Equine - Endocrine/Metabolic Dz Flashcards
Describe the divisions of the pituitary gland in the horse.
- Two embryologically distinct portions: adenohypophysis and neurohypophysis.
- Adenohypophysis can be divided into 3:
- Pars distalis: 5 endocrine cell types; releases GH, LH, FSH, ACTH, PRL, TSH.
- Pars tuberalis: rich in melatonin receptors; regulates repro seasonality.
- Pars intermedia: melanotropes and dopaminergic neurons; secretes POMC –> CLIP, B-end, a-MSH, ACTH.
- Neurohypophysis:
- Pars nervosa: nervous tissue originates from hypothalamus; secrete oxytocin and vasopressin.
Describe the physiology and anatomy of the Pituitary Pars Intermedia in horses.
- Incorporates tissue from the adenohypophysis and neurohypophysis.
- Single endocrine cell type: melanotropes.
- Innervation: nerve terminals of the hypothalamic periventricular dopaminergic neurons.
- Dopamine released from nerve terminals interacts with D2 receptors on adj melanotropes –> inhibits cell proliferation, transcription of proopiomelanocortin (POMC) and release of POMC-derived particles.
- Melanotropes are positively regulated by thyrotropin releasing hormone (TRH), which stimulates hormone release from melanotropes.
- POMC is cleaved by prohormone convertase I and II in the melanotropes to alpha-melanocyte stimulating hormone (a-MSH), beta-endorphin (b-end), corticotropin-like intermediate lobe peptide (CLIP) and a small amount of adrenocorticotropic hormone (ACTH) (NB only I in pars distalis, therefore POMC is only converted to ACTH).
Describe the role of POMC-derived peptides in the horse.
Role of POMC-derived peptides has not been extensively studied in horses, but in people and small animals:
- a-MSH: skin pigmentation, control of energy homeostasis, appetite-satiety balance and fat metabolism through leptin-melanocortin pathway; a-MSH conc positively assoc w obesity in horses; potent anti-inflammatory agent through dec cytokine release and neutrophil activity.
- b-end: endogenous opioid; analgesia and behaviour modification; supressess immune responsiveness and has effects on vascular tone.
- CLIP: ??
- ACTH: circulates to the adrenal cortex and stimulates secretion of cortisol.
List the seasonal variations of POMC-derived peptide concentrations which occur in horses.
- a-MSH and ACTH: considerably higher Aug-Oct in northern hemisphere (Autumn) than Nov-Jul.
- Why? Maybe to metabolically prepare them for decreased available nutrition during Winter.
Describe the pathophysiology of Pituitary Pars Intermedia Dysfunction (PPID) in horses.
- Hypertrophy, hyperplasia and micro- or macroadenoma formation of the PPI up to 5 times normal weight.
- Expanding PPID compresses adj pituitary lobes and the hypothalamus and may cause loss of function.
- Enlarged PPI secretes more POMC-derived peptides (up to 40-fold increase above normal range).
- CSx result from increased circulating POMC peptides and loss of neuroendocrine function of adj tissues.
- Loss of dopamine inhibition is critical in pathology of PPID. Dopaminergic neurodegeneration occurs (5 fold dec in pituitary dopaminergic nerve terminals and 50% reduction in dopaminergic periventricular cell bodies) –> dz of hypothalamic origin rather that pituitary origin?
- Dopaminergic neurodegeneration may be secondary to oxidative damage.
What is the typical signalment of horses with PPID?
15 years of age or older.
List the clinical signs of PPID in horses.
- Hirsuitism/hypertrichosis: most common sign; long, curly haircoat or failure to shed winter coat fully e.g. on legs.
- Laminitis: occurs in 30-40% of diagnosed cases.
- Muscle atrophy: earliest CSx; may be due to outside factors and protein catabolism induced by high circulating cortisol.
- Fat accumulation: crest, tailbase, sheath, superorbital fossa.
- PU/PD: mechanisms may incl compression of pars nervosa –> less ADH, osmotic diuresis secondary to hyperglycaemia, cortisol induced (interferes with ADH secretion/action).
- Secondary infections: 27-48% horses e.g. parasitism, sinusitis, dermatitis, respiratory infections.
- Lethargy
- Infertility
- Persistent lactation: due to lack of dopaminergic inhibition of PRL release from the pars distalis?
- Sweating dysregulation
- Metabolic abnormalities: incl hyperglycaemia and hyperinsulinaemia.
What are the three ante-mortem tests recommended for diagnosis of PPID?
- Endogenous plasma ACTH concentration.
- TRH stimulation test.
- Dexamethasone suppression test.
Discuss the use of endogenous ACTH concentrations in the diagnosis of PPID.
