Thyroid Hormones and Physiology

Question 1

Describe the anatomy of the thyroid

• different lobar structures
• venus and arterial supply
• large surrounding structures

Answer 1

• Left and right lobe
• Isthmus
• Pyramidal lobe

Question 2

How is the activity of the thyroid hormone regulated?

Answer 2

• Inhibited by
  
  • Somatostatin from the hypothalamus
    
    • reduces basal TRH release
  • T3 and T4 (it’s product hormones)
  • Excess Iodine
  • Thioreylenes
  • ¹³¹I
• Stimulated by
  
  • TRH (thyrotropin-releasing hormone) from the hypothalamus
  • Thyrotrophin from the anterior pituitary gland

Question 3

What three hormones does the thyroid gland release?

Answer 3

• T4- Thyroxine
• T3- Triiodothyronine

^Important for normal growth and development and controlling energy metabolism^

• Calcitonin

Question 4

Explain the structure and role of the Thyroid Follicle

Answer 4

• the thyroid follicle is the functional unit in the thyroid
• consists of a single epithelial cell around a cavity- follicular lumen
  
  • this is filled with a thick colloid containing thyroglobulin
  • this is where iodination of the tyrosine residues occurs
• Thyroglobulin is a large glycoprotein
  
  • it is synthesised and glycosylated and then secreted into the lumen of the follicle,

Question 5

Explain the Diagram

Answer 5

• process occurs in the thyroid follicle
• uptake of plasma iodine by follicle cells
  
  • occurs against a conc. gradient (25:1), using the Sodium Iodine Symporter (NIS) (basolateral membrane)
  • energy is provided by _Na/K ATPase pum_p and Pendrin- an I/Cl porter (apical membrane)
  • rapid uptake
• oxidation of iodine and iodination of tyrosine residues of thyroglobulin
  
  • oxidation of iodine and ints incorporation into thyroglobulin is catalysed by haem-containing peroxidases- thyroperoxidase
    
    • reaction requires H₂O₂ as an oxidizing agent_​_
    • severe iron deficiency could lower thyroperoxidase activity and interfere with thyroid hormone synthesis
  • After tyrosine is incorporated into thyroglobulin it is Iodinated
    
    • third position on the ring is iodinated first –> monoiodotyrosine (MIT)
    • fifth position on the ring is iodinated as well –> diiodotyrosine (DIT)
  • whilst still incorporated with thyroglobulin, they are coupled to form T3 or T4, this then forms a large store within the follicle
• secretion of thyroid hormone
  
  • endocytotic vesicles containing the thyroglobulin molecule fuse with lysosomes and proteolytic enzymes that act to release the T4 and T3
  • surplus MIT and DIT is released at the sea time: it is scavenged by the cells and the iodine is removed enzymatically and reused

Question 6

Explain the stages of thyroid hormone production

Answer 6

• process occurs in the thyroid follicle
• uptake of plasma iodine by follicle cells
  
  • occurs against a conc. gradient (25:1), using the Sodium Iodine Symporter (NIS) (basolateral membrane)
  • energy is provided by _Na/K ATPase pum_p and Pendrin- an I/Cl porter (apical membrane)
  • rapid uptake
• oxidation of iodine and iodination of tyrosine residues of thyroglobulin
  
  • oxidation of iodine and ints incorporation into thyroglobulin is catalysed by haem-containing peroxidases- thyroperoxidase
    
    • reaction requires H₂O₂ as an oxidizing agent_​_
    • severe iron deficiency could lower thyroperoxidase activity and interfere with thyroid hormone synthesis
  • After tyrosine is incorporated into thyroglobulin it is Iodinated
    
    • third position on the ring is iodinated first –> monoiodotyrosine (MIT)
    • fifth position on the ring is iodinated as well –> diiodotyrosine (DIT)
  • whilst still incorporated with thyroglobulin, they are coupled to form T3 or T4, this then forms a large store within the follicle
• secretion of thyroid hormone
  
  • endocytotic vesicles containing the thyroglobulin molecule fuse with lysosomes and proteolytic enzymes that act to release the T4 (~95%) and T3
  • surplus MIT and DIT is released at the sea time: it is scavenged by the cells and the iodine is removed enzymatically and reused

Question 7

What are the biological effects of Thyroid hormones?

Answer 7

• Increased basal metabolic rate
  
  • increased COH metabolism
  • increase in the synthesis, mobilisation and degradation of lipids
  • increased protein synthesis
• most effects are brought about in conjunction with other hormones i.e
  
  • insulin, glucagon, corticosteroids and catecholamines
• essential for normal development of the CNS- especially myelination of nerve fibres

this effect is brought about by an increase in no. and size of mitochondria and increased activity of metabolic important enzymes

Question 8

Where do thyroid hormones not increase the metabolic activity in the body?

