Endocrine Disease Flashcards
When do cats typically present with congenital hyposomatotropism?
2 months of age. Initial postnatal growth genetically determined, second phase growth hormone dependent
What are the typical clinical findings of feline congenital hyposomatotropism?
Proportional dwarfism, retained deciduous teeth, dry and dull haircoat, general weakness and lethargy
What % of cats with DM have acromegaly?
26%
Is there a sex predisposition in acromegalic cats?
70% neutered male
What non-diabetic clinical signs are often reported in cats with acromegaly?
Polyphagia, respiratory stertor, snoring, prognathia inferior, enlarged distal limbs, organomegaly, heart murmur, CNS signs
How is acromegaly screened for, what is the PPV of this test?
IFG-1 >1000 = PPC 95%
When can a false negative IGF be seen in acromegalic cats?
9% untreated diabetic cats (IGF-1 production dependent on portal insulin)
Can IGF-I levels be used as a marker of treatment success in cats with Hypersomatotropism treated with surgery or radiation?
Surgery - yes
Radiation - no
What alternative markers of Hypersomatotropism in cats have been explored?
Serum type III pro collagen peptide - marker of collagen turnover, 5x higher in FeHS DM than DM
Gherkin - lower in FeHS than controls but not diabetics. Increases post radiation
What % of FeHS cases experience diabetic remission following hypophysectomy?
85%
What medical management do cats need following hypophysectomy?
Hydrocortisone and T4 (life)
DDAVP - can be discontinued in most
What options for medical management of FeHS have been described?
Pasireotide - SST analogue - remission in 25% on long acting form
Cabergoline
What is the response to radiation treatment for FeHS?
Unpredictable
Describe GH secretion in dogs. What regulates it’s secretion?
From anterior pituitary, pulsatile
GHRH +
Somatostatin -
Ghrelin +
IGF directly inhibits and stimulates somatostatin release
From mammary - progestogen, non-pulsatile, not controlled by SS, GHRH or ghrelin
When is canine mammary GH production increased?
Dioestrus
What are the physiological effects of GH in dogs?
Rapid - insulin antagonism - ^lipolysis, gluconeogenesis, reduced glucose transport and hyperglycaemia
Slow - IGF growth factors - growth-promotion
What can cause excess GH in dogs?
Endogenous/exogenous progesterone
GH-producing mammary tumour
Hypothyroidism associated with increased GH and IGF-1
Pituitary somatotropin adenoma (RARE)
What are the clinical signs of GH hyper secretion in dogs?
Soft tissue swelling of head, neck, abdomen, snoring, stertor, joint issues (articular cartilage proliferation), PU, PP, increased organ size
How is CaHS diagnosed?
GHRH stimulation or SS suppression tests
IGF-1
What should be tested in a dog with GH excess, not receiving progestogens?
T4/TSH
How can dogs with somatotroph adenomas causing CaHS be treated medically?
Octreotide/lanreotide
What are the typical endocrine findings in GSD with pituitary dwarfism?
GH, TSH and prolactin deficiency
Normal ACTH
What mutation is associated with congenital pituitary dwarfism?
LHX3
What are the clinical manifestations of pituitary dwarfism in dogs?
Proportionate dwarfism, retained secondary hairs, lack of primary hairs, truncal alopecia, pointed muzzle, cryptorchidism/ovulation failure. Lethargy develops at 2-3 years due to secondary hypothyroidism
What are the findings on biochem for canine pituitary dwarfs?
High creatinine - GH needed for normal glomerular development
How is pituitary dwarfism diagnosed in dogs?
GHRH/clonidine/xylazine stimulation test. GH should increase 2-4x
Ghrelin suppression test can be used to exclude
What are the typical imaging findings in pituitary dwarfism in dogs?
Pituitary cysts +/- hypoplasia
How is canine pituitary dwarfism treated?
Porcine GH
Progestogens described
What is the prognosis for canine pituitary dwarfism?
Poor without treatment, guarded with
Loss of pituitary function, expansion of pituitary cysts renal failure
Describe vasopressin secretion?
AVP formed in the magnocellular neurons in the hypothalamus and transported to the posterior pituitary
What stimulates AVP release?
