A
Diagnostic Dilemma
AKC Gazette,
November, 1995, pp. 67-71.
THE ENIGMATIC NATURE
HYPOTHYROIDISM. MAKES IT DIFFICULT TO DISTINGUISH FROM OTHER DISEASES.
By Christine
Wilford, DVM, the Veterinary News columnist for the AKC Gazette.
She practices veterinary medicine in the Seattle area.
In a survey of parent breed clubs by
the AKC, hypothyroidism topped the list of diseases considered to be the
most significant problems for breeders. Every group except the Toy Group
listed it in the top three. Every year, thousands of dogs are diagnosed
with hypothyroidism and most subsequently receive lifelong thyroid
supplementation. But many of these dogs do not have the disease.
Although hypothyroidism (underactive thyroid) is reportedly the most
common endocrine disease in dogs, the actual incidence of canine
hypothyroidism remains unknown. Several factors are responsible for the
lack of hard numbers. The clinical signs of hypothyroidism resemble many
other diseases. Current diagnostic tests have limitations. The presence
of any number of diseases or the use of certain medications may alter
test results. The vague and insidious nature of hypothyroidism often
leads to misdiagnosis and inappropriate treatment.
The thyroid gland is the body's
throttle. It controls metabolism - the speed at which the body operates
- by secreting hormones into the bloodstream from two lobes located in
the neck. Metabolism increases or decreases in response to varying
energy demands. Illness and disease cause a normal decline in thyroid
function, while increased activity can cause a normal elevation.
Hypothyroidism occurs when thyroid
function falls below normal and remains there without an appropriate
cause. Hypothyroid animals cannot increase their thyroid function, even
when the body demands it.
The exact cause of hypothyroidism is
not well understood. Current evidence suggests that, in most cases, an
abnormal immune response causes the body to attack and destroy its own
thyroid gland as if it were a foreign substance. Why this happens
remains a mystery, but evidence gathered from studying Great Danes,
Irish Setters and Old English Sheepdogs suggests genetics may play a
role.
Debate continues over whether certain
breeds are more likely than other breeds or mixed breeds to develop
hypothyroidism. Most sources agree that Golden Retrievers, Doberman
Pinschers, Irish Setters, Miniature Schnauzers, Dachshunds and Great
Danes are at increased risk. Poodles, Boxers, Airedales and Old English
Sheepdogs may also be at increased risk. German Shepherds and mixed
breeds may actually be at lower risk than the average dog. Regardless of
breed, males and females are equally affected by hypothyroidism.
Compensatory Hypothyrodism. A
common condition known as compensatory hypothyroidism, or sick euthyroid
syndrome (SES), may account for many of the false diagnoses of
hypothyroidism. The difference between true hypothyroidism and SES is
that in SES, the thyroid gland retains the ability to return to normal
function. SES describes the situation in which dogs with normally
functioning thyroid glands have decreased thyroid hormone levels with an
appropriate cause. Virtually any condition trauma, stress, injury,
illness, poor diet can affect thyroid hormone levels and cause SES.
SES is actually a protective mechanism.
When the body experiences altered demands and priorities such as illness
or stress, the thyroid gland tries to compensate by minimizing energy
requirements. Energy is conserved by reducing thyroid hormone secretion.
This, in turn, lowers the body's metabolic rate.
Further compounding the problem is that
whatever initiates SES may be vague and difficult to identify. Without
comprehensive diagnostics and evaluation, low thyroid hormone levels may
be the most obvious abnormality, leading to a misdiagnosis of
hypothyroidism.
If a dog with SES is misdiagnosed and
is supplemented with thyroid hormone, the body's protective mechanism
can be negated. As metabolism increases, so do energy requirements,
which may detract from the body's other demands. And because the
underlying cause of SES is overlooked, another disease persists
undiagnosed and untreated.