Answer 8

• Brain
• Uteres
• Testes
• Spleen
• Thyroid gland
• Anterior pituitary gland

Question 9

Explain the biological activation/ activity of thyroid hormones

Answer 9

• within target tissues deiodinase enzymes convert T4 to T3 (80%) ore reverse-T3(20%)
  
  • T3 is 40x more biologically active than T4
  • reverse-T3 is biologically inactive
• 90% of biologically active thyroid hormone in a cell is in T3 form
• T3 half lif is a few hours
  
  • in hyperthyroidism and hypothyroidism half-life of T4 varies from = 3-4 days and 9-10 days
• majority of circulating thyroid hormones are protein-bound
  
  • majority of T4 binding is thyronine-binding globulin (TBG)
  • 15-20% is bound to thyroxin-binding pre-albumin (TBPA)
  • 5-10% is bound to albumin
• receptors for TH are nuclear, as they influence gene transcription and thus protein synthesis

Question 10

Explain the clinical presentation of Hyperthyroidism (Thyrotoxicosis)

Answer 10

• Escessive secretion and activity of TH resulting in
  
  • high metabolic rate,
  • increased skin temperature,
  • sweating and heat intolerance,
  • nervousness, tremor,
  • tachycardia
  • increased appetite associated with weight loss.
• Two common forms include
  
  • diffuse toxic goitre (Graves disease/ exophthalmic goitre)
    
    • autoantibodies to the TSH receptor increasing T4 levels
  • toxic nodular goitre
    
    • may develop in those with long-standing simple goitre

Question 11

What drug is used to treat thyroid deficiency?

Answer 11

• Levothyroxine
• can be used to suppress TSH secretion in the treatment of some thyroid tumours
  
  • can be given by mouth or injection
• 100% bioavailability with a high protein binding rate
• metabolised in the liver by glucuronidation
• the half-life of ~7 days
• excretion 20-40% in urine
• Adverse effects
  
  • palpitation, arrhythmias diarrhoea insomnia tremor wight loss
  • at excessive amounts

Question 12

What are the primary congenital causes of Hypothyroidism?

Answer 12

• Athyreosis
• Ectopic thyroid
• Dyshormonogenesis
• Iodide deficiency
  
  • (Transient due to illness)

Question 13

What are acquired causes of Hypothyroidism?

Answer 13

• Iodine deficiency
• Autoimmunity
• Post-I131 therapy
• Post-thyroidectomy
• Anti-thyroid drugs
• Iodine excess
• Thyroid irradiation
• Subacute thyroiditis

Question 14

What is Hashimoto’s Disease?

Answer 14

• Autoimmune destruction of the thyroid gland
  
  • can be associated with hypothyroidism- produces similar symptoms
  • causes damage and swelling –> goitre
• symptoms of
  
  • tiredness, weight gain, dry skin
• very progressive and slowly developing condition may take months or years to detect it
• usually seen in women aged 30-50, sometimes runs in families
• cannot be cured but can be treated with levothyroxine for life
• surgery is rarely needed - only if the goitre is uncomfortable or cancer is suspected

Question 15

What drugs affect Thyroid Function?

Answer 15

• Carbimazole and Methimazole
  
  • ​act by preventing incorporation of the iodide into the thyroglobulin - inhibiting TH production
• Propylthiouracil
  
  • ​prevents the peripheral conversion of T4 to T3
• ¹³¹I
  
  • selectively concentrated in the thyroid gland where it causes tissue damage and reduces TH secretion
  • indicated in hyperthyroidism and thyroid cancer - alternative to surgery
• Lithium (used to treat bipolar depression)
  
  • can induce goitre

Question 16

What is Carbimazole?

Answer 16

• a pro-drug used to treat hyperthyroidism
  
  • it’s active form is Methimazole
  • it prevents peroxidase iodinating the tyrosine residues on thyroglobulin
• Oral Biovalibly is >90%
• it has 85% protein binding
• rapidly metabolised to methimazole
• has a half-life of 6.4 hours
• 90% excreted in urine as metabolites
• Adverse effects
  
  • rashes and pruritus (treated with antihistamines)
  • neutropenia and agranulocytosis
  • has a teratogenic effect (pregnancy is a contraindication)

Question 17

What is Propylthiouracil?

Answer 17

• PTU is used to treat hyperthyroidism (including Graves’ disease)
  
  • inhibits thyroperoxidase
  • inhibits tetraiodothyronine deiodinase which converts T₄ to T₃
  • drug of choice to treat hyperthyroidism in the first trimester
• Oral bioavailability between 80-95%
• Protein binding 70%
• Metabolised in the liver by glucuronidation
• half-life of 2 hours, excreted renaly
• Adverse effects
  
  • rashes and pruritus (treated with antihistamines)
  • agranulocytosis and risk of serious liver injury

Question 18

What is meant by Primary and Secondary thyroid dysfunction?

