ENI - Hyperadrenocorticism Flashcards
Where is CRH synthesised and released?
Paraventricular nuclei in the hypothalamus
Exlain how ACTH stimulates glucocorticoid production and release
- Transported in blood via transport proteins to adrenal cortex
- Stimulates cholesterol uptake by adrenal gland
- Upregulation of enzymes
What is the effect of cortisol onthe HPA axis?
Negative feedback
What are the causes of hyperadrenocorticism?
- Spontaneous or iatrogenic
- Spontaneous can be either pituitary or adrenal dependent
Compare the incidence of pituitary vs adrenal dependent hyperadrenocorticism
- 80-90% pituitary
- 10-20% adrenal
Describe pituitary dependent HAC
- Often pituitary tumour
- Bilateral hyperplasia of glands
- Microadenomas in 80% of cases, macroadenomas also potential
- Can arise from pars distalis (70%) or pars intemedia (30%)
- Lots of stimulation, more cortisol, but will not respond to negative feedback as tumour is autonomous
- Decrease in CRH as negative feedback via long loop
Describe adrenal dependent HAC
- Adrenal tumout
- Unilateral enlargement (atrophy of contralateral gland)
- Negative feedback, reduced ACTH so atrophy of opposite but tumour side is autonomous
- Independent of pituitary control
- ACTH concentration very low or undetectable
How can pituitary and adrenal HAC be distinguished?
- Hormone levels
- Imaging
What are the physiological changes that occur in HAC?
- Increased cortisol
- Protein and fat mobilisation
- Stimulates gluconeogenesis
- Stimualtes glycogenolysis
- Stabilises lysosomes
Describe the signalment for adrenal dependent HAC in dogs
- Older dogs (11-12 years)
- Larger breeds (>20kg)
- Females more at risk
Describe the signalment for pituitary dependent HAC in dogs
- Middle aged dogs (7-9 years)
- Poodles, dachshunds and small terriers predisposed
- No sex predisposition
Give the clinical signs of canine HAC
- PU/PD
- Abdominal enlargement (pot belly)
- Polyphagic
- Muscle wastage/weakness
- Thin skin
- Hair loss
- Hepatomegaly
- Lethargy/exercise intolerance/panting
- Skin cahnges
- Reproductive changes
- Calinosis cutis
Outline the physiological basis of PU/PD in canine HAC
- Antogonism of ADH, increased glomerular filtration rate, inhibition of ADH release
- However is still unclear
- PD secondary to PU
Outline the physiological basis of pot belly in canine HAC
- Redistribution of fat into abdomen
- Hepatic enlargement
- Wasting and weakness of abdominal muscles
Outline the physiological bases of polyphagia in canine HAC
- Assumed to be direct effect of glucocorticoids
- Making up for use of stores through action of cortisol and stimulated hunger by cortisol
Outline muscle wasting/weakness in canine HAC
- Usually gradually, incorrectly considered normal ageing
- Protein catabolism
- Decreased muscle mass over limbs, spine and temporal region
- Excessive panting
- Myotonia seen occasionally
- Affected limbs are rigid and extend rapidly after passive flexion
Describe some of the skin changes that occur with canine HAC
- Thinning and reduced elasticity
- Prominent abdominal veins
- Due to protein catabolism (atrophic collagen) and loss of subcut fat
- Excessive scale and comedones
- Change in hair coat colour
- Easily bruised
- Wound healing slow
- Alopecia (normally symmetrical)
Why is wound healing slow in canine HAC?
Cortisol inhibits fibroblast proliferation and collagen synthesis
Describe what is meant by calcinosis cutis and how it occurs
- Less obvious clinically, more on biopsy
- Firm, slightly elevated plaques surrounded by erythema, secondary infection common
- Neck, axilla, ventral abdomen and inguinal areas
- Due to increased calcium uptak efrom gut, alteration in liver metabolism of calcium
- Deposition in skin and other organd
What are some complications with canine HAC?
- Are common!
