SAD - Chapter 10 - Endocrine Flashcards
What is the chemical name of T3?
3,5,3’-triiodothyronine
What is the chemical name of T4?
thyroxine
Both T3 and T4 are derived from what reservoir?
thyroglobulin
Which thyroid hormone primarily inhibits TSH secretion?
T3 (3,5,3’-triiodothyronine)
What are the main thyroid binding proteins in the dog? In the cat?
Dog: thyroxine-binding globulin, thyroxine-binding prealbumin, albumin, plasma lipoproteins; Cat: lacks thyroxine-binding globulin
Which is more potent: T3 or T4?
T3 - enters cells more rapidly, more rapid onset of action, 3-5X more potent than T4
Where in the cell do thyroid hormones principally bind?
receptors in the nuclei => hormone receptor complex then binds to DNA => influences of genes coding for regulatory enzymes
What is the major metabolically active thyroid hormone in dogs?
T3 (3,5,3’-triiodothyronine) - T4 serves mainly as a prohormone
T/F: The thyroid gland secretes all of the T4 and T3.
False - secretes all of T4, but up to 60% of T3 is formed via monodeiodination from T4 in peripheral tissues
Secretion of TSH is inhibited by what?
somatostatin (from hypothalamus), thyroid hormones, glucocorticoids, dopamine, stress
What organ produces TSH?
adenohypophysis (pituitary gland)
What organ produces TRH?
hypothalamus
TRH stimulates release of what?
TSH and prolactin
Secretion of TRH is enhanced by what?
norepinephrine, histamine, serotonin, dopamine
What is primary hypothyroidism? Where is the problem?
abnormality at the level of the thyroid gland
Where is the problem with secondary hypothyroidism?
decreased TSH secretion (problem at level of pituitary)
Where is the problem with tertiary hypothyroidism?
decreased TRH (problem at level of hypothalamus)
What are the two forms of primary hypothyroidism in the dog?
lymphocytic thyroiditis and idiopathic atrophy
Other than lymphocytic thyroiditis and idiopathic atrophy, what are other possible causes for primary hypothyroidism?
Iodine deficiency, goitrogen ingestion, congenital hypothyroidism, thyroid gland destruction by neoplasia, drug therapy, surgical removal, radioactive iodine tx
Clinical signs of hypothyroidism occur with lymphocytic thyroiditis after what percentage of the thyroid gland has been destroyed?
80%
What is the main target antigen of lymphocytic thyroiditis?
thyroglobulin, smaller percentage is due to anti-TPO antibodies (thyroid peroxidase)
T/F: Animals with idiopathic thyroid atrophy have negative anti-thyroglobulin antibiodies and negative anti-thyroid hormone antibodies.
TRUE
What cells in the pituitary gland produce TSH?
thyrotrophs
Would TSH be low or high with secondary hypothyroidism?
low to undetectable – pituitary gland is not producing enough TSH => hypothyroidism
Other than TSH, what hormones are deficient in congential abnormalities of the pituitary gland?
growth hormone, TSH, prolactin, gonadotrophins
What breeds are most commonly reported to be at an increased risk for hypothyroidism?
Golden Retriever, Doberman Pinscher
Why are seborrheic changes common in hypothyroid dogs?
thyroid hormones influence serum and cutaneous fatty acid concentrations, influence sebaceous gland function – abnormal lipogenesis and decreased sterol synthesis by keratinocytes, sebaceous gland atrophy (w/ reduced sebum excretion)
Why can cutaneous mucinosis occur with hypothyroidism?
thyroid hormones help regulate the production of dermal glycosaminoglycans => accumulation of hyaluronic acid in the dermis
T/F: Neurologic disorders can occur with or without cutaneous signs of hypothyroidism.