- Single plasma sample; stable prior to separation if kept cool for up to 12 hours.
- Sensitivity of 70%, specificity of 80%.
- Positive for PPID: Nov-Jul >35pg/ml, Oct-Aug >100pg/ml (Cornell values) BUT significant variation between labs (AU much lower, Liphook lower).
- Horses with PPID have higher seasonal peak therefore testing during Autumn is recommended as ‘natural dynamic test’.
Discuss the use of the TRH stimulation test in the diagnosis of PPID.
- Most accurate test in dx of PPID.
- Baseline plasma ACTH, inj 1mg TRH, 10min post ACTH.
- Positive for PPID: >35pg/ml baseline, >110pg/ml 10min.
- NB ACTH concentrations vary widely with laboratory!!!
- NB No published data for July-October, therefore only recommended to be performed November-June.
- TRH stimulates relates of ACTH from the equine pars intermedia, therefore horse with PPID release +++ ACTH.
Discuss the use of the overnight dexamethasone suppression test in the diagnosis of PPID.
- 5pm: collect blood (plain tube) for baseline cortisol.
- Inject 0.4mg/kg dexamethasone IV or IM.
- 11am: collect second sample for cortisol measurement.
- Normal horse: dex supresses release of ACTH from pars distalis –> serum cortisol concentration cortisol is not suppressed.
- Disadv: perceived risk of laminitis; very specific however not very sensitive - only good in end stage dz not early dz.
List the necropsy findings in horses with PPID.
- Grossly enlarged pituitary gland due to hypertrophy and hyperplasia of the pars intermedia; 2-5x normal horse; macroadenoma (>1cm) or microadenomatous hyperplasia.
- Histo: melanotropes are pleiomorphic (polyhedral or spindle shaped) with eosinophilic, granular cytoplasm. Cells are organised into nodules, rosettes, bundles or follicular structures separated with fine septal tissue. Pigment deposition is common in pars nervosa.
- Compression of pars distalis, pars nervosa, optic chiasm or hypothalamus may be seen.
- Associate lesions of other organs may be seen: laminitis, intestinal parasitism, pneumonia, sinusitis.
Outline treatment recommendations for PPID.
- Pergolide: dopamine agonist; initial dose of 0.002mg/kg PO q24h, inc by 0.002mg/kg monthly if no improvement; monitor response to therapy on basis of CSx and biochem.
- Complications of pergolide: anorexia, colic, diarrhoea.
- Cyproheptadine: antiserotoninergic, antihistaminergic, anticholinergic; not recommended on basis of lack of consistent efficacy, but may be added in if fail to respond to 0.006mg/kg pergolide at 0.3-0.5mg/kg.
- Improve general health and minimise risk of complications: dental care, FECs and deworming, good nutrition.
- Body clip horses with hirsuitism in summer.
What is the prognosis for horses with PPID?
Not documented.
Critical Illness-Related Corticosteroid Insufficiency (CIRCI) has recently been reported in horses and foals. What is the definition of this condition?
- An insufficient cortisol response or inadequate cortisol activity for the existing degree of critical illness e.g. sepsis.
- Defined by inadequate delta cortisol response to a high-dose ACTH stimulation test.
- Cortisol insufficiency is transient and resolves if patient survives the primary illness.
What is the effect of CIRCI on recovery from a critical illness?
Due to the vital role the HPA axis plays in the physiologic response to the stress of illness, the occur of CIRCI during critical illness substantially worsens the morbidity and mortality of the primary disease.
In the one study looking at critically ill adult horses, what percentage of horses had inadequate basal cortisol concentrations on admission to hospital and what percentage had inadequate delta cortisol responses to ACTH stimulation?
- 24% had inadequate basal cortisol concentrations on admission to hospital.
- 85% had inadequate cortisol responses to ACTH stim.
- Marked adrenal haemorrhage was noted in non-survivors on necropsy.
Describe the pathophysiology of CIRCI.
A combination of factors are likely involved in the development of HPA axis dysfunction in CIRCI:
- Direct damage to HPA axis components from the primary disease e.g. hypotension associated with hypovolemic, endotoxic or septic shock –> dec adrenal perfusion –> ischemic injury to metabolically active adrenocortical cells.
- Inhibition of cortisol production by medications used to treat the primary disease e.g. ketoconazole and rifampin.
- Suppression of the activity of HPAA components by infectious organisms or the patient’s own immune and inflammatory response e.g. bacterial endotoxin –> dec pituitary CRH receptor gene expression in rats and cattle and TNF-α (inc in sepsis) –> impaired pituitary ACTH release and adrenocortical cortisol synthesis.
