Equine Cushings Disease, PPID

CUSHING’S DISEASE (PPID) IN HORSES

Equine Cushing’s disease, also called pituitary pars intermedia dysfunction (PPID), is a disorder of the pituitary gland that has long been thought of as a problem of older horses. However, new information is suggesting that Cushing’s may start to develop years before there are obvious symptoms, meaning that horses can be affected by Cushing’s at a younger age than was previously thought. In the early stages of the disease, horses do not display the hallmark symptom most commonly associated with Cushing’s – the long, wavy coat that fails to shed. Nonetheless, if you know what to look for, there are usually some early clues which may suggest that monitoring for Cushing’s is in order. If your horse does have Cushing’s, it is important to realize that there is no cure, but in most cases the disease can be managed with a combination of diet, exercise, hoof care, and medication where necessary.

UNDERSTANDING EQUINE CUSHING’S, AKA PPID

Cushing’s disease is caused by a non-cancerous, hormone-secreting tumor (adenoma) in the pituitary gland, which is located at the base of the brain. In horses, the adenoma is almost always located in the middle part of the pituitary gland, which is called the pars intermedia (PI). For this reason, the AAEP says, "This syndrome is better defined as Equine Pituitary Pars Intermedia Dysfunction (PPID) because it reflects the location within the brain that is abnormal." In common parlance, the disease is still most often referred to as Cushing's, so we will use that term in this article.

Normally, the function of the PI is regulated by dopamine secreted by nerve cells that come from the nearby hypothalamus, but in horses with Cushing’s, this regulatory system fails. As a result, the PI produces too much of a protein called pro-opiomelanocortin (POMC), as well as several related hormones including adrenocorticotropic hormone (ACTH). This causes imbalances of hormones that are crucial to the regulation of metabolism, and also very important in controlling inflammatory and immune responses. In addition, states the AAEP, " In horses with PPID, the middle lobe of the pituitary gland (pars intermedia) becomes enlarged over time and results in over production of hormones. The growth of the middle lobe of the pituitary gland can compress the adjacent structures in the pituitary and hypothalamus resulting in loss of their function. The enlargement of the pituitary gland is often referred to as a pituitary adenoma."

SYMPTOMS OF CUSHING’S

The classic symptoms associated with Cushing’s disease include:

· Long, wavy hair that does not shed normally, even in hot weather (hirsutism)

· Abnormal fat deposits, especially around the shoulders, tail head, above the eyes and in the sheaths of males

· Excessive sweating

· Passing large amounts of urine

· Increased thirst

· Lethargy

· Exercise intolerance

· Chronic or recurrent laminitis

· Infertility

· Weight loss

· Muscle wasting, especially along the topline

· Slow wound healing

· Increased susceptibility to infections.

A horse may exhibit some or all of these symptoms when the disease is fairly advanced, but in the early stages, that is not the case. According to veterinarian and equine Cushing’s expert, Eleanor Kellon, DMV, “We still need a great deal more research into how Cushing’s develops, but early symptoms are likely to include unexplained fall laminitis in a horse that has no prior history of laminitis, and exaggerated seasonal ACTH rises in the fall. However, because recent research has shown that all horses have somewhat elevated ACTH levels in the fall, it is best to test for Cushing’s in the spring, when the results of the bloodwork are easier to interpret.”
Another early sign in many horses that go on to develop full-blown Cushing’s is abnormal body fat distribution, which includes cresty necks, excess “padding” above the eyes, and fatty deposits over the hindquarters. However, this is not actually a symptom of Cushing’s, but is rather a symptom of insulin resistance (IR), a metabolic condition that is often – but not always – associated with Cushing’s. Horses may be insulin resistant and never develop Cushing’s, and some horses with Cushing’s are not insulin resistant, but IR is frequently present with or a precursor to Cushing’s. A horse with abnormal fat distribution should therefore be tested for both Cushing’s and IR, as the treatment protocol would vary depending on the results. How, exactly, these two conditions are linked is not well understood at present, though more is being learned as research continues.
DIAGNOSING CUSHING’S

Testing for Cushing’s involves blood work, but there are drawbacks to certain methods that need to be carefully considered, and opinions are mixed as to which are the most effective. Christie Malazdrewich, DVM, Diplomate ACVIM, of the University of Minnesota College of Veterinary Medicine, says, “A variety of endocrinologic tests have been promoted for the purpose of diagnosing equine Cushing’s, but few have been scientifically validated in horses for which the diagnosis has been subsequently confirmed by necropsy examination. In my opinion, the two most practical and accurate tests currently available are (1) the dexamethasone suppression test, and (2) measurement of plasma ACTH concentration. The dexamethasone suppression test is an overnight protocol in which a pretreatment blood sample is collected in the late afternoon, after which a low dose of dexamethasone is administered by intramuscular injection. A second sample of blood is collected the following day at around noon and both samples are submitted for measurement of plasma cortisol. In normal horses, administration of dexamethasone stimulates a negative-feedback response that suppresses secretion of cortisol from the adrenal glands, yielding a much lower concentration in the second blood sample. In horses suffering from Cushing’s disease, however, the negative-feedback response is blunted and a lesser degree of suppression, if any, is observed.”

