Hypo- and Hyperthyroidism

Question 1

Describ the basic production and regulation of thyroid hormone

Answer 1

• Iodide enters the body in food.
• Iodide is transported into the follicular cells via the Na⁺/I^- symporter
• Iodide is then transported into the colloid across the apical membrane
• Thyroid peroxidases catalyses the majority of reactions within the follicular cell including:
  
  • Oxidation of to iodide to iodine
  • Iodine reacts with thyroglobulin to form iodotyrosines
  • TPO also catalyses reactions to form the thyroid hormones T4, T3,
    
    • Thyroglobulin is cleaved to form either mono- or di-iodotyrosines
      
      • These then combine to form either T3 or T4
• The thyroid hormones are release from the thyroid gland after stimulation by TSH from the pituitary
• TSH is under the control of TRH, released from the hypothalamus
• Negative feedback occurs at all levels, with increased T3 and T4 reducing secretion of both TSH and TRH

Question 2

Hypothyroidism has been described in dogs with lymphocytic thyroiditis and thyroid atrophy in ~equal amounts?

Explain the histological findings in each

Answer 2

• Thyroid atrophy is an “end stage” type change with marked reduction in the number of thyroid follicles and follicular cells
• There is gradual replacement of the normal thyroid tissue with adipose and collagen
• Lymphocytic thyroiditis is a destructive immune process with a marked cellular infiltrate with lymphocytes, macrophages and plasma cells.
• With progression of the inflammatory process, there is replacement of normal thyroid cells with fibrous connective tissue

Question 3

Describe the presence of thyroglobulin auto-antibodies in dogs.

How does the presence of autoantibodies correlate with clinical hypothyroidism?

Answer 3

• Thyroglobulin auto-antibodies are present when the adaptive immune system identifies thyroglobulin as non-self.
• The presence of thyroglobulin auto-antibodies +/- antibodies directed against T3 or T4 are indicative of an auto-immune thyroiditis
• These antibodies are present in ~ 50% of dogs with clinical hypothyroidism.
• However, the presence of auto-antibodies does not necessarily mean hypothyroidism will develop
  
  • Only ~ 20% of euthyroid dogs with circulating auto-antibodies will go on to develop hormonal evidence of thyroid dysfunction
  • Only 5% become clinically hypothyroid

Question 4

List and briefly describe the potential clinical signs with hypothyroidism

Answer 4

1. Dermatological signs
   
   • Very common and reported in ~80% of hypothyroid dogs
2. Cardiovascular effects
   
   • Theoretically reduced cardiac systolic function
3. Neuromuscular abnormalities
   
   • Many are difficult to prove a direct link
   • Cranial nerve and peripheral nerve abnormalities have tenuous direct link and would be difficult to prove causation even with treatment. eg. megaoesophagus
4. Ophthalmic changes
   
   • Minimal evidence but may be associated with KCS
5. Reproductive changes
   
   • gestation may be increased, birth weights reduced and pup survival decrease
   • no change in the inter-oestrus period

Question 5

What are the common abnormalities on routine clinicopathological testing of dogs with hypothyroidism?

Answer 5

• Low total and free T4
• Anaemia - usually mild and non-regenerative
  
  • Likely due to combined decrease in EPO and reduced marrow stimulation
• Hypercholesterolaemia (75%)
  
  • Reduced degradation of lipids/lipoproteins
• High triglycerides
  
  • in conjunction with elevated cholesterol
• Increased CK
  
  • mild increases only and may be due to low grade myopathy +/- reduced renal clearance
• (Increased fructosamine)
  
  • Due to reduced protein turnover, rather than prolonged hyperglycaemia

Question 6

What assay methadologies are commercially available to assess thyroid hormone levels.

Briefly note the limitations of each methodology

Answer 6

1. Radioimmunoassay (RIA)
   
   • Considered gold-standard
   • Requires the use of radio-isotopes and cannot be fully automated
2. Liquid chromatography mass spectrometry
   
   • Research utilised
3. Chemiluminescence
   
   • Most commonly used by commercial laboratories
   • Rapid and fully automated testing possible
   • Auto-antibodies may cause spuriously increased results
4. Enzymatic methods
   
   • Least accurate, rarely used
5. In-house ELISA have show variable and often innacurate results in multiple studies

Question 7

What drugs have been associated with changes in thyroid hormone concentrations?

Briefly note the changes that may be seen.

