Thyroid Flashcards
Steps of TH production in thyroid gland
thyroid is made of many folicles lined by follicular epithelial cells with adjacent capillary blood supply.
Follicular cells:
1. Export tyrosine into follicular lumen where it is converted to thyroglobulin by thyroid peroxidase
2. Absorb I- from the blood via active uptake (NA/I cotrasnporter)
–> export I- into follicular lumen where it is converted to iodide and can bind Tg
–> MIT or DIT
3. MIT/DIT combine to form complex with TPO
4. endocytosis brings hormones back into follicular cell and within phagolysosome they are further hydrolysed to release Tg and become T3/4 and any MIT/DIT recycled by the cell.
In circulation
-> majority bound to thyroid binding protein or albumin (makes up TT4)
-> at tissues can be unbound and diffuses into cells
-> cells convert T4 to more active T3
-> some diffuse out passively
-> exocytosis occurs from external stimulus
How does TH exert its effects in cells
Tissues express different deiodinases that convert T4 to T3 or rT3 (which has opposite effects). The local expression differences of these different enzymes can play a major role in homeostasis.
T3 diffuses into the nucleus of ells
-> binds thyroid hormone or retinoid X receptors
-> alters gene transcription, specifically enhancing metabolism
Systemic effects of thyroid hormone
Enhance metabolic rate by: increasing gluconeogenesis; increasing glycogenolysis; increasing lipolysis and increasing oxygen demand
Ionotropic and chronotropic (alters expression of B adrenergic receptors on cardiac myocytes and their affinity for catecholamines) –> increased HR, RR, CO
Involved in CNS development
Promotes protein synthesis -> major role in growth
–> Erythropoiesis, bone turnover
Regulation of thyroid hormone secretion - external and internal
EXTERNAL:
TRH from hypothalamus –> TSH from pituitary –> release of T3/4
(which then exert negative feedback on TRH and TSH)
INTERNAL:
- Excessive iodide –> inhibition of thyroglobulin synthesis and Iodide uptake by follicular cells
- Iodide deficiency –> increased T3 production
- variable sensitivity to TSH
Reported causes of hypothyroidism
Primary - Lymphocytic thyroiditis/idiopathic atrophy
Neoplastic (carcinoma)
Iodine deficiency
Iatrogenic - I131, surgery, medications/sulfonamides.
Congenital
Thyroid gland dysgenesis
Dyshormonogenesis
Secondary
Pituitary malformation/destruction
Iatrogenic - hypophysectomy, radiation.
schnauzers
Tertiary
Neoplasia
How does non-thyroidal illness impact thyroid hormone physiology
↓ peripheral conversion of T4 to T3
↓ binding affinity of TH binding protein
Altered thyroid hormone metabolism
Changes in thyroid hormone receptor expression/function
Altered hypothalamic-pituitary function → decreased TSH secretion.
Tests for HypoTH in dogs
NTI alters endocrine testing by reducing conversion of T4-T3, reducing TH binding affinity, altering hormone metabolism, changing receptor expression/function
Low TT4, fT4, high TSH occurs in ~1.8% of NTI, so a diagnosis of hypoTH with concurrent illness is more likely → treatment trial, stimulation testing or scintigraphy would be next steps.
Nuclear Imaging - technetium-99 should have 1:1 uptake compared to salivary gland.
→ thyroiditis may increase uptake,
→ GC or high iodine diet may reduce.
TT4 - measures protein and free hormone. Through use of TH Ab that are radiolabelled or enzyme bound. Used to r/o hypoTH but not solely for Dx.
→ Anti-Tg Ab may cause false increased result by binding some of the
→ IDEXX SNAP TT4 considered unreliable as under/over measures in dogs.
fT4 - measured by equilibrium dialysis (removes protein bound and other potential interfering substances), less affected by NTI, not influenced by presence of Ab. Normal value r/o hypoTH.
T3 - not useful, more affected by NTI
(may be useful in greyhounds as less often decreased)
TSH - increased in primary hypoTH, decreased in secondary hypoTH (but below limit of test detection)
→ 20-40% have TSH in normal range, may be due to reduced production with chronicity (TRH desensitisation)
→ can be suppressed by drugs/illness
→ low T4/fT4 and high TSH has >90% specificity for hypoTH.
Tg Ab- present before onset of hypoTH, eventually decrease with complete atrophy. Occur in ~50% of hypoTH cases
→ can help explain elevated TT4 results that are unexpected
→ not all dogs with Ab develop hypoTH
TSH/TRH Stim: reserved for dogs with ambiguous endocrine function test results.
→ increase in TT4 to >1.5x basal level in normal dog, minimal change in primary hypoTH
Human recombinant TSH used - $$, may need higher dose if concurrent disease suspected (or if on GCS)
→ scintigraphy still considered better as in a small study some normal dogs failed to respond
TRH - used to identify secondary hypoTH and dogs with hypoTH and severe NTI.
