Endocrine: non-literature Flashcards
Explain the structure of the thyroid gland
Note the thyroid follocles which are cuboidal epithelial cells surrounding colloid.
C-cells are also present (responsible for calcitonin secretion)
Highly vascularised
Outline thyroid hormone synthesis
- Iodine enters the thyroid gland, co-transported with sodium via NIS
a - The concentration gradient for sodium is generated via ATPase - Iodine diffuses through the cell and into the colloid mediated by counter-transport with chloride through pendrin (Chloride-iodide anti porter)
- Iodine is coupled to thyroglobulin, a glycopeptide containing tyrosine residues produced by the sER/Golgi
- Iodide is oxidised by thyroid peroxidase using H2O2
- Organification (coupling of Iodine to tyrosine) occurs mediated by thyroid peroxidase
- Pinocytosis into the cell occurs and proteases breakdown the colloid droplet to allow active thyroid hormones to be released into the blood.
- Deiodinases release tyrosine and iodine from inactive products to allow recycling of these compounds
Outline the different stages of thyroid iodination and number of iodine residues for each molecule
What is the majority of thyroid hormone bound to in the blood?
Thyroxine binding globulin, it can also bind to pre-albumin and albumin
Why does T4 likely have a longer duration of action than the more potent T3?
It takes longer for T4 to unbind from binding proteins in the blood.
How does thyroid hormone expert its effect?
Through binding to nuclear thyroid hormone receptors which combine with the retinoid x receptor and then bind to thyroid response elements.
What are the effects of TSH on thyroid production (5 points)
- Increased proteolysis of TG
- Increased NIS activity
- Increased iodination of tyrosine
- Thyroid hypertrophy
- Increased number of thyroid cells
What is the effect of ACTH on the adrenal cortex that results in increased steroid hormone production?
It enhances the activity of cholesterol desolate which is the first step in steroid synthesis converting cholesterol to pregnenolone.
Which steps of the steroidogenic pathway does trilostane have an effect on?
3B hydroxysteroid dehydrogenase
What is the role of 11BHSD?
It converts cortisol, which has some MC activity, into cortisone (which does not) and is present in the renal epithelium. This is why cortisol, in health, does not have a significant MC effect.
Note that 11 beta-HSD 1 has the opposite effect
What food item may inhibit 11BHSD2?
Licorice, as it contains glycorrhetinic acid
Outline the effects of MC activation and drugs that may impact on some of these effects?
- Aldosterone binds to the MR which then stimulates production of NA/KATPase, ENaC and ROMK.
- Spironolactone inhibits the MR
- Ameloride prevents Na entry into renal cells by antagonising ENaC
Factors and hormones leading to increased vs. decreased insulin secretion
At what level of serum phosphate is all filtered PO4 re-absorbed by the kidney?
<1mmol/L
What treatments have been used/described for the management of hyposomatotropism in dogs/cats?
Use of porcine or human GH products but a problem with these treatments is that antibody development may occur.
Progestin use to stimulate mammary GH production has not been effective in cats.
What is the prevalence of hypersomatotropism in diabetic cats?
18 - 32%
What is the gold standard for diagnosis of HS in people?
Oral glucose administration followed by GH measurement - this has not been described in cats. The normal response is a suppression of GH secretion in response to testing.
Testing, other than GH/IGF-1 that may be used in diagnosis of fHS?
PIIIP - serum type III pro collagen polypeptide, may be up to 5x higher in fHS DM cats compared to DM cats
Gherlin - as a GH secretagogue it is lower in fHS than in healthy cats but may not be lower that DM cats. It has also been shown to increase in response to radiation therapy even when IGF-1 does not change.
GHRG stimulation/SST suppression tests (dogs)
- 1mcg/kg GHRH will NOT stimulate GH release if it is mammary driven (discriminatory test between these types)
- 10mcg/kg SST should suppress GH production in normal animals
What drug may reduce polyphagia in fHS cats?
Fluoxitine
In what scenario is gherlin an important secretagogue for GH release?
Possibly more important in young animals, compared with GHRH
What phase of reproduction is GH secreted from mammary epithelium in dogs?
dioestrus, more often 3 - 5 weeks following oestrus
Treatment for canine acromegaly?
