Thyroid disease Flashcards
How common is thyroid disease?
200 million people worldwide have some form of thyroid disease
What does untreated thyroid disease increase the risk of?
Cardiovascular disease, osteoporosis and infertility
Increases chance of miscarriage, premature delivery and developmental problems
Describe the thyroid gland
Made of follicular cells and parafollicular cells
What do follicular epithelial cells do?
Secrete thyroid hormones
What do parafollicular epithelial cells do?
Secrete calcitonin
Describe the histology of thyroid follicules
A follicular epithelial layer of cells surrounds the colloid which contains thyroglobulin and thyroid hormone
How is the thyroid controlled?
The hypothalamic-pituitary axis
Hypothalamus senses low circulating T3 and T4
Releases thyrotropin releasing hormone
Stimulates pituitary to release thyroid stimulating hormone
T3 and T4 have a negative feedback loop on the hypothalamus
How are thyroid hormones synthesised?
TSH binding to the TSHR receptor stimulates Na/I symporter
Iodine is taken up from blood by pendrin
TSH stimulates thyroglobulin expression in the follicular cells
Exocytosed into the lumen
In the lumen thyroid peroxidase oxidises the iodine so that it can be incorporated into tyrosine residues of thyroglobulin
Thyroid peroxidase also catalyses conjugation of monoiodotyrosine or diiodotyrosine to form T3 or T4
TSH stimulates endocytosis of T3 and T4 still attached to thyroglobulin, proteolysis and transport to the blood
What does TSH drive?
Thyroid cell proliferation
Hormone release
What genes are upregulated by TSH?
Thyroglobulin
Thyroid peroxidase
Sodium iodide symporter
100+ identified in microarray analysis
List diseases of the thyroid
Hyperthyroidism Hypothyroidism Thyroiditis Autoimmune disorders: Graves's disease, Hashimoto's thyroiditis Thyroid cancer Cowden disease
What is a goitre?
A non-specific term for enlargement of the thyroid gland
Either diffuse or nodular. All previously mentioned thyroid diseases can cause goitre
What drives goitre formation?
Iodine deficiency
Increases TSH to drive TH synthesis
How common are goitre?
Palpable
4-8% of women
1-2% of men
As high as 30-40% and 20-30% in low iodine areas
What are different class of nodules?
Benign nodules Hyperplastic nodules Adenomas Cysts Carcinomas
Describe thyroid cancer
Majority forms in follicular cells, specifically papillary cancer
How are nodules classified?
Hot 85%
Warm 10%
Cold 5%
Based on their iodine levels and functional status
Describe hot nodules in Graves’ disease
There are none as it is a diffuse nodular disease
What are the different stages of thyroid goitre disease?
Simple goitre
Multinodular goitre: euthyroid (normal TSH and free TH levels), toxic multinodular (subclinical or overt hyperthyroidism)
Subclinical goitre
What do subclinical and overt mean?
Subclinical: low TSH and normal free TH
Overt: low TSH and elevated free TH
What happens to hot nodules?
They escape normal control by the pituitary gland. Produce TH in an uncontrolled manner.
Autonomously functioning thyroid nodules
What factors influence nodular growth?
Lack of iodine, smoking, radiation, high BMI, selenium/iron/vitamin A deficiency, nutritional goitrogens
Women>men 4:1
Age
Genetics
What causes hot thyroids?
Anti-TSHR antibodies
Point mutations of TSHR and subsequent coupled G-proteins
TSHR/TH crosstalk
Inactivation of TGFbeta1 signalling
Give an example of a TSHR mutation
Constitutive activation of adenylyl cyclase
What is familial non-autoimmune hyperthyroidism?
17 activating TSHR mutations identified in 24 families. Causes early onset of hyperthyroidism
What is sporadic non-autoimmune hyperthyroidism?
Rare, first case reported in 1995
10 different mutations in 14 subjects
De novo germline mutation
Describe signal modulation of the TSHR pathway
Desensitised TSHR signalling with beta-arresting and GRKs
Both over expressed in toxic thyroid nodules
What are beta-arrestins?
Block the binding of G proteins and links the receptor to internalisation machinery
What are GRKs?
Phosphorylate receptors eg. TSHR to activate them to bind to beta arrestins
What causes cold thyroid nodules?
2-3x greater risk of being cancerous
Lack of uptake by the Na/I symporter
How is NIS activity suppressed?
Altered mRNA expression
Activation of signalling pathways eg PI3kinase, Brafv600E
Hypermethylation (30% of maximal transcriptional activity)
Inhbition of NIS mRNA expression by protooncogenes
When PBF binds to NIS it causes localisation away from the membrane
Evaluate animal models of thyroid disease
Mouse models are used Realistic. Homology between mice and human genes Similarity of amino acid sequences Time, expensive, ethics Paper work Differences in genes and disease Homozygote might not be viable
What is a PBF-Tg mouse?
PTTG binding factor (PBF) Overexpressed in thyroid tumours (and others) Model of overexpression in a mouse Increased goitre formation Lesions of thyroid were hyperplastic PBF was elevating the TSHR mRNA Also increased pAkt activity 3 fold
What is Cowden disease?
Over 60% of patients have multi nodular or follicular adenomas
10% lifetime risk of thyroid cancer
1 in 200,000
80% have inherited PTEN mutation
What is PTEN?
An inhibitor if PI3K activation of Akt Disrupted PTEN elevates Akt activity KO mouse had goitrogenesis No tumours Kras KO PTEN KO had tumours
What is Graves’ disease?
Autoimmune condition
Causes hyperthyroidism
Affects 1 in 200 in the US
Thyroid stimulating immunoglobulin
What is Hashimoto’s disease?
Autoimmune condition
Causes hypothyroidism
Affects 1 in 20 in the US
What happens if hypothyroidism isn’t treated?
Develop myxedema coma
