Endocrine 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.2. TRH stimulation test.3. 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.
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.
Does non-thyroidal illness syndrome occur in horses as in other species, and if so what is its significance?
- Preliminary reports suggest this does occur in critically ill adult horses and sick and septic foals.- THs may decrease due to dec peripheral conversion of T4 to T4 by 5’-deiodinase, altered binding to serum carrier proteins and hypothalamic-pituitary dysregulation.- Thyroid concentrations were inversely related to sepsis score in foals and nonsurvivors had lower TH concentrations than surviving foals.- The magnitude of TH suppression has been correlated with the severity of disease and mortality in adult horses.
Does ingestion of continental fescue infected with Neotyphodium coenophialum result in hypothyroidism in adult horses?
- Alkaloids produced by the endophyte act as dopamine agonists –> proposed to cause hypoT as dopamine inhibits TSH release from the pituitary.- No (proven by measuring TSH levels, TRH stim tests). - Likely compensatory mechanisms override any dopaminergic effect on TSH with chronic fescue ingestion.
What changes can be expected in TH levels following a TRH or TSH stimulation test in an adult horse with normal thyroid function?
- Collect baseline values; inject 1mg TRH or 5IU TSH; take samples 2 and 4 hours post inj.- T3 should double at 2h and T4 should double at 4h.- NB significant individual variation!
What medications can be used to treated horses following confirmation of hypothyroidism?
- Iondinated casein: 5-15g/horse/day PO; contains 1% T4.- Levothyroxine: 20ug/kg/day PO; may need up to 50-100ug/kg/day.
Thyroid hormone concentrations are high in neonatal foals and then decline to adult levels over the first month of life. What may be the function of the high TH concentrations?
- Maintaining thermogenesis: inc metabolic rate, inc heat prod from brown fat.- Maturation of body systems especially respiratory, neurologic and musculoskeletal.- Stimulate lung development and surfactant production.
How is thyroid function altered in premature vs full term neonatal foals?
- Significantly lower concentrations of total and free THs.- No difference in baseline TSH concentrations.- Exaggerated TSH response to TRH administration.- Findings indicate immature hypothal-pituitary-thyroid axis.
Congenital hypothyroidism can occur in foals secondary to dietary abnormalities in the mare. What are these abnormalities and what clinical syndrome is observed in the foals?
- Low or high iodine intake or consumption of goitrogenic plants e.g. soybeans, cabbage, rape, kale, turnips.- Foals born with goitre, weak, poor suckling and righting reflexes, hypothermia, developmental musculoskeletal abnormalities e.g. contracted tendons, incomplete ossification of cuboidal bones.- Poor Px; may improve survivability by supplementing with T4 or T3.
Describe the congenital hypothyroidism syndrome reported to occur sporadically in foals in Canada and Western US.
- Prolonged gestation, signs of dysmaturity e.g. silky haircoat, goitre, musculoskeletal abnormalities incl mandibular prognathia, flexural limb deformities of FLs, ruptured digital extensor tendons, incomplete ossification.- T3 and T4 WNL at birth but decreased response to TSH stim; therefore T3/4 supplementation not recommended.- Proposed aetiologies include ingestion of nitrates e.g. sorghum, goitrogenic plants, low selenium, low iodine.
Describe the distribution of calcium in the body.
- 99% in bone (+80% phosphorus) as hydroxyapatite.- 0.9% in cell membrane, mitochondria, endoplasmic retic.- 0.1% in extracellular fluid (interstitial fluid and plasma).- ECF: 55% free/ionised form, 40% bound to proteins (32% albumin, 8% globulin) and 5% complexed to anions such as citrate, bicarbonate, phosphate and lactate.
What effect do pH and serum albumin concentrations have on ionised calcium concentrations in the blood?
- Calcium binds to negatively charged (i.e. anionic) proteins and this affinity is pH dependent.- Acidosis: more H+ –> dec Ca++ binding to anions –> increased plasma Ca++ concentrations.- Alkalosis: more Ca++ binding to anions –> decreased plasma Ca++ concentrations.- Hypoalbuminaemia –> decreased total plasma hypocalcaemia BUT Ca++ WNL (pseudohypocalcaemia).