→ measure TSH and T4 after, see reduced increase in both with hypoT4 (minimal TSH response thought due to desensitsation)
→ interpretation can be challenging due to small increases in TT4 observed
Unfortunately, discordant test results are common. In this situation, reliance on presence of clinical signs, clinicopathologic abnormalities, and clinician index of suspicion become the most important parameters in deciding whether to treat the dog with L-T4 sodium
Factors affecting thyroid function tests
Age - progressive decline with age (across TT4, fT4, fT3). May be due to decreased responsiveness to TSH, reduced activity or concurrent effects of systemic illness.
Breed - up to 91% of greyhounds are below the normal reference range, sometimes below limit of detection.
Note there is a low prevalence of thyroiditis in GH.
Body size - may see higher T4 in medium size dogs compared to other sizes
Athleticism - reduced levels after strenuous exercise in sled dogs
Gender - females in dioestrus will have higher TT4 due to increased levels of progesterone
Obesity - can cause increased T3/T4
Non-thyroidal illness - interpretation of results should take into account degree of success in treating underlying disease, if poorly controlled (eg diabetes mellitus) then more likely a true finding. NTI alters endocrine testing by reducing conversion of T4-T3, reducing TH binding affinity, altering hormone metabolism, changing receptor expression/function
Different causes of primary hypothyroidism and their pathogenesis
Lymphocytic Thyroiditis - most common cause of hypoTH in dogs. Immune mediated pathogenesis is suspected due to presence of anti-Tg (or TPO) Ig and presence of lymphoplasmacytic infiltration of the gland resulting in progressive atrophy.
→ Ab bind activating complement and cell mediated cytotoxicity
The initial inflammation is subclinical (anti-Tg Ab detectable) → second phase of compensatory increase in TSH → >80% destruction and overt hypoTH develops at 60-80% destruction of gland. With chronicity the inflammation resolves and Ab titres normalise but function does not return (4th phase)
Possible genetic predisposition
Not all dogs with Anti-Tg Ab will develop hypoTH (only about 20%, and progression rate is variable.
Possible that T3/4 serve as haptens when bound to other protein
Possibly concurrent env risk factors that modulate
Atrophic Degeneration: may be end stage thyroiditis, or primary degenerative disorder. Characterised by reducing follicle size and replacement with adipose. No inflammatory infiltrate. Tends to occur at later age.
→ May be caused by secondary (central hypoTH)
Polyglandular Autoimmune syndromes- rare reports in dogs, may involve adrenals and islet cells, PTH.
Iodide Deficiency - study in healthy adult dogs required severe restriction to decrease T3/4 but even then did not cause clinical signs.
→ may become more common with raw diets
→ Goitrogens can cause clinical signs
Systemic effects of hypoTH in dogs
Metabolic: lethargy, dullness, inactivity, weight gain, altered lipid metabolism, hypothermia
- Derm: alopecia, comedones → due to loss of TH input for anagen → shedding with no regrowth. Reduced skin FAs and PGE2
→ Myxedema: hyaluronic acid accumulation under skin → draws water in → increased thickness and non-pitting oedema. - Immunosuppression- pyoderma, UTI due to reduced T cell function
- CVS: (reduced B R, reduced ATPase function for Ca and Na exchange) asymptomatic bradycardia, reversible reduction in fractional shortening. Usually not clinical but may exacerbate concurrent heart disease.
- Neuro: various associations with both single and poly neuropathies. Proposed pathogenesis: accumulation of mucinous deposits → demyelination; altered BBB (documented experimentally); disruption of blood-nerve barrier; autoimmune; ischaemia. Has not been reproducible in experimental disease - reported improvement with TH supplementation in some but not all conditions (but also spontaneous improvement reported for neuropathies).
→ may be a link in humans b/w MG and hypoTH and polyglandular autoimmune syndrome.
→ myxoedema coma reported in very rare cases - Myopathy: may cause weakness, exercise intolerance. Can see increase in CK/AST
- Repro: reduced survival of pups, prolonged parturition. Does not affect litter size or interestrus interval. Doesnt affect males.
JVIM 2023 review of drugs affecting thyroid function - which drugs should be watched and which had no effect
In general, dogs receiving glucocorticoids, phenobarbital, NSAIDs (eg, aspirin), sulfonamides, inhalant anesthetics, clomipramine, toceranib, amiodarone, and trilostane should have thyroid function test results interpreted with caution.
