PBL 9 - Thyrotoxicosis Flashcards
1
Q
What is an endocrine Gland? - general definition
A
- 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
2
Q
What is an endocrine action?
A
- relates to the action of a hormone on a target cell
- At a distance from the source
- Transported in blood stream
3
Q
What is Paracrine action?
A
- Relates to hormones that act on nearby target cells
* Within immediate area around the source
4
Q
What is autocrine action?
A
• Relates to a hormone having an effect on its own immediate source/cell
5
Q
What are the classic endocrine glands?
A
- Pituitary
- Parathyroid glands
- Thyroids
- Adrenals
- Pancreas
- Gonads
6
Q
What are the Non-Classical Endocrine glands?
A
- 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)
7
Q
What are the 2 categories of hormones?
A
• 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)
8
Q
How are protein based hormones produced and secreted?
A
- Undergo transcription, translation and exocytosis
* Usually synthesised as a pre pro hormone and cleaved
9
Q
How is ACTH synthesized, stored and secreted?
A
- 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
10
Q
How are steroid hormones Synthesized, stored and secreted?
A
• 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
11
Q
How is cortisol synthesized, stored and secreted?
A
• 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
12
Q
How are hormones transported through the plasma?
A
• 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
13
Q
What are the differences in receptors between peptide and steroid hormones?
What is the normal concentration of hormone receptors and why?
A
• 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
14
Q
What is the signalling cascade started by ACTH to produce cortisol?
A
- 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
15
Q
What is the purpose of the Hormonal feedback mechanism?
A
- 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
16
Q
What are the biological rhythms of the pituitary hormones?
A
• 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
17
Q
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?
A
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
18
Q
What endocrine gland has the largest store of hormones?
A
The thyroid
19
Q
What is the Thyroid Follicle?
What does it do?
A
- 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
20
Q
Describe the Hypothalamic-Pituitary-Thyroid Axis
A
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
21
Q
How is Thyroid hormone synthesized?
A
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
22
Q
What is the clinical significance of Tg entering the bloodstream when T3/T4 is released?
A
- 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
23
Q
What is the clinical significance of Iodination?
A
• 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.
24
Q
What is the rate limiting step in thyroid hormone synthesis?
A
• The active symport of sodium and Iodine into the cell stimulated by TSH
25
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
26
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
• Stimulates
○ 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
27
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%
28
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
29
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
30
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
31
How are changes in free hormone levels adjusted ?
• Appropriate stimulation or suppression of hormone secretion and disposal
32
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
33
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
34
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
35
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%)
36
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
37
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
38
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
39
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
40
How would Subclinical primary Hypothyroidism present in Thyroid function tests?
TSH level = Elevated
| T4 level = Normal
41
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
```
42
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)
43
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
44
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
45
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
```
46
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
47
What is the hallmark of autoimmune thyroid disease?
• TPO antibodies
48
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
```
49
What are the Physiological effects of Having a Hyperthyroidism?
Hyperthyroidism
```
• Increased basal metabolic rate
• Carbohydrate metabolism
○ Increased gluconeogenesis
○ Increased glycogenolysis
○ Normal serum glucose
• Protein metabolism
○ Increased synthesis
○ Increased proteolysis
○ Muscle Wasting
• Lipid Metabolism
○ Increased Lipogenesis
○ Increased Lipolysis
○ Decreased Serum Cholesterol
• Increased Thermogenesis
• Increased expression of B-Adrenoceptors
○ Increased sensitivity to catecholamines which remain at normal levels
```
50
Describe the histology of the thyroid gland
* The functional unit of the thyroid is the follicle or acinus
* The follicle is made up of cuboidal epithelial cells arranged in spheroidal sacs containing colloid
* Each follicle is surrounded by a basement membrane
* Between the basement membrane and the follicle are C-Cells which secrete Calcitonin
51
What are the symptoms and signs of Hypothyroidism?