Most veterinarians consider the dexamethasone suppression test to be the most accurate one currently available, but it has two significant drawbacks: first, it requires two veterinary visits, which makes it expensive, and more importantly, it can actually bring on or worsen a laminitic episode in horses that are already predisposed to this condition – which both Cushing’s and IR horses are. “For these reasons,” says Malazdrewich, “many veterinarians prefer an alternative test, measurement of plasma ACTH. This test involves collection and analysis of a single blood sample; the pituitary gland in affected horses often secretes excessive amounts of ACTH into the bloodstream as compared to normal horses. While useful, this test is generally considered to be somewhat less accurate than the dexamethasone suppression test, and blood samples must be handled very carefully to avoid degradation of ACTH and falsely low measured values. Stress and pain due to other conditions may also result in falsely elevated values.

However, Dr. Kellon states, “There is no more solid support, by postmortem examination, for the dex suppression test than there is for ACTH. Furthermore, the same things that can give false positives on ACTH can give dex suppression false positives. I believe that we underutilize some testing options compared to what is done when testing for Cushing’s in other species (e.g. morning cortisol:creatinine ratio, POMC testing). At this point, there is no 100% reliable test, but a recent study done at the University of Tennessee indicates that the dex suppression test combined with thyrotropine-releasing hormone (TRH) stimulation is much better than the dex test alone. It may be better than ACTH, too, but it wasn’t compared to ACTH.” Regardless of whether you are doing ACTH or dex suppression, Kellon strongly recommends that the horse be tested at home, without any disruptions in normal routine, as stress can lead to a false positive test result The horse should also not be injured, in pain, or ill for any other reason, as these factors can also lead to false positive results or equivocal results. Remember to test in the spring to avoid the natural fall elevations of ACTH.

TREATMENT FOR CUSHING’S

If a horse is diagnosed with Cushing’s, the best treatment is a multifaceted approach that includes medication when necessary, dietary modification, supplementation and appropriate hoof care. The most commonly and successfully used medication is pergolide, which works by binding with receptors in the brain that control the production of dopamine. Pergolide has been shown to be more effective than the next most commonly used medication, cyproheptodine, with one study showing that 85% of horses treated with pergolide showed improvement in clinical signs, compared to only 28% of horses on cyproheptodine.

If your horse does get put on pergolide, it is best to start out with a low dose – 0.5 mg for the average adult horse, and only increase as necessary under the guidance of your veterinarian. The clinical symptoms of most horses will be controlled with doses between 0.5 and 1.5 mg. This may not bring their ACTH levels completely down to normal, but as Dr. Kellon explains, “Getting the ACTH levels down to normal again is the ideal, but not always possible. There is a pretty universal ‘real world’ agreement that you don't have to have ACTH all the way back into normal ranges to see a significant clinical improvement. What it usually boils down to is that if you have the symptoms under control, the value, if any, of obsessing over ACTH and trying to get it completely down to normal is debatable. As strict a control of ACTH as possible is most important for horses with laminitis, but an appropriate diet can go a along way in helping to control that.”

In practice, many people never repeat the ACTH tests as long as the horse is doing well, but those who wish to keep track of ACTH levels need to understand that timing is important for any retesting. Says Kellon, “If you want to keep track of progress regardless of clinical status, you should retest at the same time of year on a yearly basis. Even horses with Cushing’s show seasonal influences on ACTH – highest in fall, lowest in spring. Everyone acknowledges these occur, but they haven't been well quantified so all this does is lead to confusion in interpretation if you, say, try to compare a December to a June sample. Of course, if you sample something like 2 to 3 months after starting pergolide and your level is normal, that's significant, or if it's lower but the day length is shorter, that's significant. Otherwise, it gets a little hard to interpret. Since many horses that seem well controlled at other times of the year may get laminitic in the fall, it's generally a good idea to do your regular, post-diagnosis testing around the end of August to make sure the dose you are using is doing a good enough job of controlling the ACTH.”

If your horse’s Cushing’s is not too advanced, you may be able to alleviate the clinical symptoms without prescription medications, as there are also some natural supplements that people may find helpful for horses with Cushing’s. One is Hormonize, a preparation made from chasteberry (Vitex agnus-castus), has been used by many owners and veterinarians with good results, and some people use whole chasteberries in their natural form. A recent study by the New Bolton Center on the effects of chasteberry for the treatment of equine Cushing’s concluded that it had no measurable effect, but strong anecdotal evidence and the results from a very large, two year trial conducted in the UK by the Laminitis Trust suggests otherwise. Robin Siskel, co-owner of the Equine Cushing’s Group (http://pets.groups.yahoo.com/group/EquineCushings), a web-based support and information site for people with horses that have metabolic disorders, is aware of the New Bolton study, but still has faith in chasteberry. “Our list members have had far better results with it than was found at New Bolton,” she says, “but that could be a matter of the amounts used, the type used, the dosing schedules, etcetera.”

