Equine Endocrinopathies: PPID, EMS, and Hyperadrenocorticism Diagnosis and Clinical Signs

what are the 2 main diseases that cause endocrinopathic laminitis?

- Pituitary pars intermedia dysfunction (PPID)

- Equine metabolic syndrome (EMS)

what clinical signs are associated with PPID?

- Usually older horses (> 15 y)

- Long thick curly hair coats (hypotrichosis), hair not shed at end of winter

- Muscle wasting

- Polyuria, polydipsia, polyphagia

- Sweating

- Abnormal fat distribution = regional adiposity

- Insulin resistance and hyperinsulinaemia associated laminitis

- Immunosuppression

what clinical signs are associated with EMS?

- Some are obese, others are lean.

- Abnormal fat distribution (cresty neck, over tail head, ribs, prepuce, mammary gland) May be thin elsewhere.

- Clinical laminitis

- Divergent hoof rings suggestive of subclinical or chronic laminitis

- May have polyuria, polydipsia

what CBC/biochemistry results can be seen with PPID?

- Stress leukogram

- Mild to moderate hyperglycaemia in 25-75% cases

- Liver enzyme activities may be increased

- Cholesterol and triglycerides may be increased

what CBC/biochemistry results can be seen with EMS?

- Glucose usually normal, uncommonly may have hyperglycaemia

- Liver enzyme activities may be increased

- Cholesterol and triglycerides may be increased

what is the pathogenesis of PPID?

- the pars intermedia is controlled by dopamine producing neurons from the hypothalamus, which inhibit its hormone production.

- age-related oxidative damage in the hypothalamus leads to loss of dopaminergic neurons.

- Without dopamine inhibition, the pars intermedia overproduces ACTH and related peptides

- results in the clinical signs of PPID

How does the lack of dopaminergic inhibition of ACTH and corticotrophic peptide production by the pars intermedia affect the size of the pars distalis and pars intermedia?

- Pars distalis will be smaller (due to continual negative feedback)

- Pars intermedia will be larger (due to constant stimulation)

what diagnostic tests can be done to diagnose PPID?

- Plasma ACTH concentration

- Thyrotropin releasing hormone (TRH) stimulation test

- Overnight dexamethasone suppression test

when is the best time to measure Plasma ACTH concentrations and why?

in autumn

- the difference in ACTH concentrations between normal and PPID animals is greater in autumn than it is at other times of the year.

when would we use the THR stimulation test?

- outside NZ (not currently available)

- for horses with clinical signs suggestive of PPID but normal or equivocal ACTH results

- should be avoided in late summer and autumn.

what results of Plasma ACTH concentration are indicative of PPID?

increased ACTH above reference range

What do you think will happen to ACTH secretion after administration of TRH in the normal horse?

Small increase in serum ACTH concentration

What do you think will happen to ACTH secretion after administration of TRH in a horse with PPID?

Large increase in serum ACTH concentration

- due to increased storage of ACTH by hyperplastic cells of the pars intermedia.

what is the Overnight dexamethasone suppression test

- a time 0 blood sample is taken, dexamethasone is given, and another sample is taken 19 h later.

- Cortisol is measured.

- In normal horses; cortisol production will be low.

- In horses with PPID cortisol concentrations will remain high.

why is the Overnight dexamethasone suppression test not often used anymore?

it has low sensitivity; better to wait till autumn and measure ACTH concentrations; not an emergency diagnosis.

what is best practice for diagnosing PPID?

- measuring Plasma ACTH concentration in autumn

what is the key feature of EMS?

Insulin dysregulation

- where tissues fail to adequately respond to insulin, resulting in abnormal handling of glucose and triglycerides by the body

what are the tests used to diagnose EMS?

- Resting insulin concentration

- Oral glucose or oral sugar test

- Insulin response test

what Resting (basal) insulin concentration is seen with horses with EMS?

usually increased in horses

What will happen to insulin secretion after administration of oral glucose/sugar in the normal horse?

Normal serum insulin concentration

- increased after eating, then gone back down to normal when blood sample is taken.

what will happen to insulin secretion after administration of oral glucose/sugar in a horse with EMS?

High serum insulin concentration

- when resistant to insulin it requires greater and longer response to bring down blood glucose compared to a normal horse.

What will happen to the glucose concentration after administration of insulin in a horse with EMS?

Normal serum glucose concentration

- may drop minimally (less than 50%) and then return to normal quicker than normal horses.

What will happen to the glucose concentration after administration of insulin in a horse without EMS?

a 50% reduction in serum glucose at 30 minutes, and then return to baseline around 2 hours.

what are the 3 main causes of hyperadrenocorticism?

