When we talk generally about Cushing’s Disease or
more correctly, Cushing’s Syndrome, we are talking about two nearly
identical diseases – Equine Cushing’s Disease, and a second syndrome
now called Equine Metabolic Syndrome.
The only way to differentiate either properly is for accurate blood
tests to be done, and this, of course, presupposes that the person
asking for the tests, and interpreting them, understands a little
about the issues.
For example, a racetrack vet dealing with Thoroughbreds will have
almost no contact with horses with either of these conditions as
they generally occur in older horses. A pleasure horse vet, on the
other hand, will be well aware of these situations in older pet
horses.
Both diseases have striking similarities, as I said above – most
notably they both predispose horses to chronic laminitis, but the
underlying disease biology is quite different in both instances, so
successful management means the vet must differentiate the cause,
even while we don’t claim to understand all of the factors yet in
these diseases.
Equine Cushings Disease is a disorder of the pituitary gland that
results in excess production of the hormone Cortisol by the adrenal
gland. This causes a variety of clinical signs, including a shaggy,
long, wavy hair coat in many cases which won’t shed in normal
seasonal patterns, also excessive sweating, lethargy, poor athletic
performance if laminitis doesn’t stop them working, chronic
recurrent laminitis, infertility, weight loss, muscle wasting
especially on the topline, abnormal distribution of fat causing a
pot belly appearance and fat accumulations in the neck, tail head,
sheath and above the eyes. Horses consume large volumes of water and
pass a lot of urine. This disease tends to occur in middle age to
late teenage years, with an average of about 20 years. Without
treatment horses tend to get worse over time, and are often
eventually euthanased due to chronic laminitis, recurrent foot
abscesses or complications from other infections, as the immune
system is depressed.
Advanced cases are obviously quite easy to diagnose if hair coat is
shaggy. Diagnosis at earlier stages is considerably more difficult.
The two best tests currently are;
(1) The Dexamethasone Suppression Test – an overnight protocol where
a pre-treatment blood sample is drawn in late afternoon to evaluate
baseline Cortisol, after which a low dose of cortisone
(Dexamethasone 40mg/kg I/V or I/M – or 10mL of a 2mg/mL solution per
500kg bodyweight) is given by intramuscular or I/V injection.
A second sample of blood is drawn the next day at about midday, and
both samples are tested for levels of plasma Cortisol. In normal
horses, giving Dexamethasone stimulates a negative feedback response
that markedly suppresses secretion of Cortisol from the adrenal
glands, resulting in a much lower concentration in the second blood
sample (<25mmol/l) However, in horses with Cushing’s Disease, this
negative feedback is reduced, and less suppression, if any, is seen
in the second blood test. In a large USA study using post mortem
confirmation of results, this test was highly accurate.
This is widely accepted as the most accurate test, BUT it has two
significant drawbacks – it needs two visits by the vet, which will
increase costs to you, and, many vets rightly worry that giving
cortisone injections to horses prone to laminitis may actually
increase the risk of laminitis. For these reasons, many vets prefer
to use test (2).
(2) Measure plasma ACTH. This involves collection of one blood
sample. Because the pituitary gland of horses with Cushing’s Disease
secrete excessive amounts of ACTH into the blood (ACTH is
adrenocorticotrophic hormone, which stimulates the adrenal gland to
release Cortisol) compared to normal horses. While it is a useful
test, most vets regard it as less sensitive than test (1), and blood
samples need very careful care to avoid denaturing the ACTH before
testing. This gives false low values, of course. Stress conditions
can also lead to falsely increased ACTH levels.
Resting serum ACTH (normal about <7pmol/l) is a very sensitive and
specific test for Cushing’s but is highly limited by the stability
of ACTH in the sample bottle – ACTH is adsorbed by glass, so blood
must be taken in plastic tubes, and the test done almost immediately
9or the sample must be frozen on the way to the lab)
(3) No matter which of these primary tests are used, supplementary
tests are almost always conducted as well. These always include
simple blood glucose and insulin. Many affected horses are insulin
resistant, and some are very significantly hyperglycaemic as well,
so early identification of this state will allow proper nutritional
management.
There are few causes of resting hyperglycaemia (normal about 3.4 –
6.5mmol/L) in horses other than Cushing’s so, if this result is
elevated, the finding can be quite specific. The problem is that
most horses with Cushing’s have serum glucose within the reference
range, so this makes the test by itself quite insensitive. Other
causes of hyperglycaemia include acute stress, and cereal based food
given within the past 2-3 hours. So testing for glucose should be
done in the morning before feeding. You also need to consider any
stress occurring from transportation or from laminitis
(pain).
Resting serum Cortisol (normal about 50-175mmol/L) is of little
value in Cushing’s suspect cases there is a normal diurnal rhythm in
Cortisol secretion, so the test needs to be evaluated with caution.
