CPAT3201: The Endocrine

System (Lecture 2)

Diseases of the Thyroid

Dr Melanie White
Heart Foundation Research Fellow
The University of Sydney
melanie.white@sydney.edu.au
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 Learning Outcomes
› Thyroid – Macroscopic and microscopic features
– Diseases of the thyroid – Treatment options
• Goitre
› Hashimoto’s Disease (Hypothyroidism) › Thyroid Adenoma (Asymmetrical Goitre)
– Classification – Classification
– Clinical Features
– Pathogenesis and autoimmune influence
– Macroscopic and microscopic features
– Treatment options
› Grave’s Disease (Hyperthyroidism)
– Classification
– Clinical Features
– Pathogenesis and autoimmune influence
The University of Sydney
Lecture 2 Case Study

• Female 46 YO
• Low self-esteem
• Weight gain
despite an active
lifestyle
• Actively avoids
gluten
• Tired
• Type 1 diabetic

The University of Sydney

Classifying Diseases of the Thyroid
Abnormal (outward) growth of the thyroid
Can be classified as:
• Diffuse
• Nodular
Thyroid hormone production
• Elevated (hyperthyroidism)
• Depressed (hypothyroidism)
• Physiological
Specimen 45.812.2 Thyroid – nodular colloid goitre
Enlargement of thyroid lobes
• Symmetrical
• Asymmetrical
Functional distinctions
• Thyroid dysfunction
• Obstructive symptoms
• Asymptomatic (simple non-toxic goitre)
Specimen 45.73.2 Thyroid – diffuse hyperplastic goitre
The University of Sydney
 Hyperthyroidism vs Hypothyroidism
Epiglottis
Broadly classed as:
Hyperthyroidism (Thyrotoxicosis)
– Excessive secretion of T3/T4 hormones
– Most often primary hyperthyroidism
Constricted
Trachea • Grave’s disease (1º hyperthyroidism)
• Toxic multinodular goitre
Left lobe thyroid
atrophic • Hyperfunctioning adenoma
Tumour in • Rarely 2º hyperthyroidism (PA)
Right lobe
Hypothyroidism
– Deficiency of thyroid hormones
– Can result from destructive processes (atrophy)
• Hashimoto’s thyroiditis
• Surgery/Radioiodine/Irradiation
• Iodine deficiency
The University
Specimenof45.842.1
Sydney Thyroid – adenoma
 Hashimoto’s Thyroiditis: Epidemiology And Clinical Presentation
Hrt.org
The University of Sydney
Most common cause of hypothyroidism
– Chronic autoimmune thyroiditis
Characterised by a gradual decline in thyroid function
– Autoimmune response
Thyroid failure is seen in up to 10%
– Prevalence increases with age/sex/hereditary
Hashimoto’s thyroiditis is typically associated with:
– Fatigue
– Puffy face and weight gain
– Enlargement of the tongue
– Hair loss / brittle nails
– +/- Goitre
Presence of thyroid autoantibodies (Tg/TPO) needed for
diagnosis
Hashimoto Thyroiditis: Pathogenesis
A combination of genetic susceptibility and environmental factors
– Susceptibility ≠ active thyroiditis
– Genetic abnormalities promote failure of immune tolerance
– Similar for other forms of auto-immunity (e.g. Grave’s disease, T1DM, Coeliac disease,
Rheumatoid arthritis, Lupus)

Genetic abnormalities Auto-antibodies

Tg Tg
HLA TPO
CTLA4 TSHR
Kambayashi, T., Laufer, T. Atypical MHC class II-expressing antigen-presenting cells: can anything
VDR replace a dendritic cell?. Nat Rev Immunol 14, 719–730 (2014).

