Obesity and Cushing's Disease
Cushing's disease has been around for a long time in people, horses, and other animals. For years, theories and information concerning the affliction all centered on one source for the problem--tumors of the pituitary gland, which is located at the base of the brain. In the case of horses, it was generally felt that benign tumors in the intermediate lobe of the horse's pituitary gland resulted in an inappropriate secretion of hormones, which brought on Cushing's disease. Nowadays, the correct term is pituitary pars intermedia dysfunction (PPID), since it has been discovered that degeneration of the hypothalamic dopaminergic neurons (those in the hypothalamus using dopamine as their neurotransmitter) is the primary cause.
For years, theories and information concerning Cushing's disease all centered on one source for the problem--inappropriate secretion of hormones caused by tumors of the pituitary gland, which is located at the base of the brain. Nowadays, the correct term is pituitary pars intermedia dysfunction (PPID) since it has been discovered that degeneration of the hypothalamic dopaminergic neurons (those in the hypothalamus using dopamine as their neurotransmitter) is the primary cause.
There is an affliction that has some of the same characteristics as Cushing's, yet is different. At the same time, there is speculation that this syndrome, termed metabolic syndrome and previously called peripheral Cushing's syndrome, could be a factor in horses which develop Cushing's disease.
Classic Cushing's Disease
The hormonal imbalance in Cushing's disease results in clinical signs including a long, shaggy coat that doesn't shed out in the spring or summer, undue sweating, a heavy intake of water and resultant frequent urination, increased appetite, pot-bellied appearance, lethargy, loss of topline muscle, and laminitis.
Some Cushing's horses, but not all, also have insulin resistance. This term refers to a condition in which the horse's body cells are unable to properly respond to insulin. When the horse's body is responding as it should, insulin secretion is triggered by an increase in blood glucose or blood sugar after a meal containing sugar and starch has been consumed. The increase of glucose in the blood sends a message to the cells that they should absorb the glucose for use as an immediate energy source or convert it to fat or glycogen to be stored in the cells to satisfy future energy demands.
Generally, Cushing's disease afflicts older horses, but it has been known to strike those under 10 years of age. Regardless of the age of the horse, Cushing's disease often renders a horse infertile. There has been no scientifically proven predisposition for the disease according to gender, but you hear about it often among Morgans and various pony breeds.
Clinical signs of metabolic syndrome include obesity-associated laminitis and abnormal fat deposition. In addition, insulin resistance appears to be one of the criteria defining metabolic syndrome.
Much of the research involving metabolic syndrome has been carried out at the University of Missouri in Columbia under the direction of Philip J. Johnson, BVSc, MS, Dipl. ACVIM, MRCVS, professor of equine internal medicine at the university's College of Veterinary Medicine. Collaborating with Johnson on much of the research have been Nat Messer IV, DVM, Dipl. ABVP, an associate professor at the university and a scientist who has been involved in a number of studies on hypothyroidism in horses; and Seshu Granum, PhD, a veterinary endocrinology professor at the University of Missouri.
Much of what the Missouri researchers have learned has shed new scientific light on Cushing's disease and metabolic syndrome, but their research also has raised questions. For example, is metabolic syndrome a cause of Cushing's disease? And if so, could Cushing's disease result from changes in the brain that impact the pituitary gland, rather than the development of tumors?
In an effort to guide readers through the maze of information with as little confusion as possible, let us first examine Cushing's disease a bit more. Then, with Johnson leading the way, we will take a long look at metabolic syndrome, including cause, treatment, and prevention.
The Problems With Cushing's Disease
There are more problems associated with Cushing's disease than just the clinical manifestations listed earlier. Half of the horses with Cushing's develop laminitis and their immune systems are suppressed, opening the door to a wide variety of pathogenic agents. A Cushing's horse with laminitis can be well-managed for years.
There are drugs available that have proven to be at least somewhat effective in modifying the inappropriate activity of the pituitary gland, although there is no cure. Two of the drugs used frequently are pergolide and cyproheptadine.