Increased plasma osmolality and Na content
Angiotensin II
What inhibits AVP release?
Baroreceptor stimulation
BNP
How does AVP act?
Binds V2 receptors, increase cAMP, activates protein-kinase A - causes expression of aquaporin 2
In addition to AVP release, what are the effects of AVP binding V2 receptors?
VWF release
TPA release
ANP release
NO synthesis
FVIII release
What are the most common causes of CDI in dogs and cats?
Dogs - neoplasia
Cats - trauma
What are the causes of NDI?
HAC, pyometra, hyperCa++, pyelonephritis, liver disease, primary
What % of dogs with CDI develop neuro signs within a year?
~40%
What treatment options are described for NDI?
Thiazide diuretics - decrease Na+ absorption, reduce delivery to distal tubules
Low Na diet
What are the actions of the V1a and V1b receptors?
V1a - vascular SM, glucogenolysis, platelet activation
V1b - stimulates ACTH, catecholamine and insulin secretion
How is glargine insulin modified to increase its duration of action?
Structure modified to make soluble at pH 4 and relatively insoluble at physiological pH
How is detemir insulin modified to increase its duration of action?
Structure modified so reversibly binds albumin
How does the potency of detemir in dogs differ from other species?
4x as potent
If spaying isn’t possible in a recently diagnosed FE diabetic what is an alternative?
Aglepristone
What is fructosamine?
Glycated protein formed by irreversible non-enzymatic reaction between glucose and plasma proteins
What non-diabetic factors can alter fructosamine?
Hypothyroidism and multiple myeloma associated with increase
Where is the calcium-sensing receptor found?
Parathyroid, kidneys, bone, cartilage
How is circulating calcium found?
50% ionised
40% protein bound
10% bound to anions
What factors can falsely alter TCa/iCa measurement?
Haemolysis, lipaemia increase TCa
Hypoproteinaemia decreases TCa
Storage - RBC produce lactic acid, pH decreases, iCa increases
Air exposure - CO2 lost, pH rises, iCa decreases
What 4 hormones regulate calcium?
PTH
PTHrP
Vit D
Calcitonin
How is PTH production regulated?
CaSR activated by hypercalcaemia and reduced PTH production
Describe the anatomy of the parathyroid glands
4 glands, cranial pair external, caudal internal
How does PTH act?
Increases Ca, decreases PO4 by action in bone, kidneys and GIT
How do vitamin D and phosphate affect PTH production?
^Vit D = v PTH
^PO4 = ^ PTH
What is PTHrP
Integral in the foetus, undetectable after birth
Same physiological effects as PTH
Causes humoral hypercalcaemia of malignancy
Describe vitamin D metabolism
Cholecalciferol, hydroxylated in the liver to produce 25-OH calciferol (calcidiol) - inactive and unregulated
Activated to 1,25-OH-vit D (calcitriol) in kidney
Increased by PTH
Suppressed by PO4
Can also be catabolised to 24-OH and excreted
What is calcitonin
Produced in thyroid gland C-cells
Reduces serum Ca
Limits post prandial hypercalcaemia
What breed is predisposed to PHPT?
Keeshonden
How does hypercalcaemia cause PUPD
Ca antagonises AVP
Ca inhibits tubular uptake of Na and Cl
What are the clinical signs of PHPT?
PUPD (mild), lethargy, urolithiasis, muscle wastage, weakness
In dogs with PHPT how is the risk of urolithiasis increased?
Increased renal excretion of Ca
Increased PO4 excretion
GI absorption of oxalate increased when calcium absorption increased
Therefore urine supersaturated with Ca, PO4 and oxalate
What medications can be used to lower serum calcium, what is their MOA?
Steroids - increase renal loss, decrease intestinal absorption, decrease bone resorption
Bisphosphanates - inhibit osteoclast activity and increase apoptosis
Calcitonin - inhibits osteoclast activity and inhibits renal reabsorption
Cinacalcet - calcimemetic - interacts with the CaSR directly
How do the post operative outcomes for ethanol ablation, heat ablation and surgery in PHPT
Ethanol - 72-90%
Heat - 90%
Surgery - 94%
What oral vitamin D formulations are available. What is the active ingredient?