```
Hypothyroidism
• Cold intolerance
• Goitre (unless due to secondary/tertiary causes)
• Reproductive dysfunction
• Fatigue
• Myxoedema
• Constipation
• Bradycardia
• Bradypnoea
• Slow movements
• Depression
• Weight gain
```
52
What are the symptoms and signs of hyperthyroidism?
```
• Heat intolerance
• Goitre- unless from a thyroid tumour. With a bruit in graves' disease
• Reproductive dysfunction
• Hyperhidrosis
• Exophthalmos
• Tachycardia/AF/ Flow murmurs
• Tachypnoea
• Tremor
• Insomnia
• Weight loss
• Proximal myopathy
• Diarrhoea
• Lid Lag
• Hyper-reflexia with rapid relaxation phase
Pretibial Myxoedema
```
53
What is involved in the physical examination of the thyroid?
* Look for swelling
* Asymmetry of the thyroid
* Determine size and shape
* Evaluate consistency
* Present of nodules
* Tenderness
54
Where is Adrenaline synthesised? How is this controlled?
| What are its targets and effects
```
• Synthesized by the adrenal medulla
○ 80% of catecholamine output
• Direct control by nervous system- sympathetic preganglionic fibres
• Targets most cells in the body
• Function
○ Increases cardiac activity
○ Increases BP
○ Increases Glycogen breakdown
○ Increases Blood Glucose levels
○ Increased Lipolysis
```
55
What kind of hormone is Adrenalin and how is it synthesized?
```
• Water soluble
• Synthesised from amino acid- tyrosine
• Tyrosine is taken up by chromaffin cells in the adrenal medulla
• Adrenaline is then stored in granules
• Release by exocytosis in response to stimulation
• Secretion is stimulated by stress
○ Hypoglycaemia
○ Trauma
○ Exercise
○ Emotional stress
```
56
How do Adrenal medulla hormones mediate response to stress?
| How long does this take?
Adrenal Medullary hormones mediate an immediate short term response to crisis
Mobilise Glucose reserves:
• Increases glycogenolysis
• Increases lipolysis to then be used in gluconeogenesis
Changes in circulation:
• Constriction of blood vessels - leads to increased Blood pressure
• Dilations of pupils and bronchioles
Increase in heart and respiratory rates:
• increased rate and force of contraction of heart (b1-receptors)
○ Increase Camp signalling and leads to increased response
• Increased pulmonary ventilation
Increased Energy use by all cells
• Increased metabolic rate (adrenaline)
• Increased Oxygen consumption and heat production
57
What is a Pheochromocytoma?What are the symptoms?
Pheochromocytoma
• Adrenal Medulla tumour causing excess production of adrenaline
```
Symptoms:
• Severe HTN
• Tachycardia
• Palpitations
○ Ventricular arrhythmia and fibrillation in severe cases
• Excess sweating
• High anxiety and nervousness
• Severe headaches
• Tremor
• Weight loss
• Heat intolerance
```
Symptoms are similar to hyperthyroidism
58
How can you treat the cardiac symptoms in Hyperthyroidism?
* Treat with B-Blockers
* This will block the action of catecholamines
* Hyperthyroidism leads to an over expression of d-adrenoreceptors leading to an increased sensitivity to catecholamine's
59
How does the liver maintain glucose homeostasis?
| What level does it need to be?
• Liver plays a critical role in controlling blood glucose
○ Releases glucoses from breakdown of glycogen
○ Makes glucose from intermediates of carbohydrates, protein and fat metabolism
• Needs to be maintained at:
○ ~ 5mM
60
What happens to Glucose metabolism during stress?
• The response to stress is similar to the response in the fasting state
• Catabolic
• Adrenaline is released and antagonises insulin
• This leads to:
○ Decreased Uptake by muscle and adipose tissue
○ Mobilisation of stored energy reserves
○ Increase in plasma glucose
61
What hormones have a hyperglycaemic action?