True - both peripheral and CNS signs
What cardiovascular signs are possible with hypothyroidism?
bradycardia, weak apex beat, atherosclerosis, functional abnormalities on ECG or echo
What ocular abnormalities can occur with hypothyroidism?
corneal lipidosis, corneal ulceration, anterior uveitis – usually all secondary to hyperlipidemia
What coagulation abnormalities can occur with hypothyroidism? Why?
increased bleeding tendency, due to platelet dysfunction or clotting factor defects; T4 amplifies production of factor VIII and factor VIII-related antigen
What is the proposed mechanism for inappropriate galactorrhea or gynectomastia associated with hypothyroidism?
thought to be due to hyperprolactinemia induced by elevated levels of TRH
What changes can be seen on a CBC with hypothyroidism?
normocytic, normochromic, nonregenerative anemia; increased leptocytes (target cells) => increased erythrocyte membrane cholesterol loading
What change is commonly seen on a biochemical profile with hypothyroidism?
hypercholesterolemia +/- hypertriglyceridemia
What changes on a biochemical profile would be expected with a hypothyroid myopathy?
increase in lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase
What changes are seen on histopathology with hypothyroidism?
orthokeratotic hyperkeratosis, epidermal melanosis, follicular keratosis, follicular dilatation, follicular atrophy, telogenization of hair follicles, excessive trichilemmal keratinization (flame follicles), sebaceous gland atrophy; vacuolated, hypertrophied arrector pili muscles, increased dermal mucin, thick dermis, hyperplastic epidermis
Why is T3 a poor indicator of thyroid gland function in the dog?
most TT3 is produced by peripheral conversion of T4 - minimal amount originating from thyroid gland; T3 is conserved with early thyroid gland dysfunction => results in normal T3 in the face of low T4
What percentage of T4 is bound to plasma proteins?
99% - rest is the free T4 (the biologically active form)
When free T4 enters the cell, what is it converted to?
freeT4 is de-iodinatd to form either T3 or rT3
When is rT3 produced instead of T3?
T3 - preferentially produce during normal metabolic states; rT3 - biologically inactive, produced during illness, starvation, etc.
T/F: Serum total T4 concentration is the sum of both protein-bound and free hormone circulating in the blood.
TRUE
T/F: Baseline serum T4 concentrations are lower in healthy dogs than humans. Why or why not?
True - weaker protein binding in dogs compared to people
Anti-thyroid antibiodies are estimated to be present in what percentage of animals with clinical hypothyroidism?
2%
What breed(s) of dog has/have lower normal T4 levels?
Sighthounds
Which test of thyroid hormones has the lowest sensitivity and specificity: TT4, fT4, cTSH?
cTSH
T/F: A TSH stimulation test can be used to differentiate primary hypothyroidism from drug-induced hypothryoidism.
True - EXCEPT hypothyroidism due to sulfonamides– sulfonamides block production of all thyroid hormones
What is the utility of a TRH stimulation test?
Can be used to differentiate betweeen primary, secondary, and tertiary hypothyroidism
What is the typical response to a TRH stimulation test with primary hypothyroidism?
low basal TT4, high basal TSH, neither of which respond to TRH stimulation
What is the typical response to a TRH stimulation test with secondary hypothyroidism?
low basal TT4, low basal TSH, neither of which respond to TRH stimulation
What is the typical response to a TRH stimulation test with tertiary hypothyroidism?
low basal TT4 and low TSH => both of which should respond to TRH stimulation
What drugs can affect TT4 levels?
anticonvulsants (phenobarbital, phenytoin, diazepam), glucocorticoids, salicylates, phenylbutazone, sulfonamides, radiocontrast agents, mitotane, furosemide, cardiac drugs, androgens, estrogens
What effect do glucocorticoids have on thyroid values? Why?
decreased TT4, fT4, T3; decreased binding of T4 to carrier proteins, alterations in clearance and metabolism of thyroid hormones, decreased conversion of T4 to T3, suppressed pituitary TSH secretion
What test can be helpful in differentiating primary hypothyroidism from hypothyroidism secondary to glucocorticoids?
TSH – increased TSH is more consistent with hypothyroidism, usually normal with glucocorticoids (exogenous or endogenous)
How long after discontinuation of glucocorticoids should you wait to assess TT4 and TSH?
4-8 weeks
With phenobarbital administration, what changes would you expect in the following values: TT4, freeT4, TSH?
