Treatment for therapeuutic 10/2/03 14:44 Page 334

PAPERS

Treatment and therapeutic monitoring

of canine hypothyroidism
Thirty-one dogs with spontaneous hypothyroidism were treated with particular, the role of endogenous thy-
rotropin (canine thyroid stimulating hor-
thyroid hormone replacement therapy (THRT) and monitored for mone [cTSH]) estimation in therapeutic
approximately three months. Good clinical and laboratory control was monitoring is unclear and there is a dearth
of data concerning the routine biochemi-
ultimately achieved in all cases with a mean L-thyroxine (T4) dose of cal and haematological changes following
0·026 mg/kg administered once daily. There was a significant the start of THRT. In addition, the most
appropriate time to start monitoring after
increase and decrease in circulating total T4 and canine thyroid instituting THRT is unclear. The objec-
stimulating hormone (cTSH) concentrations, respectively, after tives of this study were to evaluate the clin-
ical response to therapy of a commonly
starting THRT. After commencing treatment, 11 cases subsequently used dosing schedule, and investigate in
required an increase and three cases required a decrease in dose to detail the endocrine and routine laboratory
changes which occur during THRT in a
achieve optimal clinical control. Median (semi interquartile range group of hypothyroid dogs.
[SIR]) circulating six-hour post-pill total T4 (53·6 [27·9] nmol/litre)
and cTSH (0·03 [0] µg/litre) concentrations were significantly MATERIALS AND METHODS
increased and decreased, respectively, in treated dogs that did not
Case material
require a dose change; corresponding values in treated dogs in which Thirty-one hypothyroid dogs referred to
an increase in dose was required were 29·3 (12·7) nmol/litre and 0·15 the University of Glasgow, Department of
Veterinary Clinical Studies, were studied.
(0·62) µg/litre, respectively. However, circulating cTSH measurement Hypothyroidism was initially suspected
was of limited value in assessing therapeutic control because, based on appropriate clinical signs and/or
supportive clinicopathological abnormali-
although increased values were associated with inadequate therapy, ties, and was subsequently confirmed in
reference range cTSH values were common in inadequately treated each case based on the results of bovine
TSH response tests, as previously described
dogs. Lethargy and mental demeanour were typically the first clinical (Dixon and Mooney 1999). Prior to start-
signs to improve, with significant bodyweight reduction occurring ing therapy, the clinical findings in each
case were recorded, and blood was collected
within two weeks of commencing THRT. Routine clinicopathological for circulating total thyroxine (T4), and
monitoring was of value in confirming a general metabolic response to cTSH estimation, as well as routine bio-
chemical and haematological analyses, as
THRT, but was of limited value in accurately monitoring cases or previously described (Dixon and Mooney
tailoring therapy in individual cases. 1999, Dixon and others 1999).
All dogs were treated with synthetic
sodium L-thyroxine (Soloxine; Daniels
R. M. DIXON, S. W. J. REID* INTRODUCTION Pharmaceuticals) at an initial dose of
AND C. T. MOONEY†
approximately 0·02 mg/kg bodyweight
Hypothyroidism is a common endocrine administered once daily each morning. At
Journal of Small Animal Practice (2002)
43, 334–340 disorder of the dog and, although emi- the outset of treatment, owners were
nently treatable, numerous therapeutic requested to return for monitoring two, six
and monitoring strategies have been rec- and 12 weeks after the start of therapy or
Axiom Veterinary Laboratory, 5 George ommended (Martin and Capen 1979, more frequently if warranted clinically. At
Street, Teignmouth, Devon TQ14 8AH
Chastain 1982, Rosychuk 1982, Ferguson each visit, a full clinical examination,
*Comparative Epidemiology and Informatics,
Department of Veterinary Clinical Studies,
1986, Dunn 1989, Panciera 1997). including bodyweight measurement, was
University of Glasgow, Bearsden Road, Despite provision of general guidelines performed, and blood was collected six
Glasgow G61 1QH (Feldman and Nelson 1996), there is little hours after exogenous T4 administration
†Department of Small Animal Clinical published data on the clinical and labora- (Nachreiner and Refsal 1992) for serum
Studies, Faculty of Veterinary Medicine,
University College Dublin, Belfield, Dublin 4,
tory response to thyroid hormone replace- total T4 and cTSH estimation in addition
Ireland ment therapy (THRT) in affected dogs. In to routine biochemical and haematological

334 JOURNAL OF SMALL ANIMAL PRACTICE • VOL 43 • AUGUST 2002

Treatment for therapeuutic 10/2/03 14:44 Page 335

Table 1. Total T4 (nmol/litre) and cTSH (µg/litre) concentrations in dogs

receiving thyroid hormone replacement therapy categorised by visit. All
treatment samples were collected six hours after T4 administration

