PBL 9 - Thyrotoxicosis Flashcards
What is an endocrine Gland? - general definition
- A Group of cells which secrete “messenger” molecules directly into the bloodstream
- Effect can be on many targets throughout the body
- Effects will take place over a relatively long time span- seconds to days
- They are DUCT-LESS- releases directly into the blood
- Richly vascularised to allow this to happen
What is an endocrine action?
- relates to the action of a hormone on a target cell
- At a distance from the source
- Transported in blood stream
What is Paracrine action?
- Relates to hormones that act on nearby target cells
* Within immediate area around the source
What is autocrine action?
• Relates to a hormone having an effect on its own immediate source/cell
What are the classic endocrine glands?
- Pituitary
- Parathyroid glands
- Thyroids
- Adrenals
- Pancreas
- Gonads
What are the Non-Classical Endocrine glands?
- Brain and hypothalamus (CRH, TRH, LHRH)
- Heart (ANP and BNP)
- Blood (cytokines)
- Kidneys (Renin, erythropoietin, 1.25 Vit D)
- Adipose Tissue (Leptin)
- GIT ( GLP-1,OXM, Ghrelin)
- Liver (IGF-1)
- Skin ( 250H D)
What are the 2 categories of hormones?
• Protein/Polypeptide/amino acid derived hormones
○ Complex polypeptides eg. LH
○ Intermediate sized peptides eg Insulin
○ Small peptides eg TRH
○ Dipetptides eg T4
○ Derived from single amino acids eg Catacholemines
Steroid hormones
○ Derived from cholesterol
○ Divided into 2 groups
§ Intact steroid nucleus (Adrenal/gonadal steroids)
§ Broken steroid nucleus (Vit D and Metabolites)
How are protein based hormones produced and secreted?
- Undergo transcription, translation and exocytosis
* Usually synthesised as a pre pro hormone and cleaved
How is ACTH synthesized, stored and secreted?
- Produced within pituitary corticotroph cell
- Specific mRNA synthesized within cell nucleus
- Translation of specific mRNA to prohormone POMC within the Rough ER
- POMC transported to golgi body where it is further processed by proteolytic enzymes to the mature active hormone ACTH
- Stored in secretory Granules in the cell cytoplasm
- Release by exocytosis into rich network of capillaries around the gland
How are steroid hormones Synthesized, stored and secreted?
• Originate:
○ Precursor cholesterol
• Transported across the cell membrane from blood stream via passive diffusion
• Once inside they are subjected to sequential action of several enzymes to produce the mature hormone
• Once produced it can freely cross the cell membrane without being packed into granules
How is cortisol synthesized, stored and secreted?
• Produced in the adrenal cortical cell
• LDL rich in cholesterol is transferred into cell by endocytosis
• Cholesterol split from lipoprotein and stored in cytoplasmic vacuoles
• Stimulation by ACTH activates cholesterol esterase which releases cholesterol from cholesterol ester depots providing a substrate for steroid synthetase
• StAR protein mediates transfer of cholesterol from outer to inner mitochondrial membrane
○ Rate limiting step
• Cholesterol undergoes a number of modifications by cytochrome P450
• Once mature hormone is produced it can freely diffuse across the cell membrane into the circulation
How are hormones transported through the plasma?
• Water soluble hormones
○ Circulate freely
• Insoluble hormones
○ Bound to plasma proteins or transport proteins
• Transport proteins
○ Act as a reservoir so that bound hormone is in dynamic equilibrium with small amount of free hormone
○ Only free hormone is biologically active
○ These buffer hormones and protect against rapid changes in hormone concentration
What are the differences in receptors between peptide and steroid hormones?
What is the normal concentration of hormone receptors and why?