Calcitriol - 1,25-(OH)2
Alfacalcidol - needs 25-hydroxylation, rapid and unregulated - no significant difference in time to become effective
What should be monitored for on the ECG when administering IV calcium
ST elevation
QT shortening
Arryhmias
What are the clinical signs of PHPT in cats?
Vomiting, PUPD, weight loss, cervical mass
What are the effects of hypoparathyroidism?
vCa
^PO4
What is the most common cause of hypoparathyroidism
Idiopathic
Evidence to support IM aetiology
What are the predispositions to hypoparathyroidism?
Females, miniature Schnauzers, Poodles, GSD, Terriers
What are the clinical signs of hypoparathyroidism?
Seizures, muscle tremors, stiff gait, inappetence, vomiting, lethargy, tacchycarrythmias
What eye change is described with hypoparathyroidism?
Lenticular cataract formation
What routine blood testing changes are found in hypoparathyroidism?
v Ca
^ PO4
Elevated CK
What are the ddx for hypocalcaemia?
Hypomagnesemia
AKI
CKD
Pancreatitis
DM
Eclampsia
Malabsorption
Urinary obstruction
Phosphate-containing enema
What ECG changes are described with hypoclacaemia?
ST and QT prolongation
In what forms (and relative quantities) is thyroid hormone found?
60% - thyroxine-binding globulin
17% - transthyretin
12% - albumin
11% - lipoprotein fractions
How does the potency of T3/T4 compare?
T3 3-5x more potent
How is T3 produced?
40% in thyroid
60% by peripheral outer ring monodeodination of T4
How is T3/4 secretion regulated
TRH (hypothalamus)
TSH (anterior pituitary)
What is rT3
Reverse T3 - metabolically inactive
How do thyroid hormones work?
Modify gene expression
In which dog breeds have congenital thyroid dyshormogenesis been described?
Toy Fox and Rat terriers
What are the common histopathological findings in primary acquired hypothyroidism?
Lymphocytic thyroiditis
Thyroid atrophy
What % of hypothyroid dogs have TgAAs?
50%
What breeds have a higher risk of developing TgAAs?
English Setter, Golden Retriever, Rhodesian Ridgeback, Cocker Spaniel, Boxer
What cardiac changes are associated with hypothyroidism in dogs and how often are they reported?
15%
Asymptomatic bradycardia
Low voltage R waves, inverted T, 1st/2nd degree AV block
Reduced FS
What neurological changes have been described in hypothyroid dogs?
Facial nerve paralysis
Laryngeal paralysis
Megaoesophagus
Peripheral/central vestibular
Lower motor neurone dysfunction
Crichopharyngeal achalasia
What ophthalmological changes have been described in hypothyroid dogs?
Arcus lipoides
KCS?
What are the 5 most common clinicopathological abnormalities in hypothyroid dogs?
Anaemia
Hypercholesterolaemia
Hypertriglyceridaemia
Increased CK
Increased fructosamine
What medications interfere with T4 measurement? Which affect TSH?
Pred (vTSH)
Phb
TMPS (^TSH)
Aspirin
Clomipramine
NSAIDs
Toceranib (^TSH)
What is the value in measuring TT3 when hypothyroidism is suspected?
Limited
Maintained in normal range in 90%
May be useful in greyhounds
What is the value in measuring TT4 when hypothyroidism is suspected?
High sensitivity
T4AA may falsely increase
What is the value in measuring fT4 when hypothyroidism is suspected?
Most specific test
What is the value in measuring cTSH when hypothyroidism is suspected?
Moderate sensitivity
WNLs in significant proportion of hypothyroid dogs
What is the value in measuring TgAAs when hypothyroidism is suspected?
May be elevated before clinical hypothyroidism
No information on thyroid function
What is the value in performing TSH stimulation when hypothyroidism is suspected? How is it interpreted?
Gold standard
Euthyroid expect >1.5x increase
Absolute level >30nmol/l
What imaging modality is the most accurate for differentiating hypothyroidism and NTI? When is it not reliable?
T-99
Steroids
How does feeding affect the bioavailability of T4?
Halves it
What are the clinical signs of hypothyroidism in cats?
Inappetence, mental dullness
Dull, dry, unkempt haircoat
Is FT4 useful to diagnose hypothyroidism in cats?
