Obesity, Laminitis, & Hypothyroidism in Your Horse
A Peripheral Cushingoid Syndrome
Leah C. Gray, DVM, diplomate ACVIM

PRAIRIE EQUINE HOSPITAL, PLLC
920 West Prairie Ave., Coeur d'Alene, ID 83858
208-762-0930 • Fax: 208-772-3386

These notes have been taken from the bluegrass equine medicine and critical care symposium in Lexington, KY.

The well-recognized syndrome of sedentary, mature horses in conjunction with the development of obesity has been described as "obesity associated laminitis." The characteristic distribution of body fat in these horses typically involves the neck and rump. Horse owners report that it is very difficult to reduce the weight of these horses by dietary restriction alone. Affected brood mares exhibit abnormal estrus cycling and are notoriously difficult to breed. Affected geldings often develop a swollen sheath. The syndrome has too often been attributed to disorders of thyroid metabolism, i.e. Hypothyroidism. It is clear that this combination of laminitis and obesity are not manifestations of insufficient thyroid production. Although lowered circulating thyroid hormones (T3 and T4) may sometimes be demonstrated in these horses, appropriate diagnostic testing, including a thyroid stimulation test, fails to support the diagnosis of hypothyroidism. Furthermore, following surgical removal of the thyroid glands in experimental situations, the clinical manifestations of true hypothyroidism in the horse included neither laminitis nor obesity.

Glucocorticoids have been implicated in the pathogenesis of laminitis. There is evidence to implicate a role for glucocorticoid steroids in the development of equine laminitis. For many years, it has been recognized that laminitis is a common and unfortunate complication of the therapeutic administration of specific glucocorticoids, especially dexamethasone and triamcinolone. Cushing's syndrome is the name used to represent the clinical effects of enhanced glucocorticoid action on the body. Although Cushing's syndrome in horses has been associated with both the exogenous administration of potent glucocorticoids and with endogenous glucocorticoid substances (i.e. pituitary gland tumor), there are five other potential mechanisms by which increased glucocorticoid effect could be explained. To better understand this concept, it is necessary to understand how cortisol is handled in the body.

Glucocorticoids are normally produced by the body in a strictly regulated fashion. Cortisol is an essential hormone, which is critical for the healthy homeostatic state. Cortisol is produced by the adrenal glands. The horse has two adrenal glands that are located near each of the two kidneys. The amount of cortisol released by the adrenal glands is affected by another hormone released by the pituitary gland, ACTH. The pituitary gland is located at the base of the brain close to the hypothalamus and it is important for the production and release of numerous hormones that govern the metabolism of different systems throughout the body. The release of hormones from the pituitary gland is regulated by other hormones produced by the hypothalamus. This network is called the hypothalamic-pituitary-adrenal axis. It can be seen that excessive cortisol production from the adrenal glands could be associated with adrenal gland disease, excessive ACTH release from the pituitary, or abnormal production by the hypothalamus. In fact, classic Cushing's syndrome in horses is virtually always associated with a pituitary gland tumor in which the adrenal glands are stimulated to secrete excessive cortisol as a consequence of increased ACTH effect.

Classic Cushing's syndrome is associated with a pituitary gland tumor in horses. The clinical signs of Cushing's syndrome have been well described in the horse. When presented to veterinarians, most horses affected with typical Cushing's syndrome are relatively older and can be recognized by the presence of specific clinical signs: laminitis, weight loss (or abnormal distribution of body fat), excessive drinking and urination, and a long hair coat that fails to shed out. Other clinical signs may include infertility, predisposition to infections (cortisol interferes with the immune system), increased appetite, and abnormal distribution of body fat.

In order to confirm the diagnosis of Cushing's disease, it is necessary to perform specific hormone tests. Although the manifestations of Cushing's syndrome are attributed to excessive production of cortisol by the adrenal glands, the level of cortisol in the blood is so variable at different times of the day (circadian rhythm) that it is not possible to differentiate between a normal horse and a horse affected by Cushing's syndrome simply by measuring blood cortisol concentration. The presence of a pituitary tumor may be confirmed by simply measuring the ACTH concentration in blood, but this test is not widely available and special precautions are needed to transport the sample because ACTH is not stable.