Dealing with Suspicion. Because
impaired thyroid secretion can cause a vast array of signs,
hypothyroidism is often suspected in almost all dogs with skin disease,
lethargy or reproductive disorders. Once clinical signs lead to
suspicion of hypothyroidism, routine laboratory tests, consisting of a
complete blood count, serum chemistries and urinalysis, are recommended,
if only to rule out other diseases. If no other disease is present,
results of routine laboratory tests may be completely normal. Routine
tests only provide supportive information; they cannot confirm a
diagnosis of hypothyroidism.
One important diagnostic clue
is that more than 75 percent of dogs with true hypothyroidism have high
cholesterol levels in blood samples drawn after a 12-hour fast. However,
other diseases can increase serum cholesterol. Therefore, high
cholesterol after a fast supports, a diagnosis of hypothyroidism, but it
is not definitive.
Another diagnostic clue is that as many
as 40 percent of hypothyroid dogs have anemia - decreased numbers of red
blood cells without signs of replenishment. This finding also supports a
diagnosis of hypothyroidism, but again, is not definitive. Other causes
of anemia should be considered.
Abnormalities in the urinalysis suggest
a problem other than hypothyroidism.
Thyroid-specific tests are necessary to
diagnose hypothyroidism, and should be completed before beginning
treatment with thyroid supplements. Levels of the thyroid hormones
thyroxine (T4) and triiodothyronine (T3) can be measured from blood
samples used for routine laboratory tests, but the analysis must be
specific for canine thyroid hormones. Analysis at human laboratories
yields unreliable results, as do in-house tests at veterinary clinics.
Even with these precautions, neither of these tests is by any means
definitive.
Because half of all truly hypothyroid
dogs maintain normal T3 levels, misdiagnoses will occur if T3 is used as
the sole method for diagnosing hypothyroidism. By far the most common
and least expensive test is the measurement of T4. This test is known by
several names, including basal T4, serum T4, resting T4 and total T4.
While slightly more consistent than total T3, total T4 also rarely
yields a definitive diagnosis and should only be used as a screening
test. Results must be interpreted in light of other clinical and
laboratory findings. If the total T4 level is in the mid to high normal
range, then hypothyroidism is very unlikely. Low normal or below normal
results support a diagnosis of hypothyroidism only in a dog with
clinical signs and with other routine laboratory test results that also
suggest the problem.
A total T4 result far below normal or
near zero strongly suggests true hypothyroidism. Still, more definitive
testing is highly recommended before committing a dog to a lifetime of
thyroid supplementation and monitoring. Though a popular test, total T4
is a poor method for evaluating thyroid function. It is limited because
many uncontrollable factors affect total T4 levels. For example, an
older dog is more likely to have lower total T4 than a younger dog. And
normal levels tend to be lower in large and giant breeds, higher in
smaller breeds. German Shepherds, Cocker Spaniels, Boxers, Beagles,
Labrador Retrievers, Alaskan Malamutes and Siberian Huskies may have
normally lower total T4 levels. Even ambient temperature can affect a
diagnosis - a car ride to the vet's office on a hot summer day may
decrease total T4 levels, causing false low results. Other known factors
that can have an influence include illnesses, medications, diagnostic
agents and stress.
The list of drugs and diagnostic agents
that potentially lower total T4 continues to grow. In addition to many
antibiotics, it includes glucocorticoids, one of the most common types
of medications dispensed. Low total T4 levels are simply unreliable in
dogs that are currently taking or have recently taken glucocorticoids
such as prednisone or dexamethasone. (While glucocorticoids can decrease
total T4, they do not cause clinical signs of hypothyroidism.)
Antibiotics containing sulfa, such as Tribrissen, Primor, Bactrim,
Septra and many generics, can lead to lower total T4, resulting in
misdiagnosis.
Hyperadrenocorticism, or Cushing's
disease, is often a diagnosis considered for dogs with symptoms
resembling hypothyroidism, and close to 40 percent of dogs with
Cushing's disease have low total T4 values. Research indicates that
while Cushing's disease may cause a hypothyroid condition, treatment of
the Cushing's disease without treating the hypothyroidism not only
returns total T4 levels to normal, but also corrects the hypothyroid
state.
