Pituitary pars intermedia dysfunction

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Pituitary pars intermedia dysfunction (PPID), or equine Cushing's disease, is an endocrine disease affecting the pituitary gland of horses. It is most commonly seen in older animals,[1] and is classically associated with the formation of a long, wavy coat (hirsutism) and chronic laminitis.

Cushing's disease commonly causes hirsutism, muscle wasting along the top line, and abnormal fat distribution.

Pathophysiology

Unlike the human and canine forms of Cushing's disease, which most commonly affect the pars distalis region of the pituitary gland, equine Cushing's disease is a result of hyperplasia or adenoma formation in the pars intermedia.[2] This adenoma then secretes excessive amounts of normal products, leading to clinical signs.

Dopaminergic control of the pars intermedia

The pituitary gland consists of three parts: the pars nervosa, the pars intermedia, and the pars distalis. The most critical structure to PPID, the pars intermedia, is regulated by the hypothalamus. The neurons of the hypothalamus innervate cells known as melanotropes within the pars intermedia, releasing dopamine which then binds to dopamine receptors on the melanotropes. Activation of these dopamine receptors leads to the inhibition of proopiomelanocortin (POMC) production from these cells.[1]

In PPID-affected horses, dopamine is not produced from these neurons, leading to dopamine levels about 10% of the level normally found in the pars intermedia.[2] This is thought to be due to neurodegeneration of the neurons, secondary to free radical formation and oxidative stress.[3] Without regulation from dopamine, the pars intermedia develops hyperplasia and adenoma formation, leading to gross enlargement and excessive production of POMC. These adenomas also have the potential to compress the hypothalamus and optic chiasm.[1][2]

POMC

POMC produced from the melanotropes of the pars intermedia is cleaved into adrenocorticotropic hormone (ACTH) and β-lipotropin (β-LPH). The majority of ACTH[1] is then cleaved into α-MSH and corticotropin-like intermediate peptide (CLIP). CLIP is thought to have an influence on subsequent insulin resistance that can be seen in PPID horses.[4]

ACTH is also produced by corticotropes in the pars distalis of the equine pituitary. In a normal horse, this accounts for the majority of ACTH production. ACTH produced by the pars distalis is subject to negative feedback in a normal horse, so high cortisol levels reduce ACTH production by the pituitary, subsequently reducing cortisol levels. In a horse with PPID, ACTH levels are high as a result of pars intermedia production, but it is not subject to negative feedback regulation. Despite the high levels of ACTH, cortisol levels vary, and are sometimes lower than normal. Additionally, hyperplasia of the adrenal cortex is infrequent.[1] The role of ACTH is, therefore, still poorly understood.

Age and breed prevalence

PPID has been diagnosed in horses as young as 7 years old,[1] although most horses are first diagnosed at ages 19 to 20.[1] An estimated 21% of horses older than 15 years have PPID.[5] All breeds may develop PPID, but pony breeds and Morgans seem to be more commonly affected.[1][6][7]

Clinical signs

Many signs are associated with PPID, but only a subset of these is displayed in any single horse. Some horses may present with chronic laminitis without other overt signs of the disease.[1]

Laboratory findings

Complete blood counts and serum chemistry profiles may be normal in affected horses.[9] Persistent hyperglycemia and glucosuria are very commonly seen.[1] Hyperlipidemia may be present, especially in ponies.[1] Other abnormalities associated with the disease include mild anemia, neurophilia, lymphopenia, eosinopenia, and increased liver enzymes.[2]

Differentiating from equine metabolic syndrome

PPID shares similarities to equine metabolic syndrome (EMS), which also causes regional adiposity, laminitis, and insulin resistance. Treatment and management may differ between the two endocrinopathies, making differentiation important. Importantly, though, horses with EMS may develop PPID, so both diseases may occur simultaneously.[12]

EMS vs PPID
EMS PPID
Age of Onset 5-15 years 15+ years
Clinical signs Resistance to weight loss Hirsutism, increased drinking and urination, muscle atrophy
Serum ACTH levels Normal Elevated

Diagnosis

Plasma ACTH concentration

This test may also be referred to as a ‘’resting ACTH’’, ’’endogenous ACTH’’, or ‘’basal ACTH’’. The majority of ACTH produced in normal horses comes from corticotrope cells in the pars distalis, with only 2% thought to come from melanotropes in the pars intermedia. In horses with PPID, melanotropes produce abnormally high concentrations of ACTH.[8] Basal plasma ACTH concentrations, which measure the blood levels of circulating ACTH, can therefore be useful in diagnosing the disease.[13]