The most widely used test for classic equine Cushing's syndrome (associated with a pituitary tumor) is the dexamethasone suppression test (DST). In this test, the effect of dexamethasone on the blood cortisol concentration is determined. Dexamethasone blocks ACTH secretion by the healthy pituitary gland and causes a marked reduction in circulating cortisol. However, dexamethasone is not able to block ACTH production by the pituitary tumor and therefore does not "suppress" blood cortisol levels in the horses affected with classic Cushing's syndrome. High cortisol levels interfere with the action of insulin. Insulin is a hormone produced by the pancreas, which is important for the tissues of the body to be able to use glucose. Insulin levels are also elevated in equine Cushing's syndrome; some veterinarians measure insulin to support the diagnosis.

Cortisol concentration is also controlled locally in the tissues of the body. Cortisol exerts its effect on cell function by entering the cell and interacting with a receptor. The concentration of cortisol within the cell is very important for the normal function of the cell. An enzyme called 11-beta hydroxysteroid dehydrogenase (HSD) is responsible for maintaining local cortisol concentration within optimal satisfactory limits. HSD has both the ability to convert cortisol to the inactive metabolite, cortisone, and when needed, to convert cortisone into active cortisol. In the healthy state, the concentration of cortisol within the cell is adjusted by the cell itself (by virtue of HSD) to meet the requirements of the cell at any given time. The local cellular concentration of cortisol can be modified in a manner independent of the level of cortisol in the circulation.

A novel cause of Cushing's syndrome has been attributed to abnormal HSD activity in the cells. It has recently been shown in human beings that, when cellular cortisol concentration is increased as a consequence of perturbed local regulation by abnormal HSD activity, affected people develop symptoms that are similar to Cushing's syndrome. Increased HSD activity in the cells leads to increased cortisol at the tissue level. The peripheral tissues become a novel source of increased cortisol production to an extent that the typical signs of Cushing's syndrome are observed. This special category of Cushing's syndrome in human beings is an important cause of central obesity and has been called "omental Cushing's syndrome." In these affected people, body fat redistribution occurs which resembles classic Cushing's syndrome. Diagnostic tests for abnormalities of either the pituitary gland or the adrenal glands are normal. Cortisol production throughout a 24-hour period is increased. Insulin levels are also increased in these patients as a consequence of increased cortisol production. Cellular HSD is also increased.

Is Obesity Associated Laminitis a manifestation of abnormal HSD activity in the peripheral tissues of affected horses? Dr. Philip Johnson at the University of Missouri at Columbia developed a test for HSD in the tissues of horses and looked at the level of HSD in the skin and in the hoof tissues of normal healthy adult horses and compared it with the level found in horses that have developed laminitis. He demonstrated that HSD could be identified both in the skin and hoof tissues and that the level of HSD was markedly increased in the tissues obtained from laminitic horses. Not only was the level of HSD increased during laminitis, but the level of the form of HSD responsible for converting the inactive cortisone to active cortisol was predominantly increased. These results suggested that elevated cortisol production by peripheral tissues could play a role in certain types of laminitis in horses.

There has been speculation that increased cortisol generation by abnormally elevated peripheral tissue HSD could be responsible for the clinical appearance of obesity associated laminitis in horses. Horses with obesity associated laminitis and people with "central obesity" both tend to have increased blood pressures and insulin resistance. Blood lipid levels are typically elevated in both groups. Other abnormalities that appear to be common to both groups include reduced fertility, difficulty with losing weight, and an abnormal distribution of fat stores. Affected horses commonly accumulate fat in the crest of the neck, at the top of the gluteal area, and in the sheath of male horses. Of further interest is the observation that lowered circulating thyroid hormone levels are often demonstrated in horses affected with obesity associated laminitis; elevated cortisol production can lead to inhibition of the thyroid gland stimulating hormone that is responsible for maintaining thyroid hormone production by the thyroid gland. Remember, however, as mentioned previously, horses that have had their thyroid glands surgically removed under experimental conditions did not show classic signs of hypothyroidism.

If you were not already confused by the previous hypotheses supporting the pathogenesis of laminitis, you probably are now with this milieu of endocrinology. Laminitis is not a difficult diagnosis to make. However, managing a severe case is one of the most challenging endeavors for veterinarians and farriers alike. Thyroid supplementation may be warranted in these cases, not to replenish inadequate stores of circulating thyroid hormones, but to modify cellular metabolism at the tissue level.

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