Lect. 7 - Hypercortisolism in dogs Flashcards
ALP
alkaline phosphatase
CRH
corticotropine releasing hormone
eACTH
endogenous adrenocorticotropic hormone
HAC
hyperadrenocorticism
HDDST
high dose dexamethasone suppression test
LDDST
low dose dexamethasone suppression test
PDH
pituitary dependent hyperadrenocorticism
Cortisol: to convert nmol/L → µg/dL multiply by
0.0362
Cortisol: to convert µg/dL → to nmol/L multiply by
27.6
For the diagnosis of hypercortisolism, plasma/serum cortisol concentration should always be assessed in what general way?
Should always be assessed dynamically meaning multiple measurements should be taken.
Basal plasma/serum cortisol concentration alone is not a useful test for diagnosis of HC .
Stress induced transitory rises in plasma cortisol are normal.
Most dogs with hypercortisolism have
normal basal plasma cortisol concentrations in the upper part of the referenc interval but measured in 24 hours, they all have cortisol excess above ref values.
ACTH is primarily produced by the anterior
pituitary under the control of
CRH
corticotropin releasing hormone
Smaller amounts of ACTH are produced by
the pars intermedia that is under dopaminergic control (CLIP).
CLIP =
corticotropin-like intermediate lobe
peptide
Trilostane (Vetoryl) selectively inhibits
3 β-hydroxysteroid dehydrogenase
Thus, Trilostane alleviates the clinical consequences of too much cortisol.
Excess cortisol has what effect on carbohydrate metabolism.
increases gluconeogenesis
(thus causes hyperglycemia - antagonistic to insulin)
Excess cortisol effect on protein metabolism.
Increased protein catabolism and thus increased release of amino acids available as substrate for gluconeogenesis.
Glucogenic AAs &
Ketogenic AAs
Why/ how does excess cortisol cause an animal to become fat?
the excess cortisol increases gluconeogenesis,
blood glucose increases, this triggers release of more insulin and increased insulin induces lipogenesis.
the ketogenic AAs released alongside the glucogenic AAs, go toward fatty acid synthesis for adipose tissue.
What is hypercorticism-type obesity referred to as?
Centripetal Obesity (accumulates in the abdomen)
typically occurs with Hyperlipidemia
How might HC effect TSH?
a possible consequence of HC is “reversible hypothyroidism”
What clinical consequences might HC have on sex hormones?
No estrus ♀ (FSH, LH)
Testicular atrophy ♂ (FSH, LH)
What clinical consequences might HC have on GH?
Retarded growth in puppies (GH)
canine HC can be divided into what two major groups:
exogenous and
endogenous HC
Etiology of Iatrogenic hypercortisolism
Treatment with excess steroids
This is an exogenous type
Etiology of Spontaneous hypercortisolism can be furtehr typed as
ACTH dependent 80% (pituitary dependent)
and
ACTH independent 15-20% (functional adrenocortical tumoro)
What could cause ACTH dependent HC
caused by a ptuitary tumor
in dogs, pituitary carcinomas and adenomas occur at equal rates
What could cause ACTH independent HC
overactive adrenal glands,
adrenal tumor
Canine hypercortisolism results
from
In decreasing order of frequency
(3)
Iatrogenic causes
↓
Pituitary/ hypothalamic lesions
↓
Adrenal tumours
nature of Adrenocortical carcinoma is
Rapid development and progression
Common dermatological signs of HC disease may be mild or lacking
The most frequent historical and clinical features of
hypercortisolism, in approximately decreasing
order of frequency
Polyphagia, a common sign of HC, does not occur in which species
cats and people
but in dogs it does!
Enuresis is
a repeated inability to control urination.
Pendulous abdomen is a common sign of HC.
What mechanism is behind it? (4)
abdominal muscle atrophy
hepatomegaly
full, over filled bladder due to weakened detrusor m.
fat accumulation into the mesentary
Calcinosis cutis is
a descriptive term for the deposition of insoluble calcium salts in the cutaneous and subcutaneous tissue.