Dr. Kellon, who is also co-owner of the Equine Cushing’s Group, supports the use of chasteberry for some cases, but not all. “Chasteberry has a pharmacological activity in the brain that is very similar to pergolide, but as an ‘herbal’ approach, it is subject to variations in potency, as is any natural product. If using the whole berries, our list members have reported favorable results feeding 2 oz/day of the freshly ground whole berries to an average sized adult horse (1000-1100 lbs.). Starting dosage for Hormonize is 10 cc/200 lbs. We currently don’t have as much experience with chasteberry as with the prescription drug options. Some horses respond to the dosages I’ve just mentioned, some may not. At this point, the best advice seems to be that if you have a very advanced case, or a horse that is already in trouble with laminitis, the prescription drug pergolide is your most reliable treatment option.”

Another extremely important aspect of treatment for horses with Cushing’s is diet, as this is the most effective way to control and prevent insulin resistance, as well as laminitis. The main feature of an appropriate Cushing’s/IR diet is that it is low in non-structural carbohydrates (NSC), which means that anything sweet or starchy should be avoided. This includes all grain and grain products likes wheat bran, anything containing molasses, carrots, apples, and all sugary treats. It also means that grazing may have to be avoided or strictly limited, as grass can be surprisingly high in NSC, even when it looks dead for the winter or dried out in the summer. High protein forages like alfalfa can also be problematic, as excess protein may raise blood glucose levels, or it could be something else about alfalfa that some horses are sensitive to. The main staple of the diet should be a low NSC grass hay, but the difficulty there is that you can’t tell if a hay is low or high in NSC unless you have it analyzed. Hays that look rough or yellow can still be very high, and even straw can contain enough sugar to be harmful. The only option, if you need to know the NSC of your hay, is to have it tested. Your local forage lab may not have the capability to test for NSC, so many people who have "special needs" horses use Dairy One/Equi Analytical labs in the U.S., and A & L Canada Laboratories, Inc. in Canada (www.alcanada.com). You can also learn more about NSC in grass and hay by going to the website of forage researcher Kathryn A. Watts, BS (www.safergrass.org).

If you are unsure about the NSC in your hay, you may want to implement a soaking program, as Watt’s research has shown that soaking hay for an hour before feeding it can remove up to 30% of the soluble sugars. Another option is to replace a portion of your hay with molasses-free beet pulp (or rinse molassed beet pulp until the water runs clear) at a rate of 1 lb. beet pulp for every 1.5-2 lbs. hay. Still another option – and one that many people find easiest of all – is to use Ontario Dehy Timothy Balance Cubes – a product that was designed specifically to meet Dr. Kellon’s specifications for horses with Cushing’s and/or IR (www.ontariodehy.com). Alfa Tec in Alberta (www.alfatec.ca) also now offers a guaranteed low NSC hay and beet pulp cube that comes with a correctly balanced mineral supplement. Many other companies are now jumping on the “low carb bandwagon” and producing products they claim are appropriate for such horses, but you have to be careful with these. Many are low starch but still contain too much sugar, and some are high in fat, which can make symptoms worse in horses with Cushing’s and/or IR.

The Ontario Dehy and Alfa Tec cubes are tested specifically for NSC, and they are also balanced in terms of minerals, which is another important factor in feeding these horses. Dr. Kellon has compiled evidence that shows that horses who have a low NSC diet with balanced minerals show greater improvement than those on a low NSC diet alone. Unfortunately, mineral balancing is not as simple as merely buying a “balanced” supplement and adding it to your horse’s feed, as that supplement may or may not be balanced in relation to the hay you are feeding. Once again, analysis is the only way to know for sure. Many owners of horses with Cushing’s and/or IR have their hay analyzed for NSC and minerals, and will customize or choose their mineral supplements based on the numbers actually present in their hay.

The importance of diet cannot be overemphasized for horses with Cushing’s and/or IR, but they also benefit greatly from regular, sensible exercise. If they are in pain from active laminitis, they should never be forced to move, which can cause further damage to their feet, but otherwise, exercise is highly beneficial. Exercise helps regulate the secretion and utilization of glucose and various hormones that affect metabolically challenged horses. Since horses with Cushing’s often tire and sweat easily, start slow and build up your exercise program slowly.

It is also very important to pay close attention to the feet of a horse with Cushing’s, as they are highly prone to laminitis. Regular trimming that follows the physiology of a natural hoof shape (see www.hoofrehab.com and www.hopeforsoundness.com to get an idea of what this looks like) seems to produce the best results, whether shod or barefoot. Ask your veterinarian to show you how to feel for digital pulses in your horse, which can help you determine if there is inflammation in the feet. Also familiarize yourself with other symptoms of laminitis so that you can catch any episode as early as possible. Of course, it is far better to prevent laminitis with appropriate diet and care whenever possible!

LONG-TERM OUTLOOK

When horses are first diagnosed with Cushing’s, it is common for their owners to feel frightened or even overwhelmed at the prospect of trying to care for them. However, most owners find that although they must make changes in the way they care for their horse, the new requirements soon become just part of the routine. Many horses live comfortably and productively for years – often well into old age – with Cushing’s disease, if it is properly managed. If you do your research, work with your veterinarian and implement the appropriate measures, your horse has a good chance for a full and happy life.