clinical concern to veterinarians.
Thyroid hormones alter renal blood flow (RBF) and GFR
via many different mechanisms. Cardiac output is increased
in hyperthyroidism because of positive chronotropic and
276
ionotropic effects on the heart. This occurs in part because of
the direct effects of thyroid hormones, and in part in response
to a marked reduction in systemic vascular resistance.8,9 The
increase in cardiac output tends to increase RBF, an effect
that is augmented by increased cortical production of the
vasodilator nitric oxide and reduced production of the
vasoconstrictor endothelin.10,11 Glomerular hemodynamics
are also influenced by the activation of the renin-angiotensin-
aldosterone system that occurs with hyperthyroidism.12 This
results in relative efferent arteriolar vasoconstriction and con-
sequently an increase in filtration fraction; this means that
GFR is increased over and above what would be predicted
from alterations in RBF. In addition, thyroid hormones
directly stimulate sodium and chloride reabsorption from the
proximal nephron,13 which decreases delivery of chloride to
the macula densa and stimulates tubuloglomerular feedback
mechanisms, which also serve to increase GFR.
Hyperthyroidism causes proteinuria. Increased glomerular
pressure is one potential cause of this. There is some evidence
to suggest, however, that the proteinuria that occurs in hyper-
thyroidism is not entirely glomerular in origin since it may
also result from changes in the tubular handling of filtered
protein.14,15
In the hyperthyroid state, renal tubules hypertrophy and
several different carrier-mediated transport processes are
activated. In addition to the insertion of chloride channels
described earlier, thyroid hormones also modulate the
expression of the sodium hydrogen exchanger and sodium-
phosphate transporters in the proximal nephron.16 These
changes result in impaired urinary acidification mechanisms
in hypothyroidism and a tendency for hyperphosphatemia in
hyperthyroidism. Hyperphosphatemia, in turn, may lead to
hyperparathyroidism in hyperthyroid cats.17,18
CHANGES IN GLOMERULAR FILTRATION RATE,
CREATININE, AND UREA WITH TREATMENT
OF HYPERTHYROIDISM IN CATS
Several studies have shown that GFR declines markedly fol-
lowing treatment of hyperthyroidism in cats. This is associ-
ated with the resolution of the hyperthyroid state, rather than
adverse effects of any particular treatment modality. It has
been demonstrated in cats treated with radioiodine,19,20 by
 CHAPTER 25  Are Methimazole Trials Really Necessary?
surgery,21 or with medical therapy.22 The changes in GFR are
marked, ranging from a 44% to 51% decrease from pretreat-
ment values.19-22 The GFR stabilizes by 30 days following
treatment, with no further significant change noted for up to
6 months.19,20
In routine clinical practice, measurement of GFR is
uncommon, and the plasma or serum concentration of cre-
atinine is used instead to provide a measure of renal function.
Creatinine concentration is a hybrid parameter that is not
only a function of GFR but also of the distribution of creati-
nine within the body, and also its endogenous rate of produc-
tion. The rate of production of creatinine in hyperthyroid cats
has not been measured. However, it is notable that although
in general GFR has stabilized by 1 month after treatment
of hyperthyroidism, creatinine concentration continues to
increase for longer than this.19,23 This may be due to increases
in muscle mass that result from the cats becoming euthyroid
or may be due to other, as yet uncharacterized influences of
thyroid hormones on the rate at which creatinine is generated
in the body. In dogs with experimentally induced hypothy-
roidism, creatinine production rate is decreased, meaning that
the creatinine concentration underestimates the reduction in
GFR that occurs.4 This effect may also be relevant to cats that
develop iatrogenic hypothyroidism following treatment for
hyperthyroidism.