Not known
Is TSH useful to diagnose hypothyroidism in cats?
Feline specific assay not available. Use of canine assay described
In hyperthyroid cats, is disease most often uni- or bilateral?
2/3 bilateral
What is the most common CBC change in hyperthyroidism?
Erythrocytosis - 50%
What biochem changes are commonly seen in hyperthyroid cats?
^ALT - 80%
^ALKP - 50%
Azotaemia - 25%
If FT4 useful for diagnosing hyperthyroidism?
No - sensitivity 98%
However, elevated in !2% cats with NTI
What suppression test can be used to diagnose hyperthyroidism in cats? How is it performed/interpreted?
T3 suppression test
Baseline blood collected. T3 administered for 2 days. Resampled. Both sampled assayed for TT4 and TT3
TT4 should be suppressed
What stimulation test can be used to diagnose hyperthyroidism in cats? How is it performed/interpreted? What are it’s limitations
TRH stimulation test
TT4 concentration increases <50% in hyperthyroid cats
Cost, limited accuracy if concurrent illness, risk of cholinergic/CNS reactions
What imaging test can be used to diagnose hyperthyroidism in cats? How is it performed/interpreted?
Scintigraphy
Thyroid:salivary >1.5 - hyperT
<1 normal
What side effects are reported with anti-thyroid medications in cats?
Agranulocytosis, thrombocytopenia, hepatopathy, bleeding
What medications are used to manage hyperthyroidism in cats? What is their MOA?
Methimazole and carbimazole (prodrug)
Thioureylenes - inhibit thyroid follicular cell peroxides, inhibit iodination of tyrosyl residues
What is the expected behaviour of canine thyroid tumours?
Malignant
What are the common canine thyroid tumours?
30% adenoma
70% carcinoma
Carcinomas - 70% follicular cell, 30% medullary (also called parafollicular or C-cell)
What has been shown to be a risk factor for the development of thyroid tumours in dogs?
Chronic exposure to excess TSH
What is the average age and sex predilection for thyroid carcinoma in dogs?
9-11
No sec predilection
Which tests have the highest sensitivity and specificity for diagnosing thyroid carcinoma?
CT - 100% spec
MRI - 93% sens
Is scintigraphy useful for screening for metastasis of thyroid carcinoma?
No
What effect does diagnosis of a malignant thyroid carcinoma have on prognosis?
None
What is the MST for dogs following removal of a unilateral thyroid carcinoma?
3 years
What is the median PFI following radiation therapy of thyroid carcinoma in dogs?
45 months
What are the treatment options for thyroid carcinoma in dogs?
Surgery
Radiation
I131
Chemotherapy - doxorubicin/cisplatin/mitoxantrone
Medical
What chemotherapy drug has been shown to be most effective in treating thyroid carcinoma in dogs and what is the MST?
Cisplatin
11 months
What proportion of thyroid carcinoma are functional?
10%
How is normal insulin secretion regulated?
Glucose enters beta cells
Metabolised to ATP
Closes ATP-sensitive K channels
Reduced K efflux, depolarisation
Ca channels open
Insulin exocytosis
What are the counter regulatory hormones secreted in hypoglycaemia?
Glucagon
Catecholamines
GH
Glucocorticoids
What unusual neurological clinical signs are recognised in insulinoma?
Peripheral polyneuropathy - posterior paresis/tetraparesis
Ddx - hypoglycaemis
Insulinoma
Extrapancreatic tumour - gastric, hepatic, intestinal
Beta cell hyperplasia
Hypoadrenocorticism
Hypopituitarism
Hepatic insufficiency
Glycogen storage disease
Sepsis
Hunting dogs
Oral hypoglycaemic, beta blockers, ethanol, ACE-i, lidocaine OD, lithium
What % dogs with insulinoma have a mass identifiable on US?
56%
Other than IV glucose, what treatment has been described for acute hypoglycaemia associated with an insulinoma? What is the MOA? What is a drawback of this treatment?
IV glucagon CRI
Promoted glycogenolysis and gluconeogenesis
Increases insulin secretion
What medical treatments of insulinoma have been described? What is their MOA?
