The thyroid gland:

Pharmacology
Kristien Boelaert
Reader in Endocrinology
Honorary consultant (Endocrinology & Diabetes)
Queen Elizabeth Hospital Birmingham, UK
Institute of Applied Health Research
University of Birmingham, UK
k.boelaert@bham.ac.uk

Control of thyroid hormone secretion

-ve
Hypothalamus
TRH
+ve -ve hypothalamus
-ve
Pituitary pituitary

TSH
+ve
Thyroid

T4 T3
Target Tissue

T3 neurological
cardiovascular digestive

Thyroid hormone synthesis

1. TSH binds to TSHR
Basolateral
Na/I symporter (NIS) membrane
I-
2. I- uptake
by NIS
I-

Thyroglobulin Apical
3. Iodination
membrane
of Tg tyrosyl
TPO 4. Coupling
residues by
of
TPO (thyro- Colloid iodotyrosyl
peroxidase)
residues by
5. Export of mature Tg to colloid
TPO
where it is stored

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 Thyroid hormones

T3: Triiodothyronine
I I
HO O CH2CH(NH2)COOH
I
T4: Thyroxine
I I
HO O CH2CH(NH2)COOH
I I

Thyroid hormones

 T3 is biologically active hormone

 Produced by mono-deiodination of T4 which is most
abundant
 Deiodinase (D1, D2, D3) enzymes present in peripheral
tissues

Tests of thyroid function

 Serum TSH
 Serum free T4
 Serum free T3

Hyperthyroidism Hypothyroidism

  Serum TSH   Serum TSH

  Serum free T4   Serum free T4
  Serum free T3   Serum free T3

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 Prevalence of thyroid disease

Hyperthyroidism - prevalence: 2.7%

Overactivity - incidence: 0.1%/yr (♀> ♂ )

Hypothyroidism - prevalence:1.9%
Underactivity - incidence: 0.4%/yr (♀> ♂ )

Goitre - prevalence 24.4 %

Enlargement - incidence: 0.2% (♀> ♂ )

Tunbridge et al (1977) Clin Endocrinol 7, 481-493

Vanderpump et al (1995) Clin Endocrinol 43, 55-68

Hyperthyroidism

Hyperthyroidism
 Prevalence: ♀: 20/1000 ♂: 2/1000
 Aetiology:
- Graves’ hyperthyroidism
- Toxic nodular goitre (single or multinodular)
- Thyroiditis (silent, subacute): inflammation

- Exogenous iodine
- Factitious (taking excess thyroid hormone)
- TSH secreting pituitary adenoma
- Neonatal hyperthyroidism

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 Symptoms and signs of hyperthyroidism

Cardiovascular Gastrointestinal
 Tachycardia (rapid heart rate)  Weight loss
 AF (atrial fibrillation)  Diarrhoea
 Shortness of breath  Increased appetite
 Ankle swelling

Eyes/skin
Neurological  Sore, gritty eyes
 Tremor  Double vision
 Myopathy (muscle weakness)  Staring eyes
 Anxiety  Pruritus (itching)

Graves’ disease
 60-80% of cases of hyperthyroidism
 Most prevalent autoimmune disorder in UK and US
 Pathogenetic antibodies to TSH receptor on thyroid
follicular cells (Long Acting Thyroid Stimulators)
 Interplay between genetic and environmental factors
 Environmental factors: gender, stress, infection,
pregnancy, drugs

Graves’ disease pathogenesis

NORMAL GD

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 Graves’ disease

Extra-thyroidal manifestations
 Eyes
Lid lag/retraction
Conjunctival oedema (swelling)
Periorbital puffiness (around eye)
Proptosis (bulging)
Ophthalmoplegia (weakness of eye muscles)
 Skin
 Pretibial myxoedema

 Acropachy

Extra-thyroidal manifestations: thyroid

eye disease

Proptosis
Lid retraction

Unilateral proptosis Ophthalmoplegia

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 Extra-thyroidal manifestations

Conjunctival Pretibial
oedema myxoedema

Neonatal hyperthyroidism

TSH-R antibodies cross

the placenta
 Control
hyperthyroidism in
mother during pregnancy

Diagnosis of hyperthyroidism
 Clinical features of Graves’
 Consider iodine uptake scan: GD vs thyroiditis
 Consider isotope imaging: GD vs TN hyperthyroidism
 TPO Abs +ve in 75% of Graves’
 TSH receptor Abs +ve in 99% of Graves’