The proportion of cats that develop azotemia (i.e., creati-
nine concentration above the laboratory reference interval)
following treatment for hyperthyroidism is dependent on
the degree to which the hyperthyroidism is controlled. In a
study of 268 initially nonazotemic cats, 28 of 106 (26.4%)
cats considered well controlled (total thyroxine <40 nmol/L
[3.1 µg/dL] for 6 months) developed azotemia, compared
with only three of 39 (7.7%) cats with poor control of hyper-
thyroidism.15 Of the cats for which control of hyperthyroid-
ism fluctuated or could not be assessed because of a lack of
follow-up, 10 of 123 (8.1%) developed azotemia.
Urea concentrations in cats with hyperthyroidism are
often mildly increased, in spite of the increased GFR that
occurs with this condition. This increase is thought to relate
to increases in dietary protein intake and protein catabolism.
This means that urea/creatinine ratios tend to be high initially
in hyperthyroid cats and normalize with treatment.
ARGUMENTS FOR PERFORMING
METHIMAZOLE TRIALS
Prediction of Cats That Will Develop
Azotemia Is Not Possible without Treatment
The proportion of cats that become azotemic following treat-
ment of hyperthyroidism has been quite variable in different
studies, ranging from 17% to 49%.19,21,22,24-28 One reason for
this disparity may be that azotemia is more likely to occur if
iatrogenic hypothyroidism develops following treatment for
hyperthyroidism,27 and the incidence of this may have differed
among the published studies. It will also depend, to some
extent, on how long after treatment the assessment of renal
277
function was made, because it will take some time for azote-
mia to develop. As discussed earlier, creatinine concentrations
may not peak until as long as 3 months after treatment.19,23
Treatment trials with methimazole would not be neces-
sary if it were possible to predict reliably which cats will
develop azotemia with treatment of hyperthyroidism; cats
unlikely to develop azotemia could have permanent treat-
ment immediately. Unfortunately, currently no single test
currently exists that will reliably predict renal function after
treatment for hyperthyroidism. Measurement of GFR was
reported in one early study to predict the cats that will
develop azotemia following treatment for hyperthyroidism.25
However, this relationship has not been borne out in other
studies in which GFR has been measured. Although pre-
treatment GFR values generally have been lower in cats that
subsequently develop azotemia than in those that do not,
there has been significant overlap between the groups.19,23
This might be anticipated because the decline in GFR is
presumably going to depend, to some extent, on the severity
of hyperthyroidism before treatment.
Pretreatment creatinine concentrations perform in a
similar manner to measurement of GFR in predicting devel-
opment of azotemia. In the largest study reported to date, the
pretreatment creatinine concentration (median [25th, 75th]
percentiles) was significantly greater (P < 0.001) in those cats
that developed azotemia with treatment (1.31 [1.18, 1.69],
n = 34) than in those that did not (1.07 [0.90, 1.28],
n = 183).15 In spite of this observation, baseline creatinine
was not considered to be a reliable indicator for the develop-
ment of azotemia following treatment in individual patients
because there was considerable overlap between the groups.
Urea performed in a similar manner.
It has sometimes been suggested that cats with good renal
concentrating ability (urine specific gravity >1.035) are less
likely to develop azotemia following treatment. However, the
studies that have objectively evaluated this claim have not
found that urine specific gravity is a useful predictor of the
post-treatment development of azotemia.15,26
Proteinuria is common in hyperthyroid cats, and it declines
with treatment. However, the magnitude of proteinuria does
not predict the subsequent development of azotemia.15 It is
correlated with overall survival time; however, this association
is relatively weak in hyperthyroidism by comparison with
studies of cats with CKD and/or hypertension.29,30
ARGUMENTS AGAINST PERFORMING
METHIMAZOLE TRIALS
Undertreatment of Hyperthyroidism Is
Common with Medical Treatment
If trial treatment is to be successful in predicting the cats that
will develop azotemia when treated with permanent therapies
(radioiodine or surgical thyroidectomy), then it must reduce
the thyroid hormone concentration to a comparable extent,
and for long enough to allow azotemia to develop. This is dif-
ficult to do in practice because with medical treatment (e.g.,
278 SECTION 3 Endocrine and Metabolic Diseases
drug therapy or iodine-restricted diet) of hyperthyroidism,
undertreatment is relatively common. In addition, reversible
treatments for hyperthyroidism are likely to result in more
day-to-day variation in thyroid hormone concentrations.
