Pathogenesis and diagnosis of equine Cushing's disease (Proceedings)


Pathogenesis and diagnosis of equine Cushing's disease (Proceedings)

Apr 01, 2010

Figure 1. Pituitary pars intermedia dysfunction (PPID) affects equids of all sizes and breeds although it may be more common in ponies (image courtesy of Dr. J. H. van der Kolk, Utrecht, Netherlands).
Although the frequency of diagnosis and treatment of pituitary pars intermedia dysfunction (PPID) in horses has clearly increased over the past decade, there is no evidence that the prevalence of PPID is actually increasing. Increased recognition of the disease is likely a consequence of clients maintaining their horses to more advanced ages as well as improved health care (e.g., diet and dentistry) being provided to older horses. A recent survey of horse owners in Queensland, Australia revealed a prevalence of 15-20% of PPID in horses and ponies 15 years of age and older. There is no gender predilection and average age of affected horses is around 20 years. All breeds and types of equids can be affected with PPID but Morgan horses and ponies appear to be at greater risk (Figure 1).


In humans and dogs, Cushing's disease is most commonly attributed to a corticotroph adenoma in the pars distalis of the pituitary gland. These adenomas are thought to arise spontaneously. In contrast, Cushing's disease in horses is almost exclusively attributed to hyperplasia or adenoma formation in the pars intermedia that appears to be due to loss of hypothalamic innervation. Abnormal pars intermedia tissue in horses contains markedly reduced amounts of dopamine, about 10% that of normal pars intermedia tissue, consistent with a specific loss of hypothalamic dopaminergic innervation. Recent evidence suggests that this loss of dopaminergic innervation is due to oxidant-induced injury to hypothalamic tissue. Thus, a risk factor for affected horses may be reduced anti-oxidant defense mechanisms in neural tissue. Further, insoluble aggregates of the neural protein α-synuclein have been found in dopaminergic nerve terminals of PPID-affected horses. These protein aggregates are also found in humans with Parkinson's disease suggesting that the two neurodegenerative disorders may share a similar pathogenesis. However, the population of neurons affected in horses, as compared to humans, appears to be somewhat different leading to the difference in clinical signs observed in each species.

Abnormal pars intermedia cells produce excessive amounts of pro-opiomelanocortin (POMC) and a number of POMC-derived peptides including adrenocoticotropin (ACTH). Also unlike Cushing's disease in humans and dogs, adrenocortical hyperplasia accompanying equine Cushing's disease is relatively uncommon, occurring in ~20% of affected horses. These differences in location and pathophysiology between human, canine, and equine pituitary adenomas have lead several authors to suggest that the disease in horses should not be called equine Cushing's disease; rather, pituitary pars intermedia dysfunction (PPID) has been advanced as a more appropriate descriptor.

Clinical signs

Figure 2. Hirsutism with coat color change (left), supraorbital fat deposition (middle), and unilateral nasal discharge due to sinusitis (right) are some of the clinical findings in horses with PPID.
The classic clinical sign of PPID in horses is hirsutism, a long and curly hair coat that fails to shed. In some affected horses, coat color changes have also been observed (Figure 2, left). The pathogenesis of hirsutism, which is characterized by arrest of hair follicles in telogen, remains unclear. Hyperhidrosis is also observed in up to two-thirds of horses with PIPD, most commonly over the neck and shoulder areas, and has been attributed to a thermoregulatory response to the long hair coat. Weight loss and lethargy, or poor performance, are also commonly observed in horses with PPID. In addition to true weight loss, protein catabolism due to increased cortisol activity leads to loss of muscle mass. This is most notable in advanced cases as a loss of epaxial and rump musculature. Despite weight loss, appetite in affected horses is normal or even increased (polyphagia). However, dental abnormalities, leading to painful mastication and quidding, may compromise feed intake and contribute to weight loss in some horses. Combined with, or often preceding, loss of muscle mass is deposition of fat along the crest of the neck, over the tail head, and in the sheath of male horses. Another area where abnormal fat deposition may occur is above and behind the eyes (supraorbital area, Figure 2, center). Horses with PPID have also been described as overly docile and more tolerant of pain than normal horses. The latter signs have been attributed to increased plasma and cerebrospinal fluid concentrations of β-endorphin that are 60- and more than 100-fold greater, respectively, in horses with PPID than in normal horses.

Chronic, insidious-onset laminitis is perhaps the major clinical complication of PPID with more than 50% of horses affected in most reports. Although the condition is more amenable to management in ponies due to their lower body weight, chronic or recurrent pain with exacerbation of laminitis or associated foot abscesses is often the reason for euthanasia. Polydipsia and polyuria (PU/PD) develops in about one-third of horses with PPID. Equids with PPID tend to have delayed wound healing and are frequently affected with secondary infections. Commonly recognized infections include skin infections (e.g., refractory "scratches" and fistulous tracts), recurrent subsolar abscesses, conjunctivitis, sinusitis (Figure 2, right), gingivitis, alveolar periostitis, and bronchopneumonia.

Other signs that have been reported in horses with PPID include persistent mammary secretions and infertility. Central nervous system (CNS) dysfunction, including ataxia, blindness, and seizure-like activity, are occasionally observed in equids with PPID. A major complication of hypercortisolism in affected human patients is osteoporosis. Although occurrence of this complication has not been investigated in horses, it is interesting to note that euthanasia of horses with PPID has been reported due to development of pelvic, pedal bone, mandibular, and multiple rib fractures.