Visit Number Mean (range) days Median (SIR) Median (SIR)

of dogs on treatment total T4 cTSH

1 31 NA 4·7 (1·9)2,3,4 1·77 (2·34)2,3,4

2 26 17·8 (9-28) 52·0 (37·2)1 0·03 (0·11)1
3 25 49·4 (29-69) 49·2 (20·9)1 0·05 (0·18)1
4 22 95·9 (77-112) 50·9 (21·1)1 0·03 (0·16)1
SIR Semi-interquartile range
1 Significantly different from visit 1, 2 Significantly different from visit 2, 3 Significantly different from visit 3, 4 Significantly
different from visit 4

analyses. The dosage of THRT was re- Data handling and statistical all, circulating serum total T4 and cTSH
evaluated at each visit and the decision as analysis concentrations were significantly increased
to whether or not to make a dose change All statistical computations were per- and decreased, respectively, at all treatment
was based solely on the clinical response to formed using Minitab 9·2 for Windows visits compared with pretreatment values
therapy. However, in dogs in which an (Minitab Inc). The effect of duration of but there was no significant change
alteration in dose was required, both the therapy on routine laboratory parameters between the treatment visits.
clinical and laboratory findings were con- was evaluated using a general linear model The dose of THRT was increased in 11
sidered when determining the magnitude analysis of variance with post hoc pairwise (35·5 per cent) and decreased in three (9·7
of that change. comparison of means performed by New- per cent) of 31 dogs as outlined in Table 2.
The duration of THRT was divided man-Keuls multiple range testing. P values The majority of dosage adjustments were
into time frames (visits); namely, visits 1 less than 5 per cent (P<0·05) were consid- made at either visit 2 or 3 and only one
(pretreatment), 2 (nine to 28 days), 3 (29 ered statistically significant. Bodyweight dosage adjustment was required in these
to 70 days) and 4 (71 to 112 days). The data were calculated and analysed as a per- dogs. The mean dose of T4 administered
clinical and clinicopathological findings centage of the animal’s pretreatment was 0·0199, 0·0210, 0·0248 and 0·0254
were compared between visits to assess the weight. Comparison of the endocrine and mg/kg bodyweight at visits 1 to 4, respec-
effect of THRT over time. If dogs were routine laboratory data at each visit tively. In one dog with chronic diarrhoea,
seen on multiple occasions within an indi- between those cases that needed an an unusually large dose of T4 replacement
vidual visit period, the visit with most increase in THRT dosage and those in therapy was required (0·076 mg/kg).
recorded data was used for statistical which the dosage was not changed Twice daily therapy was not considered
analyses. was performed using a Mann-Whitney U clinically necessary in any of the 31 dogs.
test. Median (SIR) circulating six-hour post-
Endocrinological, biochemical pill total T4 and cTSH concentrations
and haematological analyses (29·3 [12·7] nmol/litre and 0·15 [0·62]
Sample handling and determination of RESULTS µg/litre, respectively) were significantly
total T4 and cTSH, and routine biochemi- decreased and increased, respectively, in
cal and haematological analyses, including Circulating total T4 and cTSH concentra- dogs that required an increase in dose to
quality control procedures, were per- tions and the number of dog visits in each achieve optimal clinical control, compared
formed as previously described (Dixon and grouping, with the associated temporal with values of 53·6 (27·9) nmol/litre and
others 1999). The laboratory reference data, are detailed in Table 1. Pretreatment 0·03 [0] µg/litre, respectively, for all dogs
values considered indicative of euthy- circulating total T4 concentration was less in which no increase in dose was required.
roidism for total T4 (≥14·9 nmol/litre) than 14·9 nmol/litre in all but one dog Eight of 11 (72·7 per cent) samples
and cTSH (≤0·68 µg/litre) were as (actual value, 17·8 nmol/litre) and circu- from dogs requiring an increase in dosage
reported previously (Dixon and Mooney lating cTSH concentration was over 0·68 had peak total T4 values of less than 35
1999). ng/ml in 26 (83·9 per cent) animals. Over- nmol/litre compared with four of 59 (6·8
per cent) samples from dogs in which an
Table 2. Cases requiring an alteration in thyroid hormone increase was not required. Only two dogs
replacement therapy that required an increase in dose based on
Dog Visit Total T4 cTSH Direction of
an inadequate clinical response to therapy
number (nmol/litre) (µg/litre) adjustment had subnormal peak total T4 concentra-
tions. One dog (dog 24) had a peak total
2 3 38·4 0·03 Increase
T4 concentration of 8·3 nmol/litre. There
3 2 13·3 1·65 Increase
4 3 26·8 0·54 Increase was persistent diarrhoea in this case and
5 3 101·3 0·16 Decrease poor gastrointestinal absorption was sus-
6 4 23·0 4·00 Increase
pected as the reason for therapeutic failure.
10 3 103·5 0·01 Decrease
11 2 42·3 0·14 Increase Following an increase in dose, subsequent
13 3 49·2 0·39 Decrease peak total T4 results (41·9 and 40·9
14 4 31·4 0·15 Increase
nmol/litre) were consistent with adequate
22 3 39·8 0·01 Increase
23 2 29·3 0·75 Increase absorption and this was associated with
24 2 8·3 0.02 Increase resolution of clinical signs. In the remain-
25 2 29·1 0·01 Increase
ing dog (dog 3), the peak total T4 result
30 3 31·4 0·22 Increase
was subnormal (13·3 nmol/litre) and the