PTPN22
ANKRD7

The University of Sydney

Hashimoto’s Thyroiditis: Mechanisms of Injury (Environmental Factors)
– “Bystander” damage  thyroid infections
induce infiltration of lymphocytes and Thyroid follicular
epithelium

inflammation  release of local cytokines Breakdown in self-tolerance and

induction of thyroid autoimmunity

 activation of auto-reactive T cells against Plasma

cell
self-tissue. CD8+
CD4+
TH 1 cell
cytotoxic Anti-thyroid
– “Molecular mimicry”  viruses produce T-cell
IFN- antibodies

proteins that mimic host antigens 

Activated
immune response to the viral protein cross- macrophages

reacts with the self-tissue

T-cell–mediated Fc receptor
– HLA antigen presentation  HLA class II cytotoxicity
NK cell
antigens induced by IFN- in response to a
viral infection  immune response towards Antibody-dependent cell-
Thyrocyte injury mediated cytotoxicity
self-tissue
– Excess Iodine intake  excess iodination Kumar, Vinay, et al. Robbins Basic Pathology

of Tg  immunogenicity of Tg 
presentation by APC
The University of Sydney
 Hashimoto’s Thyroiditis: Macroscopic Appearance
Variability in the extent of macroscopic changes
– Depend of duration of inflammatory process
• Goitre
Tongue • Low T4/T3 stimulates TSH secretion
under • Diffuse symmetric enlargement
surface
• Atrophy
• Fibrotic changes with advanced disease

Larynx

Thyroid

Trachea
The University of Sydney
Specimen 45.000.1 Thyroid – healthy Specimen 45.532.2 Thyroid - Adv Hashimoto thyroiditis Specimen 45.532.1 Thyroid - Hashimoto thyroiditis
Hashimoto’s Thyroiditis: Microscopic Appearance
Variability in the histopathology of
Diffuse lymphoid
Hashimoto’s thyroiditis
aggregate • Diffuse mononuclear inflammatory
infiltrate with lymphoid germinal
centres
• Atrophic thyroid follicles
• Range of fibrotic changes
• Interlobular fibrosis
• Interfollicular fibrosis
• Scar fibrosis

The University of Sydney

 Advanced Hashimoto’s Thyroiditis: Microscopic Appearance

Histopathology shows
Focal lymphoid fibrotic changes and
aggregate (GC)
glandular atrophy
• Mononuclear
inflammatory infiltrate
Fibrosis
with lymphoid germinal
centres
• Low cellularity-
destruction of thyroid
Lymphoid
aggregate follicles
• Stromal fibrosis

TheQ3-1:
Slide University of Sydney
Hashimoto’s thyroiditis
 Hashimoto’s Thyroiditis: Treatment
Treatment is required unless hypothyroidism is
transient
Hypothyroidism can be best treated by
replacing T3 and/or T4
– Monitor with blood tests
Levothyroxine
– synthetic form of thyroxine (T4)
Goals of treatment:
– Alleviate symptoms
– Normalised TSH
– Reduce size of goitre
https://www.niddk.nih.gov/health-information/endocrine-diseases/hashimotos-disease

The University of Sydney

 Grave’s Disease: Epidemiology
Most common cause of hyperthyroidism
Characterised by TSH receptor (TRAb)
autoantibodies
– Autoimmune response
Prevalence increases with
– Sex
– Hereditary
– Pregnancy
– Stress
Grave’s disease is typically associated with
– Hyperthyroidism / goitre

Hrt.org
– Thyroid eye disease (Grave’s orbitopathy; GO)
– Pretibial myxedema (PTM)
The University of Sydney Presence of TRAb autoantibodies needed for
 Grave’s Hyperthyroidism: Pathogenesis
TRAb autoantibodies interact with TSHR
Stimulating TRAb (90% incidence)
• Thyroid stimulating immunoglobulins (TSI)
• Activate TSHR (GPCR)
• Cross-reactivity with insulin-like growth
factor 1 receptor (IGF1R)
Blocking TRAb competitively block TSH signalling
(10%)
• Block TSHR
• Promote hypothyroidism / Hashimoto’s

Genetic abnormalities Auto-antibodies

Davies, T.F., Andersen, S., Latif, R. et al. Graves’ disease. Nat Rev Dis Primers 6, 52 (2020).
HLA TSHR*
CTLA4
Susceptibility ≠ active Grave’s
PTPN22
The University of Sydney hyperthyroidism
Grave’s Hyperthyroidism: Mechanisms of Injury
Considering the similarities with other autoimmune diseases, similar environmental
mechanisms are suggested:
– “Bystander” damage
TRH

