Endocrine Flashcards
Apart from GHRH, what is another stimulus for GH secretion, and what is its origin & roles?
Ghrelin. More potent GH secretagogue than GHRH in young dogs. Produced & secreted from the stomach.
Potent regulator of energy homeostasis. Stimulates food intake, gastric & intestinal emptying.
Which conditions can suppress ghrelin in cats? Is this change reversible?
Suppressed in cats with HST & HST+DM.
Ghrelin levels increased in HST-DM cats post-RT –> reached similar levels to control cats, so a potential marker of treatment efficacy/monitoring (NB: IGF-1 remain unchanged). Negative feedback system with GH.
Metabolic effects of excessive growth hormone?
Direct effects: insulin resistance –> DM. Also lipolysis.
Increased insulin-like growth factor-1 (IGF-1) production –> increased tissue growth (note IGF-1 increases insulin sensitivity & decreases lipolysis - opp of GH).
Vitamin D metabolites?
Calcidiol = 25-hydroxycholecalciferol/hydroxyvitamin D3.
Calcitriol = 1,25-dihydroxycholecalciferol/dihydroxyvitamin D3.
Vitamin D binding protein
Vitamin D receptors – mostly in kidneys, duodenum (less in skin & ileum), dogs don’t really have active receptors in skin unlike humans
–> With steatorrhea & loss of fat-soluble vitamins, hypoCa can occur.
Vitamin D formation pathway?
Liver converts Vit D2 (eggs, fish) & D3 (fish, eggs + made in skin) into calcidiol + stores excess vit D.
Calcidiol is converted to calcitriol (biologically active form, 1000x potency for Vit D receptors) in the renal proximal tubules via 1-alpha hydrolase enzyme (produced in renal PTs > skin, immune cells, osteoblasts). Conversion of calcidiol to calcitriol requires PTH.
Excess calcidiol is converted to 24,25- dihydroxycholecalciferol (inactive form).
List 8 consequences of chronic hypercortisolism in dogs?
DM
Systemic hypertension
Proteinuria
Glomerulosclerosis
GB mucocele
Pancreatitis
Increased susceptibility to infections
PTE
How to differentiate histologically between phaeochromocytoma and cortical tumours?
Chromogranin stains medullary tumours.
Difficult to distinguish if benign or malignant histologically.
How to calculate urinary free water clearance? What changes are expected with SIADH?
Urinary free water clearance (%) = 1 - (Urine Na+ - Urine K+) / Serum Na
SIADH = low serum Na+ & negative free water clearance. I.e. low Na & water retention (effects of excessive ADH)
Abdominal organ changes seen in HST cats?
Increased kidney length, adrenal thickness & pancreas thickness
List types of autoimmune polyglandular syndromes (APS) reported in dogs.
Which is most common?
APS type 1: DM, ectodermal mucositis etc.
APS type 2: hypoA, hypoT.
- HypoA is the most common initial endocrinopathy observed in polyendocrine gland failure in dogs, usually followed by the development of hypoT.
APS type 3: liver cirrhosis + endocrinopathies
Tx considerations:
- Initiate tx for hypoA first, then tx for others (e.g. levothyroxine).
- Dogs with DM + hypoT - balance insulin dose & levothyroxine.
Are chemiluminescent assays reliable for fT4 measurement in dogs with hypoT?
No especially if they have thyroid globulin antibodies. 2015 study - 25-38% dogs with positive antibodies and hypothyroidism) had normal fT4 levels. Need to use equilibrium dialysis.
What % of cats have normalisation of T4 on an iodine-restricted diet, and at what time points does it typically occur? Are there any pre-treatment variables which affect outcome?
42% cats by 21-60days, 83% by 61-180 days (100% by this time in another study).
Cats with higher initial T4 had post-diet T4 that stayed above RI.
Gene mutation is reponsible for pituitary dwarfism in GSD? What other abnormality may this be associated with in GSD & Czech Wolfdogs?
LHX3 mutation
A-A instability
Consumption of what diets have been linked to thyrotoxicosis in dogs? Is this reversible?
Commercial meat-based foods/treats presumably contaminated by thyroid tissue
Reversible with diet discontinuation
Diagnostic utility of TSH for hyperT in cats?
High Sn (98% have undetectable levels) but poor Sp (69%). Increased Sp when combined with TT4/fT4.
What is the cortisol:ACTH ratio useful for?
Diagnosis of hypoA without use of synacthen.
HypoA dogs have LOW ratio. High Sn 100% & Sp 99%.
(Potential false positives due to overlap with dogs with HA-mimicking diseases)
What is the preferred test to diagnose phaeochromocytoma in dogs?
Urinary normetanephrine : creatinine ratio. No overlap with HAC or healthy dogs based on previous studies.
What findings from LDDST and/or UCCR following dexamethasone administration is consistent with PDH?
Plasma ACTH [ ] - PDH vs ADH?
50+% decrease in plasma cortisol or UCCR consistent with dex-suppressible hypercortisolism.
(Up to 30% PDH dogs don’t suppress)
PDH - plasma ACTH intermittently increased (unregulated/inappropriate secretion)
ADH - plasma ACTH low (suppressed due to neg feedback)
Pathophysiology of food-responsive HAC?
Diagnostic test findings?
Treatment?
GIP released at every meal abnormally triggers the release of cortisol by binding to aberrant receptors in the adrenal cortex.