Answer 18

• Primary: due to a thyroid problem
• Secondary: due to a hypothalamic/ pituitary problem

Question 19

What is this an image of

Answer 19

Retrosternal goitre causing tracheal deviation

Question 20

What are normal ranges for the Thyroid function test?

• TSH
• FT4
• FT3
• Thyroid autoantibodies?

Answer 20

• TSH 0.3 – 4.2 mu/l
  
  • best biomarker of thyroid status, also assumes normal pituitary function
  • shape of a curve with a ‘tail’ from 3 upwards on a linear scale
• FT4 12 – 22 pmol/l
• FT3 3.1 – 6.8 pmol/l
• Thyroid autoantibodies
  
  • Anti-TPO AB - Thyroid peroxidase auto-antibody
  • TRAB - TSH receptor autoantibody

Question 21

How can Thyroid autoantibodies be used in diagnosis?

Answer 21

• prevalence of autoAB is more common than the presence of an autoimmune disease
• a negative autoAB result does not exclude autoimmune disease; presence helps confirm the diagnosis
• is it a destructive or stimulatory autoAB
  
  • ‘destructive’ target thyroid for autoimmune destruction
  • ‘stimulatory’ stimulate TSH receptor

Question 22

What are the symptoms of Hypothyroidism?

Answer 22

• Lethargy
• Mild weight gain
• Cold intolerance
• Constipation
• Facial puffiness
• Dry skin
• Hair loss
• Hoarseness
• Heavy menstrual periods

Question 23

What are signs of severe hypothyroidism

Answer 23

• Change in appearance eg face puffy and pale
• Periorbital oedema
• Dry flaking skin
• Diffuse hair loss
• Bradycardia
• Signs of median nerve compression (carpal tunnel)
• Effusions, eg ascites, pericardial
• Delayed relaxation of reflexes
• Croaky voice
• Goitre
• Rarely stupor or coma

Question 24

What are the causes of Primary Hypothyroidism?

• what would the Thyroid function test show?

Answer 24

• High TSH, low T4, low T3
• Autoimmune hypothyroidism
• Hypothyroidism after treatment
  
  • for hyperthyroidism (iatrogenic)
• Thyroiditis
• Drugs (e.g. lithium, amiodarone)
• Congenital hypothyroidism
• Iodine deficiency (not UK)

Question 25

What are the causes of Secondary Hypothyroidism

• what would the thyroid function test show?

Answer 25

• low TSH, low T4, low T3
• the disease of the hypothalamus/ pituitary

Question 26

What is the general treatment plan for hypothyroidism?

Answer 26

• Start with thyroxine (T4) 100 mg daily
  
  • If patient has shorter symptomatic period
  • Unless elderly/ischaemic heart disease
    
    • Start 25 mg daily with increments 4-6 weekly
• Usual dose 100-150 mg daily
  
  • Some variation with bodyweight
• Aim for normal FT4 without TSH suppression
  
  • Individual variation: may need fine-tuning within reference ranges
• No evidence in properly conducted trials to support T4/T3 combination therapy

Question 27

What are the symptoms for Hyperthyroidism?

Answer 27

• Weight loss/Weight gain
• Lack of energy
• Heat intolerance
• Anxiety/irritability
• Increased sweating
• Increased appetite
• Thirst
• Palpitations
• Pruritus
• Loose bowels
• Oligomenorrhoea (infrequent occasionally light periods)

Question 28

What are the signs of Thyrotoxicosis?

Answer 28

• Tremor
• Warm, moist skin
• Tachycardia
• Brisk reflexes
• Eye signs
• Thyroid bruit
• Muscle weakness
• Atrial fibrillation

Question 29

What are the symptoms/points that would suggest Thyroid Eye Disease (TED)/ Thyroid Associated Ophthalmopathy (TAO)?

Answer 29

• associated with Graves disease - autoimmune hyperthyroidism in 20% of patients
• CT scan imaging would be helpful
• increased risk in smokers
• Inflammation of all orbital tissues except the eye
  
  • fat, muscles, conjunctive, eyelids
• Mild symptoms
  
  • ‘itchy’/ dry eyes - artificial tears help
  • ‘prominent’ eyes/change in appearance
• More severe symptoms
  
  • Diplopia/ loss of sight
  • loss of colour vision - grey/blurred patches
  • redness/ swelling of conjunctiva
  • unable to close eyes fully
  • Ache/pain/ tightness in or behind eyes

Question 30

What are physical signs associated with thyrotoxicosis?