* Glucagon
* Adrenaline
* Cortisol
* Growth Hormone
All oppose Insulin
62
Which hormone has a hypoglycaemic action?
• Insulin
63
What is the process of Glycolysis?
| Where is the main site?
* Glucose is broken down into pyruvate
* Pyruvate is then broken down into Acetyl CoA
* Acetyl CoA enters the Krebs cycle
* Electron Transport Chain
* ATP generated
Main site = The Liver
64
What happens in the Early Fasting/Post absorptive state?
How long after eating does this occur?
How long is this effective?
Post absorptive state is approx 6-12 hours after eating
Events:
• Most glucose taken up by insulin INDEPENDENT tissues such as the brain and RBCs
• Release of:
○ Glucagon by alpha cells of the pancreas (acts on liver)- main hormone
○ Adrenaline released by adrenal medulla (Acts on muscle and liver)- smaller role
• Mobilisation of glycogen
○ Adrenaline activates cAMP signalling in the liver and muscle
○ Increases Glycogen phosphorylase and decreases Glycogen synthase
○ Used for organs during fasting
○ Muscle glycogen reserves are strictly used for internal muscle use
* Liver glycogen degradation is only a short term source of energy for emergencies
* It would only be sufficient for a few hours
65
What is the difference in the location of receptors for glucagon and adrenaline?
* Glucagon = LIVER ONLY
| * Adrenaline = Muscle AND Liver
66
What happens in the liver during prolonged fasting?
| Where does the energy come from to perform this?
• Liver glycogen stores are depleted
• Liver metabolism changes to glucose PRODUCTION
• Key player = GLUCAGON
○ Stimulates gluconeogenesis in liver from non carb precursors (Lactate, Amino acids, glycerol)
• Glucose made in the liver is released into blood and transported to peripheral tissue- heart and brain to be used as energy
• BSL increases
Energy for gluconeogenesis:
• FFAs generated by TG breakdown undergo B-oxidation
• This is converted to acetyl coa then enters the krebs cycle
• Provides energy
• FREE FATTY ACIDS ARE NOT CONVERTED TO GLUCOSE
67
What are the substrates used for gluconeogenesis?
| Where do they come from and how are they used?
Lactate
• Lactate is released from skeletal muscle through conversion of glucose using lactate dehydrogenase
• This is taken up into the blood stream and transported to the liver and recycled back into glucose
• Cori cycle
Amino Acids
• Adrenaline causes amino acids to be released from proteolysis in the muscle
• Glucogenic amino acids are degraded to pyruvate or other intermediates in the TCA cycle
○ Usually Alanine
• Oxaloacetate is the precursor that is formed and used to make glucose
Glycerol
• Adrenaline activates Hormone sensitive lipase in adipocytes
• Glucagon can also induce lipolysis but it is not as effective as Adrenaline
• Lipolysis causes the breakdown of Triglycerides into
○ Glycerol
○ Fatty acids
• Glycerol
○ Transported to the liver and converted to glucose
• FFA
○ Major product but cannot be converted to glucose
○ Used as an energy substrate instead to facilitate gluconeogenesis
68
How does Glucagon and Adrenaline activate hormone sensitive Lipase?
• Adrenaline and glucagon bind to a GPCR on adipocytes
• G-protein -> Adencylate cyclase- > CAMP
• Activates Protein kinase A (Phosphorylates)
• Phosphorylation of Hormone sensitive lipase which is an Enzyme present in adipocytes
• Cleaves TG into Glycerol and FFA
○ Glycerol used for gluconeogenesis
○ FFA used for B-Oxidation
69
What happens in periods of prolonged fasting?