What are dietary calcium and phosphorus requirements for horses?
- Balanced diet: 0.15-0.6% Ca + 0.15-0.6% Phos.- Must be > 1:1 Ca:P or negative effects on Ca absorption and skeletal development.- Adult horse must absorb 20-25mg/kg/day Ca (lose 20mg/kg therefore must eat 40mg/kg) & 10-12mg/kg/day P.- Ca requirements can be up to double for growing or lactating horses.
Describe the mechanism of calcium absorption in horses and factors which affect its absorption.
- Most Ca absorption occurs in SI.- Horses absorb a greater proportion of dietary Ca than other animals i.e. 50-75% and
Dietary oxalates decrease absorption of calcium from the small intestines. List plants which contain harmful amounts of oxalates.
- Bermudagrass (Cynodon dactylon)- Buffel grass (Cenchrus cilaris)- Dallis grass (Paspalum spp.)- Elephant grass (Panicum spp.)- Foxtail grass (Setaria spp.)- Greasewood (Sarcobatus vermiculatus)- Halogeton (Halogeton glomeratus)- Kikuyu (Pennisetum clandestinum)- Kochi, summer cypress (Kochia scoparia)- Lamb’s-quarters (Chenopodium spp.)- Napier, mission grass (Pennisetum spp.)- Pangola (Digitaria decumbens)- Panic (Pancium spp.)- Para grass (Brachiara spp.)- Pokeberry (Phytolacca americana)- Purple pigeon grass (Setaria incrassate)- Purslane (Portulacca oleraceae) - Red-rooted pigweed (Amaranthus spp.)- Rhubarb (Rheum rhaponticum)- Russian thistle, tumbleweed (Salsola spp.)- Setaria (Setaria sphacelata)- Sorrel (Rumex spp.)- Soursob, shamrock (Oxalis spp.)- Sugar beet (Beta vulgaris)
Describe how calcium is eliminated in the horse.
- Eliminated through faeces, milk, sweat and the foetus.- Kidney: 60% reabsorbed by passive mechanisms in proximal tubules, 35% reabsorbed in thick ascending loop of Henle and distal tubules by active mechanisms, 5% excreted in urine.
Describe the distribution of phosphorus in the body of the horse.
- Organic (intracellular) and inorganic (extracellular) phosphates.- Most of the P in circulation is phosphate esters (phospholipids) bound to proteins and blood cells.- Inorganic PO4 is measured; 50% ionised, 35% complexed with cations (Na+, Ca++, Mg++), 15% protein bound.
What effect does pH have on ionised phosphate concentrations in the blood?
- pH 7.4: divalent (HPO4–): monovalent (H2PO4-) anions 4:1.- Acidosis: 1:1.- Alkalosis: as high as 9:1.
Describe absorption and elimination of phosphorus in the horse.
- 30-55% dietary P absorbed in SI and LI.- High albumin in diet reduces P absorption.- Kidneys: most of the PO4 is reabsorbed in the proximal tubules by a Na+ dependent mech; urinary excretion is low.
Describe aetiology of hyperphosphataemia in the horse.
- Chronic dietary excess –> nutritional secondary hyperparathyroidism.- Acute renal failure.- Hypoparathyroidism.- Conditions that result in cell membrane fragility and lysis e.g. rhabdomyolysis, haemolysis and tumour necrosis.
Describe clinical signs of hyperphosphataemia in the horse.
Chronic excess –> CSx of calcium deficiency:- Lameness.- Abnormal cartilage and bone development.- Fractures.- Osteodystrophia fibrosa (nutritional secondary hyperparathyroidism).
Describe aetiology of hypophosphataemia in the horse.
- Inadequate dietary intake.- Decreased intestinal absorption.- Renal waste.- Hyperparathyroidism.- Sepsis.- Intracellular shift (refeeding syndrome, starvation, PPN).- Some malignancies.
Describe clinical signs of hypophosphataemia in the horse.