TT4 - low, free T4 - low, TSH - within reference range
How do sulfonamide antibiotics interfere with thyroid hormone synthesis?
inhibition of thyroid peroxidase activity
With sulfonamide administration, what changes would you expect in the following values: TT4, freeT4, TSH?
Low TT4, low freeT4, elevated TSH
With aspirin administration, what changes would you expect in the following values: TT4, freeT4, TSH?
low TT4, low freeT4, normal TSH
How can thyroid supplementation improve the hair coat, even in euthyroid dogs?
thyroid hormone supplementation stimulates telogen hair follicles to become anagen hair follicles
Why must testing be delayed for 4-8 weeks after stopping thyroid supplementation to confirm a diagnosis of hypothyroidism?
exogenous supplementation suppresses pituitary TSH secretion –> pituitary thyrotroph atrophy –> thyroid gland atrophy
Why is the dosenof thyroid hormone used for dogs higher than that of humans?
poorer gastrointestinal absorption and shorter serum half-life of T4 in dogs compared to humans
Why are dogs relatively resistant to iatrogenic hyperthyroidism?
short half-life of T4
What unique precautions need to be taken when treating hypothyroidism in dogs with cardiac disease?
start at 25-50% of the usual starting dose because thyroid supplementation will increase myocardial oxygen demand, increase heart rate, and may reduce ventricular filling time
T/F: Congenital hypothyroidism is more common in cats than adult-onset hypothyroidism
TRUE
What are the clinical signs of congenital hypothyroidism in the cat?
normal at birth, but have a decrease in growth rate by 6-8 weeks of age (dwarfism); lethargy, mental dullness, constipation, hypothermia, bradycardia and retention of deciduous teeth
What are the cutaneous abnormalities associated with hyperthyroidism in the cat?
excessive shedding, matting, focal or symmetric alopecia due to excessive grooming, increased rate of claw growth, dry or greasy seborrhea, thin skin, and peripheral arteriovenous fistula
Why can hyperthyroid cats have mild elevations in PCV?
thyroid hormone stimulates erythropoietin secretion
What changes can be seen on a serum chemistry with feline hyperthyroidism?
increased liver enzymes (>75% of cases) – ALT and ALP
What zone of the adrenal gland produces glucocorticoids?
zona fasciculata (adrenal cortex)
How much of circulating glucocorticoids are protein-bound?
90% (80% bound to high-affinity corticosteroid-bindg globulin, 10% bound to albumin), the remaining 10% is free and metabolically active
What hormone secreted by the adenohypophysis stimulates glucocorticoid production?
ACTH (from the prohormone opiomelanocortin)
What provides negative feedback for corticotropin secretion?
glucocorticoids
What provides negative feedback for corticotropin releasing hormone? What stimulates its release?
glucocorticoids & serotonin antagonists; stimulated by epinephrine and serotonin
Why does the epidermis become thinned and hyperkeratotic with hypercortisolism?
suppression of DNA synthesis, decreased mitosis, keratinization abnormalities
Why does the dermis become thinned with hypercortisolism?
inhibition of fibroblast proliferation, collagen, and ground substance production; dermal vasculature also becomes fragile
What are some of the protein catabolic, antienzymatic, and antimitotic effects of glucocorticoids in dogs and cats?
1) thinning of epeidermis, hyperkeratosis; 2) BMZ becomes thinned and disrupted; 3) pilosebaceous atrophy; 4) thinning of dermis, dermal vasculature becomes fragile; 5) wound healing delayed; 6) calcinosis cutis (dogs)
Where is the tumor usually located with hypercortisolism in the dog?
pars distalis of the pituitary gland > pars intermedia > adrenal tumor
What inhibits activity of the pars intermedia?
dopamine
What parts of the adrenal glands are usually hyperplastic with hypercortisolism?
zona fasciculata and zona reticularis; zona glomerulosa is usually normal
What amount of water consumption is considered polydipsia?
