Endocrine: Hyper and hypoadrenocorticism, adrenal tumors Flashcards
Name 4 stimulators of hypothalamic corticotropin-releasing hormone (CRH) release
Inflammatory cytokines (IL-1, IL-6, TNFalpha), leptin, dopamine, angiotensin II
What is the precursor molecule to ACTH?
Pro-opiomelanocortin (POMC)
Synthesis of most adrenal steroids is mediated by what enzymes?
Cytochrome P450 oxygenase enzymes
Where in the adrenal gland are mineralocorticoids formed?
Outer zona glomerulosa
Where in the adrenal gland are glucocorticoids formed?
The middle zona fasciculata and the inner zona reticularis
What enzyme is deficient in the outer zona glomerulosa, causing this region to be unable to synthesize glucocorticoids?
17-alpha-hydroxylase
80-85% of dogs with HAC have what form of the disease?
PDH
Where in the pituitary gland do tumors causing PDH arise?
70% - Pars distalis
30% - Pars intermedia
Ectopic ACTH secretion can occur from what tissues?
Carcinomas - small cell lung carcinoma most common in humans, pancreatic carcinoma described in a GSD
What are the effects of glucocorticoids on protein and lipid metabolism?
Protein catabolic, lipolytic
Why do glucocorticoids lead to polyuria?
- Increased GFR
- Inhibition of ADH at the renal tubular level, leading to a decrease in water reabsorption
Why do glucocorticoids lead to panting?
- Decreased pulmonary compliance
- Respiratory muscle weakness
- Direct effects of cortisol on the respiratory center
What cranial nerve can be affected by HAC?
Unilateral or bilateral facial nerve paralysis can occur
Describe Cushing’s pseudomyotonia
A myopathy characterized by persistent, active muscle contraction after cessation of voluntary effort - usually affects the pelvic limbs and causes a stiff gait
How is Cushing’s pseudomyotonia diagnosed?
- Electromyography - myotonic, bizarre and high frequency discharges are noted
- Biopsy: non-inflammatory, degenerative myopathy
Describe how calcinosis cutis forms
Cortisol leads to the rearrangement of molecular protein structures and formation of an organic matrix that attracts and binds calcium, forming apatite crystals in the skin
What are the effects of HAC in intact dogs? Why?
- Testicular atrophy and anestrus
- Cortisol’s negative feedback to the pituitary gland leads to decreased synthesis and secretion of LH and FSH
Describe why a stress leukogram forms
- Lymphopenia due to steroid lympholysis
- Eosinopenia due to bone marrow sequestration
- Neutrophilia/monocytosis due to steroid-enhanced capillary demargination
How do glucocorticoids lead to hyperglycemia?
- Increase hepatic gluconeogenesis
- Interfere with insulin at the cellular level (receptor defects)
- Suppress gene expression of insulin signal molecules in the cell (post-receptor defects)
A pituitary tumor of what size is considered a macroadenoma?
> 1cm
What is the sensitivity and specificity of UCCR? What is it useful for?
- Sensitivity is nearly 100%, but specificity is terrible (20-77%)
- Great for ruling OUT HAC (normal result makes HAC very unlikely), but further testing is warranted if it is normal
To avoid the effects of stress, when should a UCCR be collected?
At home, at least 2 days after a vet visit or other stressful event
What is the test of choice for identifying iatrogenic Cushing’s? What would the result look like?
ACTH stimulation test - there would be no response (stimulation) to ACTH, resulting in a low concentration of cortisol pre and post
Dogs with naturally occurring HAC may have what response to an ACTH stimulation test?
A normal or exaggerated response
What is the sensitivity and specificity of an ACTH stimulation test for diagnosing HAC?
- Sensitivity: 85% for PDH but only 60% for FAT
- Specificity: 90%
What is the sensitivity and specificity of LDDST for diagnosing HAC?
Sensitivity 90-95%
Specificity as low as 40-50% in populations with non-adrenal illness - do no test ill dogs and do not diagnose based solely on LDDST
What drug can interfere with a LDDST?
Phenobarbital
What pattern on a LDDST is consistent with PDH? How often does this occur?
- A “V” pattern - suppression at 4 hours with a higher cortisol concentration at 8 hours confirms PDH
- Serum cortisol concentration at 4 or 8 hours that has decreased to <50% of baseline but is still >1mcg/dL is also most likely PDH
- 65% of dogs with PDH will have one of these findings
How can the HDDST be used to discriminate PDH from FAT?
