Equine endocrinopathies Flashcards
What is meant by Equine Metabolic Syndrome?
A collection of risk factors associated with an increased risk of laminitis
List the main risk factors in EMS
- Obesity (which leads to…)
- Insulin resistance (which leads to…)
- Predisposition towards laminitis
List the potential additional components of EMS
- Dyslipidaemia
- Hypertension
- Hyperleptinaemia
- Altered reproductive cycling
- Increased systemic markers of inflammation
Outline the epidemiology of EMS
- Prevalence unknown
- Age: 5-15yrs
- Breeds: any breed but ponies, minis, Arabians, Warmbloods and native breeds are predisposed
- Seasonal: spring-summer
Explain how season affects EMS
- In Spring-summer, lush grass
- Excess sugars produced in grass, converted to storage carbs e.g. fructans and starches
- Taste good, higher calories = fat
Describe the appearance of obesity in a horse with EMS
- Cresty neck
- Pad pads in front and behind shoulder, hindquarters, belly fat, tail head
- BCS >3.5/5
- Fat in middle of neck
Explain how EMS might occur in lean horses due enzymatic action
11beta-hydroxysteroid dehydrogenase-1 is an enzyme that increases local production of cortisol in adipose tissue
- High cortisol = insulin resistance
Explain how EMS might occur in lean horses due to pancreatic disease
Pancreatic disease can result in reduced insulin production and thus type 2 diabetes mellitus
Describe the lameness commonly seen in EMS
- Due to laminitis
- Bilateral
- Pottery gait, digital pulses, pain on coronary band
Describe the feet of a sound horse with EMS
Evidence of previous laminitis i..e divergent growth rings on hooves
List the elements of the pathophysiology of laminitis in EMS
- Insulin resistance
- Inflammation
- Oxidative Stress
- Altered adipocyte function
- Altered endothelial function
What are the functions of adipose tissue?
- Energy storage
- Hormone production
What hormones are produced by adipose tissue?
- Adipokines (leptin, resistin, adiponectin, apelin)
- Adipocytokines (TNF, IL-1, IL-6)
What are the consequences of the hormones produced by adipose tissue?
Chronic low grade inflammation
How does insulin resistance occur in EMS?
- Down regulation of insulin signalling by adipokines
- Accumulation of intracellular lipids (lipotoxicity) e.g. in skeletal muscle cells, liver, pancreas (insulin would normally suppress lipolysis, without get more FFAs produced)
- increased oxidative damage, altered insulin signalling
Describe the insulin and glucose levels in compensated insulin resistance
- Normal glucose levels
- Hyperinsulinaemia
Describe the insulin and glucose levels in uncompensated insulin resistance
- Hyperglycaemia
- Hyperinsulinaemia
Describe the insulin and glucose levels in type 2 diabetes mellitus
- Hyperglycaemia (persistent)
- Hypoinsulinaemia
How might endothelial cell dysfunction occur in EMS?
- Hyperinsulinaemia
- Inhibition of NO release by endothelial cells
- Endothelin-1 synthesis and sympathetic nervous activation
- Glucose toxicity
Outline the processes that lead to laminitis in EMS
- Hyperinsulinaemia leading to endothelial cell dysfunction
- Digital vasoconstriction
- Impaired glucose uptake from epidermal laminar cells
- Altered epidermal cell function/mitosis
- Matrix metalloproteinase activation
- Pro-inflammatory/pro-oxidative state in lamellar tissue
What aspects of the history are important in the diagnosis of EMS?
- Diet (quality and quantity)
- Amount of exercise
- Previous history of lameness
Compare diabetes mellitus in horses to that in other species
- Rare in horses, when occurs often associated with PPID
- Horses can remain hyperinsulinaemic for years without developing DM
- No development of amylin within pancreas as seen with horses and cats
Outline the clinical relevance of hypothyroidism in horses
- Very rare
- Testing may involve SH stim but limited applicability, T3 and T4 of little use due to wide variation in normal horse
- Affected by stress, disease, diet
What is meant by compensated insulin resistance?
Normal glucose concentrations maintained by increased insulin output, solved by weight loss
What is meant by uncompensated insulin resistance?
Glucose concentrations increasing and increased insulin to compensate for reduced effect (hyper-insulinaemia and glycaemia)
What is meant by type 2 diabetes?
Persistent hyperglycaemia and hypoinsulinaemia, end stage of insulin resistance
Why is EMS a risk factor for PPID?
- Obesity and IR associated with low-grade inflammation and pro-oxidative state
- Oxidative degeneration of dopaminergic neurons => PPID
What happens to insulin dysregulation with the development of PPID?
It is exacerbated
What are the aims of EMS diagnostic tests?
