Endo > Hyperadrenocorticism > Flashcards

Hyperadrenocorticism Flashcards

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1
Q

Where is CRH synthesised and released?

A

Paraventricular nuclei in the hypothalamus

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2
Q

Exlain how ACTH stimulates glucocorticoid production and release

A
  • Transported in blood via transport proteins to adrenal cortex
  • Stimulates cholesterol uptake by adrenal gland
  • Upregulation of enzymes
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3
Q

What is the effect of cortisol onthe HPA axis?

A

Negative feedback

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4
Q

What are the causes of hyperadrenocorticism?

A
  • Spontaneous or iatrogenic

- Spontaneous can be either pituitary or adrenal dependent

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5
Q

Compare the incidence of pituitary vs adrenal dependent hyperadrenocorticism

A
  • 80-90% pituitary

- 10-20% adrenal

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6
Q

Describe pituitary dependent HAC

A
  • 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
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7
Q

Describe adrenal dependent HAC

A
  • 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
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8
Q

How can pituitary and adrenal HAC be distinguished?

A
  • Hormone levels

- Imaging

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9
Q

What are the physiological changes that occur in HAC?

A
  • Increased cortisol
  • Protein and fat mobilisation
  • Stimulates gluconeogenesis
  • Stimualtes glycogenolysis
  • Stabilises lysosomes
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10
Q

Describe the signalment for adrenal dependent HAC in dogs

A
  • Older dogs (11-12 years)
  • Larger breeds (>20kg)
  • Females more at risk
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11
Q

Describe the signalment for pituitary dependent HAC in dogs

A
  • Middle aged dogs (7-9 years)
  • Poodles, dachshunds and small terriers predisposed
  • No sex predisposition
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12
Q

Give the clinical signs of canine HAC

A
  • 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
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13
Q

Outline the physiological basis of PU/PD in canine HAC

A
  • Antogonism of ADH, increased glomerular filtration rate, inhibition of ADH release
  • However is still unclear
  • PD secondary to PU
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14
Q

Outline the physiological basis of pot belly in canine HAC

A
  • Redistribution of fat into abdomen
  • Hepatic enlargement
  • Wasting and weakness of abdominal muscles
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15
Q

Outline the physiological bases of polyphagia in canine HAC

A
  • Assumed to be direct effect of glucocorticoids

- Making up for use of stores through action of cortisol and stimulated hunger by cortisol

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16
Q

Outline muscle wasting/weakness in canine HAC

A
  • 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
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17
Q

Describe some of the skin changes that occur with canine HAC

A
  • 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)
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18
Q

Why is wound healing slow in canine HAC?

A

Cortisol inhibits fibroblast proliferation and collagen synthesis

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19
Q

Describe what is meant by calcinosis cutis and how it occurs

A
  • 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
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20
Q

What are some complications with canine HAC?

A
  • Are common!
  • Urinary tract infections (decreased immune function)
  • Glomerulonephropathies (increased GFR)
  • Hypercoagulability
  • Hypertension
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21
Q

Describe feline HAC

A
  • Uncommon
  • Skin fragile and rips
  • middle aged to older cats
  • Most PDH, 20-25% ADH
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22
Q

Describe the symptoms of feline HAC

A
  • PU/PD
  • Polyphagia
  • Weight loss
  • Extreme skin fragility
  • Pot belly
  • UTIs
  • Diabetes mellitus
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23
Q

What cell type is found in the pars intermedia?