> 100 mL/kg/day
Cutaneous signs of hyperadrenocorticism?
thin, hypotonic skin; hyperpigmentation; easy bruising; phelbectasias; seborrhea, comedones, milia, poor wound healing, bacterial pyoderma, calcinosis cutis, striae
What are milia? What is their significance?
white keratin accumulations within the dermis (similar to comedones but without an opening to the surface); their presence always indicates steroid exposure
Why are dogs with HAC more prone to hypercoagulability and thromboembolism?
elevations of coagulation factors II, V, VII, IX, X, XII, and fibrinogen, as well as decreased levels of thrombin-antithrombin complexes
What changes can be seen on radiographs with HAC?
hepatomegaly, osteoporosis and osteomalacia, dystrophic mineralization of soft tissues, adrenocortical neoplasms
What changes on skin biopsy are suggestive of HAC?
dystrophic mineralization of collagen fibers, BMZ of epidermis and hair follicles; thin dermis; absence of arrector pili muscles
T/F: Single measurements of blood cortisol can aid in the diagnosis of HAC.
False - cortisol levels can vary with age, episodic cortisol secretion occurs in normal dogs & those with HAC, stress and nonadrenal illness can elevate blood cortisol
T/F: Elevated plasma corticotropin levels is diagnostic for HAC.
False - not all dogs with HAC with have abnormal levels - up to 30% may be in the normal range; plasma corticotropin levels fluctuate throughout the day
What special handling is recommended for corticotropin? Why?
needs to be kept frozen, corticotropin is unstable and will deteriorate when sample is unfrozen
What are the major cortisol metabolites found in urine in dogs?
cortol, 3-epiallocortol, cortolone, 3-epiallotetrahydrocortisol, tetrahydrocortisol
Why is the urine-cortisol-creatinine ratio not useful for cats?
nearly all glucocorticoid metabolites are excreted in bile
T/F: Urine cortisol/creatinine ratio has a high specificity.
True – negative predictive value is nearly 100%
Why is no one test absolutely diagnostic for HAC?
some dogs have an altered clearance of corticotropin and dexamethasone, or may have low circulating cortisol levels
ACTH stim test vs LDDS test: which test is more specific? Which is more sensitive?
LDDS = more sensitive; ACTH = more specific
Why is the LDDS test more likely to be nondiagnostic in dogs with nonadrenal illness?
accelerated clearance of dexamethasone, receptor insensitivity, chronic illness has resulted in significant adrenocortical hyperplasia
Why can’t the high dose dexamethasone suppression test be used to diagnose HAC?
causes suppression in both normal dogs and most dogs with pituitary dependent HAC
Why might dogs with HAC not exhibit suppression at 8 hours post dexamethasone with the high dose dexamethasone suppression test?
may have a tumor in the intermediate lobe, which is unresponsive to corticotropin and dexamethasone
What does the zona fasciculata of the adrenal gland produce?
glucocorticoids; 17-alpha-hydroxypregnenolone and 17-alpha-hydroxyprogesterone, precursors of cortisol and sex hormones
What does the zona reticularis of the adrenal gland produce?
sex hormones; 17-alpha-hydroxypregnenolone and 17-alpha-hydroxyprogesterone, precursors of cortisol and sex hormones
What does the zona glomerulosa of the adrenal gland produce?
aldosterone
Why can’t the zona glomerulosa produce cortisol or sex hormones?
deficient in 17-alpha-hydroxylase enzyme
Why can’t the zona reticularis or zona fasciclata produce aldosterone?
deficient in aldosterone synthase
What is the mechanism of action of mitotane (o,p’-DDD)?
causes selective necrosis and atrophy of the zona reticularis and fasciculata, while zona glomerulosa is relatively resistant
What are the adverse events associated with mitotane therapy?
hepatotoxicity, decreased aldosterone secretion/adrenocortical insufficiency, anorexia, vomiting, weakness, depression, diarrhea, disorientation, ataxia, head pressing
What enzyme does trilostane inhibit?
3-beta-hydroxysteroid dehydrogenase
What are the adverse events associated with trilostane?
lethargy, anorexia, vomiting, hypocortisolism, adrenal necrosis
What is the proposed mechanism for use of retinoic acid in HAC?
decreases ACTH synthesis
What is the proposed mechanism for use of ketoconazole in HAC?
inhibits adrenocortical steroidogenesis in dogs and humans
When using ketoconazole for treatment of HAC, how should monitoring be done?