- Weight loss.- Pica.- Weakness.- Lameness.- Developmental orthopaedic disease.- NB rickets is not a recognised dz of foals!!
List the components of the system that regulates extracellular ionised calcium homeostasis in the body.
- Hormones: parathyroid hormone (PTH), calcitonin (CT) and 1,25-dihydroxyvitamin D3 (calcitriol).2. Body systems: kidney, intestine, bone.3. Calcium-sensing receptor (CaR).
What effect does magnesium have on calcium homeostasis?
Mg++ has permissive effects on calcium homeostasis by facilitating PTH secretion and action.
What homeostatic responses occur when blood Ca++ decreases or blood PO4 increases?
PTH secretion increases –>- Inc renal Ca++ reabsorption- Dec renal PO4 reabsorption- Inc osteoclastic bone resorption- Inc vit D synthesis –> inc intestinal absorption and renal reabsorption of Ca and PO4.
What homeostatic responses occur when blood Ca++ increases?
- PTH secretion decreased –> less renal and intestinal Ca reabsorption/absorption.- Calcitonin secretion inc –> osteoclastic bone resorption inhibited.
Like Ca++, PO4 homeostasis is under the control of PTH, calcitonin and calcitriol. What additional hormone-like peptide plays a major role in PO4 control and what is its action?
- Phosphatonins (FGF-23/klotho axis).- Role unknown in the horse.- Inhibit renal PO4 reabsorption and calcitriol synthesis in other animals.
Discuss secretion and action of PTH in the horse.
- Secreted by chief cells of the parathyroid gland in response to low Ca++ or high P.- Chief cells detect changes in blood Ca++ through the CaR.- Through the PTH receptor, PTH:– Inc renal Ca++ reabsorption (distal nephron).– Dec renal PO4 reabsorption (proximal tubules).– Stimulates renal calcitriol synthesis (proximal tubules).– Stimulates odontoclastic bone reabsorption.
Describe the action of calcitriol on Ca++, PO4 and PTH.
Increases intestinal absorption and renal reabsorption of Ca++ and PO4 and inhibits PTH synthesis and secretion.
Describe the role of vitamin D in calcium homeostasis.
- Ergosterol in food –> vit D2 (ergocalciferol) and 7-dehydrocholesterol in skin + sun –> vit D3 (cholecalciferol) –> hydroxylated to 25-hydroxyvitamin D3 (calcidiol) in liver –> 1,25(OH2)D3 (calcitriol) in kidneys = active form.- HypoCa, hypoP and PTH induce renal 1 alpha-hydroxylase activity –> inc calcitriol synthesis. - HyperCa, hyperP, FGF-23 and calcitriol inhibit 1 alpha-hydroxylase.- Vit D stimulates intestinal absorption and renal reabsorption of Ca++ and PO4.- Calcitriol increases expression and activity of proteins important for transcellular Ca++ transport.- Calcitriol increases Mg++ renal reabsorption. - Calcitriol increases bone matrix synth and mineralisation and stimulates osteoclastic activity.
Describe the role of calcitonin in calcium homeostasis.
- Secreted by the parafollicular cells of the thyroid gland in response to hyperCa.- Inhibits osteoclast function and bone resorption.- Decreases renal reabsorption of Ca and PO4.
Describe the role of parathyroid hormone related protein (PTHrP) in calcium homeostasis.
- Broad range of functions in the healthy animal that having nothing to do with calcium homeostasis.- Some tumours secrete PTHrP -> humerol hyperCa of malignancy = PTHrP interacts w PTH receptors to increase bone reabsorption and inhibit renal Ca++ excretion.
How does activation of the renal CaR affect serum calcium and magnesium concentrations.
Inhibits the furosemide-sensitive Na+/K+/2Cl- co-transporter in the distal nephron –> diuresis and urinary waste of Ca++ and Mg++.
Describe the effect of acute hypocalcaemia on neuromuscular function in the horse.
- Neuromuscular excitability and decreased smooth muscle contractility.- Dec extracellular Ca++ –> inc cell membrane permeability to Na+ –> dec resting membrane potential.- Spontaneous and continuous discharges –> muscle fasciculations, tremors, tetany and seizures. - Tacchycardias and arrhythmias may progress to bradycardia.