In one of the earliest studies of methimazole treatment,
failure to control the thyroid hormone concentration was
only reported in two out of 262 cats treated, although doses
as high as 20 mg/day (divided) were given.31 However, sub-
sequent clinical experience would suggest that failure to
control hyperthyroidism with drugs is relatively common,
perhaps because lower initial doses tend to be given and
owners become disheartened when serial increases in dose
have to be made. Even in the original study, almost one third
of the cats treated for more than 100 days had a total thy-
roxine value above the reference range on one to four occa-
sions,31 demonstrating that while treatment with drugs could
be effective, consistency of therapeutic effect was difficult to
maintain.
In one large study of samples submitted to a laboratory
following once-daily administration of methimazole (n =
543) or carbimazole (n = 883), total thyroxine values were
above the therapeutic target (10 to 50 nmol/L [0.78 to
3.89 µg/dL]) in 52.9% and 49.0%, and below the therapeutic
target in 17.3% and 10.5% of samples, respectively.32 This
might reflect a conservative approach by practitioners with
an incremental increase in dosage at the start of treatment,
submission bias owing to samples being taken from cats that
were showing persistent signs of hyperthyroidism, and results
might have been better if patients on twice-daily therapy
had been included in the study. Even so, the results suggest
that many cats treated medically for hyperthyroidism are not
well controlled. This is especially true, as the therapeutic
target in that study was quite wide; optimal control of hyper-
thyroidism would usually be considered a total thyroxine
concentration within the lower half of the laboratory refer-
ence range.
Side effects are reported in 18% of cats treated with
methimazole.31 Most often this consists of simple gastroin-
testinal (GI) upset, which resolves with a dose reduction.
More serious adverse drug reactions such as blood dyscrasias
and facial excoriations necessitate drug withdrawal. Similar
side effects have been reported for carbimazole,33 which is
expected because it is a pro-drug, converted to methimazole
in vivo. Development of side effects with medical treatment
is therefore a relatively common reason for cats to be referred
for radioactive iodine therapy. This, together with the diffi-
culty of consistently controlling hyperthyroidism with
medical treatment for a period of several weeks to months,
means that a relatively high proportion of cats receiving per-
manent treatment for hyperthyroidism have never received
an effective methimazole trial. Although this has not been
studied in any objective manner, anecdotally, there have been
very few reported complications from this lack of “trial
treatment”.
Transdermal drug application has been associated with a
lower rate of GI side effects than the orally administered
drug.34 Even so, the efficacy of treatment with transdermal
formulations has been lower than with tablet treatments in
some,34 but not all,35 studies. Transdermal administration of
methimazole is not appropriate in cats that have previously
developed a serious adverse drug reaction to methimazole or
carbimazole because these drug reactions are considered idio-
syncratic and are not classically dose related. Transdermal
treatment will therefore allow for successful methimazole
trials in some, but by no means all, cats.
It is also now possible to treat hyperthyroidism in cats by
the exclusive feeding of an iodine-restricted diet (Hill’s Pre-
scription Diet y/d). There are only limited reports of the
efficacy of this treatment, with many studies having only been
published as abstracts. However, in one study of 225 cats
treated by feeding this diet, 25% of the cats were still hyper-
thyroid after 8 weeks of treatment.36 It is hard to be certain
because of the manner in which the results are reported, but
it appears that the majority of cats had total thyroxine con-
centrations that were within the upper half of the laboratory
reference range. Creatinine concentrations were actually
reduced 4 weeks after introduction of the diet in that study.