• Hormones are usually present in low concentrations in the plasma therefore the receptor must have high affinity and high specificity for a particular hormone
• Peptide hormones ○ Bind with a receptor and activates an effector system resulting in an intracellular signalling cascade ○ Cell surface receptors § GPCR § Tyrosine kinase receptor
• Steroid hormones ○ Intra-nuclear receptors ○ Enters cell by passive diffusion ○ Binds to DNA binding sites to alter gene transcription and protein synthesis
What is the signalling cascade started by ACTH to produce cortisol?
- ACTH binds to cell surface GCPR receptor
- Adenylate cyclase is activated - converts ATP to cAMP
- This activates Protein Kinase A
- The kinase activates Cholesterol esterase as well as StAR protein
- Cholesterol can now be transferred into the mitochondrial membrane
What is the purpose of the Hormonal feedback mechanism?
- Necessary for all normal endocrine homeostasis
- Hormones produced by peripheral target organ feedback onto the organ that stimulates it to control its own function
- This allows it to regulate its own function
○ Negative feedback- the most common
○ Positive feedback
What are the biological rhythms of the pituitary hormones?
• LH/FSH/GH = every 2 hours • ACTH/Cortisol = circadian variability (Suprachiasmatic nucleus) • T4 = long half life of 7-10 days • Stimuli ○ Stress = ACTH/GH/ PLH ○ Hypoglycaemia = SCTH/GH ○ Infection = ACTH ○ Sleep = GH
What is a Neuroendocrine tumour?
What are the most common?
How can you tell if it is benign or malignant?
What are the macroscopic features?
Neuroendocrine tumours make up only 2% of pancreatic tumours • They can be functioning or non functioning ○ Insulinomas = The most common ○ Glucogonoma • Benign tumours make up the large majority of insulinomas • Malignant features: ○ Metastases ○ Vascular invasion ○ Gross invasion of adjacent viscera • Macroscopic Features ○ Well circumscribed ○ Soft ○ Homogenous ○ Pink-tan colour
What endocrine gland has the largest store of hormones?
The thyroid
What is the Thyroid Follicle?
What does it do?
- It is the warehouse and factory for thyroid hormone production
- It traps circulating iodine
- Synthesizes Thyroglobulin which is the precursor of T4 and T3 which is stored into colloid reservoir
Represents half of the protein content in the thyroid
Describe the Hypothalamic-Pituitary-Thyroid Axis
Must be tightly controlled due to widespread effects of thyroid hormones
• Decreased T3 and T4 concentrations in the blood • Hypothalamus secretes Tyrotropine releasing hormone (TRH) into the portal vessels • TRH binds onto GCPR TRH receptors on thyrotrophs in the anterior pituitary • This leads to an increase in intracellular calcium • TSH secretion is stimulated • Increase in T3 and T4 concentrations in blood feedback: ○ Inhibition of the Hypothalamus TRH ○ Inhibition of the Pituitary TSH • Decrease in levels of T3 and T4
How is Thyroid hormone synthesized?
Step 1 : Trapping of Iodide into the follicle
○ Dietary iodine ingestion
§ Absorbed in the stomach and upper small intestine as Iodide ion
§ Transported in blood and taken up by the thyroid (70-80% of bodily iodine is in the thyroid)
§ Most ingested iodine is eventually excreted in the urine
○ Uptake of iodide by the thyroid gland
§ Transport by sodium-iodide symporter into cytoplasm/colloid of follicular cells to site of hormone synthesis
§ This is an active transport process stimulated by TSH
§ This is the rate limiting step in thyroid hormone synthesis
STEP 2: Iodination of Thyroglobulin
○ Oxidation of Iodide by Thyroid peroxidase (TPO)
○ Transport of active iodine to follicular cell-colloid interface
○ Iodine is incorporated by TPO into selected Thyroglobulin tyrosine residues
○ This forms Diiodotyrosine and Monoiodotyrosine depending on how many molecules of iodide is used up (Organification of iodide)
STEP 3: Coupling of MIT and DIT
○ The iodinated thyroglobulin is taken up into the colloid
○ Two residues are coupled together through TPO
○ Either:
§ 2 DIT can be coupled together to form Tetra-Iodotyrosine (the precursor for T4- at this point still attached to thyroglobulin)
§ 1 DIT and 1 MIT = Tri-iodotyrosine (Precursor for T3)
○ T3/T3 are synthesized and stored within the thyroglobulin in the colloid making it a reservoir of thyroid hormones
STEP 4: Release of Thyroglobulin to form T4 and T3
○ The T3 or T3 is imbedded within the thyroglobulin in the colloid
○ Following TSH stimulation T4 and T3 are liberated from the Tg molecule and secreted into the blood
○ TSH stimulation causes pinocytosis of colloid droplets
○ Fusion of droplets with lysosomes causing digestion of Thyroglobulin
○ This causes release of T4/T3 into the capillary
○ Some of the T4 is deiodinated in the process to become T3
○ Tg is also released in the blood as a by product
What is the clinical significance of Tg entering the bloodstream when T3/T4 is released?