ACTH stimulation 1-3 hours post ketoconazole administration (since KCZ is an enzyme inhibitor, not an adrenolytic agent)
What is the proposed mechanism for use of L-deprenyl for treatment of HAC?
increases dopamine concentration –> inhibits corticotropin releasing hormone secretion
What are the adverse events associated with L-deprenyl use?
diarrhea, vomiting, listlessness, disorientation, decreased hearing, restlessness
What is the mechanism of action of L-deprenyl?
selective irreversible monoamine oxidase-B inhibitor –> inhibition of MAO-B leads to increased dopamine –> inhibits release of corticotropin from pars intermedia
Why may L-deprenyl be ineffective in treating HAC?
unless the tumor is present in the pars intermedia, will have no effect; if tumor is related to CRH-mediated corticotropin secretion in the pars distalis, L-deprenyl has no effect
Why is iatrogenic hypercortisolism less common in the cat than the dog?
lower number of low-capacity, high-affinity dexamethasone-binding receptors
What cutaneous signs are unique to hypercortisolism in the cat?
cutaneous fragility, medial curling of the ear tips (iatrogenic exclusively)
Other than hypercortisolism, what diseases can cause skin fragility in cats?
cutaneous asthenia, pancreatic neoplasia, diabetes mellitus, liver disease, progesterone administration
T/F: Medical management of hyperadrenocorticism is often unsuccessful in cats and surgery is the treatment of choice.
True - bilateral adrenolectomy is needed in cats with pituitary-dependent disease
What medications can be helpful to reverse impaired wound healing attributed to corticosteroids?
retinoids and vitamin A
Growth hormone (somatotropin) is produced by what organ?
adenohypophysis (pituitary gland)
What catabolic activities does growth hormone have?
enhanced lipolysis and restricted glucose transport caused by insulin resistance – caused directly by GH polypeptide
What metabolites of growth hormone (somatotropin) control the anabolic activities of GH?
somatomedins (insulin-like growth factors)
What stimulates GH secretion?
neurotransmitters: norepinephrine, dopamine, serotonin; hypoglycemia, amino acids, progestogens
T/F: Male dogs have more growth hormone than female dogs.
False – only body size and age cause variation in normal levels of GH
What is the most commonly studied somatomedin?
insulin-like growth factor (IGF-1)
What impairs IGF-1 production?
glucocorticoids and estrogens
What cutaneous signs are present with acromegaly?
thickened skin, myxedematous, exaggerated folds; hypertrichosis
Excessive GH is called what?
acromegaly
GH deficiency results in what changes in the dog?
retention of the puppy coat, bilaterally symmetric alopecia and hyperpigmentation, thin, hypotonic skin
Hypopituitarism due to pituitary deficiencies is caused by what?
congenital hypoplasia, destructive lesions (infections, lymphocytic hypophysitis, infiltrative diseases, trauma, and neoplasms), vascular lesions, inherited disorder of GSD and Carnelian bear dogs
Hypopituitarism due to hypothalmic deficiences is caused by what?
trauma, encephalitis, aberrant parasite migration, hamartoma, neoplasia, neurosecretory dysfunction
Congenital pituitary dwarfism is passed through what mode of inheritence?
autosomal recessive
Congenital pituitary dwarfism is due to what abnormality in the pituitary gland?
cyst (Rathke cleft cyst)
What changes on radiographs are seen with pituitary dwarfism?
delayed closure of growth plates of long bones, delayed eruption of permanent teeth, failure of the os penis to mineralize, open fontanelles of the skin, smaller than normal heart, liver, and kidney
A characteristic metabolic abnormality of GH-deficient dogs is hypersenstivity to what?
hypoglycemic effects of insulin
What drugs are used to stimulate GH release?
clonidine (alpha-adrenergic antihypertensive drug), xylazine, GHRH
What treatments have been proposed for GH-deficiency?
bovine or porcine GH, progestin
What is the most common cause of acromegaly in dogs?
progestational stimulation (most cases occur in intact females)
T/F: Feline acromegally is more common in males.