Feedback inhibition
– “Molecular mimicry”

Stimulation
– HLA antigen presentation T 3, T 4

TSH
Pituitary

TSI TRAb stimulates uptake of iodide while providing negative feedback to T3, T4 TSH receptor
hypothalamus (TRH) and pituitary (TSH) G G protein

TRAb increases cAMP and PKC to promote GTP GDP

– T4/T3 production and secretion Thyroid

cAMP

– Cell proliferation

The University of Sydney

 Grave’s Disease: Clinical Presentation
Symptoms Clinical Assays
• Goitre and Grave’s orbitopathy • Elevated T4/T3
• Anxiety • Decreased TSH
• Weight loss • Detectable TRAb
• Palpitations / Tachycardia • Thyroid ultrasonography (exclude nodules)
• Radioiodine uptake (exclude other forms of
hyperthyroidism)
Grave’s Hyperthyroidism: Macroscopic Appearance
• Goitre
• Diffuse symmetric enlargement
• Absence of nodules

The University
Specimen of Sydney
45.73.1 Thyroid – diffuse hyperplastic goitre (Grave’s disease)
 Grave’s Hyperthyroidosis: Microscopic Appearance
Grave’s hyperthyroiditis
Reduced follicular
colloid • Hyperplastic follicular epithelium
• Intracellular colloid droplets
containing Tg (hypertrophy)
• Reduced follicular colloid with
scalloped margins
• Patchy lymphoid infiltration with
Lymphoid some germinal centres
aggregate

Intracellular colloid Healthy

Lymphoid aggregate Hypertrophy

hyperplasia
TheQ2:
Slide University of Sydney
Thyroid - hyperplastic
Grave’s Disease: Treatment
Treatment regime is defined by features of Grave’s
Disease (Goitre/GO/PTM) and reproductive state
Radioiodine
– Ablate thyroid gland
– Monitor for hypothyroidism with blood tests
(and then provide HRT)
Thionamides
– Inhibit thyroid hormone synthesis
Thyroidectomy
– Partial or total
β-blockers
Goals of treatment:
Davies, T.F., Andersen, S., Latif, R. et al. Graves’ disease. Nat Rev Dis Primers 6, 52
(2020). – Maintaining euthyroid state

The University of Sydney

Asymmetrical Goitre: Neoplasms of the Thyroid
Adenoma Epiglottis
Tumour:
• Discrete solitary masses Tongue
Calcification,
• Follicular adenomas haemorrhage &
necrosis
• Gain of function mutations is TSHR
• Macroscopic appearance of intact capsule

Carcinoma
Left lobe thyroid
• Relatively uncommon atrophic

Tumour in right lobe thyroid

Constricted
Trachea Trachea
The University of Sydney Specimen 45.842.1 Thyroid – adenoma Specimen 45.86.3 Thyroid – carcinoma
Take Home Message
Thyroid goitres are abnormal outward growth in response to increased or decreased function
Simple non-toxic goitres occur with iodine deficency
Hashimoto’s thyroiditis is most common form of hypothyroidism
Progressive autoimmune disease with autoantibodies towards Tg and TPO
Grave’s disease is most common form of hyperthyroidism
Autoantibodies directed towards TSH receptor
Stimulating TRAb promote hyperthyroidism
Inhibiting TRAb promote hypothyroidism
Common elements shared between Grave’s Disease and Hashimoto’s thyroiditis
Microscopic features include lymphocytic aggregate
Thyroid autoantibodies
Failure of appropriate immune response

The University of Sydney

Lecture 2 Case Study Outcome

• Female 46 YO
• Low self-esteem
• Weight gain
despite an active
lifestyle
• Actively avoids
gluten
• Tired
• Type 1 diabetic

The University of Sydney

Questions or Comments?
Head to the CPAT3201/3901 Piazza discussion board

If you feel you can answer a question posted – go for it!

Dr Melanie White

You can find me:

The Charles Perkins Centre
melanie.white@sydney.edu.au
The University of Sydney
The University of Sydney