How is chronic hypocalcaemia usually manifested in the horse?
Abnormal cartilage and bone development (DOD) and lameness.
List conditions which may result in hypocalcaemia in horses.
ARF, alkalosis, bicarbonate administraiton, cantharidin toxicosis, CRF, colic, lactation, transport (transit tetany), dystocia, endotoxaemia, endurace exercise, enterocolitis, furosemide administration, heat stroke, hypoMa, liver disease, magnesium toxicosis, malignant hyperthermia, oxalate ingestion, pancreatitis, pleuropneumonia, postoperative myopathy, primary hypoparathyroidism, retain placenta, rhabdomyolysis, sepsis.
Describe the mechanism and clinical presentation of diaphragmatic flutter in horses with hypocalcaemia.
HypoCa –> decreased resting membrane potential.Depolarisation of the right atrium stimulates action potentials in the phrenic nerve as it crosses over the heart –> rhythmic movement of flank from diaphragmatic contractions that are synchronous with the heartbeat.
What are the greatest risk factors for development of hypocalcaemic tetany? What clinical signs are observed in this condition?
- Transport for long distances.- Lactating mares from just pre-foaling to weaning esp if producing large vol of milk, on low Ca diet, on lush pastures, performing physical work.- CSx: anxiety, depression, ataxia, muscle fasciculations and tremors, still gait, tachypnoea, dyspnoea, dysphagia, hypersalivation and hyperhydrosis.
Describe the mechanism of hypocalcaemic seizures in horses and foals. What is the associated prognosis?
- Dec CNS extracellular Ca++ –> increased neuronal excitability –> seizures.- Px: clinical signs usually resolve with single or repeated admin of Ca; refractory hypoCa seizures –> poor Px.
Describe the mechanism of ileus and retained fetal membranes in horses with hypocalcaemia.
In smooth muscle most of the Ca++ required for contraction comes from the ECS (vs SR in skeletal m), therefore any condition which causes hypoCa –> dec smooth muscle contraction –> ileus/RFM.
What is the difference in aetiology between primary and secondary hypoparathyroidism? Are either reported in horses?
- Primrary: results from decreased secretion of PTH.- Secondary: results from Mg depletion and sepsis.- Very rare reports of primary PTH in the literature, secondary PTH not technically reported but some critically ill horses and foals with hypoCa have impaired PT function.- Neonatal idiopathic hypoCa: foals with normal or low PTH despite hypoCa, refractory to tx, poor Px.
Outline clinical signs and laboratory findings in a horse with primary hypoparathyroidism.
- Should be suspected w refractory hypocalcaemia.- Ataxia, seizures, hyperexcitability, SDF, tachycardia, tachypnoea, muscle fasiculations, bruxism, still gait, recumbency, ileus, colic.- HypoCa, hyperP, hypoMg, low serum PTH.
What are the most common causes of hypocalcaemia in horses presented to hospital? What is the mechanism by which hypoCa occurs in this case?
- Sepsis, endotoxaemia, severe GI disease.- PT dysfunction (insufficient PTH secretion) and intraceullular Ca sequestration –> hypoCa.- Inflam mediators e.g. TNF-a, IL-1 and IL-6 inc CaR activation and decrease PTH secretion by equine PT cells.
Why does hypocalcaemia develop in horses under intense exercise?
- Losses of Ca++ in sweat.- Intracellular movement of Ca++.- Increased Ca++ binding to albumin, lactate, phosphate and bicarbonate during alkalosis. - PT gland dysfunction.- NB mechanism in exertional rhadomyolysis unknown, thought to be influx of Ca++ into damaged muscle fibres and sequestration in the sarcoplasmic reticulum.
Describe the mechanism of hypocalcaemia and clinical presentation of horses with oxalate toxicity.
- 1% or greater oxalates in diet –> bind to Ca to form calcium oxalate crystals –> reduces most GI Ca absorption.- CSx are those of phosphate excess, calcium deficiency and nutritional hyperparathyroidism.