Streptozocin - nitrosurea antibiotic, destroys beta cells. Risk of DM, nephrotoxic
Red - increases gluconeogenesis and glucose-6-phosphatase activity. Decreases glucose uptake into tissue. Stimulated glucagon secretion.
Diazoxide - inhibits closure of beta cell ATP-dependent K channels. GI se’s
Octreotide - SSA, inhibits insulin secretion but also glucagon and GH - varied response
What factors influence prognosis of insulinoma?
Tumour size
Ki67 index
What % of cats diagnosed with DM have pancreatitis at the time of diagnosis?
60%
Which cat breed has an association with DM?
Burmese
What are the processes responsible for the development of DM in cats?
Insulin resistance
Reduced insulin secretion
Deposition of amylin and islet amyloid polypeptide
Oxidative damage - glucose/lipotoxicity
What % of obese cats >8yo are glucose intolerant?
20%
What % of cats in diabetic remission relapse? How many of these can achieve a 2nd remission?
25-30%
25%
What is the recommended CHO content of a diet for a diabetic cat?
12%
What oral hypoglycaemic are available for use in cats? What are their MOA?
Sulfonylureas - stimulate insulin secretion by binding ATPases - close K+ and open Ca channels
Meglitinides - bind ATPases (different site)
Biguanides - insulin sensitiser
Thiazolidinedione - bind in nucleus and alter gene expression, improve insulin sensitivity in adipose, muscle and liver
Alpha glucosidase inhibitors - inhibit action of membrane-bound brush border disaccharides - slow glucose absorption
Glucagon-like peptides - enhance beta cell survival
What % of cats with HAC have DM at diagnosis?
80%
Describe normal cortisol release regulation?
Hypothalamus - CRH
Anterior pituitary - ACTH
What stimulates CRH secretion?
Cytokines - IL-1/6, TNF-alpha
Leptin
Dopamine
AVP
Ang II
What inhibits CRH secretion?
Glucocorticoids
Somatostatin
What are the 3 regions of the pituitary - what do they secrete?
Anterior - ACTH
Intermediate lobe - A cells - alpha-MSH, corticotropin-like intermediate lobe peptide (CLIP)
- B cells - POMC (cleaved to ACTH), beta-LPH
Posterior - oxytocin, prolactin
Which regions of the adrenal gland contain 17-alpha-hydroxylase?
Fasiculata and reticularis zones
What % dogs with HAC have PDH?
80-85%
Where are tumours found in dogs with PDH?
Pars distalis in 70%
Pars intermedia in 30%
What features are consistent with adrenal carcinoma?
> 2cm
Invasion
Cytology and histo can be unreliable
What causes PUPD in HAC?
Increased glomerular filtration rates and inhibition of ADH action at renal tubular level
How do leptin levels differ in overweight HAC dogs and normal overweight dogs?
Higher in HAC
What % of HAC dogs have ALP elevation?
85-95%
How does HAC affect calcium metabolism?
Increased urinary calcium, may result in increased PTH and hyperphosphataemia
What can be determined from a mineralised adrenal mass?
About half adrenal adenomas and carcinomas calcify, does not indicate malignant potential
What % of PDH dogs have US normal adrenal glands?
25%
How do UCCR values differ between dogs with PDH and ADH?
Higher in PDH
If >100 probability of PDH >90%
What are the sensitivity and specificity of the ACTH stimulation test?
Se - 85% (PDH), 60% (ADH)
Sp - 85-90%
What test can be used for differentiation of iatrogenic and naturally occurring HAC?
ACTH stim
What are the sensitivity and specificity of the LDDST? What can affect the specificity?
Se - 90-95% (PDH), 100% (ADH)
Sp - 40-50%
Sp affected by NAI
When should a LDDST not be performed?
Phb treatment
How should a V shaped LDDST be interpreted?
Likely PDH
30% express this pattern
How can a HDDST be used to differentiated PDH from ADH?
Suppression to <40 considered diagnostic for PDH
Lack of suppression - could be ADH or PDH
In what % of cases that fail to suppress on LDDST does HDDST provide extra information?
10%
How is a UCCR/HDDST interpreted?
UCCR measured on 3 consecutive mornings, 3x dex given after 2nd sample. If 3rd sample <50% baseline, PDH likely
How does trilostane work?