Two years ago, researchers at Michigan State University (MSU) conducted research to determine which of the drugs was most effective. Hal Schott, DVM, PhD, associate professor of large animal clinical sciences at MSU, reported in a 2003 news release that from late 1996 until 2001, he and his colleagues had tracked and compared the progress of horses treated with pergolide, those treated with cyproheptadine, and those with no treatment at all.
"We found clearly that pergolide was a much better treatment," Schott stated. "It seems to help them quite dramatically. It improves their clinical signs as well as reverses or makes their dexamethasone tests (more on this later) return to normal in some, but not all cases."
There is a bad news side to pergolide--it is expensive. An average regimen of pergolide for a horse would cost $60 per month, Schott estimated. The other bad news is that the drug doesn't cure Cushing's. Eventually, the condition will worsen and euthanasia is often the ultimate outcome.
The dexamethasone suppression test to which Schott referred is one of the most definitive tests available to determine whether a horse truly suffers from Cushing's disease. However, it carries at least a small risk of exacerbating laminitis. To conduct the dexamethasone suppression test, a small sample of blood is taken from the horse, then the horse is given dexamethasone (a synthetic cortisol). A follow-up blood sample is taken the next day and compared to the sample taken before the dexamethasone injection. How the horse responds to excess dexamethasone in the bloodstream tells the tester whether the animal truly is suffering from Cushing's.
Just recently, the University of California, Davis, announced that it had developed a test that detected differences in pituitary peptides and "found that these differences were sufficient in magnitude to distinguish between normal and Cushing's-affected horses with a moderately high degree of certainty." The test is said to be totally safe. The research that resulted in development of the test was conducted under the direction of Johanna Watson, DVM, PhD, and involved radioimmunoassay kits for examining three products (peptides) produced by the pituitary gland. The researchers determined that horses with unusually high blood levels of any of the three peptides very likely was suffering from Cushing's disease. They "concluded from the results that any of the peptides measured may be used as an alternative diagnostic test in situations in which the dexamethasone suppression test is considered dangerous."
We switch now to metabolic syndrome with Johnson. However, we don't totally walk away from Cushing's disease, because there are potential connections. In the past, says Johnson, the condition now known as metabolic syndrome (MS) has been classified as hypothyroidism, peripheral Cushing's disease, or pre-Cushing's syndrome.
In both humans and horses, Johnson says, metabolic syndrome, among other things, results in insulin resistance and obesity. The sad part of this scenario is that, in the case of horses, man is at the root of the obesity problem. Johnson explains it this way:
"Under the constraints and luxuries afforded by contemporary management practices, domesticated horses tend to be fed rations that are broadly excessive with respect to the metabolic requirements for the level of physical activity to which they are subjected, and/or provide calories in a concentrated form that is far removed from the natural diet.
"It is common practice for horses to be fed grain-rich rations during long periods of physical inactivity. Moreover, some predominantly forage-based rations are based on improved pastures and hays that are considerably higher in soluble carbohydrates than wild/native grass strains. The manner in which domesticated horses are fed far exceeds in both quantity and quality the dietary intake for which the species evolved in nature. Horses have inherited 'thrifty genes' that permit highly efficient use of their dietary intake, leading to heightened ability to endure periods of environmental harshness. However, when presented with an abundance of food resources, susceptible horses quickly develop an obese phenotype (physical characteristics), especially when that excess food is coupled with restricted physical activity."
The above scenario results in horses which are loaded with fat tissue. In the past, it was believed that fat cells were nothing more than benign repositories for stored energy, says Johnson. However, it has been determined that these fat cells, called adipocytes, "represent an important source of numerous diverse hormones (adipokines) that play a role in regulation of body mass and body composition."
It also has been found, he says, that not all fat cells are identical, with some being more important and prolific than others in producing hormones. In humans, he explains, the fat cells found in the intra-abdominal area are associated with greater risk for cardiovascular disease than are the fat cells located at the subcutaneous (beneath the skin) level.