True - more than 90% occur in males
After IV glucose administration, what change in plasma GH levels is expected? With what disease does this not occur?
GH should suppress after IV glucose load; nonsuppressibility is considered a hallmark of acromegaly
Clincal features of acromegaly
increased body size, widening of interdental spaces, prognathism, thickened myxedematous skin thrown into excessive folds, hypertrichosis and thick hard claws
Treatment for canine acromegaly
OHE - most cases due to progesterone increase during diestrus
What organs produce estrogen?
ovarian follicles, zona reticularis (adrenal cortex), Sertoli and interstitial cells (testicles)
Do estrogens increase or decrease skin pigmentation? Through what mechanism?
increases skin pigmentation by increasing free melanin and melanin within melanocytes
What organs produce androgens?
interstitial cells (testicle), zona reticularis (adrenal cortex), peripheral conversion of other sex steroids
What organs produce progesterone?
corpus luteum (ovary), zona reticularis (adrenal cortex)
Hyperestrogenism of the female dog is usually due to what abnormality?
cystic ovaries or functional ovarian tumors
Hyperestrogenism of the male dog is usually due to what abnormality?
functional testicular tumor, usually Sertoli cell tumor
What is a clinical feature highly suggestive of hyperestrogenism in male dogs?
Linear preputial dermatosis
Macular melanosis is associated with what endocrinopathy?
hyperestrogenism
Histopathological features of hyperestrogenism
orthokeratotic hyperkeratosis; follicular keratosis; follicular dilatation; follicular atrophy; telogenization of hair follicles; excessive trichilemmal keratinization; epidermal melanosis; sebaceous gland atrophy
Hyperandgrogenism is usally due to what abnormality?
testicular neoplasia, esp. interstitial cell tumors
Clinical features of hyperandrogenism
seborrhea oleosa, truncal alopecia, circumanal gland hyperplasia, tail gland hyperplasia
In intact female dogs, hair loss may start during what period of the estrus cycle?
usually starts around heat (proestrus), gradually worsens and then spontaneously resolves months after the cycle is complete
A dog with clinical pseudopregnancy may experience hairloss how many weeks after estrus?
4-6 weeks
Histopathological features of hair cycle arrest
orthokeratotic and follicular hyperkeratosis, follicular dilatation, excessive trichilemmal keratinization, epidermal melanosis, telogenization of hair follicles, dysplastic follicles
Melatonin is contraindicated to use in dogs with what concurrent disease? Why?
diabetes – causes insulin resistance at high doses
Clinical features of necrolytic migratory erythema
crusting with erosions or ulcerations at areas of trauma – muzzle, mucocutaneous junctions, distal limbs, footpads
Ddx for necrolytic migratory erythema in the dog
pemphigus foliaceus, SLE, zinc deficiency, generic dog food dermatosis
DDX for necrolytic migratory erythema in the cat
thymoma-associated exfoliative dermatitis, pancreatic paraneoplastic alopecia, FeLV- or FIV-associated dermatitis, pemphigus foliaceus, or acquired skin fragility syndrome with secondary infection
Histopathological features of necrolytic migratory erythema
parakeratotic hyperkeratosis, vacuolation of keratinocytes and epidermal edema; minimal dermal changes (superficial edema and perivascular infiltrate)
____ are benign granulomatous lesions associated with an abnormality in lipid metabolism.
Xanthomas
Clinical features of xanthomatosis
multiple whitish or yellowish papules, nodules, or plaques, which may be ulcerated
Histopathological features of xanthomatosis
nodular to diffuse infiltration of foamy macrophages and variable numbers of multinucleate histiocytic giant cells; lipid lakes in dermis
Mechanism of action of minoxidil
vasodilator – increases cutaneous blood flow, has direct effects on keratinocytes – prolong life in culture, stimulate differentiation, increases mitotic activity of matrix cells), suppresses lymphocyte-mediated immunologic phenomena