- Interactions between the adrenal axis and the immune response in horses are not well characterized, but equine adrenocortical tissue has been shown to directly secrete IL-6, IL-10 and TNF-α in an ex vivo model and a positive association between plasma ACTH concentration and IL-6 expression has recently been shown in septic foals.
- Peripheral cortisol resistance may develop in some patients e.g. impaired GR binding efficiency –> functional cortisol insufficiency in the face of normal serum cortisol.
What are the presenting clinical signs of CIRCI?
- Typically vague and insidious as predominate CSx relate to primary disorder. Index of suspicion should be high in sick, septic and premature foals. Reported in humans with sepsis, massive trauma, ARDS and major surgery.
- Specific manifestations of CIRCI are directly related to inadequate cortisol support for maintenance of blood pressure, nutrient metabolism, and regulation of the immune/ inflammatory response:
- Persistent hypotension despite appropriate volume resuscitation and vasopressor support.
- Persistent hypoglycemia or hyperlactatemia despite glucose support and adequate perfusion.
- Persistent signs of SIRDS e.g. tachycardia, fever or hypothermia, neutrophilia, neutropaenia.
- Specific signs of mineralocorticoid deficiency e.g. persistent hyponatremia, hypochloremia or hyperkalemia, occasionally occur with CIRCI.
How is CIRCI diagnosed in horses and foals?
- Documentation of either during period of critical illness:
(1) An inappropriately low basal cortisol concentration.
(2) an inadequate delta cortisol response to high-dose ACTH stimulation testing. - Basal cortisol single measurement difficult to interpret and not nec reliable.
- ACTH stim: an increase from basal cortisol
Discuss treatment of CIRCI in septic foals.
- The goal of CIRCI treatment is physiologic cortisol replacement, as a number of studies in septic patients have demonstrated deleterious effects of high-dose (supraphysiologic) corticosteroid regimens in sepsis.
- Hydrocortisone dose of 1-4 mg/kg/day divided q4-6h may be appropriate for foals with CIRCI (not proven).
Does Addison Disease occur in horses?
No. Addison Disease has not been reported in horses.
In which scenarios might non-CIRCI related adrenal insufficiency occur in adult horses?
- Prolonged administration of glucocorticoids or anabolic steroids.
- Excessive racing/training (poor evidence).
- Any horse surviving endotoxaemia, SIRS or sepsis (not reported but possible).
What clinical signs might suggest non-CIRCI related adrenal insufficiency in adult horses and how could this adrenal insufficiency be confirmed?
- Persistent lethargy, weight loss, hyponatraemia, hypochloraemia, hyperkalaemia or hypoglycaemia.
- Failure to increase serum cortisol concentration greater than or equal to 1.5-2x baseline 30mins post low-dose ACTH (1ug/kg IV).
Phaechromocytomas (adrenal medullary tumours) are reported rarely in horses as single tumours or part of a mutliple endocrine neoplasia syndrome. What are clinical signs seen in a horse with a phaechromocytoma?
- Excessive sweating, agitation, colic, tachycardia, mydriasis, hyperglycaemia and hypertension.
- Phaechromocytomas are predisposed to haemorrhage e.g. acute, fatal haemoperitoneum.
- CSx result from increased circulating catecholamines.
How do you diagnose phaechromocytoma in a horse?
- Most are diagnosed at necropsy.
- Antemortem: abdominal mass, supporting clinical signs, elevated urinary catecholamine levels.
Has primary hypoaldosteronism been reported in horses?
No.
Define anhidrosis.
An inability to sweat in response to appropriate stimuli.
In what geographic locations is anhidrosis reported in horses?
Areas that experience hot, humid weather for prolonged periods of time. Clinical signs especially likely when nighttime temperatures do not drop below 21C (70F).
What is the typical signalment of horses that develop anhydrosis?
- Just moved to a hot and humid area (but can occur in long-term residents).
- Horses in work/stressed more likely to develop cond.
- WB and TB at higher risk esp if familial hx of anhydrosis.
What is the proposed pathophysiology of anhydrosis?
- Cause unknown; presumed to be abnormality in stimulation or production of sweat.
- Physiologic stim of sweating: activation of alpha2-adrenergic receptors by catecholamines and neural stim.
- Sweat glands from anhydrotic horses do not respond normally to direct stim and are atrophied; unsure if atrophy is primary or secondary problem.
- Aquaporin-5 expression decreased; unsure if primary or secondary.
- Histo of skin –> no evidence of neural disruption; circulating catecholamines higher than non-anhydrotic horses –> problem in sweat glands responding to stimulation rather than failure of thermoregulatory system perceiving need to sweat or stim to sweat.
- Hypothesis: chronic stimulation to sweat in a hot, humid enviro –> downreg and/or desens of a2-adrenoreceptors.
- Suggested genetic predisposition.
- No evidence of thyroid involvement.