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Treatment for therapeuutic 10/2/03 14:44 Page 336

Table 3. Changes in routine blood biochemical parameters (median [SIR]) in hypothyroid dogs following treatment with
thyroid hormone replacement therapy, and the associated P value for the overall effect of treatment
Visit 1 Visit 2 Visit 3 Visit 4 P value Reference range

Urea 4·7 (3·1) 5·1 (2·5) 4·3 (2·7) 4·6 (2·4) 0·463 2·5-8·5 mmol/litre
Sodium 144·0 (3·0)2,3,4 147·0 (3·0)1 146 (2·2)1 147 (3·0)1 0·000 136-159 mmol/litre
Potassium 4·6 (0·7) 4·4 (0·6) 4·4 (0·47) 4·30 (0·72) 0·457 3·4-5·8 mmol/litre
Chloride 110·5 (8·5) 112·0 (7·0) 114·0 (4·0) 113·0 (2·5) 0·093 95-115 mmol/litre
Calcium 2·68 (0·27)4 2·65 (0·27)4 2·61 (0·24)4 2·52 (0·23)1,2,3 0·007 2·34-3·00 mmol/litre
Magnesium 0·80 (0·18) 0·74 (0·23) 0·76 (0·14) 0·73 (0·15) 0·197 0·60-0·87 mmol/litre
Phosphate* 1·26 (0·29) 1·40 (0·29) 1·43 (0·44) 1·34 (0·25) 0·046 0·9-2·9 mmol/litre
Glucose 5·45 (0·78)3 5·35 (0·97) 5·50 (1·05)1 5·55 (0·90) 0·025 3·3-6·5 mmol/litre
Cholesterol 10·51 (6·25)2,3,4 5·63 (2·15)1 4·60 (2·73)1 4·68 (2·46)1 0·000 2·0-7·0 mmol/litre
Creatinine 105·0 (39·0)2,3,4 94·0 (46·0)1 93·0 (39·2)1 93·5 (28·2)1 0·000 45-155 µmol/litre
Bilirubin 1·0 (1·0) 0·0 (0·0) 1·0 (0·75) 1·0 (0·0) 0·258 0-10 µmol/litre
ALKP 138 (305)3,4 126 (181) 105 (102)1 117·0 (113)1 0·019 0-230 IU/litre
AST 24·5 (15·2)3,4 25·0 (12·0)4 21·5 (9·0)1 19·0 (7·7)1,2 0·012 0-40 IU/litre
ALT 43·5 (73·3) 52·0 (171) 42·5 (50·4) 24·5 (28·5) 0·074 0-40 IU/litre
Total protein 66·5 (10·2)3,4 64·0 (13·0) 63·0 (8·7)1 62·0 (11·7)1 0·015 50-78 g/litre
Albumin 35·0 (7·0)4 37·0 (7·0)4 35·0 (8·0) 32·5 (5·7)1,2 0·034 29-36 g/litre
Globulin 31·5 (6·2)4 28·0 (5·0)4 28·0 (4·5) 29·0 (7·25)1,2 0·021 28-42 g/litre
Creatine kinase 100 (86) 117 (97) 114 (62) 104 (67·5) 0·845 0-150 IU/litre
Triglycerides 1·56 (4·05)2,3,4 1·18 (0·81)1 0·90 (0·78)1 0·97 (0·96)1 0·003 0·1-0·6 mmol/litre
-GT 5·0 (4·0) 3·0 (2·0) 4·0 (2·0) 4·0 (1·2) 0·463 0-20 IU/litre
Fructosamine 305 (77)2,3,4 297 (53)1,3,4 250 (77)1,2,4 251 (80)1,2,3 0 102-310 µmol/litre
SIR Semi-interqualtile range, ALKP Alkaline phosphatase, AST Aspartate aminotransferase, ALT Alanine aminotransferase, -GT -glutamyl transferase
1 Significantly different from visit 1, 2 Significantly different from visit 2, 3 Significantly different from visit 3, 4 Significantly different from visit 4