Answer 7

1. Prednisolone
   
   • Reduced to normal TT4 and free T4
   • Normal to increased TSH
2. Phenobarbital
   
   • Decreased to normal TT4 and Free T4
   • Normal to mild increase in TSH
3. Sulfonamides
   
   • Decreases in TT4 and free T4
   • Increased TSH
4. Clomipramine
   
   • Decreased TT4 and free T4
   • No change to TSH
5. Aspirin
   
   • Decreased TT4 with decreased to normal free T4
   • No change in TSH
6. Carprofen
   
   • As for prednisolone

Question 8

Hypothyroidism in cats is most often iatrogenic and caused by treatment with I131.

How can feline iatrogenic hypothyroidism be identified and confirmed?

Answer 8

• The majority of cats receiving I 131 are likely to develop transient hypothyroidism.
  
  • New research is underway in an attempt to determine I 131 dose from tumour volume as determined by scintigraphy
  • Individualised I 131 doses should reduce the incidence of post-treatment hypothyroidism
• Low TT4 should be present in all hypothyroid cats
• Free T4 measurement may not add significantly to information from TT4 alone
• cTSH can be measured and should be increased - more for identification of spontaneous hypoT4
• Scintigraphy can assist in confirming hypothyroidism and differentiate from sick euthyroid syndrome (non-thyroidal illness syndrome)

Question 9

When and how should iatrogenic hypothyroidism be managed in cats following I131 treatment?

Answer 9

• Iatrogenic hypothyroidism is common if not expected in a majority of cats following I 131 treatment
• If renal function is adequate, then treatment is rarely required.
• It is recommended to wait and monitor for 3-6 months as long as renal function is adequate and there are no overt clinical signs of hypothyroidism
  
  • It must be noted that some of the clinical signs of hypothyroidism overlap with the changes seen after successful management of hyperthyroidism
    
    • weight gain, reduced drinking, reduced activity
• If there is an azotaemia (IRIS stage II-III) noted post treatment, then L-thyroxin supplementation is essential

Question 10

What are the proposed causes of hyperthyroidism in cats?

Answer 10

1. TSH receptor mutation
   
   • Leads to high constitutive secretion of T4
2. cAMP activating G protein alpha subunit mutation
   
   • Increased activation and release
3. Decreases in expression of inhibitory G proteins
   
   • Decreased ability to inhibit cAMP production resulting in sustained release of T4
4. Canned foods implicated but not proven
5. PBDE’s (polybrominated diphenyl ethers) implicated but not proven

Question 11

Describe the effects of thyroid hormone on the feline cardiovascular system

Answer 11

Most effects are regulated byT3

• Positive chronotropic effect
  
  • AV conduction time is reduced
  • Upregulation of myocardial beta adrenergic receptors
• Positive inotropic effect
  
  • Regulated through ion channel alterations that ultimately enhance the activity of myosin
• Myocardial hypertrophy due to upregulation of myocardial protein expression +/- increased blood pressure

Question 12

Hyperthyroidism may or may not cause elevated blood pressure.

Discuss the relevant evidence

Answer 12

• Early studies (1990) identified a high prevalence of hypertension in cats with hyperthyroidism - 87%
  
  • The normal was not stated in the study and hypertension was likely adjudged at a lower level that accepted today
  • White coat effect in “stress intolerant” hyperthyroid cats is real and difficult to quantify
• Later reports have identified hypertension in 5-20% of cats
  
  • Small abstracts identified no improvement in blood pressure with appropriate treatment of hyperthyroidism
  • No cats had BP >180 mmHg
• Humans with thyrotoxicosis rarely have elevated blood pressure.
  
  • When present, it is usually only systolic hypertension as thyroid hormone causes peripheral vasodilatation
• There does appear to be an association between hyperthyroidism and hypertension, but cause and effect proof is not been established

Question 13

Discuss the effects of hyperthyroidism on the urinary system

Answer 13

• Polyuria and polydipsia
  
  • Primary polydipsia may be present due to an exaggerated thirst response to changes in osmolarity
  • Thyroid hormone excess may cause down-regulation of aquaporin channels
• Thyroid hormone decreases peripheral vascular resistance - relaxation of the capilliary smooth muscle
  
  • This leads to increased renal blood flow
  • Nitric oxide synthase activity is increased –> increased NO –> augmented vasodilation
  • Increased beta-adrenergic receptors also assists vasodilatation
• RAAS may be activated by the vasodilation and increased renal blood flow. Afferent arteriolar vasoconstriction increased glomerular filtration pressures and GFR
• Tubular effects
  
  • Upregulation of chloride channels - enhanced resorption of chloride, lower chloride in the macula densa, increased tubuloglomerular feedback and increased GFR
  • Increase sodium potassium ATPase and Na+/H+ exchange
    
    • enhanced Ca++/Na+ exchange and calcium resorption

Question 14

Describe the process and interpretation of the T3 suppression test

When may this test be indicated?