* When glucose is no longer available as a fuel there is an enhancement of lipolysis
* This generates a massive amount of FFA
* This is uptaken by the liver and oxidised creating an excess amount of Acetyl Coa
* Oxaloacetate is all used up due to the excess amount of Acetyl CoA
* Acetyl CoA then cannot enter the krebs cycle
* Ketone bodies are then made instead
* These are not used by the liver however they are exported to other tissues to be used as an energy source for heart and skeletal muscle
70
What is Glucagon used for?
• The MAIN hormone that restores blood glucose when you are fasting
• Stimulates:
○ Glycogenolysis
○ Gluconeogenesis
○ Increased in lipolysis (not a big role- usually is adrenaline)
• Increases BGL
71
What type of hormone is TRH, TSH and T3/4?
• TRH is a neuropeptide - peptide secreted by a neuron in the hypothalamus
• TSH is a polypeptide derived hormone
T3 and T4 are both amino acid derived hormones
72
How sensitive is the body to changes in T3/T4?
Small fluctuations in T3/T4 cause large changes in TSH
73
What would the laboratory results look like in Primary Hypothyroidism?
Low T4 and T3
| High TSH
74
What would the laboratory result look like in Primary Hyperthyroidism?
```
T4/T3 = High
TSH = Low
```
75
What is the initial screening test for thyroid problems? Why?
TSH
• If you have a normal TSH you are UNLIKELY to have any thyroid problem
• This is a screening test only and is not true in some cases
Conversely if the TSH is high or low there is a HIGH chance there is a thyroid problem
76
What would the laboratory result look like in secondary hyperthyroidism?
```
T3/T4 = High
TSH = Inappropriately normal or high
```
77
What is the general cause of secondary hyperthyroidism?
Very uncommon
Autonomous secretion of TSH
Ie A TSHoma
78
What is the General cause of secondary hypothyroidism?
Inability to produce TSH
| Very uncommon
79
What is the TSH receptor?
• 7 transmembrane Domain receptor (GPCR)
• Anchors the protein into the lipid bilayer
TSH specific
80
What is the Clinical Importance of TPO?
• It is the enzyme that allows molecules of Iodinated tyrosine to be joined together to form T3 and T4
• It is the target for many anti-thyroid drugs such as Carbimazole and Propythiauricil
Antibodies are formed against this enzyme in Hashimotos Thyroiditis
81
What is the mechanisms of Carbimazole?
* The molecule is a structurally similar to Tyrosine
* It works as a competitive inhibitor of TPO by binding to it and preventing it from acting on tyrosine to form thyroid hormones
* It has a dose response relationship
* The higher the dose the stronger the inhibition of thyroid hormone synthesis
82
Where is TPO located?
• Colloid end Membrane of the epithelial cell of the follicle
83
What is Thyroxine?
• Synthetic T4
• Replacement for hypothyroidism
Allows for the body's own self-regulation to determine how much T3 it needs
84
What are the broad categories of Endocrine problems and examples of each?
```
Functional:
• Over production
○ Graves Disease
○ Toxic Adenoma
○ Toxic Multinodular Goitre
• Under production
○ Hashimotos hypothyroidism
○ Iodine deficiency
○ Surgery
○ Thyroidectomy
○ Hypothyroid phase of transient thyroiditis
○ Post Radio-iodine
```
```
Structural:
• Benign
○ Multinodular goitre
○ Diffuse goitre
○ Solitary nodule
• Malignant
○ Papillary
○ Follicular
○ Medullary
○ Thyroid Cancer
```
85
How common are Thyroid nodules?
• Increases with age.
• Up to 70% of the elderly have them and they are benign
• Most are benign - only 10% will develop into cancer
Investigation:
• If TFTs normal = ultrasound
If TFT abnormal = Tch99m scan
86
What are the classic signs of Hypothyroidism?
```
Symptoms:
• Fatigue
• Weight gain
• Cold intolerance
• Arthralgia
• Constipation
• Menoorrhagia
• Dry skin and hair
```
```
Physical Signs:
• Pallor
• Course skin and hair
• Bradycardia
• Goitre
• Hung up reflexes
```
87
How reliable are the signs of hypothyroidism?