- Urinary tract infections (decreased immune function)
- Glomerulonephropathies (increased GFR)
- Hypercoagulability
- Hypertension
Describe feline HAC
- Uncommon
- Skin fragile and rips
- middle aged to older cats
- Most PDH, 20-25% ADH
Describe the symptoms of feline HAC
- PU/PD
- Polyphagia
- Weight loss
- Extreme skin fragility
- Pot belly
- UTIs
- Diabetes mellitus
What cell type is found in the pars intermedia?
Melanotrophs
What hormones are produced by the pars intermedia
- POMC as precursor
- ACTH (ony 2% of total normal production of ACTH!)
- alpha-MSH
- CLIP
- beta-endorphin
- beta-MSH
- beta-LPH
What is the role of MSH?
Regulation of appetite, sexual behaviour and melanin production
What is the role of CLIP?
- Corticotropin-like intermediate lobe peptide
- Modulation of pancreaitic enzyme function
What is the role of beta-endorphin?
Behaviour (docility)
What is the role of beta-lipotrophin?
- Melanin production
- Steroidogenesis and lipolysis
Outline the control of POMC production
- Dopamine has negative feedback on POMC production Removal of negative feedback then have constant stimulation of production
- CRH and ADH have stimulatory effect
How is ACTH produced from POMC?
Cleavage by prohormone convertase 1
What is the effect of excess ACTH
Increased stimulation of adrenal glands to produce excess cortisol secretion
What is the name given to hyperadrenocorticism in the horse?
- Pituitary pars intermedia dysfunction
- aka Equine Cushing’s disease
What is the cause of PPID?
- Pars intermedia leads to excessive production of POMCs and so the derived peptides
- Leads to hyperadrenocorticism
- Lack of inhibitory control on pars intermedia cell function is what permits development of adenomas
- Neurodegeneration of paraventricular neurones due to oxidative stress (impaired negative feedback)
- Decreased peripheal cleavage of POMC peptides which remain active
Explain how hypothalamic dopamine has inhibitory control on the pars intermedia cell function
- Binds to D2 receptors
- Control of POMC mRNA expression and POMC release
Give the clinical signs of PPID (top 3 first)
- Hirsutism
- Weight loss/wastage
- PU/PD
- Laminitis
- Recurring infections
- Poor performance
- Regional adiposity (pot belly)
- Fat pads on eye socket
- Docility/lethargy
- Neurologic signs (blindness, narcolepsy)
- Infertility
Describe the physiological basis of hirsutism in PPID
- Do not shed coat
- Poorly understood
- Chronic elevation fo MSH
- Pituitary compression of hypothalamic thermoregulatory centre
- Increased production of androgens
How does PPID lead to laminitis?
- High glucocorticoid concentration
- Persistent hyperinsulinaemia and persistent hyperglycaemia
How does PPID lead to PU/PD
- Poorly understood
- Pituitary compression inducing reduced secretion of ADH
- ACTH/cortisol inhibiting ADH action
- Hyperglycaemia/glycosuria leading to osmoti diuresis
How does PPID lead to weight loss/fat mobilisation?
- Pot bellied appearnce, swayback, abnormal fat deposits
- Glucocorticoids have catabolic effect on skeletal muscle
How does PPID lead to lethargy/increased docility?
- beta-endorphin increase
- Doping effect on brain
How does PPID lead to neurologic impairment?
- Blindness due to compression of optic haism
- Narcoplespy (cause unknown, may be due to lack of dopaminergic control and hus decreased orexin that regulates sleep-wake cycles)
How does PPID lead to immunesuppression and give examples of common conditions
- Increased concentration of immunosuppressive hormones (cortisol, alpha-MSH, beta-endorphin)
- Typically skin infections, sinusitis, cellulitis
Describe the epidemiology of PPID
- Older horses (15-30% of horses >15 years)
- Minimum 7 years of age
- Ponies predisposed
- No gender prevalence
- Often pituitary microadrenomas and adenomas found at post mortem in horses with no clincal signs
What is included when diagnosing PPID?
- History
- Physical examination
- Biochemistry
- Hormone testing
- Diagnostic imaging
What would you expect to find in the history of a horse with PPID?