Describe the mechanism of hypocalcaemia and clinical presentation of horses with cantharidin toxicity.
- Cantharidin –> mucosal irritation (GI and urinary tracts).- HypoCa and hypoMg –> muscle fasciulations, SDF, ataixa, dyspnoea, laryngeal soasm, cardiac arrhythmias.- Mechanism unknown, possibly combination of GI dz, acute renal tubular necrosis and PT gland dysfunction.
What are the two divisions of hypercalcaemia in horses and what differential diagnoses fit into these divisions.
- Parathyroid gland-dependent hyperCa: develops due to PT gland hyperfunction i.e. primary hyperparathyroidism.2. Parathyroid gland-independent hyperCa: develops despite PT gland suppression e.g. secondary hyperparathyroidism, CRF, HHM, hypervitaminosis D, calcinosis and idiopathic system granulomatous dz.
Describe the aetiology and pathogenesis of primary hyperparathyrodism in the horse.
- Parathyroid adenomas or parathyroid hyperplasia.- Excessive and autonomous synthesis and secretion of PTH by the PT gland that is not responsive to negative feedback of Ca++.- Inc PTH –> inc renal Ca++ reabsorption, dec renal PO4 reabsorption, inc calcitriol synthesis and inc bone resorption (osteodystrophia fibrosa).
Describe the clinical signs and diagnostic findings identified in horses with primary hyperparathyrodism.
- Facial bone enlargement, lameness, poor body condition.- HyperCa, hypoP, hypocalciuria, hyperphophaturia, PTHrP conc low or WNL.- Rads: dec long and facial bone density, fibrous proliferation of the mandible and maxilla, loss of lamina dura surrounding the molars.- Endoscopy: narrowing of the nasal passages.
Is renal secondary hyperparathyroidism recognised in the horse?
- No. Other animals: CRF –> hyperP –> excessive PTH secretion –> hyperCa.- Horses w CRF often have hypoP and PTH conc within or below the normal range, as hyperCa is due to increased renal retention rather than elevated PTH.
Describe the aetiology of nutritional secondary hyperparathyrodism in the horse.
- Diets low in calcium high in phosphorus or with P:Ca greater than or equal to 3:1.- Pastures and plans with a high content of oxalates.- A.k.a. bran dz, millers dz, big head, osteodystrophia fibrosa, osteitis fibrosis and equine osteoporosis.
Describe the pathogenesis of nutritional secondary hyperparathyrodism in the horse.
- Excessive dietary PO4 reduces intestinal Ca absorption and results in hyperphosphataemia.- Dietary oxalates form insoluble calcium oxalate.- HyperP: directly stimulates PTH secretion, inhibits renal calcitriol synth (calcitriol inhibits PT cell hyperplasia), forms Ca2PO4 precipitates –> low Ca –> more PTH secretion.- PTH increases osteoclastic activity, bone resorption and bone loss –> facial bone loss, excessive accumulation of subperiosteal unmineralised CT –> facial enlargement.- Chronic dz as horses preserve normocalcaemia.
Describe the clinical signs of nutritional secondary hyperparathyrodism in the horse.
- Unthriftiness.- Intermittent, shifting lameness and a stiff gait.- Younger animals: physitis and limb deformities.- Typical and asymmetrical swelling of facial bones (may not occur in older horses).- Problems masticating due to bone resorption around teeth.- Severe cases: tooth loss, spontaneous fractures of the long bones.- Upper airway obstruction, dyspnoea, epiphora.- Soft tissue mineralisation reported in 1 foal.
Describe the laboratory findings and diagnostic imaging findings in horses with nutritional secondary hyperparathyrodism.
- Hyperphosphataemia.- Hypo or normocalcaemia.- Increased PTH concentrations (esp if still on high P/low Ca diet when blood drawn).- Urinary excretion of Ca low and PO4 high.- ALP may be increased.- Rads: bone density must dec 30% before ID on rads, dec facial bone density with fibrous proliferation, resorption of alveolar sockets and loss of dental lamina dura.
Outline treatment of nutritional secondary hyperparathyroidism in the horse.