ACTH levels naturally fluctuate in healthy horses, with a significant rise occurring the in autumn (August through October) in North American horses. Horses with PPID have a similar, but much more significant, rise in the autumn. Therefore, a seasonally adjusted reference range must be used that correlates with the time of year the sample is taken.[8] Failure to use a seasonally adjusted reference range may lead to false-positive results in normal horses if they are sampled in the fall.[13] Autumnal testing was thought to be more sensitive and specific than testing at other times of the year; however, this concept has been recently challenged.[5][13] Basal plasma ACTH levels may increase if the horse is severely ill or under great stress or pain, such as if it has laminitis. However, such events must be fairly significant to confound the results.[8] Additionally, ACTH levels may not be significantly increased early on in the disease, leading to false negatives.[14]

Thyrotropin-releasing hormone stimulation test

Thyrotropin-releasing hormone (TRH) receptors are present in both the melanotropes of the pars intermedia and the corticotropes in the pars distalis. The administration of exogenous TRH causes an increase in ACTH and α-MSH in plasma of both normal horses and those with PPID. In both cases, plasma ACTH peaks 2–10 minutes after administration, before slowly dropping to normal levels over the course of an hour. PPID horses, however, show a much greater peak than normal horses, especially in the autumn.[8] The test is relatively simple, involving one blood sample taken before TRH administration, and one 10 minutes or 30 minutes following TRH.[14][13]

TRH is currently not licensed for use in horses, and can cause various side effects, including yawning, flehmen, muscle trembling, and coughing.[15] This test is thought to have greater sensitivity than other tests, but has drawbacks including cost, TRH availability, limited repeatability and lack of defined seasonal reference intervals.[8][13][16] Due to a lack of seasonal references, it is only recommended for use from December until June.[14]

Dexamethasone suppression test

The dexamethasone suppression test involves administering dexamethasone, a synthetic glucocorticoid, to the horse, and measuring its serum cortisol levels before and 19–24 hours after injection. In a normal horse, dexamethasone administration results in negative feedback to the pituitary, resulting in decreased ACTH production from the pars distalis and, therefore, decreased synthesis of cortisol at the level of the adrenal gland. A horse with PPID, which has an overactive pars intermedia not regulated by glucocorticoid levels, does not suppress ACTH production and, therefore, cortisol levels remain high. False negatives can occur in early disease.[1] Additionally, dexamethasone administration may increase the risk of laminitis in horses already prone to the disease.[8] For these reasons, the dexamethasone suppression test is currently not recommended for PPID testing.

Urinary corticoid-to-creatinine ratio

Although corticoid-to-creatinine ratios are generally higher in horses with PPID, numerous false positives and false negatives occur with this test, so it is not recommended.[1]

Plasma cortisol concentration

Resting plasma cortisol may be slightly elevated in affected horses, but is commonly within normal limits or below normal. Additionally, elevations may occur secondary to stress, concurrent disease, and due to individual variation. Therefore, resting cortisol levels alone are not adequate to diagnose or rule out the presence of PPID.[2]

Current recommendations for testing

As of 2013, horses suspected of having PPID should undergo testing both for the disease and for insulin dysfunction (see below). Horses showing obvious signs of PPID will likely have a positive endogenous ACTH test. Horses with early disease may produce a false-negative result. In these horses, the thyrotropin-releasing hormone stimulation test should either be used as an initial screening test, or to confirm a false resting ACTH.[14]

Insulin dysregulation

Insulin dysregulation is commonly seen in horses with PPID or equine metabolic syndrome. It is of interest primarily because of its link to laminitis. Horses with ID will have an increased insulin response after they are given oral sugars, which will cause a subsequent rise in blood insulin levels, or hyperinsulinemia. Hyperinsulinemia results in decreased tissue sensitivity to insulin, or insulin resistance especially by the skeletal muscle, liver and adipose tissue. Tissue insulin resistance causes increased insulin secretion, which perpetuates the cycle.[4]

The trigger to insulin resistance is not fully understood. Genetics is likely to have some impact on the risk of postprandial hyperinsulinemia. Obesity, pregnancy, PPID, and inflammatory states may contribute to tissue insulin resistance. PPID is thought to result in increased insulin secretion due to higher levels of CLIP produced by melanotrophs, and to cause insulin resistance secondary to hyperadrenocorticism.[4]