MAMMARY DRIVEN:
OVH
Aglepristone
PITUITARY
As for cats
Pegvisomant (GH receptor antagonist)
Which canine breed is predisposed to pituitary dwarfism? What other hormonal deficiencies are noted in this clinical scenario?
GSD - autosomal recessive
Will typically have combined GH, TSH and PRL deficiency, however, ACTH production is preserved
Other breeds:
- Czechoslovakian wolfdog
- Karelian Bear Dog
- Lapland reindeer dog
- Lapponian herder
- Saarloos Wolfdog
- Tibetan Terrier
- White Swiss Shepherd
Clinical presentation of hyposomatotropism in dogs
Morphological Abnormalities
* Proportionate growth retardation
* Coat changes:
○ Retention of secondary (languno) hairs
○ Lack of primary guard hairs
○ Truncal alopecia (due to loss of languno hairs), sparing trunk and extremities.
○ Hyperpigmentation
○ Scale
○ Secondary bacterial infections
* Pointed muzzle
* LHX3 gene also associated with atlantoaxial joint malformation +/- instability
Reproductive Abnormalities
* Cryptorchidism (due to impaired gonadotrophs)
* Failure to ovulate
Other
May develop reduced demeanour at 2-3 years old due to hypothyroidism and impaired renal function.
What laboratory parameter is possible in congenital hyposomatotropism in dogs?
Increased creatinine
Testing to confirm a diagnosis of congenital hyposomatotropism
Basal hormone testing:
- IGF-1 (GH)
- TSH, TT4
Stimulation testing:
Determine basal GH and then re-measure 20 - 30 minutes after:
- GHRH
- Clonidine or xylaxine
- Gherlin
Other:
TRH stimulation
GnRH stimulation
Genetic testing: LHX3 mutation
What advanced imaging characteristic may be seen in cases with pituitary dwarfism?
Pituitary cysts or hypoplasia
Treatment of canine pituitary dwarfism
Porcine GH (human GH results in antibody formation)
Progestagens (to stimulate mammary production)
Vasopressin structure and sub-hormones
Neurophysin II - involved in the correct processing, transport and cleavage of AVP
Copeptin - unknown function
n.b. provasopressin is the molecule that is transported down the HPA axons to the PP
Half life of AVP
6 minutes
Main stimulators for release of AVP
Osmoreceptor stimulation: 1% increase in Osm can stimulate release
Sodium - via magnocellular neuron stimulation
High pressure baroreceptors - normally inhibit release via glossopharyngeal and vagus nerves
Low pressure volume receptors
- A drop in blood volume by 10 - 15% will remove inhibition from these systems and result in AVP release.
AVP actions based on receptors (renal V2, other V2, V1a, V1b, brain)
What breed has CDI been described in a familial fashion?
Afgan Hounds
DAMNIT V for central and nephrogenic DI in dogs and cats
Idiopathic
Traumatic
Inflammation/Infection
Cysts
Congenital defect
Neoplasia:
- Carniophayngioma
- Meningioma
- Chromophobe adenoma/carcinoma
- Lymphoma
- Metastatic neoplasia
What percentage of dogs undergoing hypophysectomy will develop prolonged CDI?
53%, 42% of which will need permanent therapy
What breed has primary NDI been reported in and what is the basis of this condition genetically?
Has been suspected in a litter of Siberian Huskeys in which it was suspected to be due to a X-linked mutation (as only males affected?). All the affected dogs had 10x lower binding affinity for AVP. It is thought to be due to reduced AQ2 expression.
Clinicopathologic features of DI in dogs and cats?
Low urea, hyposthenuria
Dehydration (if water has been restricted)
Outline how to perform a MWDT (see printed notes)
(See printed notes)
What is the potential risk of performing a DDAVP trial in an animal with psychogenic polydipsia?