*Overall effect of therapy significant (P<0·05) but no individual time points significant

clinical response was considered sub-
optimal. In the other cases that required an
increased dose, peak total T4 values were
within the euthyroid range but the clinical
response was considered inadequate.
Circulating cTSH values declined from
a pretreatment median (SIR) of 1·52
(2·24) µg/litre and range of 0·01 to 12·3
µg/litre to 0·15 (0·62) and 0·01 to 1·65
µg/litre, respectively, just before the T4
dosage was adjusted in those dogs that
required an increased dose. Circulating
cTSH was less than 0·33 µg/litre in 55 of
59 (93·2 per cent) samples from dogs in
which an increase in dose was not required.
However, seven of 11 (63·6 per cent) sam-
ples from dogs requiring an increase in
dose also had circulating cTSH concentra-
tions below this value. In total, two (18·2
per cent) of the dogs that required an
increased dosage had pretreatment cTSH
values within the reference range, while
eight (72·7 per cent) dogs had reference
range values just prior to dose adjustment.
In three dogs that required an increase in
dose, the circulating cTSH concentration
was above the reference range immediately
prior to dosage alteration. After dose
adjustment, subsequent samples were col-
lected from two of these dogs for monitor-
ing purposes and in each case the cTSH
value was found to be at the detection limit
of the assay (LoD).
In two of the three dogs that required a
reduction in dose (dogs 5 and 10), peak
total T4 results were greater than 100
nmol/litre although only mild clinical
signs of hyperthyroidism (polydipsia and
hyperactivity) were present. Two addi-
tional cases (dogs 6 and 9) had peak total
T4 concentrations of approximately 100
nmol/litre and did not clinically require a
reduction in therapy. Following the reduc-
tion in dose in dog 10, a subnormal peak
total T4 concentration (12·6 nmol/litre)
was obtained from a subsequent monitor-
ing sample. However, this was attributed
to failure of appropriate therapy on the day
of testing since the clinical condition of
this dog was well controlled and the corre-
sponding cTSH result (0·01 µg/litre) was
at the assay LoD. The dose of therapy was
not, and subsequently did not need to be,
adjusted in this case. This was the only dog
that did not require a dose adjustment in
which a circulating total T4 concentration
was below the laboratory reference value.
In the third case requiring a reduction in
dosage (dog 13), the peak total T4 result
was not excessive (49·2 nmol/litre) but the
owners reported clinical signs of hyper-
thyroidism (hyperactivity). The reduction
in dose was associated with a reduction in
these signs.
All dogs eventually exhibited either a
good or excellent clinical response to
THRT. Metabolic signs such as mental
demeanour and willingness to exercise
were usually improved within three or
four days. The mean (± sd) bodyweight of
all dogs was 95·8 (±3·9), 93·2 (±4.·8) and
91·3 (±5·5) per cent of the mean pretreat-
ment weight at visits 2, 3 and 4, respec-
tively. Dermatological improvements were
normally reported by visit 3. Commonly
there was a period of initial hair loss prior
to regrowth. In a number of cases, the hair
coat was considered normal by visit 3,
although many dogs still had some hair
coat abnormalities by visit 4. Dermatolog-
ical improvements included regrowth of
hair and resolution of pyoderma. In sev-
eral cases there was darkening of the hair
coat. In one case, the owner commented
that the dog had started barking again,
although the loss of vocalisation had not
been identified as a problem prior to start-
ing therapy. The level of activity that was
exhibited by the treated dogs improved
almost universally, including those cases in
which this was not recognised as a prob-
lem before starting therapy. In one dog
with corneal lipidosis, the ocular abnor-
malities deteriorated despite normalisa-
tion of the dog’s cholesterol and
triglyceride results. In other respects this
dog improved clinically. One dog devel-
oped an acute temporary lameness during
THRT but this was not considered to be
related to the treatment and responded to
alternative therapy.
The biochemical and haematological
results from the dogs at each visit are
detailed in Tables 3 and 4, respectively.
Median circulating cholesterol and tri-
glycerides were significantly decreased at
all treatment visits compared with pre-
treatment values but did not change
significantly between the treatment visits.
The median red blood cell (RBC) count
and haemoglobin concentration were

