Endocrinopathy (NAVDF 2021 Outerbridge) Flashcards
Thyroid hormone pathway
Hypothalamus -> TRH -> Pituitary -> TSH -> Thyroid gland -> T3, T4
How is most T4 found in the blood
Most is bound to transport proteins.
Only 0.1% is fT4
How is most T3 made in the body
Peripheral tissue deiodinization of T4 (from I4 to I3)
How does T4 enter the cell
1) Passive diffusion
2) Active receptor-mediated transport
Which thyroid hormone binds the nuclear receptor
T3
What is primary hypothyroidism
At level of the thyroid
1) Lymphocytic thyroiditis (AA)
2) Idiopathic atrophy (degenerative)
—
3) Neoplastic
4) Congenital, iodine deficiency, I131, Drug (like TMS)
How much thyroid function must be destroyed prior to seeing clinical signs
75%
Which type of hypothyroidism is most common (primary, secondary, tertiary)
Primary
What is secondary hypothyroidism
At the level of the pituitary gland
Lack of TSH
1) Tumors, congenital, trauma, surgery
What is tertiary hypothyroidism
At the level of the hypothalamus
Lack of TRH
What clinical signs would you expect to see in a congenital hypothyroidism case
Poor growth and development
Signalment of hypothyroidism
Middle-aged (4-10yr)
Medium-large breed dogs
Dog leukocyte antigen (DLA) haplotypes associated with hypothyroidism
1) Doberman pinscher
2) Giant Schnauzer
3) Rhodesian Ridgeback
4) English Setter
Non-skin clinical signs of hypothyroidism
- Muscle weakness
-Myopathy
-Peripheral neuropathy
-Laryngeal paralysis
-Megaesophagus - CNS signs with myxedema
- Ocular: corneal lipid deposits
- Reproductive
-Prolonged anestrus
-Prolonger parturition, higher puppy mortality
What causes myxedema coma in hypothyroid patients
Increase in myxedema in the brain itself!
Fatal!
Microscopic findings of hypothyroidism
*Sebaceous gland and follicular gland atrophy
*Failure to initiate anagen
*Disturbances to cornification
What causes facial myxedema in hypothyroid dogs
Increase in glycosaminoglycans in the dermis
Labwork findings in hypothyroidism
*Hypercholesterolemia
*Normocytic, normochromic, nonregenerative anemia
+/-
*ALP elevation
*CK elevation
What is the best test for hypothyroid diagnosis
fT4 + TSH
TSH increases the specificity of fT4
Which breed experiences “tiger striping” with hypothyroidism
Rhodesian ridgebacks
What is the value of a TT4 test
Screening tool
Why may a TT4 be low without true hypothyroidism
1) Old dog
2) Sight hound
3) Drugs
4) Concurrent illness
Why is TT3 not a good gauge for thyroid function
Most T3 is actually made by deiodination in the peripheral tissues, NOT by the thyroid
Clinical sign seen in 6/7 cats with spontaneous hypothyroidism
Bilateral goiter
Not all had skin lesions (but if they do, looks similar to dogs)
Which thyroid hormone has the most influence on TSH
fT4
T or F: fT4 is the predominant circulating hormone produced by the thyroid gland
False
TT4 decreases before fT4, so fT4 is more resistant to NTI influence
Is fT4 or TT4 more affected by non-thyroidal illness
TT4
TT4 decreases before fT4, so fT4 is more resistant to NTI influence
Which test is most accurate for fT4 quantification
Equilibrium dialysis.
RIA (radioimmunoassay) alone is not accurate enough
Is TSH more sensitive or specific
TSH is very specific, but not very sensitive for hypothyroidism
If you add TSH to fT4, it increases fT4 specificity!! Ideal!
T or F: TSH is always elevated in hypothyroid dogs
False
T or F: Dogs with nonthyroidal illness can have an elevated TSH
True
T or F: euthyroid dogs can have an elevated TSH
True. Transient when telling thyroid to make more T4
T or F: TgAA varies by breed
True
(low in Dobies, even with hypothyroidism)
T or F: Dogs with elevated TgAA but normal thyroid function should be monitored but NOT treated
True. Do not treat unless abnormal thyroid function
Lymphocytic thyroiditis can be slow– don’t need to treat yet
T or F: TgAA can interfere with other thyroid quantification assays
True, esp autoantibodies against T4 can be measured as elevated T4!