Supportive
- Basal plasma ACTH concentration will be suppressed.
- CRH stimulation test –> ACTH slightly increased –> consistent with ACTH-independent HAC.
- Imaging - Bilateral adrenomegaly but pituitary gland WNL
Diagnostic
- Pre & 3hrs post meal: measure UCCR, plasma cortisol, plasma ACTH. Expect rise in UCCR & plasma cortisol, but plasma ACTH concentration will remains low-undetectable.
Treatments:
- Octreotide completely prevents meal-induced hypercortisolemia (people).
- Trilostane used in case report in a dog (given 2hr before meal).
What is an incretin? Name 2 examples and how it is degraded. What is its MOA?
GI hormones release from L or K cells in the GIT
Gucagon like peptide (GLP-1). E.g. exenatide.
- Cleaved by DPP-4 (another drug target = DPP-4 inhibitors)
- GLP-1 promotes insulin release in response to glucose, inhibit beta cell apoptosis, inhibits glucagon release & delays gastric emptying. Effects are glucose-dependent.
- In DM cats receiving insulin tx, concurrent exenatide ER formulation was associated with reduced insulin requirements & higher remission.
Which 2 transition metals may be beneficial in the treatment of DM cats? What are the mechanisms?
Chromium & vanadium. Co-factors for insulin function. Chromium improves glucose tolerance in healthy cats & vanadium improves CSx & fructosamine in DM cats.
What is the recommended CHO content of food for DM cats
JFMS consensus: <12-15% ME
What is acarbose? What is the effect in healthy cats and is this diet dependent?
Oral hypoglycemic agent affecting glucose absorption. Inhibits pancreatic amylase and alpha-glucosidase.
Reduced BG in cats fed a high CHO diet but not a low CHO diet. A low CHO diet was more effective than using this medication with a high CHO diet. Best used in cats that eat all their food at once.
What is the incidence of relapse in cats with diabetic remission? What factors can predict this?
30% relapse.
Fasting BG 7.5+ and impaired glucose tolerance predicted; taking 5 hours to normalise or BG increasing to 14+
What is the average dose required for Detemir insulin? Risks/considerations?
0.12IU/kg. Hypoglycemia in 22%, caution in small dogs.
Name an example of a sulfonylurea. MOA? Adverse effects?
Glipizide.
Stimulate insulin release by binding to ATP-sensitive K+ channels & blocking their activity within pancreatic beta cells. This closes K+ channels, depolarises cell membrane so leads to increased intracellular Ca2+»_space; insulin release.
AE: GI signs, liver enzyme elevations, jaundice
Name an example of a meglitinide. MOA?
Nateglitinide.
Similar to sulfonylureas - closes ATP-sensitive K+ channels & stimulate insulin release. Short acting.
Name an example of a biguanide. MOA? Side effects?
Metformin.
Insulin sensitiser in target tissues; increases glucose uptake in muscle and reduces hepatic glucose production.
Lack of strong evidence for use, with only 1/5 cats exhibiting a response in one study and 1 cat died in a study testing it (unknown cause).
SE: potential lactic acidosis, GI signs
What is C peptide? What does it presence in circulation indicate?
C peptide is part of the proinsulin molecule (along with polypeptides A & B). It is packaged together with insulin into secretory granules & secreted in minute amounts (but in itself has no insulin activity).
Presence in circulation indicates presence of functional beta cells (so low to absent in Type 1 DM)
Glucose uptake & utilisation in which 4 organs/body systems is not influenced by insulin?
GIT - glucose absorption
RBC, kidneys, CNS - glucose utilization
Glucose uptake & utilisation in which 4 organs/body systems is not influenced by insulin?
GIT - glucose absorption
RBC, kidneys, CNS - glucose utilization.
Note neurons only use glucose for energy, thus are highly permeable to glucose.
T/F
Obesity induces an insulin-resistant state, and can predispose to development of DM in dogs.
Adipokine concentrations are decreased in DM dogs, like in people.
False - obesity does cause insulin resistance but not reported to directly cause DM in dogs.
False - not reported. BUT adiponectin may still protect beta cells against FA-induced apoptosis in dogs.
In what scenarios are dogs most likely to achieve diabetic remission?
DM associated with diestrus, pregnancy or ovarian remnant syndrome when serum GH & progesterone concentrations are increased.
* Impt to recognize & correct insulin resistant state EARLY; otherwise progressive loss of beta-cells increases risk of permanent insulin deficiency.
* Also, bitches that undergo DM remission following diestrus have high likelihood of developing permanent IDDM next estrus; so spay ASAP after DM diagnosis in these dogs.
Stopping insulin antagonist drugs (glucocorticoids, progestogens)
* Note these animals likely do not have normal beta-cell populations & are probably subclinical/pre-diabetic
During DM, …..lipase is decreased while ….lipase is activated. As a result hepatocytes produce more …….due to decreased clearance, and release of ……from adipocytes into circulation.
(Insulin inhibits lipolysis & FFA oxidation).
Lipoprotein lipase decreased
Hormone-sensitive lipase activated
TG-rich VLDL & chylomicrons
FFAs
List 5 drugs causing DM/hyperglycemia.
Glucocorticoids
Progestagens
Thyroxine (thyroid hormone)
Thiazide diuretics
Beta adrenergic agonists