Testing for insulin dysregulation

Due to the strong link between PPID and insulin resistance, testing is recommended for all horses suspected or confirmed to be suffering from PPID. There are two tests commonly used for insulin resistance: the oral sugar test and fasting insulin blood concentration.[17]

The fasting insulin concentration involves giving a horse a single flake of hay at 10 pm the night before testing, with blood being drawn the following morning. Both insulin and glucose blood levels are measured. Hyperinsulinemia suggests insulin resistance, but normal or low fasting insulin does not rule out PPID. This test is easy to perform, but is less sensitive than the oral sugar test.[14] It is best used in cases where risks of laminitis make the oral sugar test potentially unsafe.[18]

The oral sugar test also requires giving the horse only a single flake of hay at 10pm the night before the test. The following morning, karo corn syrup is given orally, and glucose and insulin levels are measured at 60 and 90 minutes after administration. Normal or excessively high insulin levels are diagnostic. However, equivocal test results require retesting at a later date, or performing a different test.[14] A similar test is available outside the US, in areas where corn-syrup products are less readily available, where horses are given a morning meal of chaff with dextrose powder, and blood insulin levels are measured 2 hours later.[18]

Management of insulin resistance

The main methods of management involve exercise and diet change, in addition to treatment of PPID. The primary goal is reduction of weight in an obese animal. Diet changes include limiting pasture access and reducing or eliminating grain. Obese animals are often best maintained on a diet consisting of ration balancer and hay, fed at 1.5% body weight and decreased if needed.[18] Feed should be selected based on low nonstructural carbohydrate (NSC) levels. Hay NSC levels may be reduced by soaking it in cold water for 30 minutes.[18]

Exercise is increased in nonlaminitic horses. Animals resistant to weight loss, despite diet and exercise changes, can be placed on levothyroxine to increase metabolism. Metformin can also be used to reduce glucose absorption through the intestinal tract.[18]

Treatment

The primary treatment of PPID is pergolide, a dopamine agonist that provides suppression to the pars intermedia in place of the dysfunctional hypothalamus. Horses should be reassessed in 30 days following the start of treatment, through evaluation of clinical signs and by baseline diagnostic testing, to ensure the appropriate dose is being prescribed. Results from that test dictate changes in dose. Horses that are responding to treatment should be retested every 6 months, including a test in the autumn when a seasonal increase in ACTH occurs, to ensure their ACTH levels are appropriately suppressed during this time. Drug side effects include a transient decrease in appetite, which can be reduced by slowly increasing the dose to therapeutic levels, and by breaking up the daily dose into twice-daily administrations.[14]

Attitude, activity levels, hyperglycemia, and increased drinking and urination are usually improved within 30 days of initiating treatment. Other clinical signs, such as hirsutism, potbellied appearance, muscle wasting, laminitic episodes, and increased predisposition to infection, usually take between 30 days and a year to improve.[14]

Cyproheptadine may be added to the treatment regimen in horses that are inadequately responding to pergolide,[14] but is usually only used in horses with advanced PPID on high doses of pergolide.[18]