336 JOURNAL OF SMALL ANIMAL PRACTICE • VOL 43 • AUGUST 2002

Treatment for therapeuutic 10/2/03
Table 4. Changes in routine haematological parameters (median [SIR]) in hypothyroid dogs following treatment with
thyroid hormone replacement therapy, and the associated P value for the overall effect of treatment
Visit 1
RBC count 5·57 (1·22)2,3,4
Haemoglobin 12·9 (2·4)2,3,4
MCV 66·0 (5·0)4
MCH 23·3 (1·9)4
MCHC 34·5 (1·3)
Platelets 365 (217)
MPV 8·3 (1·3)
WBC count 9·5 (4·7)
Band neutrophils 0·0 (0·09)
Neutrophils 6·7 (4·1)
Lymphocytes 1·8 (0·8)
Monocytes 0·57 (0·55)
Eosinophils 0·33 (0·36)
RBC Red blood cell, MCV Mean red cell volume, MCH Mean red cell haemoglobin, MCHC Mean red cell haemoglobin concentration, MPV Mean platelet volume, WBC White blood cell
1 Significantly different from visit 1, 2 Significantly different from visit 2, 3 Significantly different from visit 3, 4 Significantly different from visit 4
significantly increased at every treatment
visit compared with each previous visit.
There was a significant difference in
median circulating sodium, calcium,
phosphate, glucose, creatinine, alkaline
phosphatase (ALKP), aspartate amino-
transferase (AST), alanine aminotrans-
ferase, total protein, albumin, globulin,
fructosamine, mean red cell volume
(MCV) and mean red cell haemoglobin
(MCH) between pretreatment values and
those obtained at some time point between
visits 1 and 4. Median circulating protein
concentrations decreased after starting
THRT but took until visits 3 and 4 to be
statistically significant. Fructosamine con-
centrations were significantly decreased at
every treatment visit compared with each
previous visit. However, actual values were
usually within or not significantly outwith
their respective reference ranges. There was
no significant difference in any other mea-
sured parameter between any visits.
Circulating creatinine was the only ana-
lyte that was significantly different (at visit
2) between all dogs that needed an increase
in THRT at some point during the study
and those dogs that did not require any
dose adjustment.
DISCUSSION
Previous reports have equivocated on the
need, or most appropriate regimen, for the
therapeutic monitoring of canine hypo-
thyroidism (Rosychuk 1982, Dunn 1989,
Panciera 1994, Refsal and Nachreiner
1997). However, there are limited reports
on the clinical and clinicopathological
response to THRT in reliably confirmed
spontaneous cases on which to base such
recommendations. Based on the findings
JOURNAL OF SMALL ANIMAL PRACTICE • VOL 43 • AUGUST 2002
14:44 Page 337
Visit 2 Visit 3
5·96 (0·97)1,3,4 6·30 (1·00)1,2,4 6·72 (0·72)1,2,3
13·5 (2·2)1,3,4 14·3 (1·6)1,2
68·0 (5·5)4 66·0 (6·5)4
23·7 (1·4)3,4 23·2 (1·7)2,4
34·6 (1·6) 34·3 (2·2)
381 (224) 322 (195)
8·8 (1·8) 8·8 (1·3)
11·0 (5·3) 12·1 (6·8)
0·0 (0·06) 0·00 (0·12)
7·9 (3·5) 8·1 (6·2)
1·7 (1·2) 1·9 (1·2)
0·42 (0·61) 0·38 (0·47)
0·26 (0·38) 0·41 (0·37)
in the present study, dogs with a six-hour
post-pill total T4 concentration of less than
35 nmol/litre usually require an increase in
T4 dose, whereas adequately treated dogs
have a median peak total T4 of approxi-
mately 55 nmol/litre. This is similar to the
mean total T4 concentrations of approxi-
mately 50 nmol/litre in 30 treated
hypothyroid dogs reported by Greco and
others (1998). In these dogs the success of
treatment was confirmed by estimation of
basal metabolic rate through measurement
of resting energy expenditure. In the
present study, values between 50 and 100
nmol/litre were common but clinical
thyrotoxicosis was uncommon.
Most dogs receiving THRT demon-
strated a decrease in circulating cTSH con-
centration to or near the assay LoD within
two weeks of commencing therapy, which
remained decreased throughout the study.
No assessment of cTSH in treated dogs
was made before the two-week visit. This
confirms the findings of a similar study
using thyroidectomised dogs (Ferguson
and Hoenig 1997). Circulating cTSH was
in the lower half of the reference range
(<0·33 µg/litre) in the majority of dogs in
which an increase in dose was not required.
However, over half of the dogs that
required an increased dose had similar
cTSH values, suggesting that such a cut-
off is not as useful as the T4 value in indi-
cating which dogs require an increased
dose. In addition, overall approximately
three-quarters of the animals that required
an increased dose had reference range
cTSH values. Thus, while maintenance of
an increased cTSH value usually indicated
the need for an increase in dose, a ‘normal’
cTSH result did not confirm adequate
therapy. Similarly, oversupplementation
could not be identified by demonstration
Visit 4 P value Reference range
0 5·5-8·5 1012/litre
15·1 (1·9)1,2 0 120-180 g/litre
63·5 (5·0)1,2,3 0 60-77 fl
22·6 (1·7)1,2,3 0 19·5-24·5 pg
34·9 (1·6) 0·740 320-360 g/litre
276 (196) 0·146 200-00 109/litre
8·95 (1·5) 0·165
10·7 (4·6) 0·767 6-12 109/litre
0·0 (0·22) 0·947
7·9 (4·8) 0·799 3-11·8 109/litre
2·2 (1·0) 0·245 1-4·8 109/litre
0·47 (0·31) 0·661 0·15-1·35 109/litre
0·34 (0·43) 0·691 0·1-1·25 109/litre
of suppressed cTSH values, since two of
the three dogs in which the dosage was
decreased had values well above the assay
LoD. Furthermore, it is generally accepted
that the LoD of the assay used is too high
to identify oversupplementation.
The reason for the poor reliability of
cTSH in identifying dogs with a require-
ment for alterations in dose is unclear. The
fact that a number of dogs were inade-
quately clinically treated, despite an appar-
ent appropriate suppression of cTSH even
to within the lower half of the reference
range, suggests that the pituitary gland in