- Respiratory infection, sinusitis
- Old
- pottery when walking
- Lost weight
- Changes in demeanour, PU/PD
What would you expect to find on biochemistry of a horse with PPID?
- Hyperglycaemia/hyperinsulinaemia
- Hypertriglyceridemia
- Neutrophilia and relative lymphopaenia
What tests can be done to diagnose PPID?
- Resting ACTH
- TRH stimulation test
- Dexamethasone suppression test (DST, less common)
- Combined DST-TRH
- Insulin resistance tests
- Test for POMC
Describe resting ACTH in PPID diagnosis
- Seasonal variation in normal levels (higher August to October) so cannot compare across seasons and need to know ref range
- Collect sample and separate plasma ASAP
- Submit chilled as is very sensitive to temperature
What may cause false negatives in resting ACTH testing for PPID?
- Incorrect storage
- Early PPID
- Not accounting for season
What may cause false positive in resting ACTH testing for PPID?
- Stress/pain (laminitis)
- Not accounting for season
Describe the TRH mediated ACTH response test (now known as TRH stimulation test) in PPID testing
- Relies on aberrant response of pit adenomas to TRH with subsequent further release of ACTH
- Mechanism poorly understood
- Sample baseline, measure ACTH, administer TRH IV, sample 30 mins later
- In PPID, ACTH will be >100pg/mL after TRH
- Not suitable July to November
- Used where have normal ACTH but still suspect
Describe the dexamethasone suppression test
- OBSOLETE
- Standard and overnight
- In both would normally have suppression of plasma cortisol, no change if PPID
- Avoid July to October
Describe the old TRH stimulation test
- Same as new, but measured cortisol concentration rather than ACTH
- No longer recommended (unless in combination with DST)
Describe the DST-TRH test for PPID
- Indicated for subtle cases without obvious clinical signs
- Baseline sample
- Dex administered, sample 3 hours after dec (T2)
- Sample 3 hours after TRH (T3)
- sample 24 hours after dex (T4) i.e. 4 samples in total
- Positive if cortisol >1ug/dL at 24 hours and cortisol at T2 >66% cortisol at T3
Describe resting insulin testing for PPID
- Evaluation of insulin resistnace
- Reasonably sensitive, low specificity (EMS, stress, pain)
- ## Negative prognostic value (higher risk of laminitis with IR)
Discuss imaging in PPID diagnosis
- CT, MRI may identify pituitary enlargement
- CT: difficult positioning
- MRI: hardly avaialble
- Require GA, costly, poor sensitivity
Explain why the ACTH stimulation test is not useful in PPID diagnosis
- Will not stiulate cortisol production from maximally stimulated adrenal glands
- Equine Cushing’s disease is central and not peripheral in origin
- Horses do not get adreanl dependent Cushing’s
What is the main treatment for PPID?
- Administration of D2-agonists (pergolide, bromocriptine)
- Ameliorates clinical signs of PPID
- Decreases ACTH concentration in most cases
Define polydipsia and give values for the dog and cat
- Excessive water intake
- Dog: >90-100ml/kg/day
- Cat: >45ml/kg/day
Define polyuria and give an approximate value
- Excessive urine output
- >50ml/kg/day
List factors external to an animal that would influence their water intake
- Temperature
- Activity level
- Stress
- Hunger
- Humidity
- Water content of diet
- Drugs
- Other diseases
- Access to water
Give the cause of primary nephrogenic diabetes insipidus
Congenital/familial lack of ADH receptors
Give the potential causes of secondary nephrogenic diabetes insipidus
- Acquired condition
- Several diseases/toxicities that interfere with binding of ADH to its receptors and/or its action in the kidney
Give causes of central diabetes insipidus
- Tumour or degeneration of hypothalamus/neurohypophysis preventing or reducing release of ADH
- Idiopathic
- Trauma
List endocrinopathies that can cause secondary nephrogenic diabetes indipidus
- Hyperadrenocorticisim
- Hypoadrenocorticism
- Hyperthyroidism
- Hypercalcaemia
List non-endocrine disease that can cause secondary nephrogenic diabetes insipidus
- Chronic renal disease
