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Introduction
Hypothyroidism is the most common endocrine disorder of canines, and
up to 80% of cases result from autoimmune (lymphocytic) thyroiditis.
The heritable nature of this disorder poses significant genetic
implications for breeding stock. Thus, accurate diagnosis of the
early compensatory stages of canine autoimmune thyroiditis leading
up to hypothyroidism affords important genetic and clinical options
for prompt intervention and case management.
Although thyroid
dysfunction is the most frequently recognized endocrine disorder of
pet animals, it is often difficult to make a definitive diagnosis.
As the thyroid gland regulates metabolism of all body cellular
functions, reduced thyroid function can produce a wide range of
clinical manifestations. Many of these clinical signs mimic those
resulting from other causes and so recognition of the condition and
interpretation of thyroid function tests can be problematic (Table
1).
Baseline
Thyroid Profiles
A complete baseline thyroid profile is measured and typically
includes total T4, total T3, free T4, free T3, T3AA and T4AA, and
can include cTSH and/or TgAA. The TgAA assay is especially important
in screening breeding stock for heritable autoimmune thyroid
disease.
The normal reference
ranges for thyroid analytes of healthy adult animals tend to be
similar for most breeds of companion animals. Exceptions are the
sighthound and giant breeds of dogs which have lower basal levels.
Typical thyroid levels for healthy sighthounds, such as retired
racing greyhounds, are at or just below the established laboratory
reference ranges, whereas healthy giant breeds have optimal levels
around the midpoint of these ranges.
Similarly, because
young animals are still growing and adolescents are maturing,
optimal thyroid levels are expected to be in the upper half of the
references ranges. For geriatric animals, basal metabolism is
usually slowing down, and so optimal thyroid levels are likely to be
closer to midrange or even slightly lower.
Genetic
Screening for Thyroid Disease
Most cases of thyroiditis have elevated serum TgAA levels, whereas
only about 20-40% of cases have elevated circulating T3 and/or T4
AA. Thus, the presence of elevated T3 and/or T4 AA confirms a
diagnosis of autoimmune thyroiditis but underestimates its
prevalence, as negative (non-elevated) autoantibody levels do not
rule out thyroiditis. Measuring TgAA levels also permits early
recognition of the disorder, and facilitates genetic counselling.
Affected dogs should not be used for breeding (Table 2).
The commercial TgAA
test can give false negative results if the dog has received thyroid
supplement within the previous 90 days, thereby allowing
unscrupulous owners to test dogs while on treatment to assert there
normalcy, or to obtain certification with health registries such as
the OFA Thyroid Registry. False negative TgAA results also can occur
in about 8% of dogs verified to have high T3AA and/or T4AA.
Furthermore, false positive TgAA results may be obtained if the dog
has been vaccinated within the previous 30-45 days, or in some cases
of non-thyroidal illness. Vaccination of pet and research dogs with
polyvalent vaccines containing rabies virus or rabies vaccine alone
was recently shown to induce production of antithyroglobulin
autoantibodies, a provocative and important finding with
implications for the subsequent development of hypothyroidism
A population study of
287,948 dogs was recently published by the MSU Animal Health
Diagnostic Laboratory. Circulating thyroid hormone autoantibodies
(T3AA and/or T4AA)) were found in 18,135 of these dogs (6.3%). The
10 breeds with the highest prevalence of thyroid AA from their study
were: Pointer, English Setter, English Pointer, Skye Terrier, German
Wirehaired Pointer, Old English Sheepdog, Boxer, Maltese, Kuvasz,
and Petit Basset Griffon Vendeen. Prevalence was associated with
body weight and was highest in dogs 2-4 years old. Females were
significantly more likely to have thyroid AA than males.
A bitch with
circulating thyroid AA has the potential to pass these along to the
puppies transplacentally as well as via the colostrum. Furthermore,
any dog having thyroid AA may eventually develop clinical symptoms
of thyroid disease and/or be susceptible to other autoimmune
diseases. Thyroid screening is thus very important for selecting
potential breeding stock as well as for clinical diagnosis.