List the clinical signs of anhydrosis in horses.
- Exercise intolerance.
- Tachypnoea, initially exercise-related then at rest.
- Less sweating than expected for level of exercise; may still be able to sweat under mane, axilla, inguinal, saddle.
- Dilated peripheral skin vessels.
- Hyperthermia with exercise; prolonged cooling period.
- Haircoat becomes dry and thin in chronic cases.
How do you diagnose anhydrosis in horses?
- Intradermal sweat test: six serial 10-fold dilutions of 0.1ml terbutalin inj intradermally along neck or pectorals:
- Normal horse: sweats within 5m, sweat inc w conc.
- Hypohydrotic horse: takes longer to sweat or sweat only at higher concentrations.
- Anhydrotic horse: no sweat production.
- In hypohydrotic confirm with exercise test: TPR, lunge at trot for 30mins on hot day, TPR q10 mins –> if RR not back to baseline by 30min post-exercise likely hypohydrotic.
What treatments are available for anhydrosis in horses? Is there any evidence for their use?
- Only consistent tx: move horse to cooler climate.
- Stop workload; decrease stress level.
- Tx concurrent problems e.g. airway diseases.
- Cool environment: fans, shade, misting, air conditioners.
- Electrolyte supplementation esp KCl.
- Reported success in some cases but no evidence of improved blood flow/stimulation of sweat glands: One AC (t-tyrosine, ascorbin acid, niacin, cobalt), vit E, acupuncture, Chinese herbs.
- Clenbuterol: may be used in hypohydrotic horses at particularly bad times of year, but no evidence and traditional recommend against using a2-agonists as may precipitate complete anhydrosis.
What can you do to try and prevent anhydrosis in horses that have been previously diagnosed with it before the hot part of the year begins?
- Commence on any supplements that have been helpful in that horse previously.
- Make sure the horse is cardiovascularly fit.
- Make sure any respiratory problems are under control.
- Avoid procedures that may require admin of heavy doses of a2 sedatives.
- Work horse during cool times of day and wet to cool off.
Describe the normal pathway of thyroid hormone release in the horse and substances which stimulate and inhibit this release.
- TRH (hypothalamus) –> TSH (pituitary) –> T3 and T4 (thyroid) –> T3 and T4 bound to proteins (inactive) and fT4 and fT3 (active; fT3>fT4).
- Circulating THs feedback negatively on TRH/TSH.
- Alpha-adrenergics: stimulatory.
- Dopamine and somatostatin: inhibitory.
- Glucocorticoids, TNF, IL-1beta: inhibit TSH secretion.
List thyroid gland neoplasias reported in horses. How common/uncommon are these neoplasia?
- Thyroid adenoma: not uncommon; often incidental finding at necropsy.
- Thyroid carcinomas, adenocarcinomas, C-cell tumours not common.
- Most are benign in horses but scattered reports of horses w hypoT/hyperT secondary to thyroid neoplasia.
Is it necessary to treat thyroid gland neoplasia in horses? If so what treatment is indicated?
- Most are benign in horses but scattered reports of horses w hypoT/hyperT secondary to thyroid neoplasia.
- Tx when physically enlarge enough to compromise breathing/swallowing or alterations in TH concentrations.
- Tx: thyroidectomy followed by thyroid hormone supplementation.
How common is hyperthyroidism in adult horses?
- Extremely rare. Only 3 case reports in the literature and all associated with thyroid gland neoplasia.
- Can see transient elevations in THs in horses exposed to excess iodine.
List clinical signs of hyperthyroidism in adult horses.
- Weight loss.
- Tachycardia.
- Tachypnoea.
- Hyperactive behaviour.
- Ravenous appetite.
- Cachexia.
Outline the diagnosis and treatment of hyperthyroidism in adult horses.
- Dx: measure circulating THs +/- T3 suppression test.
- Nuclear scintigraphy to determine if one or both thyroid glands involved.
- Unilateral or bilateral thyroidectomy +/- TH supplement.
- One report of successful tx w oral propylthiouracil.
How common is hypothyroidism in adult horses? List possible aetiologies.
- Controversial. AI thyroid disease (as in dogs/ppl) only confirmed in one case report via histo following necropsy.
- People have claimed benefits in using thyroid supplementation to tx many conditions e.g. obesity, laminitis, anhydrosis, but unsubstantiated.
List clinical signs of hypothyroidism in adult horses.
- Lethargy.
- Exercise intolerence.
- Poor haircoat.
List management and therapeutic interventions which can alter circulating thyroid hormone concentrations in horses.
- Fasting –> decreased circulating THs.
- Phenylbutazone.
- Dexamethasone.
- Strenuous exercise.
- Diets high in energy, protein, zinc and copper.