- Confirm insulin resistance combined with clinical signs
- Rule out PPID
List the possible tests for EMS
- Resting glucose and insulin
- Proxies of insulin sensitivity
- Dynamic testing e.g. CGIT
- In feed glucose challenge
- Blood pressure measurement
- Adipokine measurement
Outline the use of resting glucose and insulin testing in the diagnosis of EMS (advantages, result interpretation, specificity/sensitivity)
- Simple, cheap
- High resting insulin strongly suggestive of IR
- Low insulin and glucose = T2 DM
- Low sensitivity and specificity (false negatives likely)
What factors may affect a resting glucose and insulin result?
- Stress
- Fed/fasted
- Season (if at pasture)
Outline the method for an oral glucose challenge test
- Fast overnight
- Administer non-glycaemic feed (e..g chaff) with known amount of glucose powder (e.g. 1g/kg)
- Measure insulin at 2hr
What result on an oral glucose challenge test would indicate insulin resistance?
At 2 hr insulin >95IU/ml
Outline the features of an oral glucose challenge test (advantages, disadvantages, additional)
- Convenient in ambulatory settings
- Better than basal insulin
- Need to be organised and instruct owner to feed at a certain time, arrive and sample on time
- Can also use a variation with sugar syrup rather than glucose powder
Describe the method for a combined glucose insulin test (CGIT)
- Fast overnight
- Obtain basal glucose and insulin
- Give 150mg/kg glucose IV and immediately +0.1IU/kg soluble insulin (<10sec from glucose)
- Measure glucose at 1 min, 5 min, then every 5 min until 45 min
- Then measure every 15 min for 2-3 hours (17-20 samples total)
- Measure insulin at 45 min
Outline the features of the CGIT (advantages, disadvantages, interpretation)
- Provides detailed information of insulin response to glucose challenge
- Expensive, time-consuming
- Prolonged hyperglycaemia (above baseline within 30-45 mins) suggests IR, high insulin (>100IUml) at 45 min suggests exaggerated insulin response
Why does insulin higher than baseline >45 mins following CGIT suggest insulin resistance?
Insulin half life in the horse is only 40 mins
What are the 2 broad ways in which EMS can be managed?
- Husbandry (including diet)
- Pharmaceutical
Give the key husbandry aspects in the management of EMS
- Reduce caloric intake, starch in diet
- Soak hay
- Limit lush pasture grazing
- Exercise increase
- Laminitis management
Explain the soaking of hay in the management of EMS
- Washes away hydrosoluble carbohydrates
- Soak minimum 45 mins (most practical overnight/during day)
- Add vitamin balancer
Explain the restriction of pasture grazing in the management of PPID
- Green grass is unregulated source of sugars and starches
- Best use small, bare paddock
- Limit time outside <1h
- Grazing muzzles
- Co-graze with small ruminants
- Supplement vitamins and minerals
Explain exercise in the management of PPID
- Intense exercise most effective, 30min/day minimum (increase to this gradually)
- Increase work on hillsides
- Supplement diet if very intense or lean phenotype
- Increases calorie use and improves insulin sensitivity
Outline the management of EMS with ongoing laminitis
- Non exercise
- Manage entirely with diet
What drugs are used in the management of EMS?
- Levothyroxine
- Metformin
What are the 2 indications for the use of levothyroxine?
- Short term use (3-6 months while wait for response to diet and exercise)
- In refractory cases
What are the actions of metformin?
- Increase insulin sensitivity by increasing GLUT4 in membranes
- Inhibit gluconeogenesis and lipogenesis (acctivate AMPkinase)- INcreased fatty acid oxidation and lipolysis
What are some disadvantages of metformin?
- Poor bioavailability
- Some horses may show mild signs of hypoglycaemia initially
Describe the mechanism of action of levothyroxine
- Synthetic form of thyroxine (T4) and acts as a metabolic stimulant
- Increases basal metabolic rate
What are the potential side effects of levothyroxine?
- Mild hyperthyroidism
- Excitation
What is the expected benefit of levothyroxine administration?
Reduced size of adipose deposits
What monitoring is required when using levothyroxine?
- Total T4 concentrations
- Signs of hyperthyroidism (tachycardia, polyphagia, excitability, nervousness, panting)
What is the approximate cost of levothyroxine treatment for 1 month?
- Expensive
- 0.1mg/kg -> £10-15/day
What are the potential side effects of treatment with metformin?
- Oral irritation/ulceration
- Metabolic acidosis (in other species)
- (Colic, severe respiratory problems also noted)
What is the expected benefit of treatment with metformin?
Blunts post-prandial hyperglycaemia and hyperinsulinaemia => reduces the risk of laminitis
What monitoring is required with metformin treatment?
None
What is the approximate cost of metformin treatment for 1 month?