The authors speculate that this could be because of the low
heat-processed meat content of the diet.36 Alternatively, it
could be due to poor control of the hyperthyroidism; approxi-
mately half of the cats in the study had been receiving anti-
thyroid drugs before the diet being introduced, so it is possible
that the thyroid hormone concentration increased in some of
the cats after introduction of the diet. These results suggest
that dietary management of hyperthyroidism is unlikely to
suppress thyroid levels to the same extent as permanent ther-
apies and is therefore less likely to “unmask” underlying CKD
than are other forms of treatment.
If Iatrogenic Hypothyroidism Occurs
Following Definitive Treatment, Then
Azotemia May Still Develop
Iatrogenic hypothyroidism can occur following radioactive
iodine therapy, bilateral thyroidectomy, or treatment with
antithyroid medication. It is also theoretically possible for
hypothyroidism to occur in cats fed an iodine-restricted diet,
but it appears to be much less common.36 It used to be
thought that iatrogenic hypothyroidism was of very little
clinical consequence. However, it has since been shown that
cats with iatrogenic hypothyroidism are more likely to be
azotemic than those that remain euthyroid following treat-
ment.27 In another study, restoration of euthyroidism in cats
with iatrogenic hypothyroidism resulted in a significant
reduction in plasma creatinine concentration, with azotemia
resolving in half of the cats.37
These observations emphasize the point that unless the
degree of control of hyperthyroidism is equivalent with dif-
ferent treatments the effect on renal function will not be
comparable. Thus, it is quite possible for a cat that has been
pretreated with methimazole to have a significant increase
in creatinine concentration following the administration of
radioactive iodine because of the development of iatrogenic
hypothyroidism. It has been reported that approximately 30%
of cats treated with radioactive iodine develop hypothyroid-
ism.38 In humans treated with radioactive iodine, the
 CHAPTER 25  Are Methimazole Trials Really Necessary?
development of hypothyroidism continues to occur for many
years following treatment.39
Undertreatment of Hyperthyroidism May Be
Damaging to the Kidney
Why do so many cats treated for hyperthyroidism develop
azotemia? Hyperthyroidism and CKD are both very common
feline problems, and both increase in prevalence with advanc-
ing age, which may explain the association between these two
conditions. Alternatively, it is possible that the frequency
with which CKD is diagnosed following treatment is because
hyperthyroidism is actually damaging to the feline kidney.
One mechanism by which hyperthyroidism could cause
injury is through the process of hyperfiltration. In patients
with CKD, the remaining functional nephrons hyperfiltrate;
this means that although the global GFR for the patient is
decreased, each of the remaining nephrons individually has
an increased filtration rate. This process is largely due to an
increase in filtration pressure across the glomerular barrier.40
This increase in glomerular pressure has been associated with
proteinuria and with accelerated nephron loss, resulting in
progressive renal injury. Hyperthyroidism has the potential
to exacerbate these processes. Ameliorating this glomerular
hypertension is the rationale for treating patients with CKD
with angiotensin-converting enzyme inhibitors. Although
the effectiveness of such therapies in management of (pre-
dominantly tubulointerstitial) CKD in cats is questionable,41
it does not seem logical to deliberately undertreat hyper-
thyroidism with the aim of causing renal hyperfiltration.
Such an approach will inevitably decrease the patient’s cre-
atinine value; however, it does nothing to improve nephron
health.