- Levels of Tg correlate with thyroid mass and levels of TSH stimulation
- Blood thyroglobulin test can be used to monitor certain thyroid cancers and treatment efficacy
- There is an increase in the amounts of thyroglobulin release into blood stream by the tumour
What is the clinical significance of Iodination?
• There is a critical role of iodine trapping in thyroid function
• Iodine is very rare in the diet so it must be efficiently concentrated
• Abnormalities can lead to thyroid disease
○ Deficiency in iodine or TPO can lead to Hypothyroidism
○ Anti-TPO antibodies = autoimmune thyroid disease
○ Inactivating mutations or autoantibodies to symporter gene
• Sodium-iodide symporter cannot distinguish between normal and radioactive iodide so it can be used for diagnostic imaging and treatment for cancer.
What is the rate limiting step in thyroid hormone synthesis?
• The active symport of sodium and Iodine into the cell stimulated by TSH
Overview: Thyroid hormone synthesis and release
- Iodide enter via sodium iodide symporter and is concentrated in follicular epithelial cells
- Oxidation to iodine by TPO
- Conversion of Tg to either MIT or DIT
- Coupling of iodinated tyrosines to form either T4 or T3
- Tg endocytosis
- Tg hydrolysed in lysosomes to release T4 and T3
- Transport and release of T4 and T3 in blood
What is the role of TSH in the synthesis and release of Thyroid hormones?
What is the clinical significance of the TSH receptor and TSH levels?
- Activation of TSH receptors (GCPR) on thyroid follicle
- Leads to CAMP signalling and activating gene expression
○ Iodine trapping
○ Thyroid hormone synthesis and release
○ Cell proliferation and differentiation• Clinical significance
○ Rates of T4/T3 synthesis is directly related to TSH levels
○ Mutations in TSH receptors can lead to increased activations leading to an adenoma
○ Autoimmune activation of TSH receptors - leading to hyperthyroidism
What is the primary secretory product of the thyroid?
- T4
- In the normal thyroid state the thyroid gland secretes 100% of the body’s total T4 but only a small percent of the body’s T3- 10-20%
Where does the majority of the body’s T3 come from?
• Most of the body’s T3 is derived from deiodination of T4 in extra thyroidal tissues rather than from the Thyroid
What are the differences in half life and concentration In the plasma between T3 and T4?
What is the clinical significance of this?
Half Life:
• T4 = 7 days- it is a pro hormone and serves as a reservoir
• T3 = 1 day- shorter than T4-
Clinical significance:
• Usually only synthetic T4 given as a replacement drug to patients because the half-life is long
• The body will convert this T4 as needed into T3
• When giving T4 it will take time to readjust dosing due to long half life
• If you gave T3 it is faster acting and you can dangerous peaks of activity- not well tolerated.