Water intoxication and hyponatraemia
Indications for and how to perform HH test
Indication: useful to distinguish primary polydipsia from medullary washout from NDI after negative water deprivation and exogenous ADH testing
Procedure
1. Instil 20ml/kg water via stomach tube and measure urine flow via urinary catheter (ml/min) 2. Infuse 2.5% NaCl at a rate of 0.25ml/kg/min over 45 minutes 3. Measure urine volume every 15 minutes during infusion followed by every 15 minutes for 45 minutes afterwards
Interpretation
Normal = Decrease in urine production due to stimulation of ADH release from increase serum osmolality
NDI = no real change or even potentially ain increase in urine production
PP = Should have a normal response as the hypertonic saline should have
Risks
* Risky in patients with CHF * May cause hypernatraemia in animals that cannot excrete a sodium load
What tests other than DDAVP response, MWDT, HH and ADH administration have been described in diagnosis of DI in dogs/cats/humans?
AVP Measurement
* Generally not useful as it is pulsatile * Handing is challending * No widely available assays
AQ2 Expression
* Not been used clinically although should reflect AVP exposure (experimentally)
Copeptin Measurement (Plasma)
* Shown to reflect AVP concentrations in people but not evaluated in small animals.
Advanced Imaging
* Useful if a structural disease process is suspected * Intensity of the PP on T1w MRI has been shown to be proportional to AVP content in dogs (and has been sued to represent phospholipid or secretory granules in people) but has not been evaluated clinically.
Treatment for CDI?
DDAVP, although may not always work that well
Treatment for NDI
Diet: reduce solute load through low sodium and low protein diets
Thiazide diuretics
* Decrease Na absorption from distal tubules which will decrease blood volume and therefore increase PCT resorption of Na and water (due to slowed GFR)
* Possible that there is also a tubuloglomerular feedback which results in:
* Upregulation of AQ2
* Upregulation of DCT Na transporters
NSAIDs
May have a synergistic effect with thiazide diuretics but side effects are common.
Potassium-Sparing Diuretics
More for avoiding iatrogenic hypokalaemia
Chlorpropamide
* Usually for patial CDI * Unknown MoA (may upregulate AVP receptors)
What is the reported incidence of iatrogenic hypothyroidism following RAI in cats?
5 - 83%
What is a risk factor for development of iatrogenic hypothyroidism following RAI in cats?
Pertechnetiate uptake from both thyroid glands prior to treatment
What types of congenital hypothyroidism have and have not been reported in cats?
- Two categories:
○ Dyshormonogenesis
○ Dysmorphogenesis (hypo/aplasia)- Both are likely due to autosomal recessive traits (known to be the case in people)
- Dyshormonogenesis is a problem of hormone synthesis therefore there is a lack of negative feedback on the pituitary, TSH is high and the gland enlarges.
○ Defective thyroid peroxidase and impaired iodine organification has been found in related DSH and Abyssinian cats - Dsymorphogenesis does not cause gland enlargement, it has been documented in related cats with an inheritance pattern consistent with an autosomal recessive trait.
- There has been a case of hypothyroidism associated with TSH resistance in a family of Japanese cats.
- Central congenital hypothyroidism (Hypothalamic or pituitary deficiencies) have not been reported in cats.
What dermatologic change associated with hypothyroidism in dogs does not often develop in cats?
Alopecia, however, cats can get coat changes such as a sebbhoraeic coat
What is the radiographic feature of congenital hypothyroidism?
Delayed growth plate closure
How are cats tested for hypothyroidism.
Both TT4 and fT4 can be used to rule out the condition but given that they can be low for a variety of non-thyroidal reasons they cannot confirm the diagnosis.
cTSH can be measured alongside one of the above for diagnosis of iatrogenic hypothyroidism.
TSH stimulation testing can be used to rule out euthyroid sick syndrome in cats treated with RAI.
- Measure basal TT4
- Administer 25mcg rhTSH IV
- Measure TT4 6 hours later
Outline how the use of scintigraphy can be useful in the diagnosis of feline hypothyroidism (iatrogenic vs. congenital forms).
- Sensitive and specific
- Reduced or absent pertechnetate (99m TcO4-) uptake supports the diagnosis
- Use of I123 can help determine between dysmorphogenesis and dyshormonogenesis.
○ Dysmorphogenesis - absent uptake
○ Dyshormonogenesis - may be normal, but since organification is deficient, administration of perchlorate will cause the I123 to be discharged from the gland (perchlorate discharge test)
What is the prevalence of hyperthyroidism in cats?
2 - 4 %, although this may rise to >6% in cats >9 years old
What is the prevalence of ectopic thyroid tissue and thyroid carcinoma in cats?