Even in the absence of these
influences, total T4 fluctuates irregularly in a normal dog over the
course of a normal day. Attempting to time the blood sample collection
in an effort to improve the reliability of the test is also futile. In
fact, total T4 levels can vary significantly from hour to hour,
especially in dogs with any degree of illness such as skin infections or
allergies. Ironically, truly hypothyroid dogs have more stable and less
dramatic total T4 fluctuations. (Fortunately for diagnostic
considerations, in hypothyroid dogs fluctuations into the normal range
are rare and transient.)
To what degree various factors affect
total T4 remains unknown. But it is clear that a diagnosis of
hypothyroidism based solely on the results of total T4 is seriously
flawed. It is subject to tremendous error, which can lead to the
inappropriate treatment of many dogs.
Aside from the limitations described,
measuring total T, and total T4 neglects to evaluate thyroid function.
Because inadequate thyroid function is the distinguishing characteristic
of a truly hypothyroid dog, a thyroid function test is imperative for
proper diagnosis. There are two main tests of thyroid function: the
thyroid releasing hormone (TRH) response and the thyroid stimulating
hormone (TSH) response. The TRH is of limited value. An abnormally low
response is difficult to identify because a normal response is already
very low. Also, 25 percent of healthy dogs have little or no increase in
post-TRH total T4 values. Normal dogs release TSH to stimulate thyroid
hormone secretion. The TSH response test mimics the body's method for
raising thyroid hormone levels. The procedure involves collecting a pre-TSH
blood sample, injecting TSH and collecting a post-TSH blood sample
several hours later. By knowing the time administered, and the dose,
thyroid function can be assessed. The TSH response test is not only more
accurate for identifying true hypothyroidism, but is especially useful
for differentiating hypothyroidism and sick euthyroid syndrome.
While the advantages of the TSH
response test are more accurate assessment of thyroid function and much
less risk of misdiagnosis, injectable TSH is not widely marketed and
cannot be stored for long periods. Other disadvantages are cost and
time. Although prices and protocols vary, a half day to full day at the
veterinary hospital and lab fees upward of $80 are typical. However,
owners refusing this test based on cost should compare the expense of
lifelong thyroid supplementation and monitoring. And if another disease
is misdiagnosed as hypothyroidism, inappropriate treatment may not only
cost more money, but may cost the dog's life, since it won't receive
treatment for the underlying disease.
Although experts agree that TSH
stimulation is the test of choice for the most definitive diagnosis,
they disagree about the dose, the route of administration and the best
time to collect the second blood sample. They also have different ideas
about which results should be considered as falling in the normal range
and which indicate hypothyroidism.
Most hypothyroid dogs respond to TSH in
a way consistent with most guidelines. A small group of dogs will have
discordant results and appear normal by one criteria and hypothyroid by
another. For such inconclusive or equivocal results, options include
observing for progression of clinical signs or repeating the TSH
response test in two to four months. Other alternatives are
submitting a free T4 or conducting a therapeutic trial.
Free T4. The latest test
available is called the free T4, a measurement of the biologically
active form of thyroxine. Besides being a more specific indicator of
thyroid function than total T4, free T4 is not subject to the
spontaneous fluctuations or drug-induced changes that occur with total
T4, making it useful in discriminating between hypothyroid dogs and dogs
with low total T4 levels caused by other factors such as illness or
medication. Like total T4 and total T3, a blood sample is all that is
required for a free T4 measurement. However, how the sample is analyzed
determines the reliability of the result.
The most common way of measuring free
T4 is by a process called radioimmunoassay. Though a rapid and practical
method for laboratories, radioimmunoassay's validity is seriously
questioned. In fact, this method received considerable technical
criticism from the American Thyroid Association for its use in human
medicine. Free T4 analyzed by radioimmunoassay offers no more value than
measuring total T4. A more accurate method for measuring free T4 is
equilibrium dialysis. In fact, it is considered the gold standard.