They may be absent in mild disease
Also common in people without thyroid disease
Not sensitive or specific
88
What is the classification of overt hypothyroidism?
TSH > 10
| T4/T3 = low
89
What is the classification of subclinical Hypothyroidism?
TSH 4-10
| T4/T3 = normal
90
What is the most common cause of Primary Hypothyroidism?
• Chronic Autoimmune thyroiditis (Hashimotos)
91
What is the Pathophysiology of Hashimotos Thyroiditis?
| What are some other considerations?
• TPO antibodies and TG antibodies
• Lymphocytic infiltrate and Germinal centre
• Impaired production of thyroid hormone
• Get a goitre from inflammation or atrophy from long term scarring
• More common in women
• Clusters with other autoimmune conditions:
○ Coeliac disease
○ Pernicious anaemia
○ T1DM
○ Addisons disease
○ Vitiligo
92
What are the investigations for Hypothyroidism?
```
• Primary Hypothyroidism
○ Anti-thyroid antibodies (Anti TPO antibody)
• Secondary Hypothyroidism
○ Pituitary Biochemistry
○ MRI pituitary
```
93
How do we measure the efficacy of Thyroxine replacement?
* Measure TSH levels
| * Feedback should lead to normal range TSH
94
How Long does it take to achieve steady range T4 and TSH after starting thyroxine replacement therapy?
4-6 weeks
95
What is the treatment for Primary hypothyroidism?
* Replacement with thyroxine
* Compliance from patient
* Monitor TSH levels to see efficacy of replacement
* Target should be reached at 4-6 weeks
96
What are the classic Symptoms of Hyperthyroidism?
```
Symptoms:
• Weight loss
• Heat intolerance
• Palpitations
• Breathlessness
• Anxiety
• Diarrhoea
• Tremor
• Proximal muscle weakness
```
```
Physical Signs
• Fine Tremor in the hands and sweatiness of the palms
• Tachycardia (100 or above) /AF
• Ophthalmopathy- Graves Disease
• Goitre
• Difficulty rising from a squat
```
Most patients will complain of these signs and they respond well to treatment
97
Briefly- What is the Pathogenesis of Graves' Disease?
How common is it?
Who gets it?
What are the clinical clues?
What are the associated Autoimmune conditions?
What are the key investigations?
What is the initial Treatment?
Graves' Disease: Most common type of hyperthyroidism (50-80%)
• More common in females
• Peak incidence is between 40-60 years old
Pathogenesis:
• Stimulating IgG antibody to TSH receptor
• Binds to the GPCR causing hyperplasia and hypertrophy of the thyroid follicles
• Increased Thyroid size and increased hormone production
```
Clinical Clues:
• Diffuse Goitre
• Thyroid Bruit
• Opthalmopathy
• Pretibial myxoedema
```
Associated Autoimmune conditions
• alopecia, T1DM, Pernicious anaemia
```
Investigations:
• Radionucleotide scan
○ Symmetrical increased uptake
○ Ie will not be able to see the salivary glands or ratio would be 15-20
• TSH receptor antibodies
```
Initial Treatment:
• Anti-thyroid drugs
○ Carbimazole
98
Briefly- What is the Pathogenesis of Hashitoxicosis/ lymphocytic thyroiditis?
What are the clinical clues?
What are the key investigations?
What is the initial Treatment?
Hashitoxicosis
Pathogenesis:
• Destructive autoimmune thyroiditis
• Causes release of stored thyroid hormone creating transient hyperthyroidism
• Followed by transient or permanent hypothyroidism
Clinical Clues:
Often none
Investigations:
• Radionucleotide scan
• Thyroid peroxidase antibodies
Initial Treatment:
• Usually none- consider B-Blockers if symptomatic
99
Briefly- What is the Pathogenesis of Subacute thyroiditis?
