The Latest on PPID
Not too long ago, when an old horse started losing weight, became increasingly grumpy and had a little trouble getting around, it was assumed that his advancing years were simply catching up with him. Likewise, susceptibility to infections, a dull shaggy coat and muscle wasting were considered an inevitable part of the aging process. Horses who didn’t develop these problems were considered lucky or unusually hearty.
But in the late 1970s, studies suggested that these problems weren’t, in fact, the norm in older horses. Investigators discovered that a pituitary gland malfunction commonly known as equine Cushing’s disease—and later more accurately described as pituitary pars intermedia dysfunction (PPID)—was responsible for many of these changes.
Further research over the following decades led to more reliable diagnostic tests and treatments. These advances, combined with an increased awareness about the disease among horse owners and veterinarians, have greatly improved the prospects of aging horses: They do not have to spend their later years contending with the unpleasant and potentially deadly effects of PPID.
This, however, doesn’t mean that the problem of PPID is solved. Far from it. If anything, research efforts have increased as we strive to learn even more about why horses develop the condition, what effects it has and the very best ways to identify and control it.
Most recently, the world’s leading researchers of PPID met in Boston last fall. The two-day conference, called the Equine Endocrinology Summit, was a chance to review the most current information about the disease, including what the latest research means for earlier diagnosis and how treatment options have improved dramatically in recent years. I was fortunate to be able to attend and now share that information. Here’s an overview of what we currently know about PPID and what the future may hold.
The damage PPID does
Harvey Cushing, an American neurosurgeon, published his first paper about endocrinological imbalances caused by pituitary gland dysfunction in 1932. The disease was dubbed “Cushing’s” and it wasn’t long before similar conditions were identified in other animals, but with important distinctions.
In people and dogs, Cushing’s disease is caused by a hormone-secreting tumor on the portion of the pituitary gland called the pars distalis. In horses, however, there is no tumor. Instead, the part of the pituitary gland called the pars intermedia becomes enlarged and produces more hormones than necessary. This distinction is one of the reasons why PPID has become the preferred term for the disease in horses and treatment options do not include surgery, as they do for Cushing’s in other species.
Why horses develop PPID is unclear, but those with equine metabolic syndrome seem to be at higher risk, as do ponies. Age is also a significant factor. The statistics are still being collected, but veterinarians know from experience that the incidence of PPID is higher among older horses. Research has shown that as a horse ages the pars intermedia also increases in size. That’s why some veterinarians assume that if a horse lives long enough, he’s going to get PPID.
To understand the effects of PPID, consider the varied functions of the pituitary gland. Located on the underside of the brain, just above the roof the mouth, the pituitary gland controls numerous bodily processes by secreting several different hormones, including adrenocorticotrophic hormone (ACTH). ACTH, in turn, regulates the production of the steroid hormone cortisol by the adrenal glands, located near your horse’s kidneys. In normal horses, ACTH is produced primarily in the pars distalis of the pituitary gland. In a horse with PPID, however, the pars intermedia secretes abnormal ACTH and other hormones such as α-MSH and β-endorphins. Hormonal imbalances account for many of the signs of PPID in horses. These include:
• a long, curly coat that is slow to shed in springtime. Long hairs under the chin and belly are particularly indicative of the condition.
• excessive sweating
• muscle wasting
• development of fat deposits on the top of the neck, tailhead and around the eyes. These fat “pouches” persist even if the horse loses weight.
• a potbelly.
Clearly, PPID horses can have a particular “look.” Veterinarians are becoming increasingly adept at identifying which horses need to be tested for the condition. It’s my hope that with increased awareness, more horse owners will be able to recognize these signs early, rather then ascribing them to old age (see “On Watch for PPID,” page 35).
In addition, slow-healing wounds, increased drinking and urination, stubborn respiratory, skin or sinus infections, and persistent low-grade laminitis can signal PPID. Whenever an older horse develops these problems, alert veterinarians do not view them in isolation; rather they consider them possible indications of underlying PPID. This is important because unless the PPID is identified and controlled, the associated problems will never go away.
Laminitis is, by far, the most serious complication of PPID. The link between the two is still being explored, but the generally accepted theory is that elevated insulin0 concentrations in the blood may trigger the devastating hoof condition. Unlike acute laminitis, however, where a horse is suddenly unable to walk and in obvious pain, chronic laminitis associated with PPID can be extremely subtle. A horse may seem only a bit “tender footed” or take shorter strides, signs easily attributable to arthritis or other age-related deterioration. Often, by the time the diagnosis of laminitis is finally made (assuming it ever is), the damage done to the hoof structures is advanced and difficult to manage.