• Can give combination if the patient has trouble converting the T4 to T3
Concentration:
• T4 is greater than T3
• This means that it is easier to measure in a thyroid function test
How is T4 and T3 transported in the blood stream?
• 99% is bound to carrier proteins
• This is because it is lipid soluble
• 75% is bound to thyroxine binding globulin (TBG) - this one has the most affinity
• 25% is bound to albumin and thyroxine-binding prealbumine (TBPA)
• Carriers provide a reservoir of hormones and delay hormone metabolism
○ Ie conserves iodine
• Only a tiny fraction of total thyroid hormone is free
○ Only free hormones can enter cells as they are metabolically active
How are changes in free hormone levels adjusted ?
• Appropriate stimulation or suppression of hormone secretion and disposal
What is the clinical significance of carrier proteins?
• There is a careful control over the number of carriers
• There is a ratio of hormone and carrier that is generally kept in proportion to keep the amount of free hormone constant
• Alterations in the number of protein carriers are usually quantitative rather than affinity changes
• Concentrations of carriers can be affected by physiologic changes, drugs, diseases
○ Pregnancy increases TBG
○ Cushings disease decreases TBG
○ Corticosteroids decreases TBG
• Hereditary or acquired variations in TBG/albumin could cause false thyroid function test results
○ Now we order only free Hormone levels so that it does not give false results
How is T4/T3 taken up into the cell?
T3 is the biologically active thyroid hormone (has a higher affinity for receptors)
• Only 20% of T3 is secreted by the thyroid
• T4 or T3 enter the cell via either passive or facilitated diffusion by plasma membrane transporter MCT8
• Free T4 is then converted into T3 by intracellular deiodinases
• This occurs primarily in the liver
• Peripheral tissues regulate local T3 levels according to needs by increasing or decreasing T3 synthesis from T4
• The free T3 binds to intracellular receptors (either in the nucleus or mitochondria)
○ The receptors have a much lower affinity to T4 then T3
• Genes are now activated that control energy utilisation
What are the effects of T3?
• OVERALL - increases in basal metabolic rate
Widespread effects in peripheral tissue
○ Increased rates of oxygen and increased energy consumption
§ Increased demand for metabolites like glucose
§ Increased expression of enzymes necessary for energy production
○ Increased Heat production
○ Increased heart rate and force of contraction
○ Increased sensitivity to sympathetic stimulation
○ Accelerates turnover of minerals in bone (excess causes osteoporosis)
• Essential for normal brain development
○ Untreated in childhood can cause mental retardation/cretinism
• Initiate or sustain cell growth and differentiation
○ Stimulates production of proteins exerting trophic effects on tissues
How is T4 and T3 metabolised in the periphery?
• T 4 can be converted by monodeiodination to either the active T3 or the inactive rT3 metabolites
• If there is an excess of T4 you can metabolise it to the inactive form using a different enzyme = adjusted depending on what the body needs.
• T3 and rT3 are further metabolised by deiodination to inactive T2
○ All deiodination is catalysed by tissue specific Selenium/Selenoenzymes to work
• Some T4/3 is eliminated directly via liver conjugation/excretion and kidney excretion (21%)
What are the bodily uses of RT3?
• used to clear body from excess T4 and to balance T3 levels to body needs
• Example:
○ Used to slow down the body’s metabolism when you are starving or in serious illness or under high stress
What is involved in a Thyroid Function test?
Thyroid function test
• TSH and Free T4 • There should be an inverse relationship between TSH and thyroid hormones • TSH concentrations are more sensitive indicators of thyroid dysfunction due to very small amounts of Free T4 levels in the blood • There will be an abnormality in the TSH much earlier than changes in T4 • The T4 level will show you the severity of the problem ○ Measured because there is more circulating T4 than T3 ○ Measure the free amount because this is not effected by changes in carrier protein numbers
What are some causes of Primary Hypothyroidism?
What is the mechanism?
What would thyroid function tests show?