- adrenal dependant (functional tumour of adrenal cortex)

- pituitary dependant (functional tumour of the pituitary)

- iatrogenic (chronic high dose treatment of corticosteroids)

why is it important to determine the cause of hyperadrenocorticism?

the treatment options differ

what main clinical signs are associated hyperadrenocorticism?

- Polyuria/polydipsia

- Polyphagia

- Pot bellied appearance

- Endocrine alopecia

- thinning of skin

- wounds slow to heal

what will happen to the size of the adrenal glands when there is a functional pituitary tumour producing ACTH?

they will both become hyperplastic (increase in size) due to increase in activity due to stimulation by ACTH

What will the size of the adrenal glands be when there is adrenal gland neoplasia?

- adrenal with the tumour will be enlarged

- other adrenal will be smaller than normal (due to negative feedback)

what CBC / biochem results are indicative of hyperadrenocorticism?

- Increased ALP without biliruben = main finding (corticosteriod induced isoform)

- Increase in ALT (glycogen accumulation in hepatocytes)

- stress leukogram

- hyperglycaemia

- hypercholesterolaemia

what urinalysis results would you expect with hyperadrenocorticism?

- Urine specific gravity is often < 1.020, due to polyuria.

- Urinary tract infections (UTIs) are common (bacteriuria)

what mechanisms contribute to urinary tract infections in dogs with hyperadrenocortism?

- immunosuppression

- incomplete emptying due to muscle weakness

- urolith formation leading to mechanical obstruction

- dilute urine

what are the screening tests used for hyperadrenocorticism?

- Urine cortisol:creatinine ratio

- Low dose dexamethasone suppression test

- ACTH stimulation test

what result would an animal with hyperadrenocorticism show with urine cortisol:creatinine ratio?

increased urine cortisol:creatinine ratio.

what is the Low dose dexamethasone suppression test?

Blood samples are obtained prior to (time 0), and then at 4 and 8 hours after administration of 0.01 mg/kg dexamethasone IV.

what results would you expect from a normal animal when LDDST is done?

cortisol remains suppressed for over 8 hours after dexamethasone administration.

what results would you expect from an animal with ADH when LDDST is done?

show no suppression of cortisol

what results would you expect from an animal with PDH when LDDST is done?

- 85-95% show no suppression at 8 hours.

- 30% show temporary suppression at 4 hours, but cortisol rebounds by 8 hours.

What size response in serum cortisol concentration would happen when hyperplastic or neoplastic adrenal glands are stimulated with ACTH?

a much bigger increase than normal.

- as hyperplastic or neoplastic adrenal glands have greater stores of cortisol

what are the discriminatory tests for hyperadrenocorticism?

- High dose dexamethasone suppression test

- Plasma ACTH concentration (not available in NZ)

- Abdominal imaging (ultrasound, CT, MRI)

what are the results of HDDST indicative of?

- Suppression of cortisol production at 3-4 h +/- 8 h -> ~75% of PDH

- No suppression of cortisol production ADH and ~25% of PDH

- no suppression = still unclear.

if you have no suppression of cortisol production with HDDST what would be your next step?

imaging (ultrasound, CT) of the adrenal glands

- bilateral adrenal enlargement (PDH)

- unilateral adrenal enlargement (ADH)

In a dog with ADH what would the ACTH concentration be compared to normal?

Decreased - due to negative feedback from cortisol produced by the tumour.

In a dog with PDH what would the ACTH concentration be compared to normal?

normal to increased due to production of ACTH by the tumour.

what clinical signs are associated with Hyperadrenocorticism in cats?

- PU/PD

- abdominal enlargement

- polyphagia

- skin atrophy

- skin fragility (skin tearing even with gentle handling)

- alopecia, weight loss, lethargy, and muscle loss.

what CBC/biochem results are seen in cats with Hyperadrenocorticism?

- stress leukogram

- Hyperglycaemia

- Hypercholesterolaemia

- ALP often not increased (don't have glucocorticoid induced ALP isoform)

what are the types of adrenal neoplasia that can occur?

- Adrenocortical tumours (Adenomas and Adenocarcinomas)

- Phaeochromocytomas

what are Phaeochromocytomas?

- Tumours of the adrenal medulla

- often large and may be bilateral, with brown to red colouration due to haemorrhage/necrosis

how can we diagnose the type of adrenal neoplasia?

Histology is required for definitive diagnosis of each tumour

- Gross appearance can't reliably distinguish tumour types

what are the main causes of hypoadrenocorticism?

- Idiopathic cortical atrophy (Leads to primary hypoadrenocorticism and likely immune mediated)

- Loss of ACTH stimulation due to pituitary damage (causes secondary hypoadrenocorticism)

- Medical treatment for hyperadrenocorticism

- Abrupt withdrawal of long-term or high dose corticosteroids

what are the most common clinical signs of hypoadrenocorticism?