Thyroid testing for
genetic screening purposes is less likely to be meaningful before
puberty. Screening is initiated, therefore, once healthy dogs and
bitches have reached sexual maturity (between 10-14 months in males
and during the first anestrous period for females following their
maiden heat). As the female sexual cycle is quiescent during
anestrus, any influence of sex hormones on baseline thyroid function
will be minimized. This period generally begins 12 weeks from the
onset of the previous heat and lasts one month or longer. The
interpretation of results from baseline thyroid profiles in intact
females will be more reliable when they are tested in anestrus. In
fact, genetic screening of intact females for other disorders such
as von Willebrand disease (vWD), hip dysplasia, and wellness or
reproductive checkups (vaginal cultures, hormone testing) is best
scheduled during anestrus. Once the initial thyroid profile is
obtained, dogs and bitches should be rechecked on an annual basis to
assess their thyroid function and overall health. Generation of
annual test results provides comparisons that permit early
recognition of developing thyroid dysfunction. This allows for early
treatment, where indicated, to avoid the appearance or advancement
of clinical signs associated with hypothyroidism.
Canine autoimuune
thyroid disease is very similar to Hashimoto’s thyroiditis of
humans, which has been shown to be associated with human major
histocompatibility complex (MHC) tissue types. A similar association
with canine MHC genes in hypothyroid dogs has recently been reported
in Doberman Pinschers, English Setters and Rhodesian Ridgebacks, who
share a rare dog leukocyte antigen (DLA) class II haplotype which
contains a unique DLA-DQA1*00101 genetic determinant. While the
presence of this determinant doubles the risk of a dog developing
hypothyroidism, it was not found in boxers affected with thyroiditis,
nor was it found in the Shih Tzu, Yorkshire Terrier, or Siberian
Husky, although more studies are needed in these and other
susceptible breeds to establish their true status with respect to
this marker DLA antigen. This exciting finding of a common genetic
determinant associated with thyroid disease in several breeds
hopefully will lead to development of a genetic marker test to
identify affected breeding stock and allow for selective breeding to
reduce disease incidence in pure-bred dogs.
Polyglandular
Autoimmunity
Individuals genetically susceptible to autoimmune thyroid disease
may also become more susceptible to immune-mediated diseases
affecting other target tissues and organs, especially the bone
marrow, liver, adrenal gland, pancreas, skin, kidney, joints, bowel,
and central nervous system. The resulting “polyglandular autoimmune
syndrome” of humans is becoming more commonly recognized in the dog,
and probably occurs in other species as well. The syndrome tends to
run in families and is believed to have an inherited basis. Multiple
endocrine glands and nonendocrine systems become involved in a
systemic immune-mediated process. This multiple endocrinopathy often
occurs in patients with underlying autoimmune thyroid disease (hypo-
or hyperthyroidism) and concurrent Addison’s disease, diabetes,
reproductive gonadal failure, skin disease and alopecia, and
malabsorption syndrome. The most common nonendocrinologic autoimmune
disorders associated with this syndrome are autoimmune hemolytic
anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), chronic
active hepatitis, and immune-complex glomerulonephritis (systemic
lupus erythematosus; SLE).
The most commonly
recognized polyglandular endocrinopathy of dogs is Schmidt’s
syndrome (thyroiditis and Addison’s disease). Examples of breeds
genetically predisposed to this disorder include the Standard
Poodle, Old English Sheepdog, Bearded Collie, Portuguese Water Dog,
Nova Scotia Duck Tolling Retriever, and Leonberger, although any
breed or mixed breed can be affected. Our study cohort of 162 cases
of autoimmune blood and endocrine disorders in Old English Sheepdogs
(1980-1989) included 115 AIHA and/or ITP, 99 thyroid disease, 23
Addison’s disease, 7 vaccine reactions, 3 SLE, 2 diabetes, 1
rheumatoid arthritis and 1 hypoparathyroidism. The group comprised
110 females (15 spayed) and 52 males (3 neutered). Seven of the most
recent 103 cases had two or more endocrine disorders, and 101 of the
108 cases where pedigrees were available showed a familial
relationship going back several generations. Data from surveying the
Bearded Collie breed reported 55 hypothyroid, 17 Addison’s disease,
and 31 polyglandular autoimmunity (5 were hypothyroid).
Aberrant
Behavior and Thyroid Dysfunction
The principal reason for pet euthanasia stems not from disease, but
undesirable behavior. While this abnormal behavior can have a
variety of medical causes, it also can reflect underlying problems
of a psychological nature.