High doses of dexamethasone can overcome resistance to suppression in most PDH cases, but FAT cases will still fail to suppress
- If cortisol drops to <1.4, it’s diagnostic for PDH
- BUT 35% of PDH will still fail to suppress, so failure to suppress is not diagnostic for FAT
What is a potential side effect of both trilostane and mitotane on the pituitary gland?
Both decrease plasma cortisol => increased ACTH secretion, which can enhance pituitary tumor growth
What is the mechanism of action of trilostane?
- Synthetic steroid analogue
- Acts as a competitive inhibitor of the enzyme 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD), which catalyzes the conversion of pregnenolone to progesterone
- Blocks synthesis of cortisol and to a lesser extent aldosterone
When monitoring trilostane therapy, what time should an ACTH stimulation test be performed?
Peak: 2-3 hours post-pill
Trough: just before the next dose
Should mitotane be given with or without food?
With - fat soluble drug
Cats with adrenocortical tumors secreting what hormone may mimic signs of HAC?
Progesterone
Unlike dogs, cats with HAC do not exhibit what clinical signs?
PU/PD - unless diabetic or CKD
What Na:K ratios can be used for ruling out hypoadrenocorticism or raising suspicion for it?
<24 = hypoadrenocorticism is likely
>27 or 28 = hypoadrenocorticism is very unlikely
Why do 60% of dogs with hypoadrenocorticism display a metabolic acidosis?
Aldosterone facilitates urine H+ ion excretion
When monitoring DOCP, Na and K should be checked 14 days after administration. If the Na:K ratio is above 32 at day 14, what can be done at the next administration?
Reduce dose by 10%
When monitoring DOCP, if the Na:K ratio is above 32 at day 25, what can be done?
Wait at least 5 days to give the next injection
What other pituitary hormone can be increased in dogs with untreated hypoadrenocorticism? How long does it take to normalize after treatment?
TSH - can take up to 4 months to normalize
Careful when diagnosing hypothyroidism in new Addisonians
In one study, what was the median duration of action of DOCP and how frequently did dogs require dosing?
Median duration: 62 days
Median dosing interval: 58 days
How does age impact DOCP dosing?
Young animals and growing animals require higher doses of DOCP compared to older dogs
The labeled starting dose of DOCP is 2.2mg/kg. In one study, what dose could be used instead?
One study: A starting dose of 1.5mg/kg was effective in the majority of dogs. Many dogs needed lower doses (1.1mg/kg median) to maintain an injection interval of 28-30 days
Another study: 1.1mg/kg was effective
Describe the urine electrolyte changes in dogs with hypoadrenocorticism
Urine Na:K ratio is twofold higher, median fractional excretion of sodium is fourfold greater compared to controls
However, too much overlap exists with controls to be diagnostically useful
What UCCR cut off value yielded a 100% sensitivity and 97% specificity for diagnosing hypoadrenocorticism?
<1.4 in the Italian study
Describe changes in calcium homeostasis in dogs with HAC
Dogs with HAC had increased urinary fractional excretion of Ca, higher serum PTH concentrations, but no change in iCa or calcitriol
What percent of dogs develop systemic hypertension during the first year of treatment for HAC, despite control of clinical signs?
1/3 - always check a BP on HAC dogs
What dose of cosyntropin is needed for the diagnosis of HAC? For monitoring treatment?
For diagnosis, 5 ug/kg is still needed
For monitoring treatment or diagnosing hypoadrenocorticism, 1ug/kg can be used
What test should not be used as a sole monitoring tool for treatment of HAC with trilostane?
Baseline cortisol
Dogs with PDH and a gallbladder mucocele had higher circulating concentrations of what hormone?
Leptin
What percent of dogs with HAC are hypertensive?
82% - 46% had severe hypertension
Hypertension was common among HAC dogs with what other abnormalities?
Thrombocytosis (all dogs had hypertension)
Lower median potassium
UPC >0.5
What percent of dogs are alive 4 weeks post-hypophysectomy? What percent are in remission from HAC?
91% alive
Of those, 92% in remission
What percent of dogs developed recurrence of HAC after hypophysectomy and when?
27%, median of 555 days
What predicted recurrence of HAC in dogs post-hypophysectomy?