Answer 14

1. Blood is collected, serum separated and frozen
2. The following day, T3 is administered at 25 mg/cat PO q 8 hours for 7 total doses
3. Blood is drawn on the morning of the third day, after the final T3 dose
4. Both assays are run together, to mitigate inter-assay variation

Interpretation:

• ​​​Low T3 in the second sample - poor owner compliance
• Low T4, High T3: not hyperthyroid
• High T3 no or blunted decrease in T4: Hyperthyroid

Indicated for assessment of suspected hyperthyroid cats with normal basal hormone results

Question 15

Describe the mechanism of action of methimazole for the treatment of feline hyperthyroidism

Answer 15

• Methimazole (and the pro-drug carbimazole) inhibit thyroid follicular cell thyroperoxidases
• Inhibition of iodination of tyrosyl residues into thyroglobin and coupling of tyrosyl residues into T3 and T4
• The drug contributes to a decrease in thyroid hormone production depleting stores

Question 16

Briefly note the major differences and considerations when using transdermal methimazole in place of the oral medication

Answer 16

• Gloves must be worn as the drug can traverse human skin
• It may be slower to reach euthyroidism, therefore monitoring can start at ~ 4 weeks
• Response can be less consistent than with the oral drug, and overall, transdermal methimazole is likely to be less effective
• Reduced GIT adverse effects should be expected with the transdermal formulation
• All other adverse effects from the drug - neutropenia, hepatotoxicity and facial excoriation are similar

Question 17

Discuss the potential role of TSH in thyroid tumour development in dogs?

Answer 17

• TSH directly stimulates thyroid cell mitogenesis (cell division) and hormone synthesis
• TSH has been shown to induce angiogenesis in thyroid tumour cell lines
• Excessive TSH has been shown to cause benign toxic nodular goiter in humans
• ~ 50% of a beagle colony developed thyroid tumours after the induction of lymphocytic thyroiditis - which leads to decreased negative feedback and persistently elevated TSH.
• VEGF is a target for TSH activation fo angiogenesis
• Mutations in the TSH receptor leading to constitutive G protein signalling has also been linked to hyperthyroidism

Question 18

Describe the clinical staging of canine thyroid carcinoma

Answer 18

• Tumours are staged based on:
  
  • Tumour size
  • Presence of local lymph node involvement
  • Presence of distant metastasis
• Stage 1: < 2 cm, no mets
• Stage 2: < 2 cm and ipsilateral local LN involvement OR 2-5 cm without LN involvement
• Stage 3: > 5 cm with local node involvement, NO distant metastasis
• Stage 4: > 5 cm, local and distant metastatic disease

Question 19

List the treatment options for thyroid carcinoma in order of relevance. Note the specific indications and contra-indications for each treatment modality

Answer 19

1. Surgery: treatment of choice for mobile tumours without distant metastatic disease. Local lymph nodes should be removed if considered abnormal on staging
2. Radiation therapy: Primarily used when surgery is contraindicated or if the tumour is large and adhered to underlying structures.
3. ¹³¹Iodine: primarily used in humans following surgery. Limited studies in dogs with variable study protocols, so comparison is not straighforward. Appears best utilised post-surgery in dogs with stage II-IV disease. Large doses mat be of safety concern
4. Chemotherapy: limited data available, but cisplatin/carboplatin single agent therapy may improve survival. Best used as an adjunct post-surgery in dogs at risk of metastasis or recurrence.

Question 20

What is the prognosis for dogs with thyroid carcinoma?

Answer 20

• Prognosis is highly dependent on stage of disease, histopathology (especially evidence of invasiveness) and treatment modality
• Prognosis for grade I and II tumours following complete surgical excision is generally good at ~ 3 years for unilateral disease or 30-39 months for bilateral disease. Ectopic thyroid carcinoma may be less amenable to surgery
• Radiation treatment of stage I-III tumours carries a favourable prognosis with 1 and 3 year progression free survival of 80% and 72% respectively.
• Palliation or local therapy alone in the presence of metastatic disease, survival of 6-8 months has been reported