What thyroid values would you expect in a dog with nonthyroidal illness (like HAC)
- Low TT4
*Low T3 (less deiodination from T4 to T4) - TSH is normal, possibly increased
- fT4 is normal, possibly decreased
Why is Total T4 decreased with nonthyroidal illness
1) Decreased T4 binding to transport proteins; reduced concentrations of transport proteins
2) Decreased TRH or TSH leads to decreased T4 production
3) Direct effects on thyroid gland -> suppressed T4 production
Next step in a dog you suspect has a nonthyroidal illness
Treat the nonthyroidal illness, then reassess thyroid once resolved
Effect of corticosteroids on thyroid
Decreased TT4
fT4, TSH is either decreased or no change
T or F: Glucocorticoid effect on thyroid function testing is dose and duration dependent
True
Longer on GCs, more impact on TT4
How long prior to thyroid testing should glucocorticoids be discontinued
At least 4 weeks
Effect of Sulfonamides on thyroid
*TT4, fT4, T3: Low
*TSH: High
TRUE HYPOTHYROIDISM –> reversible
TMS will decrease follicle function
Increase in TSH because no negative feedback from fT4
How long off Sulfa antibiotic prior to evaluating thyroid
3 weeks
T or F: KBr will influence thyroid values
FALSE. KBr should not affect thyroid values
PHENOBARB will (like GCs)
T or F: Response to thyroid supplementation can happen in a euthyroid dog
True
Which type of dog is more likely to develop iatrogenic hyperthyroidism
Large breed
(less likely if you do body surface area dosing)
Impact of estrogen on hair cycle
Estrogen inhibits anagen –> alopecia
Causes for hyperestrogenism in dogs
- Testicular tumors (Sertoli, Seminoma, Interstital cell). Usually cryptorchid!
- Cystic ovaries, granulosa cell tumors
- Iatrogenic- estrogen (Incurin, estriol) for USMI
- 2nd hand exposure to human topical estrogens, esp in small dogs
Clinical sign common in testicular tumor dogs
Linear preputial erythema or hyperpigmentation
Often cryptorchid
Pattern of alopecia on hyperestrogenism dogs
Perineal/perigenital –> progress to ventrum
Labwork finding of hyperestrogenism dogs
Bone marrow suppression
-Thrombocytopenia
-Anemia
-Leukopenia
Hypothalamic-Adrenal pathway
Hypothalamus -> CRH -> Pituitary chromophores -> ACTH -> Adrenal gland -> Cortisol
Affects BOTH zona fasciulata and zona reticularis. BUT cortisol is only from fasciculata
Which region of the adrenal gland makes cortisol
Zona fasciculata
Which region of the adrenal gland responds to ACTH from pituitary gland
BOTH Zona fasciculata (cortisol) and Zona glomerulosa (sex hormones)
Product of the Zona glomerulosa in the adrenal gland
Mineralcorticoids
What percent of HAC is due to pituitary tumors
85%
Usually adenoma
High cortisol and high ACTH
Bilateral adenomegaly
What percent of HAC is due to adrenal tumors
15%
May be adenoma OR adenocarcinoma
High cortisol, low ACTH
Unilateral adenomegaly
T or F: The likelihood of HAC in cats being due to a pituitary tumor is the same as in dogs
True. Both ~85% pituitary origin
Why does cortisol cause increased PUPD in dogs (2)
1) Increased GFR, increased vascular volume + renal blood flow
2) Steroids inhibit responsiveness to ADH, resulting in decreased resorption of H2O by the renal tubules –> polyuria w/compensatory polydipsia
*ADH change does NOT occur in cats!!
Why do cats with HAC have PUPD
1) Increased GFR, vascular volume
2) 2’ to concurrent diseases. Over 60% of HAC cats have concurrent DM! r/o CKD
ADH resistance does NOT happen in cats!
What percent of cats with HAC have concurrent diabetes
60%!
What are 2 cutaneous clinical signs associated with steroids/HAC in cats
- Acquired skin fragility
- “Ear tipping”- weak cartilage on pinnae result in curling. Usually iatrogenic
Impact of hyperthyroidism on adrenal gland AUS
Bilateral adrenomegaly! Can make it challenging to see if cat has pituitary or adrenal HAC
T or F: the best test to confirm adrenal HAC is the HDDST
FALSE! HDDST cannot confirm adrenal tumor.
eACTH is better
What results of endogenous ACTH test would you expect with a pituitary tumor derived AHC
+ ACTH if pituitary origin
-ACTH if adrenal origin (negative feedback)
What dose of dexamethasone do you use for LDDST testing in cats
10x the dexamethasone dose as you’d use in dogs!