See also

References

  1. ^ a b c d e f g h i j k l m n o p q r s Reed SM, Bayly WM, Sellon DC (2010). Equine Internal Medicine (3rd ed.). St. Louis, MO: Saunders/Elsevier. ISBN 978-1416056706.
  2. ^ a b c d e f g h i Robinson E (2003). Current Therapy in Equine Medicine (5th ed.). Elsevier. pp. 807–811. ISBN 978-0-7216-9540-2.
  3. ^ McFarlane D, Dybdal N, Donaldson MT, Miller L, Cribb AE (February 2005). "Nitration and increased alpha-synuclein expression associated with dopaminergic neurodegeneration in equine pituitary pars intermedia dysfunction". Journal of Neuroendocrinology. 17 (2): 73–80. doi:10.1111/j.1365-2826.2005.01277.x. PMID 15796757. S2CID 39443723.
  4. ^ a b c Frank N, Tadros EM (January 2014). "Insulin dysregulation". Equine Veterinary Journal. 46 (1): 103–112. doi:10.1111/evj.12169. PMID 24033478.
  5. ^ a b c d McGowan TW, Pinchbeck GP, McGowan CM (January 2013). "Evaluation of basal plasma α-melanocyte-stimulating hormone and adrenocorticotrophic hormone concentrations for the diagnosis of pituitary pars intermedia dysfunction from a population of aged horses". Equine Veterinary Journal. 45 (1): 66–73. doi:10.1111/j.2042-3306.2012.00575.x. PMID 22563728.
  6. ^ a b c d e f g McGowan TW, Pinchbeck GP, McGowan CM (January 2013). "Prevalence, risk factors and clinical signs predictive for equine pituitary pars intermedia dysfunction in aged horses". Equine Veterinary Journal. 45 (1): 74–9. doi:10.1111/j.2042-3306.2012.00578.x. PMID 22594955.
  7. ^ Miller MA, Moore GE, Bertin FR, Kritchevsky JE (March 2016). "What's New in Old Horses? Postmortem Diagnoses in Mature and Aged Equids". Veterinary Pathology. 53 (2): 390–398. doi:10.1177/0300985815608674. PMID 26459516. S2CID 1596503.
  8. ^ a b c d e f g Durham AE, McGowan CM, Fey K, Tamzali Y, Van der Kolk JH (April 2014). "Pituitary pars intermedia dysfunction: diagnosis and treatment". Equine Veterinary Education. 26 (4): 216–223. doi:10.1111/eve.12160.
  9. ^ a b c d Horn R, Bamford NJ, Afonso T, Sutherland M, Buckerfield J, Tan RH, et al. (July 2019). "Factors associated with survival, laminitis and insulin dysregulation in horses diagnosed with equine pituitary pars intermedia dysfunction". Equine Veterinary Journal. 51 (4): 440–445. doi:10.1111/evj.13041. hdl:11343/284846. PMID 30417404. S2CID 53282993.
  10. ^ a b McFarlane D (April 2011). "Equine pituitary pars intermedia dysfunction". The Veterinary Clinics of North America. Equine Practice. 27 (1): 93–113. doi:10.1016/j.cveq.2010.12.007. PMID 21392656.
  11. ^ Hofberger S, Gauff F, Licka T (March 2015). "Suspensory ligament degeneration associated with pituitary pars intermedia dysfunction in horses". Veterinary Journal. 203 (3): 348–350. doi:10.1016/j.tvjl.2014.12.037. PMID 25641552.
  12. ^ Frank N, Geor RJ, Bailey SR, Durham AE, Johnson PJ (May 2010). "Equine metabolic syndrome". Journal of Veterinary Internal Medicine. 24 (3): 467–475. doi:10.1111/j.1939-1676.2010.0503.x. PMID 20384947.
  13. ^ a b c d e Horn R, Stewart AJ, Jackson KV, Dryburgh EL, Medina-Torres CE, Bertin FR (January 2021). "Clinical implications of using adrenocorticotropic hormone diagnostic cutoffs or reference intervals to diagnose pituitary pars intermedia dysfunction in mature horses". Journal of Veterinary Internal Medicine. 35 (1): 560–570. doi:10.1111/jvim.16017. PMC 7848300. PMID 33368633.
  14. ^ a b c d e f g h i Frank N, Andrews F, Durham A, Kritchevsky J, McFarlane D, Schott H, et al. (PPID Working Group) (2015). Recommendations for the diagnosis and treatment of pituitary pars intermedia dysfunction (PPID) (PDF). Equine Endocrinology Group. pp. 4–5. Archived from the original (PDF) on 22 May 2020.
  15. ^ Beech J, Boston R, Lindborg S, Russell GE (August 2007). "Adrenocorticotropin concentration following administration of thyrotropin-releasing hormone in healthy horses and those with pituitary pars intermedia dysfunction and pituitary gland hyperplasia". Journal of the American Veterinary Medical Association. 231 (3): 417–26. doi:10.2460/javma.231.3.417. PMID 17669045.
  16. ^ Kam YN, McKenzie K, Coyle M, Bertin FR (October 2021). "Repeatability of a thyrotropin-releasing hormone stimulation test for diagnosis of pituitary pars intermedia dysfunction in mature horses". Journal of Veterinary Internal Medicine. 35 (6): 2885–2890. doi:10.1111/jvim.16281. PMC 8692209. PMID 34642962. S2CID 238747245.
  17. ^ Bertin FR, de Laat MA (September 2017). "The diagnosis of equine insulin dysregulation" (PDF). Equine Veterinary Journal. 49 (5): 570–576. doi:10.1111/evj.12703. PMID 28543410. S2CID 39553871.
  18. ^ a b c d e f Frank N, Geor R (January 2014). "Current best practice in clinical management of equine endocrine patients". Equine Veterinary Education. 26 (1): 6–9. doi:10.1111/eve.12130.
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