The risk of laminitis in PPID horses fuels much of the urgency in research and our clinical management of cases. PPID itself won’t kill an older horse, but associated laminitis certainly can.
Advances in diagnostic testing
When a horse is showing obvious signs of PPID, it’s possible to diagnose the condition simply by starting treatment and seeing if he improves. And veterinarians will often do this, especially in cases where we suspect advanced PPID and don’t want to delay treatment. However, our ultimate goal is to identify PPID well before the horse becomes hairy, infection-prone, laminitic and miserable. Laboratory diagnostic tests can confirm suspicions in horses with less-than-obvious PPID.
Three tests are available for PPID. None of them are perfect, but each has its benefits and drawbacks.
Dexamethasone suppression test. In this test, a blood sample is taken from the horse around 4 p.m. That sample is tested to determine the horse’s baseline cortisol concentration. The horse is then given a dose of the steroid dexamethasone. Nineteen hours later, a second blood sample is taken, which is also tested for cortisol. A healthy horse will show a dramatic drop in cortisol concentrations between the two samples because the steroid suppresses the body’s natural production of cortisol. In a horse with PPID, however, the deranged hormonal system does not shut down cortisol production in response, and the second cortisol concentration will not be dramatically reduced.
The “dex suppression” test was one of the first reliable tests for PPID and remains an accurate one. There is, however, some risk involved. The injection of steroids may trigger a laminitic episode in horses who are already showing signs of PPID. This risk isn’t particularly high, but the outcome can be tragic and is impossible to predict. For this reason, researchers have spent quite a bit of time and energy exploring other diagnostic approaches.
ACTH test. A one-time blood test to measure ACTH concentration and other related hormones, this is the simplest diagnostic test for PPID, but it has to be interpreted extremely carefully. Elevated ACTH is considered indicative of PPID, but recent research has shown that levels of these hormones fluctuate. Specifically, in the fall they increase subtly in normal horses but spike dramatically in horses with PPID. It is actually fine to use ACTH concentrations to test for PPID in the fall, but it is essential that the laboratory provide seasonal reference ranges for their particular ACTH assay. If seasonal reference ranges are not used, then a single ACTH test can lead to false positive results for PPID in the fall and false negative results in the spring, particularly in the absence of clinical signs.
Any veterinarian using ACTH concentrations must consider hormone levels in other horses in the locality to properly interpret the results. There are also some mild variations in ACTH concentrations over time, and a more representative result can be obtained by taking two blood samples 30 minutes apart, mixing them and submitting the combined sample for ACTH testing.
ACTH tests have another application in the management of PPID. They can be useful in monitoring the success of treatment over time. Twice-yearly monitoring of ACTH concentrations are recommended. Ideally, this testing will be performed in the same months each year. It’s also important to send the blood tests to the same laboratory for testing every year. Different testing assays can yield very different results— a 26 pg/ml from one lab might be the equivalent of a 46 pg/ml from another —giving a false impression of changes in the horse.
Thyrotropin-releasing hormone (TRH) stimulation test.
In this test, the veterinarian draws a blood sample and measures the baseline concentrations of ACTH. Then, she gives the horse a dose of synthetic TRH and draws a second blood test 10 to 30 minutes later. In normal horses, the pituitary gland will produce small amounts of ACTH in response to TRH, so a second blood test will reveal a slightly increased ACTH concentration.
Horses with PPID will produce much more ACTH in response to TRH stimulation, and so their second sample will be markedly increased. There are also seasonal variations, and therefore use of laboratory-specific seasonal reference ranges are required.
The TRH stimulation test holds great promise for early diagnosis of PPID. Several studies have shown that it’s extremely sensitive; it can identify horses with the earliest changes in their pituitary gland, well before any clinical signs are noticeable and before any of the other testing methods detect PPID. If I see a horse who is, say, 16 and losing weight for an unknown reason, the TRH stimulation test can be a great option to detect subclinical PPID. The sensitivity of the TRH stimulation test is one of the most exciting developments in PPID research lately.
The downside of the TRH stimulation test is a matter of supply. TRH is available only in either a human-grade formulation, which is prohibitively expensive, or a chemical-grade formulation, which is not sterile. Because of this, TRH testing is mainly being used in a research setting or by equine veterinary specialists who can obtain and formulate the TRH.
In the future, perhaps a pharma-ceutical company will begin manufacturing TRH in a controlled, sterile setting, to give us a commercially available product approved for test- ing horses. When that happens, practitioners will be able to identify cases of PPID very early on, which will help more horses sooner.