Causes of Primary Hypothyroidism (90%) • Iodine deficiency • Autoimmune • Surgery • Drugs • Congenital
Mechanism:
• There is decreased synthesis and release of T4/T3
• This leads to an increase in TSH synthesis and release through the feedback loop to try to increase thyroid hormone levels
Results of thyroid function tests?
• Low level of T4
• High TSH
What is Secondary and Tertiary Hypothyroidism?
What would the Thyroid function tests show?
Secondary Hypothyroidism = < 10% of cases
• pituitary failure to synthesise/secrete TSH
Tertiary Hypothyroidism = Rare
• hypothalamus failure to synthesise/secrete TRH
Results of Thyroid function tests:
• Low T3 and T4
• No increase in TSH - may be inappropriately normal or Low
• Feedback loop not working
How would Subclinical primary Hypothyroidism present in Thyroid function tests?
TSH level = Elevated
T4 level = Normal
What is Hyperthyroidism?
What is the most common cause?
What is the mechanism?
What would results of thyroid function tests show?
Hyperthyroidism
Causes: • primary causes (90%) ○ Graves disease (autoimmune) ○ Too much iodine or synthetic T4 ○ Cancer ○ Thyroiditis • Secondary (rare) ○ Pituitary adenoma
Mechanism of disease:
• Increased synthesis and release of T4/T3
• Leads to a decrease TSH synthesis and release through a feedback loop to try to decrease T4/T3 synthesis and release
Thyroid Function tests • Primary Hyperthyroidism ○ TSH decreased ○ T4 Increased • Secondary ○ T4 Increased ○ TSH inappropriately normal due to non-functioning feedback loop
What is involved in Thyroid antibody tests?
• Look for antibodies to:
○ Anti-TSH receptor antibodies (Graves)
○ Anti TPO antibodies (Autoimmune thyroid disease hashimotos)
○ Anti-Thyroglobulin antibodies (Thyroiditis)
What is TRH stimulation testing and when is it used?
TRH stimulation tests
* Used to evaluate pituitary function (rare) and to determine the cause of a low TSH * Giving someone TRH should increase the TSh levels if there is an intact hpothalamic pituitary axis
When would you use a thyroglobulin test?
Thyroglobulin test:
• Used to monitor Thyroid cancer and treatment efficiency or recurrance
• Levels of thyroglobulin correlate with thyroid mass and TSH receptor stimulation
What kind of things would affect a Thyroid function test interpretation?
• Physiological conditions ○ Pregnancy ○ Ageing ○ Hepatic dysfunction ○ Ill patients - euthyroid sick • Drugs ○ B-Blockers and amiodarone inhibit the conversion of T4 to T3 ○ Corticosteroids and dopaminergic drugs inhibit TSH secretion ○ Lithium inhibits T3 and T4 Secretion • Test variability ie reference range
How does Graves Disease effect the thyroid?
Graves Disease:
• Presence of anti-TSH receptor antibodies that STIMULATE the receptor
• Effect of constant activation:
○ The Gland grows
○ Follicles to increase iodine uptake
○ Increased synthesis of T4/T3
○ Hyperthyroidism
• Feedback of increased T4/T3 causes a decreased level of TSH to be released from the Pituitary
• Anti-TPO antibodies are also found in 75% of cases of Graves
What is the hallmark of autoimmune thyroid disease?
• TPO antibodies
What would be the phsyiological effects of having Hypothyroidism?
• Decreased Basal metabolic rate • Carb Metabolism ○ Decreased gluconeogenesis ○ Decreased Glycogenolysis ○ Normal serum glucose • Protein Metbaolism ○ Decreased Protein synthesis ○ Decreased Proteolysis • Lipid Metabolism ○ Decreased Lipogenesis ○ Decreased Lipolysis ○ Increased Serum Cholesterol • Decreased Thermogenesis • Normal levels of serum catecholamines
