Equine Cushings disease: new developments to an old disease! (Proceedings)

Equine Cushings Disease (Pituitary Pars Intermedia Dysfunction [PPID]) is a disorder that likely affects more than half the population of horses aged 14 years and older. If unmanaged, affected horses are at risk for laminitis and insulin resistance (IR) and are immune-suppressed, increasing their risk of numerous infections.

PPID is caused by an excess of particular hormones and glucocorticoids. The term itself, pituitary pars intermedia dysfunction, refers to the overproduction of hormones in the pars intermedia, an anatomic region of the pituitary gland. In a normal horse, the cells in this particular portion of the pituitary gland have very little activity, because they are inhibited by the neurotransmitter dopamine. But when a horse with PPID ages, the dopamine levels decrease. The inhibition is released, allowing the cells there to start secreting high levels of hormones including adrenocorticotrophic hormone (ACTH), alpha-melanocyte stimulating hormone (MSH), Cortotropin-like-intermediate peptide, and beta-endorphin.

Unregulated, these hormones, in turn, cause excess production of glucocorticoids, a group of cortisteriods, secreted by the adrenal glands, involved in carbohydrate, protein, and fat metabolism, and which are anti-inflammatory and immunosuppressive. When these corticosteroids run amuck, they cause all kinds of adverse changes.

MSH is important for stimulating the skin cells to be the proper pigment, but in excess can cause dark-colored skin or the haircoat to grow at inappropriate times. ACTH stimulates production of cortisol which is important for proper body metabolism, resisting stress, and fighting off minor illness. Too much cortisol results in a decreased immune response, leaving horses prone to pneumonia, infections of the teeth, sinuses, and hooves. Also, the horse is prone to chronic bacterial, fungal, or parasitic infections, and according to a recent article, Equine Protozoal Myeloencephalitis (EPM). Excess hormones also cause weakened muscle mass; redistribution of muscle over the neck, croup, rump, and eyes; and increased fat pads — a combination of which leads to saggy abdominal muscles, a pot-bellied appearance, and bulgy eyes. Increased thirst, resulting in increased water consumption and urinary output, is another common side effect, as is laminitis.

Although PPID resembles human Cushing's disease — and hence its popular moniker, equine Cushing's disease — PPID differs somewhat. Generally, the human form is caused by a tumor in the frontal lobe of the pituitary gland, whereas most equine cases are attributed to abnormal pituitary function in the pars intermedia, the intermediate lobe. Equine Cushing's used to be thought to be a pituitary adenoma (a benign tumor), but more up-to-date thinking refers to it as a dysfunction. The pars intermedia is especially important for herbivores: Its functions include getting ready for winter (lengthening the haircoat, adding weight before winter, etc). With pre-winter preparation, pituitary gland activities normally increase, but for unknown reasons in many older horses, this normal increased activity is not properly suppressed in the spring and becomes perpetual.

Aspects of Cushings Disease can also occur in horses that have been treated with synthetic corticosteroids such as betamethasone, dexamethasone, prednisone, triamcinolone and in rare instances, ECD has been attributed to cancer of the adrenal glands.

Risk factors

The primary, predisposing factor for acquiring PPID is age. Dopamine levels seem to decrease as horses get older. A recent study, found that 56% of horses 13 years or older were affected and is quite common in horses 18 years and older. Although rare in horses younger than 10, horses as young as 7 years have been diagnosed with ECD. The condition appears to be more common in pony and Morgan breeds, in horses being fed high concentrate rations and inactive obese horses and especially ponies in their younger years. Also, a potential role of oxidative stress in dopamine nerves in the brain of ECD-affected horses has been reported. Recently published information suggests that although oxidative loss of some dopamine nerves is probably normal with age, it is significantly more severe in ECD-affected horses and ponies.

Making the diagnosis

In absence of a definitive, universally accepted test, diagnosis is based on history, clinical signs, and/or tests that rule out some diseases and suggest PPID.

History

The development of infectious diseases that might not typically be seen in older horses such as chronic respiratory infections, recurring dermatitis, and dental abscesses are features of PPID. Also noteworthy is laminitis or founder in absence of an initiating event (exposure to lush pastures, grain overload, spending a lot of time pavement). A 1993 study found that 24% of PPID-affected horses were laminitic. That same study found a strong association with IR in affected PPID-horses — 38% of affected horses had signs consistent with IR. Increased water intake and urinary output are also typically reported.

Clinical signs

The telltale long shaggy haircoat is one of the most obvious suggestions of PPID. As a result of this heavy coat, many horses will sweat excessively, making them more prone to skin infections and rain rot. A pot-bellied appearance with or without a loss of muscle mass over the croup and rump. Owners often report their horses have been losing weight but it's not always a true weight loss, just a redistribution of muscle mass that makes them look skinnier on the topline. Some horses also have an enlargement of the fat pads above their eye, giving them a bulgy-eyed look.

Diagnostic testing:

Routine bloodwork can reveal a stress response related to the cortisol stimulation, hyperglycemia (an increase in blood glucose concentration), and increased liver enzymes. Although nonspecific for PPID, these results suggest PPID if the horse also has signs such as the long, wooly haircoat and laminitis with no probable cause.