(0.01mg/kg in dogs, 0.1 mg/kg in cats)
Causes of enlarged abdomen in HAC patients
1) Enlarged liver
2) Weak abdominal musculature
3) Fat redistribution to the ventral abdomen
What causes calcinosis cutis
Dystrophic mineralization
Abnormal Ca:Phos
Which species have calcinosis cutis
Dogs and chinchillas
What breeds are predisposed to calcinosis cutis
Labs
Rottweilers
Boxers
Staffordshire terriers
What is the mineral in calcinosis cutis
Calcium apatite
Labwork findings in dogs with HAC
Stress leukogram (increased neut, decreased lymph, eos)
Thrombocytosis
Increased ALP, ALT
Hypercholesterolemia
Decreased BUN (high GFR, medullary washout)
Dilute USG
Proteinuria
Labwork findings in cats with HAC
Stress leukogram
Anemia
Do NOT have elevated ALP, no steroid isoenzyme for this!
Increased BUN: concurrent CKD common
Hyperglycemia: concurrent DM common
Normal USG, more mild proteinuria
Expected thyroid panel in dogs with HAC
Low TT4, Low FT4, but NOT ACTUALLY hypothyroid! Low TSH
DO NOT TEST THYROID IF NONTHYROIDAL ILLNESS IS PRESENT
Sensitivity, specificity of ACTH stim
Poor sensitivity, moderate specificity
Non-adrenal illness will increase your cortisol! False +
Useful for iatrogenic HAC, because you will have a lack of response 2’ adrenocortical atrophy
Expected findings on ACTH stim of a dog with PDH
Look at 8hr first. If ABOVE 40nmol/L: consistent with HAC.
Then we need to know if PDH or uncertain origin:
PDH confirmed if:
* 4-hr: <40 nmol/L (in normal range)
* 8-hr: >40 nmol/L BUT >50% reduction from baseline
Urine cortisol creatinine ratio: sensitivity and specificity
A good test to rule out cushings
Very sensitive, not specific
Stress will increase cortisol
(Cats have a naturally higher UCCR, need to use a cat range for HAC cats)
Urine cortisol: creatinine ratio combiend WITH oral low dose dexamethasone suppression test can tell us _____
Differentiates PDH from ADH. PDH cat will suppress UCCR w/oral dexamethasone
Day 1, Day 2: AM free catch urine
Day 2: give dexamethasone PO q8hr
Day 3: AM free catch
Interpretation:
*If Day 1, 2 are WNL: NOT HAC
*If Day 1,2 are elevated –> likely HAC. AND If Day 3 UCCR is <50% of average of Days 1,2 –> cat has PDH
What treatment can be pursued in PDH cats refractory to oral treatments
Bilateral adrenalectomy
MOA: Trilostane inhibits _____
3-beta hydroxysteroid dehydrogenase
Cannot convert:
1) Pregnenolone to progesterone
2) 17-OH prenenolone to 17-OH progesterone
ACTH stim 2-3hr post dose
Best tests to perform prior to changing trilostane dose
Combo UCCR with ACTH stim
Severe AE of trilostane
Rare, IRREVERSIBLE coagulation necrosis of adrenal glands
Hypocortisolemia
MOA mitotane
Adrenocorticolytic
Cytotoxic to Zona fasciculata and Zona reticularis
As efficacious as trilostane in dogs
INFERIOR to trilostane in cats
What metabolic changes cause the clinical signs of HAC
1) Gluconeogenesis
2) Lipolytic
3) Immunosuppressive effects of GC
4) Protein catabolism
How do glucocorticoids affect thyroid levels
Decreased TSH secretion
Decreased TT4, fT4
Normal TSH
How does phenobarbital affect thyroid levels
Changes hepatic metabolism, so increased clearance of thyroid hormones
Decreased TT4, fT4
Normal TSH
How does TMS affect thyroid levels
Inhibits thyroid peroxidase/TPO (which adds iodine to tyrosine). Results in true, reversible hypothyroidism
Low TT4, fT4
High TSH
May result in a goiter
How does clomipramine, aspirin affect thyroid levels
Low TT4, fT4
How does phenylbutazone affect thyroid levels
Alters serum binding
Low TT4
How does euthyroid sick syndrome affect thyroid levels
1) Inhibits 5’/3’ deiodinase, which converts T4 to T3 in the peripheral tissue