The theory is that Cushing’s horses show similar levels in both
tests taken about 8 hours apart, where normal horses will show about
a 30% variation. Clearly stress and pain, as well as diet, can have
a huge effect on Cortisol secretion. Results of this test would be
most valuable in a pain free horse not receiving any hard feed for
at least 4 hours before the test
period.
Resting serum insulin (normal about 5-36microU/mL) can be useful,
but needs care in interpretation. Many Cushing’s horses have
elevated resting insulin levels due to Cortisol induced insulin
antagonism, and diet and stress again have profound effects on
insulin secretion. A hard feed meal can elevate serum insulin for
over 5 hours. Pain can elevate insulin very rapidly as well.- so
insulin is not a really effective test for horses with active
laminitis pain, for example.
The urinary corticoid / creatinine ratio (normal about <20 x 10^6)
in urine samples collected first thing in the morning is used by
some vets. This is a simple test with reasonable reliability, but
may not be as reliable in the dilute urine samples seen commonly in
horses with polydipsia and polyuria in advanced Cushing’s cases.
(4) The TRH Stimulation Test is primarily used when concerns
over the use of Dexamethasone suppression exist as with laminitis.
This involves measuring baseline Cortisol, injecting 1mg TRH I/V
(Note: this is expensive!), then a post treatment sample about 30
minutes later.
Normal horses usually show no real difference between the Cortisol
concentrations in both samples, whereas Cushing’s horses tend to
show elevated Cortisol in the second sample (at least 20% rise, but
usually much greater). This test is reasonably reliable but there
are false negatives and positives recorded.
Now, the second disease syndrome is Equine Metabolic Syndrome.
This has long been recognised as a related syndrome of obesity,
insulin resistance and chronic laminitis, seen in a slightly younger
group of horses generally. Almost all of these horses were
originally considered to be a subgroup of Cushing’s Disease, but a
long, shaggy hair coat is not a feature of this condition, and, most
importantly, tests of pituitary function, including the
Dexamethasone suppression test and plasma ACTH concentrations, give
normal results! In addition, these horses do not respond to classic
Cushing’s drug therapy.
So, if the initial diagnosis is not 100% clear, then the treatment
will be ineffective!
This condition is classified by obesity, especially involving fat
accumulation in the abdomen, insulin resistance and hyperglycaemia
(which you will be very familiar with). Obesity appears to be the
central problem. Body fat is tremendously active both metabolically
and hormonally, and when in excess it can trigger a cascade of
metabolic disturbances leading to insulin resistance and a
persistent hyperglycaemia. These abnormalities exert major effects
on other systems, including increased synthesis and release of
Cortisol from the adrenal glands.
This Cortisol probably explains the predisposition to chronic
laminitis, just as in Equine Cushing’s Disease.
Diagnostically, we have to show that there is no problem with the
pituitary gland /adrenal gland axis as in Cushing’s above, so the
tests we use to diagnose true Cushing’s should all have normal
results. Diagnosing this disease usually starts when owners see
laminitis become recurrent, especially in fat horses where the
normal triggers for laminitis don’t seem to be present high grain,
lush feed, etc.
Diagnostic tests that help obtain a diagnosis are;
(a) Serum insulin and glucose after a fasting period
(b) I/V glucose tolerance test
(c) Tests as above for Equine Cushing’s Disease (to rule it out)
Resting insulin is probably the most common screening test, but for
interpretation it is imperative that blood is taken following a
minimum 5 hour fast, and that the horse is not stressed or in pain
at the time.
In obese horses with advanced metabolic syndrome, fasting
concentrations of insulin are almost always elevated, and blood
glucose concentrations are frequently elevated. In less severe
cases, the I/V glucose tolerance test may be needed to demonstrate
insulin resistance. This test requires serial measurements of blood
glucose and insulin following intravenous injection of glucose. In
normal horses, concentrations of both insulin and glucose rise
initially, but return to normal within 1-2 hours. Insulin resistant
horses, in contrast, show greater elevations in insulin and glucose,
and these levels stay higher for longer in resistant horses.
The big difference between these two disease conditions is in
treatment. Metabolic Syndrome horses focus on reversing the obesity
and insulin resistance through very strict diet and exercise if
possible. The most important principle is
strict limitation of soluble carbohydrate. Nutritional needs should
be met with exclusively fibre based feeds such as good quality grass
hay. Do anything to completely
eliminate soluble carbohydrate sources such as grain, sweet feed,
carrots, apples, fresh pasture, as even very small amounts will
maintain insulin resistance. If exercise is possible, energy intake
once excess weight is lost should be obtained from fat such as
Racing Oil.
It is really important to maintain good supplementation of essential
minerals – calcium, magnesium, phosphorus, copper, zinc, manganese
and selenium should be at least 150% of recommended NRC levels.
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