For some drugs, such as glucocorticoids and sulfonamides, drug dosage and treatment duration dictate whether a clinically relevant impact on thyroid function will occur
No effect of KBr, propranolol, imepitoin
Zonisamide also no evidence of effect but it is a sulfonamide based drug so further studies are needed
Drugs that affect thyroid hormone levels and mechanisms (9)
Glucocorticoids: suppress hypothalamic-pituitary thyroid axis; impair peripheral thyroid hormone metabolism (inhibition of peripheral iodinases). Effects take 3-5 weeks, most consistently observed at higher doses, withdrawal of 1 week results in normalisation
→ GC reduce release of TSH is reported
→ Topical and otic preparations also reported to decrease T4/3
Phenobarbital - reduce T4 and fT4 in 15-75% (by inhibiting secretion from thyroid gland), increase hepatic metabolism of thyroid hormones by deiodinases and biliary excretion. Changes resolve 5-6 weeks after discontinuation
→ increase TSH due to reduction in thyroid hormones (although has been reported to be suppressed by pheno in rats, doesnt seem to occur in dogs)
→ intersecting CS of pheno AEs and hypoTH CS intersect making interpretation of thyroid function tests difficult.
→ if cant withdrawal drug then consider treatment trial
NSAID - displace thyroid hormones from serum plasma protein carriers → transient increase and suppression of TSH → decreased production, free thyroxine is rapidly excreted and returns to normal.
→ aspirin has the biggest effect on thyroid hormone, decreasing levels after one dose and remaining decreased for up to 4 weeks of Tx
→ decrease TT4 (60%), usually dont affect TSH (meloxicam, carprofen and ketoprofen did not cause changes - variable TT4 decrease in low numbers)
Sulfonamides - inhibit thyroid peroxidase thus preventing production → increased TSH which can cause follicular hyperplasia (goitre)
→ decreased TT4 and FT4 with increased tSH after 3 weeks (low doses <2 weeks unlikely to cause effects). Take up to a month to resolve.
Inhalant Anaesthetics: peracute effect on TT4 within 14 days, should wait longer than this to test.
Tricyclic antidepressants- inhibit TH synthesis, enhance deiodinases, and interfere with HPT axis. Drug forms complexes with iodine in the follicles.
→ Clomipramine study found no evidence of suppression though values did decrease. Unclear the duration of these effects as yet.\
→ study did not find increased TSH after TRH stim, which suggests clomipramine may suppress TSH secretion also.
Toceranib - impair iodine uptake, TPO inhibition, deiodinase induction thyroid capillary regression.
→ studies report increased TSH with normal TT4 and TT3, though in people can take prolonged use to cause suppression
→ still need more studies to evaluate in dogs.
Trilostane: - lack of studies assessing effects, fT4 reported to decrease at 6mo of Tx with increased TSH in prospective uncontrolled study.
Amiodarone - iodine rich class III antiarrhythmic that resembles T4 in structure. Inhibits deiodinases in humans and inhibits entry of hormone into tissue. Thyroid gland suppression through presence of excess iodide (Wollf Chaikoff effect)
→ could cause thyrotoxicosis or hypothyroidism
what are goitrogens
What substances are proposed as possible causes of feline hyperTH
thyroid disruptors) in food (phenols, halogenated hydrocarbons), decrease the effective circulating serum thyroid hormone concentration leading to chronic overproduction of TSH due to reduced negative feedback
Environmental/food components that may disrupt thyroid function: iodine deficiency, herbicides, methimazole, soy, polychlorinate biphenyls, PBDEs, Selenium deficiency
Categories of Feline hyperTH and clinical approach
1) Classical = >1 clinical sign and high TT4
2) Suspect FHT with probable NTI
→ upper ref TT4, retest with fT4 in 2-4 weeks if high then confirms Dx, if normal investigate concurrent dz.
3) Enlarged thyroid with normal TT4
→ monitor CS and TT4 every 6 months, could be carcinoma
4) No clinical FHT but TT4 elevated
→ repeat in 2 weeks, if still elevated Tx, if normal re-eval in 6 months
5) Clinical FHT, elevated TT4 and concurrent dz
→ CKD, hypertension, GI disease, low B12, DM
→ Tx still recommended in all comorbidities
6) Elevated TT4 with no clinical signs
→ repeat with fT4 by ED and if elevated Tx
Effects of hyperTH on renal function
- increased Cl reabsorption in distal tubule → macula densa tubuloglomerular feedback and increased GFR
- Vasodilation and direct effect of TH on renin expression → RAAS activation → Na retention
** reduced vascular resistance, increased CO, increased blood volume → increases renal blood flow → increased GFR → lowers creatinine (as does reduced muscle mass) which can mask CKD - TH enhances Na/Ca exchanger in tubule → increased Ca reabsorption
- Proteinuria common in hyperTH and CKD. Mechanisms in hyperTH is not well understood, and hypertension uncommon so unlikely to be this causing it
→ improves with return to euthyroid state. - Polydipsia: psychogenic/CNS effects of TH - exaggerates thirst response to osmolality changes and downregulates aquaporin expression in tubules preventing water retention