- Liver disease
- Infection (sepsis, pyelonephritis, pyometra)
- Drugs (diuretics
Describe how exogenus ADH can be used to distinguish central from primary nephrogenic diabetes insipidus
- In central: ADH would increase USG as are able to concentrate urine again as have corrected lack of ADH
- In nephrogenic: no effect on USG as problem lies with nephrons and lack of ADH receptors
Describe changes expected in biochemistry with HAC
- High ALP (alkaline phosphatase, steroid induced)
- Mid to moderate increase in ALT
- Cholesterol incerase
- Bile acids increased
- Fasting glucose increase
- BUN decreased
Describe changes expected in complete blood count (CBC) with HAC
- Stress response: neutophilia and lymphoenia
- Produced in reposne to increased steroids
Describe changes expected in urinalysis with HAC
- USG often <1.015 but can be hyposthenuric (<1.008)
- UP:UC ratio >1
- Proteinuria
- Evidence of UTI (inflam cells, but may be reduced due to steroidal effects)
Describe common radiographic findings in HAC
- Hepatomegally, pot-bellied, calcinosis cutis, distended bladder (PUPD), adrenal enlargement/calcificationin ADHAC
- On thoracic sometimes tracheal and bronchial wall mineralisation, pulmonary metastasis, osteoporosis
Describe common ultrasonographic findings in HAC
- Normal size woudl be 12-33mmx3-7mm
- Hyperplastic adrenals large but normal echogenicity
- Compare size of both glands
- Thickness >7.5mm for left gland considered sensitive
- Distinguish between ADHAC and PDHAC (unilateral vs bilateral enlargment)
- May see evidence of metastatic disease in vena cava
What are the features of HAC diagnosis?
- Strong index of suspicion (sgnalment etc)
- History
- Thorough clinical examination
- Blood test investigations (Biochem, CBC)
- Urinalysis
- Imaging
- Specific diagnostic tests
What are the 2 types of specific diagnostic tests for HAC?
- Screening
- Differentiating (ADHAC or PDHAC?)
What are the HAC screening tests?
- Urinary cortisol:creatinine ratio
- ACTH stimulation test
- Low dose dexamethasone suppression (LDDS) test
- 17-alpha-OH progesterone
Describe urinary cortisol:creatine ratio in HAC diagnosis
- Cortisol has diurnal variation
- But ratio tells us what cortisol has been doing over last few hours
- Low ratio makes HAC extremely unlikely i.e. high sensitivity
- High ratio could be HAC but not necessarily i.e. low specificity
- Good for ruling out but false positives possible
Describe the ACTH stimulation test in HAC diagnosis
- High sensitivity
- Best specificity of screening tests
- Good for ruling in disease
- Starve overnight, baseline at any point in day (heparin sample) T0, admin ACTH IV, sample 30-60 min later (heparin tube)
- Normal: pre-stim <200nmol/, post-stim:<600nmol/l
- Positive: post-stim >600nmol/l
- Supraphysiological admin of ACTH should lead to increased cortisol
- Exaggerated response with Cushings (both forms)
Describe the low dose dexamethasone test in HAC diagnosis
- More sentitive, low specificity (more false positive)
- Few false negatives
- prolonged hospital stay
- Starve overnight, collect baseline heparin sample, Admin dex IV, heparin samples 3 and 8 hours later
- Measure cortisol in each
- Normal: neg loops stimulated, endogenous cortisol reduced
- Positive: cortisol not suppressed, >50nmol/l at 8 hours
Describe the 17 alpha-OH progesterone test in HAC diagnosis
- Measure intermediate steroid hormones in cortisol production pathway rather than cortisol
- Assays available
- Uncommon to be used in practice
Explain the importance of differentiation between ADHAC and PDHAC
- Different treatments
- For ADHAC: adrenalectomy
- ADHAC usually more resistant to treatment
- PDHAC has better prognosis
- With pituitary macroadenomas diagnosed ened to monitor for neurological signs
List the HAC differentation tests
- High dose dexamethasone suppression test
- Endogenous ACTH
- Adrenal imaging
- Pituitary imaging
Describe the high dose dexamethasone suppression test in HAC differentiation
- Not good at differentiating but is calssed as one!