hypothyroid dogs may be particularly sen-
sitive to the negative feedback effects of
THRT. Certainly the results of this study
suggest that exogenous T4 can suppress cir-
culating cTSH concentrations without
necessarily achieving clinical euthyroidism.
An alternative explanation is poor owner
compliance on days other than when dogs
were blood sampled, with subsequent sup-
pression of a previously elevated cTSH.
However, this seems less likely since circu-
lating total T4 values proved a good predic-
tor of the clinical need for an increase in
dose. The monitoring samples in this
study were collected six hours after exoge-
nous T4 administration and it is plausible
that cTSH concentrations may vary at
other times of the day in treated dogs.
However, recent studies suggest that this is
also an unlikely explanation (Dixon and
others 1997, Bruner and others 1998,
Kooistra and others 2000). In addition, a
complicating factor is the significant pro-
portion of hypothyroid dogs that initially
have reference range cTSH values (Dixon
and Mooney 1999).
The cTSH concentration was increased
above the laboratory reference value in two
dogs (on only one occasion each) in which
337
Treatment for therapeuutic 10/2/03 14:44
an increase in therapy was not clinically
required. One of these had developed a
temporary, unrelated musculoskeletal con-
dition when the increased cTSH result was
identified. It is possible that the dog was
recovering from the concurrent illness at
the time of testing and this may have
affected the cTSH concentration (Spencer
and others 1987). No change in THRT
was made at that time, none was subse-
quently required and the cTSH was appro-
priately decreased at the subsequent visit.
The THRT dose in the remaining case had
been spontaneously decreased by the
owner who considered the animal to be
hyperexcitable four weeks prior to sam-
pling. However, this dose reduction was
client-driven and the authors are of the
opinion that it was done for owner conve-
nience rather than because of any real
underlying physiological problem. This
dose decrease is likely to have contributed
to the increased circulating cTSH result in
this dog, although the peak total T4 con-
centration remained within the euthyroid
range.
The recognition that cTSH and peak
total T4 are usually within their reference
ranges within approximately two weeks
after the start of therapy, and that there is
limited change unless an actual dose
adjustment is made, suggests that THRT
can be adequately monitored sooner than
previously realised (Rosychuk 1982, Fer-
guson 1986, Panciera 1990, Brent and
Larsen 1996, Refsal and Nachreiner
1997). This has obvious beneficial effects
for the welfare of treated dogs, particularly
those which require dosage changes to
achieve an optimal clinical response. The
THRT dose adjustments in the present
study were numerically small, ranging
from a reduction of 0·2 mg/day to an
increase of 0·3 mg/day and were usually
guided by the available tablet sizes. The
median dosage increase in those dogs
requiring a change was 50 per cent of the
original dose. This resulted in a median
circulating total T4 increase of approxi-
mately 80 per cent. This is in contrast to
the findings of Nachreiner and Refsal
338
Page 338
(1992) who reported an approximate 50
per cent increase in circulating total T4
concentrations after doubling THRT
doses. This difference probably reflects the
small sample numbers in the present study
and confirms that monitoring should take
place to ensure therapeutic adequacy after
each dosage adjustment.
Overall, there was a slow increase in the
mean (per kg) dose of T4 administered to
the dogs over the course of the study. This
partly followed the average reduction in
bodyweight of approximately 10 per cent
that occurred after starting treatment.
However, the mean dose of THRT
increased by approximately 30 per cent in
those dogs requiring a dose increase, indi-
cating a genuine physiological requirement
to achieve optimal clinical control. All
dogs were ultimately well clinically con-
trolled on once-daily (SID) therapy. How-
ever, many clinicians routinely advocate
twice-daily (BID) therapy. Although SID
therapy is less physiologically normal than
BID therapy, this approach reduces the
cost of treatment and assists owner compli-
ance. In addition, total tissue exposure to
T4 is similar using both protocols
(Nachreiner and Refsal 1992). Greco and
others (1998) treated 30 dogs with sponta-
neous hypothyroidism with 22 µg/kg
SID, increasing to BID if required, and
also reported a good clinical response.
However no indication of how many dogs
ultimately required BID therapy was
given.
It was considered that BID therapy
would not have substantially improved the
clinical response of the dogs in the present
study, since three cases required a reduc-
tion in dose. While BID therapy may have
reduced the number of dogs requiring a
dosage increase, it was expected that it
would simply have increased the number
of dogs requiring a reduction. There is
wide individual variation in circulating
thyroid hormone concentrations resulting
from any given dose of THRT in dogs
(Nachreiner and Refsal 1992) and, there-
fore, it is likely that some dogs will need a
dose increase and others a reduction, irre-
JOURNAL OF SMALL ANIMAL PRACTICE
spective of whether a SID or BID regimen
is used. At a nuclear level, thyroid hor-
mones act largely as transcription factors
promoting processes such as protein syn-
thesis. Consequently, the biological half-
life of the thyroid hormones extends
beyond their circulating half-life. This is