Higher pituitary height/brain area ratio
Higher pre-operative UCCR
In dogs undergoing hypophysectomy, pituitary size correlated with what?
Survival time and disease free fractions - prognosticator
What percent of adrenal tumors are metastasis from other locations?
Dogs: 30%
Cats: 60%
Is FNA of the adrenal glands diagnostic?
90-100% accurate for distinguishing between cortical and medullary origin, but cannot distinguish between benign and malignant tumors
Odds of malignancy are increased if the greatest diameter of the adrenal tumor is larger than what?
> 2cm
What stimulates aldosterone secretion?
- Directly: increases in serum potassium
- Indirectly: decreases in blood pressure, which activate RAAS => angiotensin II stimulation of aldosterone secretion
What is primary hyperaldosteronism? How does it affect the RAAS system?
- Autonomous aldosterone secretion by adrenocortical cells
- Increased circulating aldosterone => negative feedback and suppression of renin release
What is secondary hyperaldosteronism? What would renin levels be with this condition?
Increased aldosterone due to conditions that stimulate RAAS (CKD, CHF) - renin concentrations would be increased
What are the clinical signs of feline primary hyperaldosteronism (aldosteronoma)?
Related to hypokalemia and hypertension - weakness, tortuous retinal vessels or detachment, heart murmur/arrhythmia due to left ventricular hypertrophy from hypertension
Why is hypernatremia uncommon with feline primary hyperaldosteronism?
Aldosterone escape occurs - hypernatremia leads to volume expansion and hypertension => pressure induced natriuresis
What is the acid/base status of patients with feline primary hyperaldosteronism?
Usually metabolic alkalosis - aldosterone results in hydrogen ion excretion
Why might a progestin secreting tumor result in clinical signs similar to glucocorticoid excess?
Progestins may bind glucocorticoid receptors or displace cortisol from its binding protein, leading to increased serum free cortisol concentrations
In dogs, increased serum progestins cause what changes to ACTH release and adrenal size?
Suppress ACTH secretion and cause adrenal atrophy (looks like exogenous glucocorticoids)
What cells give rise to pheochromocytoma?
Chromaffin cells of the adrenal medulla
What amino acid are catecholamines synthesized from?
Tyrosine
What triggers release of catecholamines from the adrenal medulla?
Stimulation of the chromaffin cells by acetylcholine from the sympathetic nervous system
What is the function of alpha 1 adrenergic receptors?
Mydriasis
What is the function of alpha 2 adrenergic receptors?
Vasoconstriction, decrease in insulin and glucagon secretion, increase in urinary sphincter tone
What is the function of beta 1 adrenergic receptors?
Increased heart rate and contractility
What is the function of beta 2 adrenergic receptors?
Vasodilation of skeletal muscle arterioles and coronary arteries, relaxation of bronchial muscles, decreased GI motility, increase in insulin/glucagon secretion, increased lipolysis, relaxation of the detrusor
How do pheochromocytomas induce PU/PD?
Catecholamines interfere with ADH release in the hypothalamus
Are right or left sided adrenal tumors more likely to invade the caudal vena cava?
Right
Which urine catecholamine test has the highest sensitivity?
Urine normetanephrine : creatinine ratio
What is the mechanism of action of phenoxybenzamine?
Alpha-adrenergic receptor antagonist - binds irreversibly to alpha1 and alpha2-adrenergic receptors
How long before surgical removal of a pheochromocytoma should you start pretreating a dog with phenoxybenzamine?
2 weeks at least
If a patient with a pheochromocytoma is displaying tachyarrhythmias, what drug can be added to help? When should it be added?
Beta blocker - atenolol
Only add after phenoxybenzamine is on board, as loss of beta-adrenergic vasodilation leaves alpha-adrenergic stimulation unopposed and can cause a hypertensive crisis
Dogs weighing <12kg should have an adrenal thickness less than what? Dogs weighting >12kg?
<12kg: <0.62cm
>12kg: <0.72cm
What is critical illness-related corticosteroid insufficiency?
Inadequate endogenous corticosteroid activity in relation to the severity of a patient’s illness - causes increased mortality in humans
Does the use of hydrocortisone improve outcome in patients with suspected critical illness-related corticosteroid insufficiency from septic shock?
No, treated patients did worse :(
- Higher mortality, took longer to respond to vasopressors and to maintain BP