Inhibits 3-beta-hydroxysteroid dehydrogenase
Prevents conversion of pregnenolone into progesterone
How do survival times compare in dogs with ADH treated with trilostane, mitotane and surgery?
Similar
What proportion of cats with HAC have PD/AD disease?
85/15%
What are the most common clinical signs observed with feline HAC?
DM
PUPD
PP
Abdo distension
Alopecia
Skin fragility
Weight loss
Weakness
What proportion of cats with HAC are hypertensive?
20%
What condition can be associated with a false positive ACTHST in cats?
Hyperthyroidism
What is the sensitivity of ACTHST for HAC in cats?
56-80%
What is the screening test of choice for feline HAC?
LDDST
What is the recurrence rate for dogs with PD-HAC undergoing hypophysectomy?
25%
What is the MOA of trilostane?
Competitice inhibitor of 3beta-hydroxysteroid dehydrogenase
What tumours have the highest rates of adrenal gland metastasis in dogs?
Pulmonary, mammary, prostatic, gastric and pancreatic carcinoma and melanoma
What % of primary ATs are adrenocortical or neuroendocrine in origin?
75/25%
What are the strengths/weaknesses in cytology of adrenal masses?
90-100% accuracy in determining cortical vs medullary
Not reliable for distinguishing benign vs malignant
What imaging features are suggestive of a AT being malignant?
Size >2cm
Invasion
What acid-base abnormality is commonly seen with hyperaldosteronism?
Metabolic alkalosis (aldosterone-mediated H+ excretion)
How is primary hyperaldosteronism diagnosed?
PRA and aldosterone concentrations
Fludrocortisone suppression test
What are the layers of the adrenal cortex?
Out
ZG
ZF
ZR
In
Where are glucocorticoids and mineralocorticoids secreted?
Glucocorticoids - all 3
Mineralocorticoids - ZG
What causes secondary hypoadrenocorticism?
Pituitary failure to produce ACTH
or hypothalamus failure to produce CRH
What acid-base analysis is common in HA and why?
Metabolic acidosis in 60%
Aldosterone facilitates urinary H+ excretion
What ECG features are seen with HA?
Absent p waves
Wide QRS
Tall T-waves
+/- heart block
What is an alternative test to the ACTHst for diagnosis HA ?
Cortisol:eACTH
Where is secretin produced?
S cells (duodenum)
Where is glucagon produced?
Pancreatic alpha cells
What are the main effects of glucagon?
Hepatic glycogenolysis and gluconeogenesis
Where is gastrin produced?
G cells (antrum and duodenum)
Where is CCK produced?
I cells (duodenum and jejunum)
Where is somatostatin produced?
Hypothalamus, delta cells (pancreas), enteric nervous system
Where is motion produced?
GI cells
Where is ghrelin produced?
Stomach
What are the clinical hallmarks of gastrinoma?
Antral hypertrophy, hyperacidity and ulceration
What are the common clinical signs of gastrinoma?
V/D/weight loss
What can cause increased blood gastrin levels in dogs?
Gastrinoma, gastropathies, hepatopathies, acid blocking medication
What diagnostic tests are used to diagnose gastrinoma?
Serum gastrin/gastric pH
Secretin/Ca++ stimulation (normally gastrin doesn’t increase)
Where are gastrinoma most often found?
Right limb/body of pancreas
Where are carcinoids found?
Neuroendocrine cells of GIT, bronchial tree, biliary epithelium
What do carcinoids produce?
5-HT (serotonin) or kinins
How do carcinoids present?
Normally non-functional
From which cells to pheochromocytoma arise?
Chromaffin cells of adrenal medulla
From which amino acid are catecholamines synthesised?
Tyrosine
Draw the pathway of catecholamine production
Ettinger pg 1839
What test is most reliable for diagnosing pheochromocytoma in dogs?
UMN:crea
What medication has the potential to interfere with MN/NMN testing
Phenoxybenzamine
What test other than MN testing can be used to differentiate pheochromocytoma and HAC in dogs? When is this test not applicable?
Serum inhibit - undetectable in pheo
ME/FE dogs
MOA phenoxybenzamine?
Alpha-adrenergic receptor antagonist
Irreversibly bings a1 and a2
