How to Differentiate and Diagnose Pituitary Pars Intermedia Dysfunction and Equine Metabolic Syndrome

1. Introduction

Pituitary pars intermedia dysfunction (PPID; equine Cushing’s disease) and equine metabolic syndrome (EMS) are by far the most common equine endocrine disorders, affecting up to 30% of some breeds of horses and ponies during the course of their lifetimes.^1–3  PPID and EMS are distinct diseases with different pathophysiology that typically require different therapeutic approaches. PPID results in dysregulation of the hypothalamic-pituitary-adrenal (HPA axis) due to increased activity of the pars intermedia of the anterior pituitary gland resulting in overproduction of adrenocorticotropic hormone (ACTH) and other related hormones. Progressive loss of dopamine-producing neurons in the hypothalamus with aging in some animals results in loss of dopamine-mediated inhibition of the pars intermedia, leading to hyperactivity, hyperplasia, or a functional adenoma of this portion of the pituitary gland. Specific mechanisms that cause this dopaminergic neuron loss in the hypothalamus are not well characterized, but long-term, low-grade oxidative injury may play a role and helps explain why PPID is a disease of older horses and ponies.²  Persistently increased ACTH concentrations theoretically should increase adrenal activity in horses and ponies with PPID, and some clinical features of equine PPID are often attributed to increases in cortisol levels or activity. However, increased circulating total cortisol is not a typical finding in horses and ponies with PPID, suggesting that other noncortisol-mediated hormonal pathways may play a role in the clinical features of PPID.

In contrast, whereas the pathophysiology of EMS is poorly understood, it is clear that it does not result from primary HPA axis or thyroid gland dysfunction. EMS seems to be at least in part an adipose-derived endocrinopathy, in which abnormal or excessive adipose tissue produces a hormonal and/or inflammatory environment that alters insulin responses to feeding and the activity of insulin in peripheral tissues.^1,4 Hyperinsulinemia and exaggerated insulin responses to feeding is a key aspect of EMS pathophysiology.^1,4

However, despite their different underlying pathophysiology, these two diseases share several common clinical features. Most importantly, acute or chronic laminitis—often seasonal or pasture associated—is a common and typical presentation for both PPID and EMS, and the development of laminitis seems to be associated with underlying insulin dysregulation in both diseases.^1,2 Because of the potential career- and even life-ending effects of laminitis, and the distinct therapeutic strategies necessary to control PPID and EMS, accurate diagnosis of one or both of these disorders in affected animals is paramount to successful management of these disorders.

A number of different diagnostic strategies for PPID and EMS have been assessed in recent years. Although a single perfect test to diagnose and differentiate these disorders is not yet available, using a combination of clinical features, measurement of basal concentrations of several hormones, and dynamic tests to measure endocrine responses to various stimuli, can permit accurate diagnosis of PPID and EMS in most animals. This session will summarize currently recommended diagnostic strategies for differentiating PPID and EMS in horses and ponies.

2. Materials and Methods

The recent literature on diagnostic evaluation for PPID and EMS was reviewed to determine current and practical recommendations for field and in-hospital testing for these disorders. The first, and arguably the most important, step in the diagnosis of PPID and EMS is the clinical evaluation of the patient to detect typical clinical signs. In some cases, clinical findings alone are enough to make a diagnosis of one or both diseases. However, in most cases, to distinguish between and definitively diagnose these two disorders, and to assess response to therapy, further hormonal testing—including screening tests to measure resting hormone concentrations and/or dynamic testing to measure hormonal responses to specific stimuli—is necessary. These tests are discussed in detail below and summarized in Table 1.

Clinical Findings

Typical clinical features of classic presentations for PPID and EMS and predisposed breeds are outlined in Table 2. The classic presentation of PPID is an older animal (usually late teens or older) that presents with pasture-associated or seasonal laminitis, generalized muscle wasting/weight loss, and hair coat abnormalities (delayed, incomplete, or absent shedding). In fact, the clinical sign of failure to shed (typically called hirsutism, but more appropriately termed hypertrichosis) is a more sensitive and specific test for late-stage PPID than any hormonal assay studied to date.² In contrast, the classic presentation for EMS is also an animal that presents with pasture-associated laminitis, but in contrast this is a younger-to-middle-aged animal with a normal hair coat that has always been an easy keeper and is clearly obese with obvious fat deposits in the crest of the neck and tail-head.¹

However, these classic presentations are most helpful in horses with rather advanced stages of either disease; in early-stage disease, the only clinical sign of PPID or EMS might be an episode of acute pasture-associated laminitis in a middle-aged animal. Further, both diseases can have atypical presentations, so testing for PPID and EMS should be considered in animals with unexplained laminitis even if no other typical clinical signs are present. In addition, it is important to note that PPID and EMS can occur concurrently, so individual animals might present with signs consistent with both diseases. Thus, unless the laminitic animal is very young and very obese (consistent with EMS) or very old, muscle-wasted, and completely fails to shed out (most consistent with PPID), hormonal testing should be performed to differentiate between these two diseases.

Screening Tests—Measurement of Resting Hormone Concentrations

The simplest approach to hormonal testing to screen for PPID and EMS in suspect cases is measurement of resting hormone concentrations. This can easily be performed in the field, and thus is not typically subject to confounding by stress or transport effects.

PPID Screening

At present, the best commercially available screening test for PPID is measurement of plasma adrenocorticotropic hormone (ACTH) concentration. Measurement of other hormones, such as plasma cortisol or insulin concentration, are not as sensitive or specific for diagnosis of PPID as measurement of ACTH. Measurement of another anterior pituitary hormone, α-melanocyte stimulating hormone (α-MSH) is also a good test for PPID diagnosis, but at present this test is only available in a research setting.

To screen for PPID by measurement of resting plasma ACTH concentration, blood may be collected at any time of day and the animal does not need to be fasted. However, extreme excitement, transport, illness, and routine change can transiently increase ACTH concentrations, so testing under these circumstances should be avoided. The sample should be collected into a plastic tube with EDTA as an anti-coagulant given that glass seems to falsely lower ACTH concentrations.⁵ ACTH is very labile at room temperature, so the sample should be refrigerated or placed on ice immediately after collection. For accurate results, the sample must be centrifuged to separate the plasma as soon as possible after collection (within 4 h), and only the plasma should be submitted for analysis (ideally in a plastic vial). It is imperative that the plasma remain cold on arrival at the testing laboratory: this can be ensured by either 1) freezing the sample and shipping it overnight on dry ice, or 2) freezing the sample and shipping it overnight with several frozen ice packs in a styrofoam shipping cooler. [...]