What are the clinical clues?
What are the key investigations?
What is the initial Treatment?
Subacute thyroiditis
Pathogenesis:
• Destructive, viral thyroiditis causing release of stored thyroid hormone
• Transient hyperthyroidism
• Possibly followed by transient Hypothyroidism
Clinical Clues:
• Preceding Viral Illness
• Painful, tender thyroid
Investigations:
• Radionucleotide scan
• C-Reactive Protein
Initial Treatment:
• Usually none- consider B-Blockers if symptomati
• If painful give NSAIDs for analgesa
• Rarely prednisolone
100
Briefly- What is the Pathogenesis of Toxic Nodular Goitre/Toxic adenoma?
What are the clinical clues?
What are the key investigations?
What is the initial Treatment?
Toxic nodular goitre/Toxic Adenoma
Pathogenesis:
• Single or multiple adenoma secreting thyroid hormone
Clinical Clues:
• Asymmetric, Irregular Goitre
Investigations:
• Radionucleotide scan
Initial Treatment:
• None or anti-thyroid drugs
101
What are the two most important investigations for diagnosis of Hyperthyroidism?
What investigations are not useful?
* Anti-TSH receptor antibodies
* Nuclear Thyroid Scan - Most important
Not useful:
• Anti-thyroid antibodies- unless it is a lymphocytic cause
• Ultrasound is usually NOT useful unless malignancy suspected
102
How does a Nuclear Thyroid scan work?
| How Is it interpreted?
* Injection of TC 99 m- radioisotope
* Is taken up by the iodine/sodium symporter in the thyroid
* Shows what the thyroid is doing with iodine
Interpretation
• Need to look at the uptake relative to the rest
• Compare the uptake to the salivary glands
• It is normal to see the salivary glands
• Look at the ratio of uptake
○ This is measured using the neck to thigh ratio
○ Low uptake ratio = Not much going on in the thyroid
○ High uptake ration = lots going on in the thyroid
• Normal ratio is between 4-10
• Uptake should be symmetrical
103
What is the treatment of Hyperthyroidism?
• Thionamides- structural analogues of tyrosine that reduce the synthesis of thyroid hormones
○ Propylthiouracil
○ Carbimazole
• Radioiodine Treatment- good for toxic adenoma
○ Destructive dose delivered in a capsule
○ Selectively goes to the areas of the thyroid that are active
○ Preferentially destroys only toxic adenoma in 50% of people
• Surgery
○ Remove all or just the defective part of the thyroid
104
What are the side effects of carbamazapine and PTU?
Carbamazepine:
• Rash
• Agranulocytosis
• Teratogenesis
PTU:
• Liver toxicity - not preferred as first line treatment
• Teratogenesis- less than carbimazole
105
How common are benign thyroid nodules?
| What causes them?/
• 10% lifetime risk
Causes of Benign nodules : MOST COMMON
• Degeneration nodule
○ More colloid then there should be
○ Possibly haemorrhaged into them
○ Possibly to cycles of stimulation and suppression- unknown
• Adenomatous Nodule
○ Clonal proliferation of cells that are benign
○ Can be Functional or non-functional
○ Functional nodules are almost never cancer! (99%)
§ Radio-nucleotide scan would show increased uptake.
106
What are the types of Thyroid Cancer?
Who is it most common in?
How is it investigated and treated?
What is the prognosis?
* 8th most common cancer
* 3 x more common in women
* Usually diagnosed in middle age
Causes of cancerous nodules:
• Almost all of them develop from the Follicular epithelium
○ papillary is most common
○ Follicular cancer (makes microfollicles)
○ Anaplastic - undifferentiated- aggressive
• A minority are derived from the neuroendocrine cells in the medullary (2%)
○ Occurs in the C-cells that make calcitonin
Presentation:
• Neck lump or incidental imaging
• Diagnosed with ultrasound and biopsy
Treatment:
• Thyroidectomy
• Radioactive Iodine
Prognosis:
• 98.1% survival rate in 5 years
107
What factors increase the risk of the thyroid nodule being malignant?