• Hands
• Pulse
• Neck
• Eyes

Answer 30

• Hands
  
  • Fine tremor
  • Warm
• Pulse
  
  • Sinus tachycardia
  • Atrial fibrillation
• Neck
  
  • Goitre
  • Move when swallowing
  • Smooth / not
  • Bruit / not
• Eyes
  
  • Lid retraction / lid lag
  • Proptosis / exophthalmos
  • Ophthalmoplegia
    
    • Abnormal eye movements
    • Causes diplopia
  • Inflammation (conjunctiva)

Question 31

What are the causes of Thyrotoxicosis?

• what diagnostic features would make one cause more likely?

Answer 31

• Graves’ Disease - autoimmune hyperthyroidism
  
  • personal or family history of any autoimmune thyroid/ endocrine disease
  • Goitre with a bruit
  • TED
  • +ve thyroid autoAB titre
• Toxic multinodular goitre
• Toxic adenoma
• Thyroiditis
• Drugs (e.g amiodarone)

Question 32

What is Gestational thyrotoxicosis?

Answer 32

• Placental ß-human chorionic gonadotrophin is structurally similar to TSH, therefore, has a TSH-like action on the thyroid
• more likely if hyperemesis (severe vomiting during pregnancy)/ twin pregnancy
• settles after 1st trimester of pregnancy

Question 33

What are treatment options for Graves disease?

Answer 33

• Medical
  
  • Carbimazole or propylthiouracil
  • for 18 months- 2years
  • Titrate or block replace
  • rare side effect: agranulocytosis
    
    • 2/3 relapse within the first year, unpredictable
• Radioiodine - ¹³¹I
  
  • ​~ 40% risk of permanent hypothyroidism
  • not if pregnant or breastfeeding- future pregnancy risks 6-4months wait
  • avoid prolonged contact with others 1-2 wks after treatment
  • airport security system alarming
• Surgery
  
  • hypo/hyperthyroidism
  • vocal cord palsy (recurrent laryngeal nerve damage)
• Symptom control
  
  • Beta-blockers (propranolol)
    
    • not if asthmatic

Question 34

What is the treatment for toxic adenoma or toxic multinodular goitre?

Answer 34

• Initially: short term medical therapy to control thyroid function tests
• Subsequent curative tx: radioiodine

Question 35

What treatment options are there for Thyroid Eye Disease (TED)?

Answer 35

Active

• encourage smoking cessation
• steroids:
  
  • pulsed IV methylprednisolone/ oral prednisolone
• immunosuppressive/ steroid-sparing agents
• radiotherapy

Burnt out

• may be left with disfigurement causing impaired quality of life
• ​surgical treatment
  
  • orbital decompression
  • eyelid surgery

Question 36

When and who gets a Thyroid storm

(Thyrotoxic crisis)

Answer 36

• prevelanet in those with 2y Graves
• unrecognised
• Incompletely treated thyrotoxicosis
  
  • ‘start-stop;
  • erratic/ poor compliance
  • early on in course of treatment
  • surgery/radioiodine without adequate preparation
• triggered by
  
  • surgery
  • childbirth
  • acute severe illness
    
    • infection
    • trauma/ stroke
    • pulmonary embolus
    • diabetic ketoacidosis

Question 37

What is a Thyroid storm, and what are its features?

Answer 37

an extreme manifestation of thyrotoxicosis due to overproduction of thyroid hormones

• multisystem impact
• indicated in those with Graves
• Hyperpyrexia (adverse effects of anaesthesia)
• CNS: agitation delirium
• Cardiovascular
  
  • Tachycardia >140bpm
  • Atrial dysrhythmias
  • Ventricular dysfunction
  • Heart failure
• GI
  
  • N&V
  • Diarrhoea
  • Hepatocellular dysfunction

Question 38

What is Thyroiditis?

• describe management

Answer 38

• mild thyrotoxicosis
  
  • always resolves within (1-2m)
  • B-blockers if required
  • Isotope scan would be ‘cold’
  • anti-thyroid drugs will not work
• longer hypothyroid phase (4-6m)
  
  • 80% normal after 1 year
  • may require thyroxine treatment for a while
• Annual TFTs: 30% hypothyroid at 1yr, 50% at 3yrs

Question 39

What part of the patient hx/exam/investigations would suggest Thyroiditis?

Answer 39

• Patient is pregnant / within 1 year post-partum
  
  • increased risk T1 diabetes, FHx thyroid disease, smoker
• Patient has very tender thyroid
  
  • May be raised inflammatory markers
• Clinical thyroid status does not fit with lab results
  
  • Rapidly changing thyroid function tests
• No diagnostic features of Graves disease
• Current/recent treatment with immunomodulatory medication

Question 40

What other pathologies are autoimmune thyroid diseases associated with?

Answer 40

other autoimmune endocrine diseases

• Type 1 diabetes
• Pernicious anaemia
• Coeliac disease
• Premature ovarian failure
• Addison’s disease

syndromes + drugs/ mx

• Turner syndrome
• Down’s syndrome
• Lithium/ Amiodarone
• annual thyroid function tests are recommended