Several once-common methods for diagnosing PPID have been discredited or replaced with better options. For example, measuring a horse’s cortisol concentrations once or twice daily reveals little useful information because they fluctuate greatly over the course of a day.
Blood tests for insulin and glucose are not good indicators of PPID because many horses with the condition also have elevated insulin and sometimes glucose concentrations that are asso-ciated with equine metabolic syndrome. The results, therefore, will not tell you which disease you’re dealing with. Blood tests of thyroid concentrations are similarly useless for the diagnosis of PPID because there is no evidence that the thyroid gland plays a role in the disease. True hypothyroidism is very rare in horses and is best diagnosed by measuring the concentrations of thyroid hormones before and after TRH administration. Measurement of baseline thyroid hormones on their own can be very misleading, given that they can be low for many reasons unrelated to hypothyroidism.
While diagnosis may still be tricky, treatment of horses with PPID is fairly straightforward and has gotten even easier in the past two years. The medication of choice is pergolide, a dopamine receptor agonist. Long used to treat Parkinson’s disease in people, pergolide was discovered to be helpful in treating horses with PPID in the early 1990s. It works by binding with drug receptors in the brain that control the production of dopamine, decreasing the blood levels of ACTH, α-MSH and β-endorphins.
Veterinarians initially made anecdotal observations of improvements in PPID horses given pergolide, and studies later confirmed its effectiveness. The medication quickly became the treatment of choice for horses with PPID, replacing the much less effective alternative, cyproheptadine. In 2007, however, complications in Parkinson’s patients resulted in the withdrawal of pergolide from the market, which meant that veterinarians had to turn to compounding pharmacies to obtain it.
Although this ensured that PPID horses could continue to receive this important medication, it was far from an ideal solution. When a drug is compounded it does not undergo quality control or efficacy testing. Each batch is simply mixed and shipped out. When practitioners began seeing inconsistencies in how well the drug seemed to work, even in the same horses over time, researchers tested multiple batches of pergolide and found wide variations in the levels of active ingredients. How quickly the drug deteriorated during storage, even in optimum conditions, also varied. All of this increased concern about compounded pergolide, but there were no alternatives.
Then, in early 2012, the Food and Drug Administration approved a pergolide formulation made specifically for horses. Sold as Prascend, this medication eliminated all the problems associated with compounded formulations.
In recent efficacy studies of Prascend, 76 percent of horses on the medication began showing improvement in their clinical signs and/or laboratory testing results within three months. After 180 days of treatment, 89 percent of those horses had shed out their long hair and 46 percent showed an improvement in muscle tone.
One important question about pergolide remains: Will it prevent a horse with PPID from developing laminitis? As of now, we don’t have the data to say for sure, and it will take several years and multiple large studies to collect it. I tell clients that while I can’t guarantee pergolide will prevent laminitis, I do know it will help with all the other clinical signs, which is justification enough for using it. And it may indeed help prevent laminitis; we just can’t say that with certainty yet.
It sometimes takes a bit of trial and error to find the correct dose of pergolide for a particular horse. After PPID is diagnosed, we typically start a horse on one milligram a day. If, after 60 days, we see an improvement in clinical signs, we retest the horse to see if his ACTH concentrations or response to a dexamethasone suppression test have improved. If they have, we’ll keep the horse on that dose until we have reason to believe it might need to be adjusted. If we don’t see an improvement after 60 days, we increase the dosage to two milligrams per day. Pergolide does have some side effects, the most common being a loss of appetite, so veterinarians try to use the lowest dose necessary to obtain results without creating other problems. It can be a tricky calculation to get just right, so it’s important that it be done by a veterinarian based on careful monitoring of the horse.
Once an effective dose of pergolide has been determined, a horse can remain on it for the rest of his life. Rarely, horses can develop “dose tolerance” to the medication, with mild clinical signs returning. In those cases, the dose can be gradually increased until the results of testing show improvement. Occasionally horses will require five or even 10 milligrams of pergolide per day. This, again, is something that needs to be done by a veterinarian.
Whenever I see an older horse in the clinic, for any condition, I keep the possibility of PPID in mind. Even if it ends up having nothing to do with the issue at hand, identifying and treating the condition is an important part of maintaining an older horse’s health.
I’d like to see testing for PPID become standard for all horses over the age of 16, as part of an annual geriatric health screening, so we can catch every case, but I know that’s not feasible. So, ultimately, it comes down to horse owners to be on the lookout for the subtle, earliest signs of PPID and get help for horses before it begins to affect their quality of life. With all that we are able to do for them, it’s a good time to be an older horse.
This article first appeared in the EQUUS magazine issue #424 January 2013.