likely to explain the clinical success of
once-daily treatment as predicted by
experimental studies (Ferguson and
Hoenig 1997).
This study confirmed the resistance of
dogs to clinical hyperthyroidism despite
markedly increased total T4 concentra-
tions, as has been previously reported
(Kaptein and others 1994). However, it is
unclear why the presence of hyperthyroid
signs apparently occurred in one dog with
a relatively unremarkable peak total T4
concentration. The reduced dose require-
ment in this dog was largely owner driven
and, while the dog may well have been
hyperexcitable, it is difficult to confirm
that this was pathological and not simply a
nuisance behaviour.
Several dogs with concurrent non-
thyroidal illness (NTI), including diabetes
mellitus (n=2) and dilated cardiomyopathy
(n=1), were treated and no complications
of THRT were recognised. It has been pre-
viously suggested that dogs with concur-
rent NTI should have THRT gradually
introduced or used at a lower dose, usually
half the routine dose recommended
(Ferguson 1986, Jeffers 1990, Panciera
1990). However, most of these authors
tend to use BID therapy as the routine
starting protocol, sometimes reducing to
SID if the clinical response is adequate.
Thus, the protocol used in the present
study already utilised a relatively lower
starting daily dose of THRT and, although
the numbers are small, such a protocol
may obviate the need for dose adjustment
in the presence of NTI while ensuring
good therapeutic efficacy.
Broadly speaking, the changes in clini-
cal signs that occurred following the start
of THRT were similar to previous reports
(Rosychuk 1982, Jeffers 1990, Panciera
1997). Not surprisingly, the clinical
• VOL 43 • AUGUST 2002
Treatment for therapeuutic 10/2/03 14:44
improvements were progressive and there-
fore less amenable to categorisation. How-
ever, general conclusions can be drawn and
the time taken for improvement of clinical
signs did undoubtedly depend on the body
system affected. Lethargy was almost with-
out exception improved by visit 2. Exercise
tolerance appeared to improve continu-
ously throughout the study as dogs became
stronger and more athletic. The reduction
in bodyweight probably also contributed
to this finding. Few dogs exhibited any
change in hair coat by visit 2, although this
was usually improved by visit 3. An initial
period of deterioration with a subsequent
improvement in alopecia was commonly
reported and tended to occur during this
interval.
Bodyweight changes occurred more
rapidly than had been expected based on
previous reports (Rosychuk 1982, Panciera
1997). Weight loss continued throughout
the study and, although no dog suffered
excessive weight loss, the mean body-
weight was significantly decreased at visit 4
compared with visit 3. While it is accepted
that exercise and food intake were not
standardised throughout the study period,
and particularly in the light of the contin-
uing change in weight and RBC count, it
is possible that the metabolic normalisa-
tion associated with THRT continues up
until, and possibly beyond, three months
after starting THRT. Although not specif-
ically detailed, a number of the cases were
intermittently checked for over a year
beyond the initial study. No substantial
clinical problems or complications were
noted.
To the authors’ knowledge, the effect of
THRT on routine biochemical and
haematological parameters has not been
previously reported in detail. It is generally
accepted that hypothyroidism is particu-
larly associated with hypercholestero-
laemia and a mild anaemia and that these
should resolve with adequate therapy
(Feldman and Nelson 1996, Dixon and
others 1999). In the present study, circu-
lating cholesterol and triglycerides were
significantly decreased at all treatment vis-
JOURNAL OF SMALL ANIMAL PRACTICE • VOL 43 • AUGUST 2002
Page 339
its, compared to pretreatment values but
were not significantly different between
treatment visits, suggesting that lipid
metabolism is rapidly restored following
the start of THRT. This may be useful
when monitoring dogs receiving THRT
since these tests are easily performed and
relatively inexpensive. The RBC count was
significantly increased at every visit when
compared with the previous visit, confirm-
ing reversal of the physiological anaemia
that is associated with hypothyroidism
(Green and Ng 1986). The RBC count
decreased between the final two visit
periods, indicating that it may not have
stabilised by the end of the study. The
RBC count increased within two weeks of
commencing THRT and its measurement
may therefore be of value in monitoring
cases throughout stabilisation. The mecha-
nisms responsible for the circulating
haemoglobin changes are presumably as
for the RBC count.
There were significant differences in
many of the other parameters measured
over the course of the study. Blood glucose
concentration was significantly decreased
at visit 3 compared with visit 1, but not
between any other time periods. This find-
ing was considered to be a statistical and
not a biologically relevant effect. Circulat-
ing total protein concentrations decreased
significantly during treatment. These
changes were probably due to an increase
in protein turnover associated with nor-
malisation of the metabolic rate. There was
a highly significant reduction in mean cir-
culating fructosamine concentrations fol-
lowing the start of THRT. In humans with
hypothyroidism, increased fructosamine
concentration is recognised and considered
to be due to reduced protein turnover rate
rather than any abnormality of glycaemic
control (Waterson and Mills 1988). A sim-