~£15 for a 500kg horse
Describe the signalment of PPID
- > 7yo, average 19-21yo/15yo
- No gender predilection
- Ponies predisposed
In a horse, what would the following clinical signs be indicative of?
- Weight loss, muscle wastage
- PUPD
- Hirsutism
- Quieter demeanour
- Lethargy
- Poor performance
- Potbelly
- Chronic laminitis
- Recurrent infection
- PPID May also see (rare): - hyperhidrosis/anhydrosis - Neurologic (blindness, seizures, narcolepsy) - Absent reproductive cycle/infertility
What areas are prone to adiposity in PPID vs EMS?
- Supraorbital area
- Tail base, shoulder blade and neck more common in EMS
Where is ACTH normally produced in the horse?
The pars distalis of the anterior pituitary gland, and very small amounts from the pars intermedia
What is ACTH normally released in response to?
Stressful situations e.g. pain, illness, excitement, exercise, travel
What leads to the hormonal changes that occur in PPID?
- Lack of dopaminergic inhibition of the pars intermedia
- Hyperplastic/neoplastic changes with functional cells of the pars intermedia
What metabolic factor leads to the loss of dopaminergic inhibition in PPID?
Oxidative damage due to obesity
How does loss of dopaminergic inhibition lead to PPID?
- Dopaminergic neurons are inhibitory
- Loss of these leads to loss of inhibition of melanotropes
- Melanotropes become hyperplastic and increase hormone secretion = functional pituitary adenomas
Name the hypothalamic tracts and identify which one is involved in pars intermedia activity
- Tuberoinfundibular, tuberohypophyseal, periventricular
- Periventricular is involved in PI activity
Explain why EMS is a risk factor for PPID
- Obesity and insulin resistance lead to low grade inflammation, pro-oxidative state
- Increases oxidative degeneration of dopaminergic neurons
- PPID develops earlier in horses with EMS
Briefly outline pituitary independent Cushing’s syndrome in horses
- Primary adrenocortical tumours rare in horses and usually non-functional
- Not worth considering as part of differentials
How do the hormonal imbalances in equine Cushing’s lead to weight loss and muscle wastage?
- Loss of abdominal muscle mass/strength and heavy viscera = rounded appearance
- Hypercortisolaemia = increased gluconeogenesis and protein catabolism
How do the hormonal imbalances in equine Cushing’s lead to PUPD?
- Hypercortisolaemia = increased GFR, reduced ADH, increased water loss
- Hyperglycaemia leads to osmotic diuresis
- Neurogenic diabetes insipidus due to compression of pars nervosa from adenoma of pars intermedia (less ADH)
- Increased water loss through hyperhydrosis
How do the hormonal imbalances in equine Cushing’s lead to hirsutism?
- Lack of decrease in MSH (normally occurs in spring)
- Lack of rise in prolactin which triggers shedding
- Hair held in telogen phase due to increased MSH
How do the hormonal imbalances in equine Cushing’s lead to lethargy?
- Increased beta-endorphins in plasma and CSF
- Increased tolerance to pain and lethargic demeanour
How do the hormonal imbalances in equine Cushing’s lead to increased risk of chronic laminitis?
Hypercortisolaemia increases insulin resistance, leading to hyperinsulinaemia (causes laminitis alone) and hyperglycaemia (glucose toxicity can also lead to laminitis)
How do the hormonal imbalances in Cushing’s lead to increased susceptibility to disease?
Hypercortisolaemia leads to immunosuppression and reduced neutrophil function
How do the hormonal imbalances in equine Cushing’s lead to poor fertility?
- Increased size of pituitary gland leading to destruction of gonadotrophs of anterior pituitary and suppression of gonadotrophin by glucocorticoids and androgens produced by adrenal cortex
- Leads to abnormal oestrus activity and oestrus suppression
What tests are required for diagnosis of PPID?
- Haematology
- Biochemistry
- Resting ACTH concentration
- TRH stimulation test
What haematology and blood biochem results would be expected in a horse with PPID?
- Anaemia
- Neutrophilia/lymphopaenia (stress leukogram)
- Hyperinsulinaemia
- Hyperglycaemia
- Hyperlipaemia
- High liver enzymes
- Glucosuria
What can an oral glucose test be used for?
Ruling OUT EMS and to assess insulin sensitivity status in a horse with PPID
Is a resting ACTH test better for ruling in or out PPID?
Ruling in, it has a low sensitivity so false negatives are likely
Describe the processing of a resting ACTH test
- Submit EDTA plasma
- Needs to be separated and refrigerated within 3 hours of collection as ACTH degenerates at room temperature
- Samples must be submitted chilled
What may lead to a false positive on resting ACTH?