Unfortunately, this method of testing is not widely available. Samples
must be sent to a special laboratory proficient in this time-consuming
and technically complex method. Direct dialysis is an alternative
method, with results reportedly correlating well with equilibrium
dialysis. Because it is more practical to perform and just as accurate,
it may eventually become more available. Whether free T4 evaluation by
dialysis will replace the TSH response as the test of choice will depend
on its accuracy in clinical practice.
A Therapeutic Trial. Under
certain circumstances, a therapeutic trial is an option for diagnosing
hypothyroidism. When results of thyroid tests are neither clearly within
normal limits nor diagnostic of hypothyroidism, supplementation with
thyroid hormone may help confirm or exclude a diagnosis. Other
indications for a therapeutic trial are if the TSH injection is
unavailable or if a free T4 test is not readily accessible.
A therapeutic trial requires
administration of a brand-name, synthetic levothyroxine supplement.
Generic thyroid supplements, or those of animal origin, do not produce
reliable results, and may lead to misdiagnosis in a therapeutic trial.
Some dogs may do well on generic products after a diagnosis is
confirmed, but a therapeutic trial should be performed with brand-name
products only. Initial dosage recommendations vary, but the drug should
be administered every 12 hours. If hypothyroidism is confirmed,
once-daily treatment can be attempted. (NOTE: Current recommendation
[1998] is that the daily supplement be divided and given approximately
every 12 hours).
If hypothyroidism is truly present and
thyroid supplementation is appropriate, all of the clinical signs and
lab work results associated with hypothyroidism can be reversed.
Depending on the dog, some changes may be visible within the first week
of treatment. Initial improvements include increased mental alertness,
activity and appetite. Noticeable improvement of the skin should follow
within the first month or six weeks.
Initially, the coat may appear worse if
the old coat is shed in large quantities. Several months are required
for complete hair regrowth and noticeable reduction in pigmentation. If
fertility problems are being linked to hypothyroidism, they are usually
the last problems to be resolved. In addition, lab work abnormalities
may require several months to clear up.
Even if a completely positive response
to therapy is observed, the diagnosis is in no way certain until thyroid
supplementation is withdrawn. If clinical signs begin to recur, further
thyroid testing should be performed or therapy can be reinitiated. If
clinical signs do not recur after discontinuing treatment,
hypothyroidism should not be suspected and thyroid supplementation
should not be reinitiated.
The take-home message is this: Lifelong
thyroid supplementation for a diagnosis of hypothyroidism based on a
total T4 and an apparent response to treatment is perhaps the single
greatest reason for misdiagnosis and overtreatment. Many diseases may
respond to thyroid supplementation in the absence of hypothyroidism.
Because a non-thyroid disease seems to improve with thyroid
supplementation does not signify a cure, a treatment or, for that
matter, even a benefit.
Treatment. Once diagnosis is
confirmed, treatment is straightforward: supplement thyroid hormone,
1-thyroxine. Although most experts tend to agree on the dose, there are
a few veterinarians recommending unusually high doses and frequency.
Higher doses can cause signs of hyperthyroidism (an overactive thyroid),
including elevated heart rate, weight loss, increased appetite and
nervousness. There is also disagreement over when and how to monitor
therapy.
Because of its indefinite symptoms and
its resistance to conclusive test results, accurate diagnosis is the
critical factor in treating hypothyroidism. While inappropriate
supplementation is expensive, a more important concern is the toll taken
on a dog that is unnecessarily receiving supplementation - especially
when the body decreases thyroid secretion as a protective mechanism.
In the absence of a single superior
test, a diagnosis must not be made until a comprehensive history is
collected, a thorough physical exam is conducted, blood work and
urinalysis are evaluated, and special tests are submitted for thyroid
function evaluation.