Two overt signs of hypercortisolism
- Centripetal obesity
- Skin and muscle atrophy
Typical breeds predisposed to hypercortisolism. (7)
terrier breeds
toy poodle
beagle
german shepherd
boxer
irish setter
dachshund
macroadenomas are larger than
10 mm
begin to compress adjacent structures such as the hypothalamus
Serum biochemistry Clinicopathologic abnormalities that may be seen in HC (not specific)
High ALP activity (ALP) (≈90%)
Hyperglycemia (≈ 50%)
+ CIALP = cortisol- induced alkaline phosphatase
hematology Clinicopathologic abnormalities that may be seen in HC (not specific)
Stress leukogram
* Neutrophilia
* Eosinopenia
* Lymphopenia
* Monocytosis
most frequent Urinalytical abnormalities that may be seen in HC
- Usually low urine specific gravity
- Low-grade proteinuria is present in the majority
- Glucosuria (concurrent diabetes mellitus)
- Hematuria and bacteruria. Pyuria ±
HC dogs frequently have concurrent UTI, probably due to lowered immune response due to glucocorticoid excess. Dilute urine also increases susceptibility.
symmetric adrenocortical hyperplasia is due to what chain of events?
typically seen in ACTH-pituitary dependent HC, a chronic excess of ACTH causes symmetrical hyperplasia of the adrenalcortices and thus excess cortisol secretion.
suppressed ACTH secretion is seen in which type of HC?
(spontaneous) functional adrenocortical tumors secrete excess cortisol which participates in a negative feedback loop and suppresses ACTH secretion.
over time it will also cause atrophy of the contralateral adrenalcortex. and eventually atrophy of all non-neoplastic adrenalcortical cells, both sides.
Screening tests are designed to determine if HC is present. Name two.
LDDST
ACTH stimulation test
UC:CR (urine cortisol:creatinine ratio)
Differentiation tests should be performed to determine if PDH (pituitary dependent hyperadrenocorticism) or FAT (functional adrenocortical tumour) is present.
Name 3.
- LDDST
- HDDST
- (e)ACTH (endogenous, so plasma ACTH concentration)
Which liver enzyme elevation is conducive to indicating HC in conjunction with clinical signs?
ALP
alkaline phosphatase
But note, its possible that an HC dog has ALP within ref range!
What specific urinary test might be conducted in association with HC screening tests?
urine cortisol:creatinine ratio before and after stimulation with either LDDST or ACTH stim
Once determination of whether HC is present, we proceed to?
differentiating tests to determine whether pituitary dependent hypercortisolism or functional adrenocortical tumor is present.
This Information is crucial to therapeutic decisions and an accurate prognosis.
Differentiatiating tests SHOULD NEVER BE
PERFORMED before a diagnosis of HC is made via screening tests.
The amount of cortisol in the urine reflects the
average amount of cortisol in the blood.
Note that urine SG may affect results.
Client collects urine sample(s) at home (no stress).
Hypercortisolism cases should see what change in UCort:UCrea?
An increase in UCort:UCrea.
- 90-100% with HC (high sensitivity)
- Many false positives (low specificity)
- Normal ratio – HC very unlikely (≤10% chance) which makes it a good exclusion test.
What test is considered the test of choice for hypercortisolism?
Low-dose dexamethasone suppression test LDDST
Explain the basic steps of the Low-dose dexamethasone suppression test LDDST
a) A blood sample (plasma or serum – check with the lab)
b) Dexamethasone or dexamethasone sodium phosphate is given 0.01-0.015 mg/kg IV or IM. IV preferred.
c) Blood samples taken: first before dexamethasone administration, 4h and 8 h after dexamethasone administration.
In normal dogs, what should happen in the LDDST?
Dexamethasone will feedback and turn off ACTH secretion from the pituitary.
Cortisol concentrations will be low 4h and 8h later.
In PDH dogs, what should happen in the LDDST?
In PDH dogs, the hypothalamic adrenal axis feedback mechanism does not work normally.
No or only partial suppression of ACTH occurs. Compatible changes in cortisol concentration occur.
In functional adrenalcortical tumor dogs, what should happen in the LDDST?
The tumour secretescortisol mainly or wholly autonomously of ACTH’s influence.
Suppression has little to no effect on cortisol conc. It will remain high.
How do you interpret the different samples taken for a LDDST?
You first look at the result of the 8h post sample. If it is above ref values, the dog has hyperadrenocortisolism.
Next, we want to see if we can differentiate between PDH and ADH. You look first at the change between 0. sample and the 4h post sample. Whether the baseline value is suppressed by more than half in which case we would have PDH. Note: counting 50% of baseline starts from the 2/cut-off value.
If there is no suppression then we can not differentiate whether there is PDH or FAT (= functional adrenocortical tumor).
What is a reason that PDH may not be susceptible to influence by glucocorticoids such as from suppression tests?
In about 1/4 to 1/5 of cases, the tumor is in the pars intermedia of the pituitary.
The pars intermedia is principally under dopaminergic neural control which suppresses the expression of glucocorticoid receptors which explains why PDH of pars intermedia origin is resistent to suprression by dexamethasone.
So test results such as the ones pictured make it impossible to differentiate HC types.