- Freezing full blood
- Stress e.g. pain, infections, hospitalisation, transport
Describe the results expected in a PPID positive animal in Autumn or Summer
- Autumn (Aug, Sept, Oct): >47pg/ml
- Summer: >29pg/ml
Outline the TRH stimulation test for PPId
- Inject 1.0mg thyrotroping releasing hormone IV at T0
- take samples at 0mins and at 10 mins (+/- 30 mins sample)
- Should stimulate release of ACTH from PI
Outline the seasonality of TRH stimulation testing
Should avoid testing August to September (sensitivity 77%, specificity 82%)
What is TRH stimulation best used for?
Ruling out PPID in early suspicion cases i.e. cases with borderline elevated resting ACTH
What results on a TRH stimulation test would be expected in a PPID positive patient?
- At T0: ACTH >35pg/ml
- At T10: ACTH >110pg/ml
Outline the dexamethasone suppression test
- Historical, rarely used now
- Inject 0.04mg/kg dex IV or IM, measure cortisol at 19-24h
What is the sensitivity and specificity of the dexamethasone suppression test for PPID?
- Sensitivity: 65% or less
- Specificity: 76-100%
What results would be expected on a dexamethasone suppression test in a horse with PPID?
Failure to suppress below 2nmol/L
Outline process for the combined DST and TRH stimulation test for PPID
- Dex 40ug/kg IV at 8-10am
- Then TRH 1mg IV 3.5h after dex
- Collect blood at 0h, 3h, 3.5h, 24h
- More samples, more time consuming, more expensive
Describe the sensitivity and specificity of the combined DST/TRH stimulation test
- Increased sensitivity for early PPID cases
- Sensitivity 88%, specificity 76%
What results would be expected in the combined DST/TRH stimulation test in a horse with PPID?
- ACTH > 27nmol/l at 24 h
- Or greater than 66% increase between 3h and 3.5h (post TRH addition) sample
What are the treatments available for the treatment of equine Cushing’s disease?
- Pergolide (dopamine agonist)
- Cyproheptadine (serotonin antagonist)
- Chasteberry/Vitex agnuns castus
- Trilostane
- Diet management
- Laminitis management
- Antimicrobials
- Vit E supplementation
What is the mechanism of action of pergolide?
- Dopamine receptor agonist
- Replaces the dopamine inhibition of melanotrophs
How is ACTH produced and why does this lead to increases in other hormones in PPID?
- Melanotrophs produce POMCs
- Cleaved by prohormone convertase 1 to produce ACTH
- POMCs further cleaved to produce MSH, beta-endorphins, CLIP
- Loss of inhibition leads to increased production of all POMC derived hormones
What are the potential side effects of pergolide?
- Transient anorexia and lethargy
- Mild CNS signs (mild depression, mild ataxia)
- Diarrhoea, colic, sweating
What monitoring is required while treating a horse using pergolide?
- Plasma ACTH concentration
- Or TRH stimulation tests
Give the approximate cost of a month of pergolide treatment in a 500kg horse
~£30
Pack of 60 = £70, pack fo 160= £140
Outline the dosing regime for pergolide
- First start at 1mg total q24h by mouth
- If no improvement at first 4-6 week interval increase by 0.5mg/kg
- Maximum dose 5mg total/d1ay
- Each tablet 1mg
What is the mechanism of action of cyproheptadine?
Serotonin antagonist
Describe the dosing regime with cyproheptadine
- Only in combination with pergolide
- 0.25mg/kg PO q24h for 2 weeks
- Then increase to q12h
- 125mg for 500kg horse
Give the approximate cost of treatment using cyproheptadine
4mg = 1 tablet = 4pence at whole sale/7pence at retail
What side effects may occur with cyproheptadine treatment?
- Drowsiness
- Ataxia
What are the expected benefits of treatment with pergolide?
- Initial improvement in attitude
- Then improvement in PUPD
- Then improvement in muscle mass and haircoat
Outline the use of Trilostane in the treatment of equine Cushing’s
- Some subjective clinical improvement
- Older studies found no improvement
- Currently not recommended
Outline the use of vitex agnus castus in the treatment of equine Cushing’s
- Herbal product (aka Chasteberry)
- Supposedlystimulates dopamine receptor activity but no positive effect found in studies
Outline the dietary management of a PPID patient
- Adequate caloric intake
- Consider insulin sensitivity status
- Free choice hay (2%BWT)
- OIl to supplement calories (1-2 cups daily)
Outline the management of laminitis in a PPID patient
- NSAIDs
- Farriery (choose experienced farrier)
Outline the use of vitamin E supplementation in the management of PPID
- Little evidence, but may prevent further oxidative damage
- Costly
Why are regular faecal egg counts and dental examinations advised for PPID patients?
- Immunosuppression
- Increased risk of dental infection and GI parasitism