- Lethargy

- Anorexia

- Vomiting

- Other potential clinical signs include diarrhoea (may have melaena or haematochezia), PU/PD, weakness, shaking, shivering.

what can cortisol deficiency cause and what are the related clinical signs?

- Hypoglycaemia → ataxia, tremors, seizures

- Lethargy and poor response to stress

- GI ileus → worsens vomiting and diarrhoea

- GI ulcers → bleeding, haematochezia, melaena, abdominal pain

- Hypovolaemia, hypotension, and shock due to reduced vascular sensitivity to catecholamines

what can aldosterone deficiency cause and what are the related clinical signs?

- Hyponatraemia and hyperkalaemia

- Impaired absorption of Na⁺, Cl⁻, and water from GIT → contributes to vomiting and diarrhoea

- Sodium and water loss → dehydration, hypovolaemia, hypotension, ↓ cardiac output, ↓ tissue perfusion (prolonged CRT, weak pulses, hypothermia), ↓ GFR → shock

- Hyperkalaemia → ↓ myocardial excitability, bradycardia, ↓ cardiac output → potentially fatal

what CBC/biochem changes can be present in an animal with hypoadrenocorticism?

- mild non-regenerative anaemia

- normal lymphocyte count or lymphocytosis (may have eosinophilia)

- hyperkalaemia

- hyponatraemia

- Na:K is < 25:1

- azotaemia

- inadequately concentrated urine i.e. <1.030.

why can animals with hypoadrenocorticism have inadequately concentrated urine i.e. <1.030?

- aldosterone deficiency

- increased Na loss

- decreased medullary concentration gradient

- medullary washout

- inability to retain water

- inappropriately low USG

what are the confirmatory tests for hypoadrenocorticism?

- One-off resting cortisol concentration

- ACTH stimulation test

how must One-off resting cortisol concentrations be interpreted?

Low cortisol concentrations must however be backed up with an ACTH stimulation test to confirm the diagnosis, as low basal cortisol can be due to non-adrenal illness

what results would you expect from ACTH stimulation test from an animal with hypoadrenocorticism?

Failure of cortisol to double or increase into the reference range is diagnostic

what gross lesions are associated with hypoadrenocorticism?

- a thin adrenal cortex as a result of atrophy and fibrosis

what are the characteristics of atypical hypoadrenocorticism?

- present with vague signs (weight loss, lethargy, inappetence, vomiting ,diarrhoea) without the classic electrolyte changes seen in Addison's disease

- These dogs are typically older and have a chronic history

- Common lab findings include Hypoalbuminaemia, Hypocholesterolaemia, Hypoglycaemia, Anaemia

- show the same ACTH stimulation test response

what are thyroid hormones are involved in?

- glucose metabolism

- heart rate and contractility

- body heat production

- fat mobilisation

- brain development

- affect nearly all cells in the body

what can cause hypothyroidism?

- (95%) primary (i.e. due to thyroid gland disease).

- few cases due pituitary disease (secondary hypothyroidism)

what are some causes of Primary hypothyroidism?

- lymphocytic thyroiditis

- idiopathic thyroid atrophy

what is lymphocytic thyroiditis?

- immune-mediated destruction of the thyroid.

- results in progressive destruction of the thyroid gland and, eventually fibrosis.

what is Idiopathic thyroid atrophy?

degeneration of thyroid follicles and replacement with fat and fibrous tissue

when does Hypothyroidism develop?

once more than 80% of thyroid function has been lost.

what do clinical signs of hypothyroidism result from?

- lack of thyroid hormone, leading to a decrease in metabolic rate.

- Thyroid hormones affect just about every cell in the body, so the effects can be wide ranging.

what clinical signs can be seen with hypothyroidism?

- Lethargy

- Weight gain & obesity, despite decreased appetite

- Constipation, vomiting & diarrhoea

- Exercise intolerance

- Cold intolerance/heat seeking

- Mental dullness

- Alopecia and slow hair regrowth (often bilaterally symmetrical on trunk, may also be focal eg "Rat tail")

- Dry, brittle, dull hair coat

- Seborrhoea

- Recurrent secondary skin infections

- Lipid keratopathy, keratoconjunctivitis sicca

- Weakness, ataxia, proprioceptive deficits, peripheral neuropathies

- Infertility, irregular/absent oestrus cycles

- Bradycardia - uncommon

- "Tragic facial expression" - due to myxoedema.

- Myxoedema coma (rare emergency presentation)

what CBC/biochem changes are seen with hypothyroidism?

- normocytic normochromic anaemia

- Hypercholesterolaemia (most common finding)

- mild increase in liver enzymes

- mild increase in creatine kinase (CK)

- may have pre-renal azotaemia

what are the confirmatory tests for hypothyroidism?