Interpret the results pictured.
a) probably no HC
b) 5-10% PDH The dog may have early pituitary disease and the
pituitary gland is still responding to a pharmacologic dose of dexamethasone by decreasing ACTH production, thereby reducing
serum cortisol concentrations.
Next dgn step:
a) ACTH stimulation
b) Repeat 4-6 w
basic principle is that suppression tests are used in case of
hyperfunctioning and stimulation tests in cases of hypofunctioning.
basic principle is that stimulation tests are used in case of
hypofunctioning and suppression tests in cases of hyperfunctioning.
Why should we move away from the ACTH test for cushings diagnosis?
Its Less sensitive than LDDST and UC:CR
ACTH-stimulation test basic steps:
a) Collect a blood sample (plasma or serum
– check with your lab)
b) Synthetic ACTH (e.g. Synacthen depot®) (IV or IM). Preferrable IV.
* 5 µg /kg
* max dose 250 µg (dog) or 125 µg (cat and very small dogs)
c) Collect a blood sample 60 min later
So samples 0. and 1, over 1 hour..
the only test that can diagnose iatrogenic HC
An ACTH stimulation test is the only test that can diagnose iatrogenic HC.
Basal and post-ACTH cortisol concentrations are typically low to unmeasurable.
- Full diagnosis is made with a history of glucocorticoids exposure by any route, presence of consistent clinical signs and a post-ACTH cortisol concentration below the reference range.
How does HDDST differ from other tests?
High-dose dexamethasone suppression test is the same as LDDST, but dexamethasone dose is
0.1 mg/kg so 10 times higher drug dose.
The principle is that due to the higher
dexamethasone dose used, more suppression of the cortisol secretion may be seen in specifically PDH cases than when a low dose is administered.
Interpretation of HDDST: two suppressive responses are consistent with
PDH.
- Complete suppression at 4h and/or 8h post dexamethasone
- Concentrations are <50% of baseline 4h and/or 8h post-dexamethasone
HDDST can never confirm the presence of
A functional adrenocortical tumor.
HDDST can be used to confirm PDH.
so; if criteria for diagnosis of PDH is NOT met, there is a 50/50 chance the patient has PDH or FAT.
Measurement of Plasma endogenous ACTH (eACTH) is the most accurate test for differentiation of
PDH and FAT.
In PDH, endogenous ACTH levels are variable but usually plasma levels are normal or high.
In FAT, endogenous ACTH levels are low due to negative feedback from excessive cortisol producing tumor.
ACTH hormone testing is finicky because ACTH is so sensitive to degradation - so it isnt performed often.
Endogenous ACTH testing result is normal or increased so we interpret it as what diagnosis?
PDH
Endogenous ACTH testing result is below normal so we interpret it as what diagnosis?
FAT aka functional adrenal tumor
( eACTH is the only test that can be used to confirm the presence of FAT)
WithOUT cutaneous signs, the differential
diagnosis is usually that of polyuria/polydipsia, so: (6)
- Chronic kidney disease
- Chronic liver disease
- Diabetes mellitus
- Diabetes insipidus
- Hypoadrenocorticism
- Psychogenic polydipsia
WITH cutaneous signs, the differential diagnoses
includes the diseases for withOUT cutaneous signs, plus the following: (3)
- Hypothyroidism
- Adrenal sex hormone dermatosis
- Sex hormone imbalances
Treatment options for hypercortisolism
Drug therapy:
Trilostane/Vetoryl
Surgical:
hypophysectomy
adrenalectomy
Differentiation tests should never be performed before
a diagnosis of HC is made via screening tests.
Feline hypercortisolism is uncommon. Most cases are of what type?
pituitary-dependent but functional adrenal tumours have been described
Closely resembles the canine condition.
Cats are more prone to developing hyperglycaemia and overt diabetes mellitus than affected dogs.
The specific glucocorticoid-induced isoenzyme
of CIALP as seen in dogs does not occur in
cats.
Cats with insulin-resistant diabetes mellitus should
always be tested for
hypercortisolism.
Clinical features of Feline hypercortisolism
- Middle-aged to older cats
- Moderate to severe polyuria/polydipsia
Often secondary to diabetes mellitus. - Fragile skin syndrome!
- Loss of muscle mass
- Pendulous abdomen
What substance is measured in LDDST?
cortisol levels
How do you choose whether to use HDDST or LDDST?
The principle is that due to the higher dexamethasone dose used in HDDST, more suppression of the cortisol secretion may be seen in specifically PDH cases than when a low dose is administered. So it can be used to differentiate or confirm a case of PDH.