An association
between behavioral and psychologic changes and thyroid dysfunction
has been recognized in humans since the 19th century. In a recent
study, 66% of people with attention deficit-hyperactivity disorder
were found to be hypothyroid, and supplementing their thyroid levels
was largely curative. Furthermore, an association has recently been
established between aberrant behavior and thyroid dysfunction in the
dog, and has been noticed in cats with hyperthyroidism. Typical
clinical signs include unprovoked aggression towards other animals
and/or people, sudden onset of seizure disorder in adulthood,
disorientation, moodiness, erratic temperament, periods of
hyperactivity, hypoattentiveness, depression, fearfulness and
phobias, anxiety, submissiveness, passivity, compulsiveness, and
irritability. After episodes, most of the animals appeared to come
out of a trance like state, and were unaware of their bizarre
behavior.
The mechanism whereby diminished thyroid function affects behavior
is unclear. Hypothyroid patients have reduced cortisol clearance, as
well as suppressed TSH output and lowered production of thyroid
hormones. Constantly elevated levels of circulating cortisol mimic
the condition of an animal in a constant state of stress. In people
and seemingly in dogs, mental function is impaired and the animal is
likely to respond to stress in a stereotypical rather than reasoned
fashion. Chronic stress in humans has been implicated in the
pathogenesis of affective disorders such as depression. Major
depression has been shown in imaging studies to produce changes in
neural activity or volume in areas of the brain which regulate
aggressive and other behaviors. Dopamine and serotonin receptors
have been clearly demonstrated to be involved in aggressive pathways
in the CNS. Hypothyroid rats have increased turnover of serotonin
and dopamine receptors, and an increased sensitivity to ambient
neurotransmitter levels.
Investigators in
recent years have noted the sudden onset of behavioral changes in
dogs around the time of puberty or as young adults. Most of the dogs
have been purebreds or crossbreeds, with an apparent predilection
for certain breeds. For a significant proportion of these animals,
neutering does not alter the symptoms and in some cases the
behaviors intensify. The seasonal effects of allergies to inhalants
and ectoparasites such as fleas and ticks, followed by the onset of
skin and coat disorders including pyoderma, allergic dermatitis,
alopecia, and intense itching, have also been linked to changes in
behavior.
Many of these dogs
belong to a certain group of breeds or dog families susceptible to a
variety of immune problems and allergies (e.g. Golden Retriever,
Akita, Rottweiler, Doberman Pinscher, English Springer Spaniel,
Shetland Sheepdog, and German Shepherd Dog). The clinical signs in
these animals, before they show the sudden onset of behavioral
aggression, can include minor problems such as inattentiveness,
fearfulness, seasonal allergies, skin and coat disorders, and
intense itching. These may be early subtle signs of thyroid
dysfunction, with no other typical signs of thyroid disease being
manifested.
The typical history
starts out with a quite, well-mannered and sweet-natured puppy or
young adult dog. The animal was outgoing, attended training classes
for obedience, working, or dog show events, and came from a
reputable breeder whose kennel has had no prior history of producing
animals with behavioral problems. At the onset of puberty or
thereafter, however, sudden changes in personality are observed.
Typical signs can be incessant whining, nervousness, schizoid
behavior, fear in the presence of strangers, hyperventilating and
undue sweating, disorientation, and failure to be attentive. These
changes can progress to sudden unprovoked aggressiveness in
unfamiliar situations with other animals, people and especially with
children.
Another group of dogs
show seizure or seizure-like disorders of sudden onset that can
occur at any time from puberty to mid-life. These dogs appear
perfectly healthy outwardly, have normal hair coats and energy, but
suddenly seizure for no apparent reason. The seizures are often
spaced several weeks to months apart, may coincide with the full
moon, and can appear in brief clusters. In some cases the animals
become aggressive and attack those around them shortly before or
after having one of the seizures. Two recent cases involved young
dogs referred for sudden onset seizure disorder shortly after
puberty. Both dogs were found to have early onset autoimmune
thyroiditis, which was clinically responsive to thyroid
supplementation, to the extent that anticonvulsant medications could
be gradually withdrawn. The numbers of animals showing these various
types of aberrant behavior appear to be increasing in frequency over
the last decade.