- Serum Total T4 (TT4) concentration

- - Thyroid stimulating hormone (TSH)

- free T4 (if equivocal results)

What do you expect the TT4 concentration will be in a hypothyroid dog?

- Lower than reference range

In a dog with hypothyroidism and low TT4, what do you expect would happen to the TSH concentration?

TSH would increased

In a dog with hypothyroidism and low TT4, what do you expect would happen to the free T4 concentration?

FT4 would be decreased

what else can cause low TT4 levels?

- common illnesses include: hyperadrenocorticism, inflammation/fever, diabetes mellitus, chronic kidney disease, liver diseases, chronic skin disease and neoplasia.

- numerous drugs

- breed

- older dogs

what may finding finding low T4 and normal TSH mean?

- euthyroid sick syndrome - animal is responding appropriately to non-thyroidal illness

- medications - the animal is on medication that suppresses T4 concentrations

- hypothyroidism - the animal is one of the proportion of hypothyroid dogs in which increased TSH is not seen

what are key points to do with the diagnosis of hypothyroidism?

- Low TT4 and high TSH in combination is highly reliable for diagnosing hypothyroidism (95% specificity)

- Only test dogs that you suspect to have hypothyroidism for TT4 and TSH

- Try to test dogs when they are well, this is not an emergency diagnosis.

what is goitre?

a non-neoplastic, non-inflammatory enlargement of the thyroid gland commonly seen in livestock due to Iodine deficiency and/or goitrogenic substances

what are different causes of thyroid enlargement?

- nodular hyperplasia or adenoma

- thyroid carcinoma

- adenomatous hyperplasia

what is a thyroid carcinoma?

- uncommon, usually non-functional tumour in dogs

- can arise in the thyroid gland or ectopic thyroid tissue.

- typically firm, non-painful, and may be fixed due to local invasion

- it can metastasise directly to the lungs

what does cytology of a thyroid carcinoma show?

- clusters of epithelial cells forming acini.

- are highly vascular, so FNA often yields blood-rich samples, and tumours may bleed after FNA.

- usually malignant even tho it looks pretty uniform.

what is the most common endocrinopathy of cats?

hyperthyroidism

what clinical signs are associated with hyperthyroidism?

- weight loss

- polyphagia (occasionally anorexia)

- tachycardia, gallop sounds, systemic hypertension

- PU/PD

- irritability/nervousness

- intermittent GI signs (vomiting, diarrhoea)

- palpably enlarged thyroid gland

what do cats with hyperthyroidism often develop?

hypertrophic cardiomyopathy.

how does hyperthyroidism lead to HCM?

- Thyroid hormones directly stimulate cardiac muscle protein production, and increase myocardial contractility which enhances stroke volume, and cardiac output.

- indirectly boost cardiac output by; Activating the adrenergic (sympathetic) system, Stimulating the renin-angiotensin system (↑ blood volume) and Increasing erythropoietin (↑ red blood cells).

- These effects contribute to hypertension, increasing cardiac workload and leading to myocyte hypertrophy.

what heart related clinical signs can cats with HCM due to hypothyroidism have?

- tachycardia

- gallop sounds

- heart murmur

- systemic hypertension

- arrhythmias

- cardiomegaly on radiographs

- hypertrophy of the left ventricular wall on echocardiography

- may progress to congestive heart failure, with pleural effusion or pulmonary oedema

- aorto-iliac thromboembolism

what are the 5 P's of aorto-iliac thromboembolism?

- pain

- paralysis/paresis

- pulsenessless

- pale

- poikilothermy (cold)

what CBC/biochem results can occur with hyperthyroidism in cats?

- mild increase in PCV due to either increased erythropoietin production or dehydration (from polyuria).

- stress leukogram

- mildly to markedly increased Liver enzymes, particularly ALT, lesser extent ALP. (most common finding)

- low serum creatinine

- Urea may be high

- hyperglycaemia

- changes in Ca and P

how can treatment of hyperthyroidism lead to chronic kidney disease?

- In cats with hyperthyroidism, glomerular filtration rate is often increased

- Treatment of hyperthyroidism decreases heart rate and blood pressure, decreasing glomerular filtration rate

- can tip a teetering kidney over into chronic kidney disease

what confirmatory testing can be used for hyperthyroidism?

- Total T4 (TT4)

- Free T4 (if other test is equivocal)

what cells produce glucagon?

alpha cells

What cells produce insulin?

beta cells

what pathways are stimulated by insulin?

- glycogenesis

- glycolysis

What pathways are inhibited by insulin?

- glycogenolysis

- gluconeogenesis

what is Diabetes mellitus?

a metabolic disorder resulting from inadequate insulin to meet the metabolic demands of the body.