ilar mechanism is likely to be responsible
in dogs, and the changes following instiga-
tion of THRT are presumably simply a
reversal of this process. The decrease in
fructosamine concentration was statisti-
cally significant between every visit,
indicating that fructosamine, like the
RBC count, may not have completely
normalised by the end of the study.
Mean circulating sodium concentration
was significantly increased at all visits after
starting therapy. This was attributed to
resolution of sample lipaemia, which arte-
factually decreases the measured blood
sodium concentration (Harrington and
Cohen 1973). Impaired renal water excre-
tion and retention of water by hydrophilic
deposits in tissues have also been suggested
as possible mechanisms for the develop-
ment of hyponatraemia in hypothyroidism
(Greco and others 1998). The change in
blood calcium concentration was of no
clinical significance and was considered
secondary to the reduced albumin concen-
tration. Creatinine concentration was sig-
nificantly reduced at visits 2, 3 and 4
following the start of THRT. This is a pre-
viously unreported finding and may be the
result of improved glomerular filtration
rate, which is known to be reduced in
human hypothyroid patients (Moses and
Scheinman 1996). Circulating ALKP con-
centration was significantly decreased at
visits 3 and 4 compared to visit 1. To the
authors’ knowledge, this is also previously
unreported in treated dogs. Possible expla-
nations include the progressive normalisa-
tion of hepatic metabolism, including the
mobilisation of hepatic lipid deposits. Cir-
culating AST concentrations were also sig-
nificantly decreased at various times
during treatment.
The changes that occurred in MCH
were considered to be a reflection of the
alteration in haemoglobin concentration.
The MCV value was significantly reduced
at visit 4 compared to all previous visits.
This was not considered to be of any bio-
logical significance, although the cause of
the mild reduction was not apparent.
However, in most of these cases, the
numerical changes were small, values were
often maintained in the reference range
and, therefore, would be difficult to inter-
pret in individual dogs.
Theoretically, identifying a routine
clinicopathological parameter that poten-
tially identifies those dogs that require an
339
Treatment for therapeuutic 10/2/03 14:44
increased dose would be valuable in the
routine early monitoring of canine
hypothyroidism because of the time and
expense implications of hormone analyses.
Unfortunately, there was no significant
difference in circulating cholesterol or
triglyceride concentration or RBC count at
visit 2 in those cases that needed no
increase in THRT at any point during the
study compared with those cases in which
an increase was required at some time. As
such, while a change in these parameters
gives an indication of an overall response
to therapy, it does not indicate that the
therapy has been successful. Circulating
creatinine concentration was the only
parameter that was significantly lower in
the dogs that did not require a dose adjust-
ment compared to those in which an
increased dose was required. This finding
has not been previously reported. How-
ever, while statistically significant, the
numerical changes within individual dogs
were not sufficiently large to make the
decrease easily interpretable in an individ-
ual case, making this particular finding of
limited practical utility.
Conclusions
Canine hypothyroidism can be adequately
treated in the vast majority of cases with
oral Soloxine therapy administered once
daily. A mean starting dose of 0·02 mg/kg
is adequate in most dogs. Clinical resolu-
tion of metabolic signs such as lethargy
and mental dullness can be expected
within two weeks of starting therapy, while
other abnormalities, including dermato-
logical signs, may take up to three months
to resolve. A mean reduction in body-
weight of 10 per cent occurs within three
months. Biochemical therapeutic moni-
toring is required because of a variable
individual response to treatment and dose
adjustments are required in approximately
half of all cases. Dogs can be monitored
after two weeks of starting treatment by
measurement of circulating total T4 and
cTSH six hours after Soloxine administra-
tion. A median total T4 value of approxi-
mately 55 nmol/litre is associated with
340
© British Small Animal Veterinary Association. All rights reserved
Page 340
good clinical control in most dogs, whereas
values of less than 35 nmol/litre usually
indicate the need for an increase in dose.
Maintenance of an elevated circulating
cTSH concentration is a reliable predictor
of an increased therapeutic requirement
but suppression of cTSH concentration
into the reference range does not guarantee
the adequacy of therapy. A decrease in cir-
culating cholesterol and triglyceride con-
centration and an increase in the RBC
count can be used to indicate an overall
effect of THRT but is not valuable in reli-
ably confirming therapeutic efficacy.
Acknowledgements
The routine biochemical and haematolog-
ical analyses were performed by technical
staff of the University of Glasgow Depart-
ments of Veterinary Clinical Studies and
Veterinary Pathology. The authors grate-
fully acknowledge the assistance of Profes-
sor Max Murray of the University of
Glasgow, Department of Veterinary Clini-
cal Studies, for assistance throughout the
study. The diagnosis of hypothyroidism in
the dogs in this study was part funded by a
BSAVA Petsavers award, for which the
authors are extremely grateful.
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