- Same protocol as LDDS, but more dex
- Theory: in PDHAC should inhibit pit ACTH secretion through negative feedback and suppress cortisol
- Adrenocortical tumours are autonomous and thus cortisol not suppressed
- But often fails to suppress PDH so no longer recommended
Describe endogenous ACTH in HAC differentiation
- ACTH measured
- PDHAC should be high (pit tumour producing lots of ACTH)
- ADHAC should be low (-ve feedback dur to high levels of cortisol from adrenal tumour)
- Difficult sample to handle, needs to remain chilled
Describe adrenal imaging in HAC differentiation
- PDHAC: symmetrical enlargement and normal conformation
- ADHAC: one enlarged gland and one atrophied gland
- May see invasion of malignant tumour
Describe pituitary imaging in HAC differentation
- Uncommon
- CT or MRI
- 505 of dogs with PDHAC have detectable pit mass on MRI
- Normal vs enlarged ot clearly defined
- Contrast agent used to highlight tumour
Describe diagnosis of feline HAC
- Uncommon, diagnosis difficult
- Urine cortisol:creatinine sensitive screening test
- ACTH stim (but 50% cats have within reference range results)
- LDDS test combined with ACTH stim more reliable
- Usually concurrent diabetes mellitus
Expain how PPID can lead to laminitis
- Hyperinsulinaemia
- Endothelial cell dysfunction (inhibition of NO release by endothelial cells, endothelin-1 synthesis and sympathetic nervous activation enhancing vasoconstriction)
- Digital vasoconstriction takes place
- Impaired glucose uptake from epidermal laminal cells
- Altered epidermal cell function or mitosis
- Matrix metalloproteinase activation
- Pro-inflammatory/pro-oxidative state also in lamellar tissue
Compare PPID and EMS
- EMS = equine metabolic syndrome
- Defined by presence of obesity, insulin resistance and predisposition to laminitis, younger animals, pro-inflammatory
- PPID is loss of regulation of hormonal output from pars intermedia of pituitary gland
Outline the diagnosis of EMS
- Aim to confirm IR status combined with clinical signs and rule out PPID
- Resting insulin and glucose measurement
- Proxis of insulin sensitivity
- Dynamic testing e.g. in-feed glucose challenge
- Blood pressure measurement
- Adipokine measurement (research)
Desribe basal insulin/glucose measurement for EMS
- Simple, cheap
- High resting insulin highly suggestive of IR
- Low insulin and high glucose point towards T2 diabetes
- Little sensitivity and specificity
- Affected by stress, whether fed or fasted and season (if at pasture)
Describe the oral glucose challenge test for EMS diagnosis
- Fast overnight
- Administer non-glycaemic feed (chaff) with 1g/kg glucose powder orally
- Measure insulin at 2h
- Insulin >85IU/ml indicative of IR
Describe the combine G-I test (CGIT) for EMS diagnosis
- Fast overnight
- Obtain basal glucose and insulin
- Administer glucose
- Measure glucose 1 min after admin then every 5 mins after for 45 mins, then every 15 mins for 2-3 hours
- Measure insulin at 45 min
- Prolonged hypercalcaemia suggests IR
- High insulin at 45 mins suggests exaggerated insulin response
What are the anatomical landmarks used to locate the adrenal glands on ultrasound?
- Kidneys
- Vena cava
- Aorta
What is the normal size of the adrenal glands in the dog?
- Width upper limit: 7.5-10m
- Length: 20-30mm
What is the normal size of the adrenal glands in the cat?
- Width: 3/9-4.3mm
- Lenght: 10.7mm
What ultrasonographic and radiographic signs, other than adrenomegaly, support a diagnosis of hyperadrenocorticism?
- Hepatomegaly
- Enlarged/displaced bladder +/- cystoliths
- Dystrophic mineralisation of soft tissues e.g. kidney
- Osteopaenia (thinning bones)
- Adrenal mass
- Excellent contrast on radiography due to intra-abdominal fat
- Calcinosis cutis