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 Treatment options

• Antithyroid drugs to block

hormone synthesis

• Surgical removal of thyroid

• Radioiodine (131I) therapy

Anti-thyroid drugs -Thionamides

 Carbimazole (methimazole)
TPO
 Propylthiouracil
Block iodine incorporation and organification
through inhibition of thyroperoxidase
 Short-term preparation of patients for definitive
treatment
 Induction of remission in Graves’ disease (12-18
month course)

Thionamide therapy considerations

 Rapid control, well tolerated
 Side effects
 Rash (5%), joint pains (5%), sickness (5%)
Agranulocytosis: no white blood cells, infection
risk, rare, 1:1000 or less
Liver disease with propylthiouracil
 Low cure rate
30-40% (lower in men)

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 Surgical treatment of
hyperthyroidism
 Used infrequently
 Pre-treatment with antithyroid drugs
 Indications:
 Large goitre (especially if suspicion of co-existing
thyroid cancer)
 Pregnancy (serious side-effects of drugs)
 Pronounced ophthalmopathy
 Patient preference

Franklyn & Boelaert (2012) Lancet 379,1155

Iodine -131
 Capsule (fixed dose)
 Highly effective (85% cure)
 Usually pre-treatment with
drugs
 May worsen eye disease
(steroids)
Risks
 Hypothyroidism (~60%)
 (Cancer)
 (Infertility)
 Teratogenesis (contra-indicated in pregnancy and
breastfeeding)

Treatment aims and prognosis

Treatment Aims
 To relieve symptoms
 To restore T4 and T3 values within normal range
 To obtain long-term normal thyroid function

Prognosis
 30% of patients with Graves’ disease have normal
thyroid function long-term following drugs
 131-I and surgery associated with > 50% risk of
long-term hypothyroidism

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 Hypothyroidism

Hypothyroidism
 Prevalence 40/1000 females
 5% of over 60’s
 Aetiology:
Autoimmune – Hashimoto’s thyroiditis (TPO and Tg
antibodies - genetic predisposition)
After treatment for hyperthyroidism
Subacute/silent thyroiditis
Iodine deficiency
Congenital (thyroid agenesis/enzyme defects)

Hashimoto’s thyroiditis

Fibrosis and
shrinkage

Normal thyroid
gland
Inflammation
and
goitre/swelling

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 Iodine deficiency

 Major cause of goitre and

hypothyroidism world-wide
 WHO identified in 7% of
world’s population
 Range from near 0% (Japan) to
80% (Andes, Zaire)
 Supplementation programmes

UK iodine deficiency
 Common in many areas
up to 1960’s
 Main source of iodine is
from milk and dairy
products
 Evidence for iodine
deficiency in vegans

UK Iodine status

Vanderpump et al. (2011) Lancet 377, 2007

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 Congenital hypothyroidism - Cretinism

Symptoms and signs of hypothyroidism

Cardiovascular Skin
 Bradycardia (slow  Myxoedema
heart rate)  Rash on legs
 Heart failure  Vitiligo
 Pericardial effusion
Neurological
Gastrointestinal  Depression
 Weight gain  Psychosis
 Constipation  Carpal tunnel syndrome

Clinical features of hypothyroidism

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 Treatment of hypothyroidism
 2010: 3rd most prescribed medication in UK
 23 million tablets of levothyroxine prescribed
 Most common endocrine condition
 Goal of therapy is to restore patients to euthyroid
state and to normalise serum T4 and TSH
concentrations

Treatment of hypothyroidism

Thyroid nodules / goitres

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 Prevalence of goitre
Wickham Survey
Palpable goitre: 8.6% (♀: 12.1% - ♂: 4.5%)
Visible goitre: 6.9%
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14
Prevalence (%)

12
10
8 males
females
6
4
2
0
18-24 25-34 35-44 45-54 55-64 65-74 75+
Age in years

Adapted from Tunbridge et al. Clin. End 1977;7:481-793.