- Eliminate or reduce any grain-based diet.- Avoid high oxalate feeds.- Add alfalfa to diet.- Calcium carbonate (limestone) 100-300g/day (35% Ca).- Diet with Ca:P 3-4:1.- Confinement +/- NSAIDs.- 9-12mo for recovery (bony lesions may not change).
Describe the aetiology of hypervitaminosis D in the horse.
- Ingestion of plants containing calcitriol-like compounds.- Solanum glaucophyllum - South America.- Cestrum diurnum (jessamine) - USA.- Solanum sodomaeum - Hawaii.- Trisetum flavescens (golden oat) - Europe.
Describe the pathogenesis of hypervitaminosis D in the horse.
- Increases intestinal absorption and renal reabsorption of Ca and PO4.- Results in PT cell atrophy and dec PTH secretion.
Describe the clinical signs associated with hypervitaminosis D in the horse.
- Weight loss.- Poor appetite.- Lameness and painful stiffness.- Polyuria and polydipsia.- +/- renal failure (due to kidney mineralisation).
How do you diagnose hypervitaminosis D in horses?
- HyperP, hyperCa or normoCa.- Azotemia or hyposthenuria may be present.- Rads: inc bone density, dec size of medullary cavity and inc calcification of soft tissues.- Necropsy: soft tissue mineralisation, osteopetrosis of epiphyses and metaphyses, atrophy of PT gland.
Outline the treatment and prognosis of hypervitaminosis D in horses.
- Reduce dietary calcium intake.- Calcium binding agents e.g. sodium phytate.- Dexamethasone to dec intestinal absorption of Ca, inc urinary excretion of Ca and dec bone resorption.- Severe hyperCa can tx w 0.9% NaCl and loop diuretics –> inc urinary excretion of Ca (not thiazides as –> inc Ca reabsorption).- Poor prognosis.
Describe the aetiology and pathogenesis of Humoral Hypercalcaemia of Malignancy (HHM).
- Tumours secrete PTHrP which interacts with PTH receptors –> inc renal reabsorption of Ca++ and bone reabsorption.- Assoc w SCC, adrenocortical carcinoma, lymphosarcoma, multiple myeloma and ameloblastoma in horses.- Suspected in hyperCa, no evidence of renal disease and normal PTH concentrations.
Define hyperlipaemia and hyperlipidaemia in horses.
Hyperlipemia is defined as serum triglycerides greater than 500 mg/dL, grossly discolored plasma or serum (lipemia), and concurrent fatty infiltration of the liver (hepatic lipidosis). Hyperlipidemia is an elevation in serum triglycerides without lipemia.
What are the risk factors for development of hyperlipaemia in equids?
- Breed: ponies, donkeys, miniature horses, horses with Cushings; rare in light horses or Draughts. - Overweight body condition.- Predisposing factors to negative energy balance: intestinal dz, choke, pregnancy, dental disorders, transportation, decrease in available feed or appetite, parasitism, lactation, laminitis, respiratory dx and PPID. - On rare occasions, lipemia will be noted in horses with neoplasia; may be due to inc TNF and its effect on enhanced lipolysis and dec LPL activity.
Describe the pathogenesis of hyperlipaemia in equids.
- Dec feed intake, increased energy req and inc stress hormone release → prod of insulin (anti-lipolic), dec insulin sensitivity, un-regulation of hormonesensitive lipase (HSL) and adipose triglyceride lipase.- Lipolysis of triglycerides stored in peripheral fat → release of non-esterified free fatty acids (NEFFAs) and glycerol.- NEFFAs are taken up by the liver → oxidized in the Krebs cycle for energy, stored as triglycerides, or released back into circulation as lipoproteins.- LPL (enzyme needed to hydrolyse triglycerides into FFAs so they can be used as energy substrate or stored as triglycerides in the peripheral tissue (fat deposits) is inc in ponies w hyperlipaemia –> result of exaggerated lipolysis and increased hepatic secretion of triglyceride-rich VLDLs and is not commonly a primary problem with decreased peripheral clearance of triglycerides.- Azotemia –> uraemic inhibition of LPL –> dec clearance of triglycerides. - Enhanced lipolysis can quickly –> lipemia and hepatic lipidosis and without prompt treatment death from metabolic abnormalities, liver failure, or occasionally rupture of the liver and hemorrhagic shock.