Ectopic tissue in <4% cases
Prevalence of thyroid carcinoma 1 - 2%
What condition should you consider in an older unwell cat with erythrocytosis?
HyperTH - as most other conditions would be expected to cause a mild non-regenerative anaemia
What would be expected of TT4 and fT4 concentrations in a cat with euthyroid sick syndrome?
May expect TT4 to be low and fT4 to be high
How to perform a T3 suppression test
- d0 Collect a blood sample and separate serum before storing frozen or refridgerated
- d1-2 initiate T3 administration 25mcg/cat q8h PO for 2 days (6 doses)
- d3 morning give 7th dose of T3 before the cat returns to the clinic for repeat blood sampling
- Measure tT3 and tT4
○ T3 should be higher in the second sample if the owner has been administering it properly (this is why you are measuring this)
○ T4 should be suppressed if the cat is not affected, there is little overlap in results between FHT and unaffected cats so it can be a useful test
Indications for and interpretation of thyroid scintigraphy
- Uptake of pertechnetate or radioactive iodine
○ Can calculate pertechnetate uptake or thyroid-to-salivary ratio
○ 99% of FHT cats will have a thyroid to salivary ratio of >1.5
○ Healthy cats have a ratio <1- Thyroid-to-background ratio is less sensitive than the thyroid-to-salivary ratio.
- Another indication is pre-thyroidectomy to determine unilateral vs. bilateral disease and whether there is thyroid tissue elsewhere, and to increase level of suspicion for thyroid carcinoma.
Considered a GOLD STANDARD. It is very useful in animals that are not responding well to anti-thyroid medication as it can detect ectopic thyroid tissue. Uptake of radioactive iodine is compared to that of the salivary gland.
Disadvantages of TRH stimulation testing
○ Commercial TRH is not available
○ Lab-grade TRH cannot be recommended for clinical patients
○ Possibly limited usefulness in cats with oncurrent illness
○ Can cause cholinergic and CNS reactions e.g. SLUDGE-M
What is the therapuetic target range for TT4 when treating cats with hyperTH with thiourylene anti-thyroid drugs?
Lower half of the RI
Frequency of adverse effects of thiourylene anti-thyroid drugs
What is the efficacy of Hills y/d in the treatment of hyperTH?
- Heterogenous population of FHT cats given the diet exclusively for 8 weeks
- Clinical signs improved significantly by week 4 with no observed adverse effects
- TT4 decreased to the RI in 68% of cats by week 4 and in 75% of cats by week 8 but remained in the upper RI (interesting as with other therapies often signs do not resolve until T4 in the lower RI)
No change in creatinine - this may be good, or it may indicate that it was not effective.
Random treatments for hyperTH and disadvantages
- Ultrasound guided percutaneous radiofrequency heat ablation or intrathyroidal ethanol injections
○ Not recommended!!
○ Questionable efficacy and safety- Iopanic acid
○ An orally administered contrast agent used for cholecystography
○ Can lower serum thyroid hormones
○ Has transient effects so long term treatment not recommended
- Iopanic acid
What is the evidence for treatment of iatrogenic hypothyoidism following RAI in cats?
There is no difference in survival between cats that develop azotaemia post RAI vs. those that do not. However, azotaemic hypoTH cats do have a worse prognosis than azotaemic non-hypoTH cats.
What handling considerations can affect iCa concentrations?
Prolonged storage will cause lactic acid production from red cell metabolism which will decrease pH and increase iCa
Exposure to air results in CO2 loss from the sample, therefore raising the pH of the blood and reducing iCa.
Ocular change that is associated with primary hypoPTH
Lenticular cateracts
How do thyroid histopathology, TGAA status and TSH/T4 concentrations vary with silent, subclinical and clinical hypothyroidism?
What opthalmic disease(s) have been linked to hypothyroidism in dogs and which breed may be overrepresented here?
Arcus lipoides - GSD
KCS
Conceptually consider the relationship between severity of non-thyroidal illness and its effect on T3, TT4, fT4 and TSH concentrations
The point I want to remember here is that T3 seems to decrease dirst, followed by TT4 and fT4. TSH can be increased in the recovery phase along with decreased TT4/fT4.
8 conditions that can cause pseudohypoadrenocorticism