In dogs with aberrant aggression, a large collaborative study
between our group and Dr. Dodman and colleagues at Tufts University
School of Veterinary Medicine has shown a favorable response to
thyroid replacement therapy within the first week of treatment,
whereas it took about three weeks to correct their metabolic
deficit. Dramatic reversal of behavior with resumption of previous
problems has occurred in some cases if only a single dose is missed.
A similar pattern of aggression responsive to thyroid replacement
has been reported in a horse.
Tables 3-4 summarize
results of complete thyroid diagnostic profiling on 634 canine cases
of aberrant behavior, compiled by this author in collaboration with
Drs. Nicholas Dodman, Linda Aronson, and Jean DeNapoli of Tufts
University School of Veterinary Medicine, North Grafton, MA. Ninety
percent (568 dogs) were purebreds and 10% were mixed breeds. There
was no sex predilection found in this case cohort, whether or not
the animals were intact or neutered. Sixty-three percent of the dogs
had thyroid dysfunction as judged by finding 3 or more abnormal
results on the comprehensive thyroid profile. The major categories
of aberrant behavior were aggression (40% of cases), seizures (30%),
fearfulness (9%), and hyperactivity (7%); some dogs exhibited more
than one of these behaviors (Table 4). Within these 4 categories,
thyroid dysfunction was found in 62% of the aggressive dogs, 77% of
seizuring dogs, 47% of fearful dogs, and 31% of hyperactive dogs.
Outcomes of treatment
intervention with standard twice daily doses of thyroid replacement
were evaluated in 95 cases, and showed a significant behavioral
improvement in 61% of the dogs. Of these, 58 dogs had greater than
50% improvement in their behavior as judged by a predefined 6-point
subjective scale (34 were improved > 75%), and another 23 dogs had
>25 but <50% improvement. Only 10 dogs experienced no appreciable
change, and 2 dogs had a worsening of their behavior. When compared
to 20 cases of dominance aggression treated with conventional
behavior or other habit modification over the same time period, only
11 dogs improved more than 25%, and of the remaining 9 cases, 3
failed to improve and 3 were euthanized or placed in another home.
These initial results are so promising that complete thyroid
diagnostic profiling and treatment with thyroid supplement, where
indicated, is warranted for all cases presenting with aberrant
behavior.
Our ongoing study now
includes over 1500 cases of dogs presented to veterinary clinics for
aberrant behavior. The first 499 cases have been analyzed
independently by a neural network correlative statistical program.
Results showed a significant relationship between thyroid
dysfunction and seizure disorder, and thyroid dysfunction and
dog-to-human aggression.
Collectively, these
findings confirm the importance of including a complete thyroid
antibody profile as part of the laboratory and clinical work up of
any behavioral case.
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|
Table 1. CLINICAL SIGNS OF
CANINE HYPOTHYROIDISM |
|
Alterations in Cellular
Metabolism |
| lethargy |
weight gain |
| mental
dullness |
cold
intolerance |
| exercise
intolerance |
mood swings |
| neurologic
signs |
hyperexcitability |
|
polyneuropathy |
stunted
growth |
|
seizures |
chronic
infections |
| |
|
|
Neuromuscular Problems |
| weakness |
knuckling
or dragging feet |
| |
|
|
Table 1 (cont’d) |
| stiffness |
muscle
wasting |
| laryngeal
paralysis |
megaesophagus |
| facial
paralysis |
head tilt |
| "tragic"
expression |
drooping
eyelids |
|
incontinence |
ruptured
cruciate ligament |
| |
|
|
Dermatologic Diseases |
| dry, scaly