Other possible mechanisms by which hyperthyroidism
could cause renal injury include activation of the renin-
angiotensin-aldosterone system, development of hyperpara-
thyroidism, and increases in renal oxidative stress. These
mechanisms have been implicated in progression of CKD,
either in cats with naturally occurring disease and/or in
experimental models of renal injury. It has been shown
that plasma renin activity and aldosterone concentrations
are increased in cats with hyperthyroidism.42 Hyperthyroid
cats also have increased plasma phosphate and parathyroid
hormone concentrations, although this is not associated with
the development of azotemia following treatment.17,18 Urinary
concentrations of 8-isoprostanes, eicosanoids generated by
lipid peroxidation, are increased in cats with hyperthyroidism
and decrease with treatment, suggesting that hyperthyroid-
ism causes reversible oxidative stress.43
Even If Azotemia Develops, Effective
Treatment for Hyperthyroidism Is
Still Advised
In most cats that develop newly diagnosed azotemia follow-
ing treatment for hyperthyroidism, the degree is mild (usually
International Renal Interest Society [IRIS] stage 2) and asso-
ciated with few, if any, clinical signs other than mild polyuria
279
or polydipsia. Owners of cats that have developed azotemia
still usually report that the clinical condition of their cat is
improved overall following treatment, and notice weight gain
and reversal of other clinical signs of hyperthyroidism.
The survival time of cats that develop azotemia following
treatment of hyperthyroidism is not significantly different
from that of those that do not.27 This finding may be surpris-
ing to practitioners who will tend to assume that the develop-
ment of azotemia is associated with a worse prognosis.
However, CKD is relatively slowly progressive in cats, and
only about half of all cats diagnosed with mild CKD will
ultimately succumb to the disease, with many dying from
other causes.44 Additionally, the cut point between azotemic
and nonazotemic is somewhat arbitrary, and it is likely that
many old cats, even among those that are classified nonazo-
temic, have a degree of renal compromise. Therefore, the
distinction between these two groups (azotemic and nonazo-
temic) may not be as great as initially thought.
In contrast to the situation in cats that are euthyroid fol-
lowing effective treatment of hyperthyroidism, the develop-
ment of azotemia in cats with iatrogenic hypothyroidism
appears to have a negative effect on patient welfare. In one
study, survival of hypothyroid, azotemic cats was significantly
worse (median 456 [25th, 75th percentiles; 362, 841] days)
than that of the hypothyroid, nonazotemic (905 [625, 1701]
days) cats.27 Thus, the current treatment recommendation is
to maintain total thyroxine concentrations within the lower
half of the laboratory reference range, but not below it, to
ensure that hyperthyroidism is being effectively treated.
Progression of Chronic Kidney Disease
Is Inherently Unpredictable
Many cats with CKD have nonprogressive or slowly progres-
sive disease, and the magnitude of azotemia remains very
stable for months or even years. When cats are diagnosed
with azotemic CKD, approximately half will die from unre-
lated causes.44 In a study of cats with naturally occurring
CKD, only a minority of the cats with IRIS stage 2 disease
progressed to IRIS stage 4 before death.45 Similarly, studies
of cats with surgical reduction of renal mass have shown that
renal function remains stable for protracted periods.46
Although risk factors for progressive renal disease have
been identified on a population basis (e.g., proteinuria, phos-
phate concentration, and packed cell volume),30,45 it remains
very difficult to predict longevity in any individual patient.
Cats with CKD often seem to demonstrate a “stepwise” pro-
gression of their azotemia, with their renal function remain-
ing stable for a long period and then seemingly showing an
abrupt increase. Given the inherent unpredictability of when
this deterioration in renal function occurs, this means that
occasionally a cat is treated with radioactive iodine and shows
an abrupt clinical decline. This is possible whether the patient
has previously completed a methimazole trial. In fact, in some
ways, if an abrupt decline does occur this can be worse for
the owner if the patient has been through a methimazole
trial because they thought they were protected from this
eventuality.
