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 sight
hound and giant breeds of dogs which have lower basal
levels. Typical thyroid levels for healthy sight hounds,
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.
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 5% 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 auto
antibodies, 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 auto antibodies
(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.
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 hyper-thyroidism) 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 Leon Berger, 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 Behaviour and Thyroid
Dysfunction
The principal reason for pet euthanasia stems not from
disease, but undesirable behaviour. While this abnormal
behaviour can have a variety of medical
causes, it also can reflect underlying problems of a
psychological nature.
An association between behavioural and
psychological 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 behaviour 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, hypo attentiveness, 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
behaviour.
The mechanism whereby diminished
thyroid function affects behaviour 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
behaviours. 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 behavioural 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 behaviours 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, and 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 behaviour 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 1-2 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 2). 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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