2) Decreased TSH secretion
3) Decreased thyroid protein binding
Low TT4, fT4
Normal to low TSH
Which breed is more predisposed to myxedema coma
Doberman pinscher
Which breed has reported autosomal recessive inherited lymphocytic thyroiditis
Borzoi
What protein is most T4 bound to in circulation
Thyroxine-binding globulin
(not in cats)
Most common cause of equine hypothyroidism
Congenital
Low dietary Iodine by mom (or endophyte infested fescue, high nitrate diet)
Leads to congenital goiter, limb abnormalities
Which caprine breed has autosomal recessive congenital hypothyroidism
Saanan Dwarf crossbreeds
Issue with thyroglobulin synthesis
Which ovine breed has autosomal recessive congenital hypothyroidism
Merino sheep
Issue with thyroglobulin synthesis
MOA methimazole
Inhibit TPO
Most common cause of hyperthyroidism in cats
Thyroid adenoma
Clinical sequelae of hyperthyroidism in cats
Thyrotoxic cardiomegaly
(Hyperthyroidism masks CKD too! Careful when starting tx)
Which test should you do to diagnose a cat with hyperthyroidism
Ideally both TT4 and fT4
fT4 is more sensitive but less specific than TT4
fT4 is less affected by nonthyroidal illness than TT4
Other name for growth hormone
Somatotrophin
What hormones regulate somatotrophin (GH)?
GnRH and stomatostatin
Anabolic downstream molecule of GH
IGF
Best indirect measurement of GH?
Result in acromegaly vs GH deficiency?
IGF-1 levels
Acromegaly: High IGF-1
GH deficiency: Low IGF-1
Impact of glucocorticoids and estrogens on IGF
IGF is decreased by GCs, estrogens
Breeds predisposed to pituitary dwarfism
GSD
Carnelian Bear Dog
Most common etiology of pituitary dwarfism
Cyst in Rathke’s cleft of pituitary gland
Hormone changes in pituitary dwarfism
Low TSH, GH, Prolactin, Gonadotropin
Which breed has a hereditary immunodeficient dwarfism
Weimeraner
Impact of clomipramine, aspirin on thyroid values
Low TT4, fT4
Which enzyme is NOT present in the zona glomerulosa, resulting in its inability to make cortisol or androgens
17-alpha hydroxylase
Gene, mode of inheritance for GSD pituitary dwarfism
LHX3
Autosomal recessive
How can ketoconazole be effective for HAC treatment
Can inhibit steroidogenesis at high doses (20 mg/kg/d) by DIRECTLY suppressing ACTH
MOA of selegiline hydrochloride
IRREVERSIBLE inhibitor of monoamine oxidase (MAO)
-Increase in dopamine
-Downregulate ACTH secretion
-Best in dogs with pars intermedia tumor
DOES NOT WORK FOR HAC. But owners like it bc selegiline is metabolized to amphetamine –> increased alertness
MOA of Cabergoline
D2 dopaminergic receptor agonist
Anti-proliferative, pro-apoptotic
Affects cleavage of ACTH to form alpha-MSH
Most effective in dogs with pars intermedia tumors
Impact of retinoic acid on HAC
Suppresses tumor synthesis POMC ad ACTH
Suppresses tumor growth
Teratogenic risk
Which cells of the pars intermedia stimulate melanin production
A cells, make alpha-MSH
Which cells of the pars intermedia produce POMC
B cells
Controlled by dopamine inhibition
CRH secretion is stimulated by _____ (7)
IL-1
IL-6
TNFa
Leptin
Dopamine
ADH
Angiotensin II
CRH secretion is inhibited by ______ (2)
Glucocorticoids
Somatostatin
Precursors of ACTH
POMC
MSH
What hormone competes with the cortisol receptor, which can lead to acquired skin fragility syndrome in cats
Progesterone
Increased progesterone (from tumor) = more unbound cortisol –> fragile skin
Which enzyme is NECESSARY for cortisol AND sex hormone production
17-alpha hydroxylase
Which enzyme is necessary for sexhormone production
17,20 lyase
Congenital hypothyroidism breeds
Giant schnauzers, toy fox terriers, scottish deerhounds