Thyroid nodules: epidemiology

 May be discovered on palpation, imaging, incidentally
 Most common in women (4:1) and in older populations
 Increased in areas of low iodine intake
 CT, MRI: 16%, Carotid doppler: 9.4%, PET scan 2-3%

4-7% 20-67% 2-16%

Cooper DS et al. 2009 Revised ATA Guidelines Thyroid 2009 ,19: 1167-1214
Popoveniuc & Jonklaas Med Clin North Am 2012, 96: 329-349

Significance of thyroid nodules

 May cause thyroid dysfunction
 May cause compression
 Need to exclude thyroid cancer

 Prevalence of malignancy is 4 – 6.5%

 Independent of nodule size
 Malignancy risk in incidentalomas remains controversial
 Risk of PET-positive thyroid nodule: 27%

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 Prevalence of nodules

 Nodules in 50-67% on high resolution ultrasound

 Autopsy: 50% of population
 Lifetime risk for developing palpable thyroid nodule in
US: 10%
 Increasingly found incidentally in patients undergoing
imaging (CT, MRI, carotid doppler)

Features suggestive of malignancy

Clinical features associated with increased risk of
malignancy
Age < 20 or > 60
Firmness of nodule on palpation
Rapid growth
Fixation to adjacent structures
Vocal cord paralysis
Regional lymphadenopathy
History of neck irradiation
Family history of thyroid cancer

Popoveniuc & Jonklaas Med Clin North Am 2012, 96: 329-349

Hegedus 2004 NEJM;351:1764-1771

BUT: Thyroid cancer is rare

 Less than 10% of nodules selected for surgery

 Less than 0.5% of new malignancies diagnosed in
England and Wales
 Diagnosed annually in 0.004% of USA population
 Important to select those with thyroid cancer

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 Investigation of thyroid nodules/goitre
1. Assessment of thyroid function
 Serum TSH
 Serum free T4, serum free T3
 Thyroid antibodies

2. Assessment of thyroid size

 Symptoms
 X-ray thoracic inlet
 CT or MRI of neck
 Respiratory flow loop

Investigation of thyroid nodules/goitre

3. Assessment of thyroid pathology
 Radionuclide scanning
 Ultrasound scanning
 Fine needle aspiration cytology

Role of ultrasound scanning

 Differentiation of solid from cystic nodules

 Differentiation of single from multiple nodules
(superior to palpation)
 Criteria suggestive of malignancy (irregular margin,
calcifications, solid, increased blood flow)
 Guidance of fine needle aspiration

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 Ultrasound features
Benign nodule Malignant nodule: Follicular lesion
Papillary/medullary
Spongiform/honeycomb Solid and hypoechoic Hyperechoic/
homogeneous/halo
benign
Purely cystic Irregular margin Hypoechogencity/loss of
halo suspicious
Egg shell calcification Intranodular vasularity
Iso/hyper echoic Absence of halo
(hypoechoic halo)
Peripheral vascularity Taller than wide
Microcalcifications

British Thyroid Association, RCP 2014 Revised guidelines for the management of thyroid cancer
Clin Endo (2014) 81: 1-122

Fine needle aspiration cytology

Thyroid cancer
Pathology
 Papillary carcinoma (72-85%) Differentiated cancers
 Follicular carcinoma (10-20%) (from follicular cells)
 Anaplastic carcinoma (<1%)
 Medullary carcinoma (1.7-3%) From C-cells
Aetiology
 External irradiation
 Iodine deficiency
 Oncogene expression
 Genetic factors (medullary Ca – MEN)

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 Management of differentiated thyroid
cancer

External beam DXT

Chemo Rx
TK inhibitor Rx
British Thyroid Association, RCP 2014 Revised guidelines for the management of thyroid cancer
Clin Endo (2014) 81: 1-122

Key Learning Points

 Negative feedback mechanism of secretion TH
 Thyroid disease is common
 Graves’ disease most common cause of
hyperthyroidism
 Most patients with hyperthyroidism will receive
antithyroid drugs (short/medium/long term)
 Treatment with 131I very effective
 Hashimoto’s thyroiditis most common cause of
hypothyroidism
 Treatment with thyroxine until normalisation of TFT

Key Learning Points

 Goitres/thyroid nodules are very common
 Aim of investigation is to identify patients with
malignancy
 US and FNAC remain gold standards to evaluate
thyroid nodules

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