It's a bit of grey area but in horses with a long shaggy hair coat, I usually prefer to go ahead and put the horse on a treatment as opposed to recommending further testing. But testing every horse may be an alternative to putting the horse on treatment. The problem is some tests, especially the dexamethasone suppression test, where dexamethasone is administered, can cause some horses to founder. But in horses that have very subtle clinical signs, that don't have the classic changes in their haircoat or laminitis, weight loss or increased water intake/urine output, we recommend doing further testing.

When further testing is desired the low-dose dexamethasone suppression test (DST), whereby the veterinarian obtains a blood sample, gives an injection of dexamethasone, then measures the cortisol level in blood several hours later. In normal horses, the cortisol levels are suppressed and very low; in affected horses, the cortisol levels are much higher. Unfortunately, the test can produce false negatives and false positives. However I recommend the use a combined dexamethasone suppression /thyrotropin-releasing hormone stimulation (DST/TRH) test, developed by the team at the University of Tennessee. "This test is more accurate in the diagnosis of PIPD (this paper was given at the 2004 AAEP Meeting in Denver, CO and is currently being reviewed for publication in the Journal of Veterinary Internal Medicine) because it combines two independent measures — a rise in plasma cortisol concentration after TRH administration and the lack of suppression of plasma cortisol concentration after dexamethasone is administration.

Other means of testing include measuring the ACTH levels and insulin levels, neither of which provide a reliable diagnosis, but can be used in horses with a high risk of laminitis. However, ACTH levels can be high because the horse is in a stressful environment or because the horse has PPID, so there is variable concentration, in general. Insulin levels are also variable, and can be high in obese horses with Equine Metabolic Syndrome.

A more accurate test, not yet available for veterinary diagnostics, could be an alpha-MSH test. It simply involves taking a blood sample. This test has not been validated for the horse, but tests are currently being run at Oklahoma State University in Stillwater, Oklahoma, but Dr. Diane McFarlane. PPID has no cure, but medication and management can relieve the clinical signs and side effects related to this disease. The most commonly-prescribed drug approach is low-dose pergolide treatment, a pharmaceutical given orally every day for the remaining life of the PPID-affected animal. Pergolide is a dopamine replacement agent, used to treat Parkinsonism in people. Studies show over-all improvement in most areas for the majority of treated horses, although long-term efficacy is unknown.

Another drug sometimes recommended for PPID-affected equids, but seems to be less effective, is cyproheptadine. Cyproheptadine is an antihistamine used to inhibit the serotonin hormone that stimulates the gland. Studies found that clinical signs were reduced in only 25% of treated horses, although cyproheptadine is not as effective as pergolide in decreasing clinical signs and laminitis. Thus, I recommend pergolide for long term treatment.

The third drug that has shown promise in treating PPID-affected animals is trilostane, used in Europe and Canada but is not yet available in the US. Trilostane inhibits the release of cortisol from the adrenal gland. It works farther down the line (blocking the cortisol that is a result of pituitary over-stimulation), after the hormones have already been released (as opposed to pergolide which inhibits the release of the hormones from the pituitary). It's been used in dogs quite effectively and found to be fairly effective in horses. The data looks pretty good." A study following horses for one or two years found 81% of treated horses showed improvement in laminitis, and all horses had reduced lethargy, excess thirst, and excess urination.

Besides drug therapy, management changes and supportive treatments that address side effects of PPID are important for helping to keep the horse healthy. Due to the horse's reduced immune response, maintain vaccination and deworming programs and treat infections quickly and aggressively.

Because sugar and starch can exacerbate diabetes and increase laminitis risk, limit sugar and starch intake. I recommend that owners avoid treats, apples, and especially sweet feeds — anything that is high in soluble sugars. If you have to feed a grain, choose whole oats or crimped oats, something that is relatively high in fiber and low in soluble sugars. Testing for IR can be helpful to determine if dietary management is needed. If needed the hay can be tested for the presence of sugars and sugar content of less than 10% is ideal. If sugar content is greater than 10% then hay should be soaked in water for 30 minutes prior to feeding to reduce the amount of sugars.

Limit pasture grazing, as well, especially early in the year when the pastures have a high sugar content and the mornings after a hard, overnight freeze in late fall, when the sugar content in cool season grasses such as orchard grass, timothy, and fescues have the highest concentration of soluble sugar (up to 35%). Because some dead or dormant grass and weeds have increased amounts of carbohydrate, which can trigger laminitis in susceptible horses, they should be avoided.

We also recommend supplementing with chromium to improve insulin effectiveness and vitamin E, vitamin C, and zinc to improve immune function. However, these supplements have not been proven to be helpful for PIPD, but probably are not harmful.

Thyroid-releasing hormone source

Practitioners can obtain TRH from Phoenix Pharmaceuticals, Inc. 530 Harbor Boulevard Belmont, California 94002, www.phoenixpeptide.com, 1-800-988-1205. Cost of TRH is $35 for a 25 mg vial.