skin and dandruff |
chronic
offensive skin odor |
| coarse,
dull coat |
bilaterally
symmetrical hair loss |
| "rat tail";
"puppy coat" |
seborrhea
with greasy skin |
|
hyperpigmentation |
seborrhea
with dry skin |
| pyoderma or
skin infections |
myxedema |
| |
|
|
Reproductive Disorders |
| infertility |
prolonged
interestrus interval |
| lack of
libido |
absence of
heat cycles |
| testicular
atrophy |
silent
heats |
| hypospermia |
pseudopregnancy |
| aspermia |
weak, dying
or stillborn pups |
| |
|
|
Cardiac Abnormalities |
| slow heart
rate (bradycardia) |
|
| cardiac
arrhythmias |
|
|
cardiomyopathy |
|
| |
|
|
Gastrointestinal Disorders |
|
constipation |
|
| diarrhea |
|
| vomiting |
|
| |
|
|
Hematologic Disorders |
| bleeding |
|
| bone marrow
failure |
|
|
low red blood cells (anemia), white blood cells, platelets |
| |
|
|
Ocular Diseases |
| corneal
lipid deposits |
corneal
ulceration |
| uveitis |
keratoconjunctivitis sicca or "dry eye" |
| infections
of eyelid glands |
Vogt-Koyanagi-Harada
syndrome |
|
(Meibomian gland) |
|
| |
|
|
Other Associated Disorders |
| IgA
deficiency |
loss of
smell (dysosmia) |
| loss of
taste |
glycosuria |
| other
endocrinopathies |
chronic
active hepatitis |
|
adrenal |
|
|
pancreatic |
|
|
parathyroid |
|
Table 2. DIAGNOSIS
OF THYROID DISEASE
- Complete Basic Profile
- -- (T4, T3, FT4, FT3, T4AA,
T3AA)
- Additional Tests
- Older Tests (T4, T4 + T3)
- Serum T4 and/or T3 alone are not
reliable for diagnosis because:
-- overdiagnose hypothyroidism
-- underdiagnose hyperthyroidism
-- fail to dectect early compensatory disease and thyroiditis
-- influenced by nonthyroidal illness and certain drugs
- Newer Tests
- Free (Unbound) T4
Less likely to be influenced by nonthyroidal illness or drugs
Valid
-- equilibrium dialysis
-- solid-phase analog RIA
-- chemiluminescence solid-phase
Less reliable -- liquid-phase analog RIA
- Endogenous Canine TSH
In primary hypothyroidism, as free T4 levels fall, pituitary
output of TSH rises
-- elevated TSH usually indicates primary thyroid disease
-- 20-40% discordancy observed between expected and actual
findings
-- published normal ranges may need revising upwards
-- affected by concomitant chronic renal disease
- Canine TgAA
Thyroglobulin autoantibodies are present in serum of
cases with lymphocytic thyroiditis.
-- positive results confirm diagnosis ; 8% false negative
-- 20-40% of cases have circulating T3 and/or T4AA
-- allows for early diagnosis and genetic counseling
|
Table 3. CANINE ABERRANT BEHAVIOR * |
|
| Total No. Cases |
Purebreds |
Mixed Breeds |
Thyroid Dysfunction |
Euthyroid |
|
| 634 |
568 |
66 |
401 † |
233 |
|
| * Mean
Age, 3.7 years ( Range 0.5-12 years ). Median Age, 2.5 years. |
Table 4. MOST COMMONLY
REPRESENTED BREEDS WITH THYROID
DYSFUNCTION AND ABERRANT BEHAVIOR * |
|
|
Breed† |
Thyroid
Dysfunction
401/634
(63%) |
Aggression
251/634
(40%) |
Seizures
189/634
(30%) |
Fearful
55/634
(9%) |
Hyperactive
42/634
(7%) |
|
|
Golden Retriever |
50/73 |
12/16 |
22/30 |
4/6 |
1/6 |
|
German Shepherd |
34/53 |
10/22 |
14/16 |
3/7 |
2/2 |
| Akita |
27/38 |
24/33 |
0/1 |
0 |
0/2 |
|
Labrador Retriever |
8/30 |
6/11 |
12/16 |
2/15 |
0/3 |
|
Shetland Sheepdog |
14/25 |
3/6 |
2/3 |
2/4 |
3/3 |
|
Collie |
8/9 |
0 |
7/7 |
0 |
0 |
|
English Setter |
4/6 |
1/1 |
0 |
1/3 |
1/2 |
| Other
Purebreds |
217/334 |
89/135 |
72/93 |
10/15 |
5/16 |
| Mixed
Breed |
39/66 |
11/27 |
16/23 |
4/5 |
1/8 |
|
|
Totals |
401/634 |
156/251 |
145/189 |
26/55 |
13/42 |
| |
(63%) |
(62%) |
(77%) |
(47%) |
(31%) |
|
* Some dogs had more than 1 abnormal
behavior. Numerator = Thyroid dysfunction Denominator = Aberrant
behavior † Total 634 cases; 72 dogs breeds represented.
|