• Age < 20 or > 70
* Age < 20 or > 70
* Male gender
* Dysphagia or hoarseness
* Childhood neck irradiation
* Hard irregular and fixed lump
* Rapid growth
* Lymphadenopathy
* Previous/family history of thyroid cancer.
108
What investigations are performed on someone with a thyroid nodule?
1. TSH - Everyone gets this- if its normal then go straight to USS
2. Nuclear Scan
3. If suspected malignancy
a. Ultrasound
b. Biopsy
109
What are the Eye signs in Thyroid Disease?
| What do they suggest.
General non specific hyperthyroidism:
• Lid Lag
• Lid Retraction
```
Graves Disease:
• Exophthalmos
○ Diplopia- eye is restricted
○ Chemosis- redness and irritation
○ Compression of the optic nerve and visual failure
```
110
Where is the concentration of TRH the most high?
• In the median eminence and the Paraventricular nuclei
111
What is are some Thyroid hormone changes that occur in normal pregnancy?
* Have higher iodine requirements
* TRH and TBG both increase leading to an elevated T4 and T3
* Bhcg has weak TSH like properties due to structural similarities- these can cause subclinical hyperthyroidism early in the pregnancy
112
What is the most common thyroid disease in pregnancy?
Most common Thyroid disease is pregnancy:
• Autoimmune thyroid disease
• Antibodies can cross the placenta causing foetal thyroid problems
113
What are the considerations for pregnancy and thyroid disease investigation and treatment?
Investigation considerations:
• Radio-active Iodine studies are contraindicated during pregnancy
• Newborn babies are screened for congenital hypothyroidism
Treatment considerations:
• Both Carbimazole and PTU cross the placenta and are secreted in breast milk
• PTU is favoured because Carbimazole can cause rare foetal abnormalities
114
List the causes of hyperthyroidism:
* Autoimmune thyroid disease: Graves, Hashitoxicosis
* Autonomous thyroid tissue
* Toxic adenoma
* Multinodular goiter
* Over replacement with Thyroxine
* Thyroiditis
* Drug related
* Amiodarone
* Lithium
* Iodine
* Factitious
* Pituitary causes
* TSH producing adenoma (rare)
115
When would a thyroid ultra sound be useful?
* When there is a Goiter or thyroid lump however NORMAL TFTs
* Thyroid cancer is not usually functional
116
Why are b-blockers beneficial to people with hyperthyroidism?
• They are effective for symptom control in the early stages whilst awaiting for the anti-thyroid medications to become effective
117
Side effect profile of carbimazole versus thyroxine?
Carbimazole has many side effect whereas thyroxine doesn’t.
118
What role does amiodarone have in thyroid disease?
* Can cause both over or under active thyroid problems
* Have 2 iodine atoms attached to its structure
* It prevents the extrathyroidal conversion of T4 to T3 is all patients
119
In Graves disease- which thyroid hormone is typically higher?
T3
120
When would you measure Tg?
* Thyroglobulin can be used as a marker of remaining or recurrent cancer in patients who have had a total thyroidectomy or ablation
* These patient should have NO Tg if there is no thyroid
121
What are the indications for thyroidectomy?
What procedure is preferred for nodules?
What are the risks of surgery?
* Thyroid carcinoma
* Large goitres with compressive symptoms
* Positive pembertons sign
* Dysphonia
* Dysphagia
* Dyspnoea
* Hyperthyroidism in some circumstances
* Failure of medical treatment
* Intolerance of treatment for example in pregnancy
* Subtotal or lobectomy preferred for nodules
```
Risks:
• Hemorrhage
• Recurrent laryngeal nerve damage
• Airway injury
hypocalcaemia
```