The accumulation of a great many fat cells in the horse, says Johnson, is accompanied by the production of excessive quantities of endocrine signals. In addition, fat cells in the abdominal area possess an enzyme that converts circulating inactive cortisone to the physiologically active glucocorticoid called cortisol. Many of the endocrine signals emanating from the fat cells, including cortisol, directly inhibit the action of insulin and cause insulin resistance.
Elevated production of endocrine signals from the fat cells, Johnson says, is believed to represent the link between obesity, insulin resistance, and the risk for development of cardiovascular disease in human patients. Could there be the same link in horses between obesity, insulin resistance, and laminitis? Johnson believes it could be possible, but notes that there is no scientific evidence available to back that assertion.
"Although it is suspected that the similar situation exists with respect to risk of laminitis in some obese adult horses, further work is needed to better characterize any pathophysiological relationships between obesity, hyperinsulinemia (an excessive amount of insulin in the blood), insulin resistance, and laminitis in the horse," he says. "The metabolic syndrome is probably more likely to develop in animals with inherited tendencies toward insulin resistance and in which the development of obesity represents a compounding factor.
"Veterinarians should consider a diagnosis of metabolic syndrome in adult horses that are recognized as obese and in which laminitis has been identified, or in any case of unexplained laminitis," says Johnson. "Other physical characteristics of metabolic syndrome in horses include abnormal body fat distribution, such as a thickened, cresty neck; fatty accumulations at the tail and near the shoulders; and fatty thickening in the prepuce of male horses. Affected broodmares are commonly reported to be infertile and often exhibit abnormal cycling. Easy weight gain usually occurs on caloric intakes that are well below those that would be predicted to maintain a normal body weight."
In addition, the metabolic syndrome horse often has a prodigious appetite.
However, Johnson points out, it should be noted that not all horses afflicted with metabolic syndrome are obese, and not all already have laminitis.
A diagnosis of horses suffering from metabolic syndrome, he says, can be made by testing for the amount of insulin in the blood. If it is excessive, chances are strong that the horse is suffering from metabolic syndrome.
Treating Metabolic Syndrome
Johnson then switches attention to treating horses with metabolic syndrome. First, he points out, treating horses suffering from the syndrome with pergolide and cyproheptadine, as is done for horses with Cushing's disease, won't be productive for this malady and could exacerbate the condition because the two drugs suppress pancreatic insulin secretion. And, as has been noted, one of the characteristics of metabolic syndrome is insulin resistance.
"There are anecdotal reports," says Johnson, "that both drugs have resulted in clinical improvement in horses affected with laminitis and insulin resistance. However, since diet control is used simultaneously with introduction of these drugs, it is generally impossible to determine specifically drug-related responses."
Johnson then opens the door of speculation further: "Nevertheless, this observation raises the intriguing question as to whether metabolic syndrome is a risk factor for equine Cushing's disease."
It just could be, he suggests, that metabolic syndrome affects the horse's brain, thus impacting the pituitary gland and predisposing the horse to an onset of Cushing's disease. More research is required before a definitive answer is known.
Step number one in the treatment process, he says, involves a loss of weight. In humans, it has been found that modest weight reductions in the neighborhood of 5-10% are associated with substantial clinical improvement in many aspects of metabolic syndrome, such as decreased insulin resistance, reduced high blood pressure, and improved lipid values.
Research in ponies has shown that significant improvements in insulin resistance can be made through a combination of controlled food intake as well as increased physical exercise. However, it gets a bit more complicated if the horse is suffering from laminitis. When that is the case, says Johnson, the horse also is suffering from stress, and "stress associated with the development of laminitis leads to activation of neuroendocrinological mechanisms (such as increased cortisol secretion) that tend to further promote the persistence of insulin resistance.
"The most important aspect of feeding a horse with metabolic syndrome (especially one suffering from laminitis) is limitation of soluble carbohydrate in the diet," explains Johnson. "Simply eliminating grain products and using a hay-only diet may result in dramatic improvements in laminitis pain within the space of a few days." (For a discussion of reducing carbohydrate content of hay by soaking, see article #4777 online.)