280 SECTION 3 Endocrine and Metabolic Diseases

small changes in GFR will result in large changes in creati-

SPECIAL CIRCUMSTANCES IN WHICH
METHIMAZOLE TREATMENT IS STRONGLY
ADVISED BEFORE DEFINITIVE TREATMENT
Treatment Trials before Surgery
Radioiodine is considered to be the treatment of choice for
hyperthyroidism based on its high efficacy and lack of com-
plications, although initial cost and length of hospital stay
may be a deterrent for some owners.47 Surgical thyroidectomy
is also an effective and permanent treatment option, particu-
larly in cats where thyroid scintigraphy has been performed
first to exclude the possibility of ectopic hyperplastic thyroid
tissue.48
In cats treated by surgical thyroidectomy, prior medical
treatment not only allows for the assessment of renal function
in the euthyroid state but also has the added benefit of poten-
tially reducing the risks associated with general anesthesia. In
this situation, medical treatment is not so much a trial therapy
as a consideration for preoperative stabilization of the
patient’s clinical condition. Even so, recommendations for
prior medical treatment of hyperthyroidism vary. Some
authors recommend initial medical treatment routinely,49,50
whereas others recommend this approach only for cats with
cardiac hypertrophy, arrhythmias, or tachycardia,48,51 or cats
that are severely clinically affected.52 In the author’s practice,
medical treatment of hyperthyroidism is usually advised
before surgery unless the cat has a history of adverse reactions
to antithyroid medications, or the cat shows no clinical signs.
Treatment of Cats with Pre-existing Azotemia
In cats that are azotemic before treatment for hyperthyroid-
ism, it is generally recommended that they be treated medi-
cally initially (and with a gradually escalating dose), so that
if their condition deteriorates the antithyroid medications
can be discontinued and the cat will return to a hyperthyroid
state. If the biochemical deterioration is mild following treat-
ment, and the well-being of the cat is improved, then per-
manent treatment for hyperthyroidism (thyroidectomy or
radioiodine therapy) can be considered. However, in general,
the survival of cats that have azotemic CKD before treatment
of hyperthyroidism is poor; in one study performed in first-
opinion practices (and so likely to have included an unselected
population of cats), the median survival time for azotemic
cats was only 178 days (range 0 to 1505 days).15
It is worth remembering that the relationship between
GFR and creatinine is not linear; once renal function is poor,
nine concentration. Thus, when treating hyperthyroidism,
a comparable decrement in GFR in a cat that is initially
nonazotemic will result in a much smaller change in creati-
nine concentration than in a cat that is already azotemic at
baseline.
In cats with elevated creatinine concentrations before
treatment for hyperthyroidism, starting with a low dose of
medication initially is prudent; the dose can then gradually
be escalated if this is necessary and well tolerated.
SUMMARY
In summary, in the opinion of the author, treatment trials
with reversible therapies (i.e., methimazole, carbimazole, or
diet) need not be routinely recommended for all hyperthy-
roid cats. This was also the consensus opinion of a panel of
European key opinion leaders,53 because medical treatment
may not be immediately successful, necessitating an adjust-
ment in dose or a change in modality because of side effects
or poor owner and patient compliance. Even if euthyroidism
is achieved, this state needs to be maintained for a reasonable
length of time (more than one month) to determine if azo-
temia will develop. The requirement for multiple visits to the
veterinary clinic and the cost associated with repeated blood
tests during this period are likely to lead to owner frustration
and may make subsequent permanent treatment unafford-
able for some. Added to which, when permanent treatment
(radioiodine or surgical thyroidectomy) is performed, azote-
mia may still develop because the thyroid hormone concen-
tration may not be identical to that achieved with medical
management. In any case, survival of cats that develop azo-
temia following treatment for hyperthyroidism is no differ-
ent from that of those that remain nonazotemic, provided
that the cats are not hypothyroid; clinically, many of these
patients do very well. Even though there is no direct evi-
dence that hyperthyroidism is actually damaging to the feline
kidney, maintaining cats in a mildly hyperthyroid state to
improve numerically their creatinine values is no longer
recommended.
Treatment trials with methimazole or other reversible
therapies should be reserved for cats that are azotemic when
hyperthyroidism is diagnosed and before any treatment is
instigated. Consideration should also be given to providing
thyroid hormone replacement in cats with iatrogenic hypo-
thyroidism following radioiodine therapy or bilateral thyroid-
ectomy (see Chapter 23).

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