A

Melanotrophs

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24
Q

What hormones are produced by the pars intermedia

A
  • POMC as precursor
  • ACTH (ony 2% of total normal production of ACTH!)
  • alpha-MSH
  • CLIP
  • beta-endorphin
  • beta-MSH
  • beta-LPH
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25
What is the role of MSH?
Regulation of appetite, sexual behaviour and melanin production
26
What is the role of CLIP?
- Corticotropin-like intermediate lobe peptide | - Modulation of pancreaitic enzyme function
27
What is the role of beta-endorphin?
Behaviour (docility)
28
What is the role of beta-lipotrophin?
- Melanin production | - Steroidogenesis and lipolysis
29
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
30
How is ACTH produced from POMC?
Cleavage by prohormone convertase 1
31
What is the effect of excess ACTH
Increased stimulation of adrenal glands to produce excess cortisol secretion
32
What is the name given to hyperadrenocorticism in the horse?
- Pituitary pars intermedia dysfunction | - aka Equine Cushing's disease
33
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
34
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
35
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
36
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
37
How does PPID lead to laminitis?
- High glucocorticoid concentration | - Persistent hyperinsulinaemia and persistent hyperglycaemia
38
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
39
How does PPID lead to weight loss/fat mobilisation?
- Pot bellied appearnce, swayback, abnormal fat deposits | - Glucocorticoids have catabolic effect on skeletal muscle
40
How does PPID lead to lethargy/increased docility?
- beta-endorphin increase | - Doping effect on brain
41
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)
42
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
43
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
44
What is included when diagnosing PPID?
- History - Physical examination - Biochemistry - Hormone testing - Diagnostic imaging
45
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
46
What would you expect to find on biochemistry of a horse with PPID?
- Hyperglycaemia/hyperinsulinaemia - Hypertriglyceridemia - Neutrophilia and relative lymphopaenia
47
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
48
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
49
What may cause false negatives in resting ACTH testing for PPID?
- Incorrect storage - Early PPID - Not accounting for season
50
What may cause false positive in resting ACTH testing for PPID?
- Stress/pain (laminitis) | - Not accounting for season
51
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
52
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
53
Describe the old TRH stimulation test
- Same as new, but measured cortisol concentration rather than ACTH - No longer recommended (unless in combination with DST)
54
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
55
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) -
56
Discuss imaging in PPID diagnosis
- CT, MRI may identify pituitary enlargement - CT: difficult positioning - MRI: hardly avaialble - Require GA, costly, poor sensitivity
57
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
58
What is the main treatment for PPID?
- Administration of D2-agonists (pergolide, bromocriptine) - Ameliorates clinical signs of PPID - Decreases ACTH concentration in most cases
59
Define polydipsia and give values for the dog and cat
- Excessive water intake - Dog: >90-100ml/kg/day - Cat: >45ml/kg/day
60
Define polyuria and give an approximate value
- Excessive urine output | - >50ml/kg/day
61
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
62
Give the cause of primary nephrogenic diabetes insipidus
Congenital/familial lack of ADH receptors
63
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
64
Give causes of central diabetes insipidus
- Tumour or degeneration of hypothalamus/neurohypophysis preventing or reducing release of ADH - Idiopathic - Trauma
65
List endocrinopathies that can cause secondary nephrogenic diabetes indipidus
- Hyperadrenocorticisim - Hypoadrenocorticism - Hyperthyroidism - Hypercalcaemia
66
List non-endocrine disease that can cause secondary nephrogenic diabetes insipidus
- Chronic renal disease - Liver disease - Infection (sepsis, pyelonephritis, pyometra) - Drugs (diuretics
67
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
68
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
69
Describe changes expected in complete blood count (CBC) with HAC
- Stress response: neutophilia and lymphoenia | - Produced in reposne to increased steroids
70
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)
71
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
72
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
73
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
74
What are the 2 types of specific diagnostic tests for HAC?
- Screening | - Differentiating (ADHAC or PDHAC?)
75
What are the HAC screening tests?
- Urinary cortisol:creatinine ratio - ACTH stimulation test - Low dose dexamethasone suppression (LDDS) test - 17-alpha-OH progesterone
76
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
77
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)
78
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
79
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
80
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
81
List the HAC differentation tests
- High dose dexamethasone suppression test - Endogenous ACTH - Adrenal imaging - Pituitary imaging
82
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
83
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
84
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
85
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
86
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
87
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
88
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
89
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)
90
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)
91
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
92
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
93
What are the anatomical landmarks used to locate the adrenal glands on ultrasound?
- Kidneys - Vena cava - Aorta
94
What is the normal size of the adrenal glands in the dog?
- Width upper limit: 7.5-10m | - Length: 20-30mm
95
What is the normal size of the adrenal glands in the cat?
- Width: 3/9-4.3mm | - Lenght: 10.7mm
96
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
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