Johnson, Messer, and Eleanor Kellon, VMD, an equine nutritional consultant based in Ephrata, Pa., have prepared a paper discussing treatment of equine metabolic syndrome. In one section, they drew on a study conducted by Ann Rodiek, MS, PhD, professor of animal science in the Department of Animal Sciences and Agricultural Education at California State University, concerning levels of glucose in certain feeds. Rodiek used a scale that rated the feedstuffs from 0 to 100--the higher the number, the more glucose.
Plain beet pulp had the lowest (best) score of 1, followed by rice bran at 22, Bermuda hay at 26, alfalfa cubes at 30, timothy hay at 32, wheat bran at 37, carrots at 51, and vetch blend hay at 53.
Here are some other suggestions on diet from Johnson, Messer, and Kellon for horses with metabolic syndrome:
- Hays fed to insulin-resistant horses should contain no more than 10% sugar and starch combined. The only way to know for sure what hay contains is through laboratory analysis.
- It is not necessarily a good thing to restrict the intake of hay. When good grass hay is being fed, it should be at the rate of about 15-20 pounds per day for a 1,000-pound horse. Horses which spend a lot of time in stalls would be fed at the lower end of the scale, while those that get turned out in a herd situation would be at the upper end.
- Grain and fruit treats of any kinds should not be fed. That includes everything from oats to apples.
- While horses suffering from metabolic syndrome usually do well on a hay-only diet, beet pulp is an excellent addition to the diet because it actually is more digestible than hay and has a caloric value that is roughly equivalent to plain oats.
- The proper intake of minerals is highly important. The intake of each individual mineral should be set at a minimum of 150% of current National Research Council (NRC) minimums. This extra intake of minerals is needed to help combat the problem rather than just maintain a proper balance.
- Long-term diets that are high in fat can worsen insulin resistance in some breeds and ponies.
- Adequate--but not excessive--protein is advisable. Grass hays containing 7.5% protein consumed at the rate of 2% of body weight per day will meet crude protein requirements.
- Free-choice access to grass should be avoided to cut down on the possibility of ingesting too much sugar.
One problem in dealing with metabolic syndrome in the past, says Johnson, is that it often was misdiagnosed as hypothyroidism. Extensive research on his part (as well as work done by Messer) has done much to change thinking concerning hypothyroidism. The two researchers maintain that horse owners have wasted millions of dollars through the years--and continue to do so--by administering hormone therapy to horses suspected of suffering from hypothyroidism.
"There is an association between obesity and low thyroid hormone levels in some other species, and some horses with metabolic syndrome have low levels of circulating thyroid hormones," Johnson says. "However, endocrinological changes associated with obesity lead to low thyroid levels, and low levels of thyroid hormone do not primarily cause obesity in (research) horses following surgical thyroidectomy (removal of the thyroid gland). The existence of bona fide primary hypothyroidism in horses is rare. The justification for exogenous thyroid hormone administration to induce weight loss in obese horses is questionable at best, and there have been no well-designed studies to determine if such supplementation is either effective or safe."
Thus ends our trek through the maze of information concerning Cushing's disease and metabolic syndrome--a malady that just might be a contributing factor in the development of Cushing's. Much has been learned by scientists, but much more needs to be learned.
The take-home message for horse owners on the prevention front is simple and straightforward. It is highly important to develop a feeding program on a horse-by-horse basis. Know what you are feeding, and learn the requirements of each horse being fed to prevent the onset of obesity. Your veterinarian or a nutritionist can provide you with the basic information you need, and your county extension agent can tell you where to get feedstuffs tested.
About the Author
Les Sellnow is a free-lance writer based near Riverton, Wyo. He specializes in articles on equine research, and operates a ranch where he raises horses and livestock. He has authored several fiction and non-fiction books, including Understanding Equine Lameness and Understanding The Young Horse, published by Eclipse Press and available at www.exclusivelyequine.com or by calling 800/582-5604.
POLL: University Equine Hospitals