Describe the clinical signs and clinical pathologic abnormalities in equids with hyperlipaemia.
- Depression in almost all cases. - Anorexia.- Jaundice.- Signs of HE.- Discolored urine.- Dysphagia.- Ventral oedema in 30% of cases. - Tachycardia in most cases. - Serum triglycerides: >500mg/dL.- Liver enzymes: variable.- BA: generally increased (often 80-120mmol/L).- Ammonia: often high.- PT and PTT: prolonged.- Direct bilirubin: increased. - Blood glucose: variable.
Outline the treatment and prognosis of hyperlipaemia in equids.
- Tx goals: tx underlying dz, reverse negative energy balance, normalise plasma lipid concentrations, tx hepatic lipdosis/failure. - Enteral or parenteral nutrition: carb and protein and either no fat or low fat e.g. glucose, whey, alfalfa slurry.- If IV glucose used, eneteral feeding not possible and marked hyperglycaemia insulin may be indicated.
What is the prognosis for equids with hyperlipaemia?
- Mortality rate from hyperlipaemia and hepatic lipidosis in one case series was approximately 50%.- Px is variable depending on the successful and prompt correction of the predisposing cause(s) and on the ability to supply adequate nutritional support.
What two other names is hepatic lipidosis in post-partum dairy cattle know by?
Fat Cow Syndrome and Lipid Mobilisation Syndrome.
What cattle are at risk of developing Fat Cow Syndrome?
Postparturient dairy cows which were overconditioned in the during late lactation and the dry period.Obese/well conditioned cows with a large amount of omental and subcutaneous fat.
List the clinical signs of Fat Cow Syndrome.
Depression, anorexia, weight loss, weakness –> recumbency.Non-specific signs may include decreased ruminal motility and milk production.Other signs related to concurrent conditions e.g. mastitis, metritis, parturient paresis and displaced abomasum.
How do you diagnose Fat Cow Syndrome in a cow?
- Liver enzymes: often a poor indicator of dz severity; most consistently elevated are OCT, TBili, AST.- CBC: often leukocytosis with a left shift (non-specific).- Increased NEFAs and decreased cholesterol and triglycerides.- BSP excretion > 9mins –> guarded Px.- U/S: may see increased echogenicity of liver, rounded margins.- Liver biopsy: % hepatocytes containing fat vacuoles - mild 75%. Liver will float in distilled water when >34% (NB all high-producing, post-parturient dairy cows will have fatty infiltration).
Describe post-mortem findings in a cow with Fat Cow Syndrome.
- Generalised obesity if sick
How do ruminants differ from monogastric animals in their intake of dietary energy?
- Most of the energy is absorbed is VFAs not glucose.- Glucose is still needed and must be produced by gluconeogenesis, 85% of which occurs in the liver.
List conditions in which negative energy balance occurs in cattle.
- Lactation.- Foetal growth.- Exercise.- Decreased feed consumption.- Environmental chilling.- Disease.
Describe the changes in insulin, glucose and hormone sensitive lipase (HSL) that occur in cattle during periods of negative energy balance or prior to lactation.
- Blood glucose concentration decreases.- Insulin:glucagon ratio drops.- Glucose, insulin, catcholamine, growth hormone changes activate HSL production.- HSLs convert tissue fat to FFAs/NEFAs and glycerol.
What happens to the glycerol and NEFAs produced by breakdown of fat in cattle in negative energy balance?
- Glycerol –> liver –> produce glucose OR combine with FFAs to make triglycerides (TGs).- FFAs –> combine w glycerol to make TGs OR degrated through beta-oxidation –> acetyl CoA –> krebs cycle –> glucose.- If there is not enough oxaloacetate for acetyl CoA to combine with to enter the krebs cycle, acetyl CoA is converted to ketone bodies. - NB ketones reduce feed consumption and perpetuate negative energy balance.
