Thyroid & hormones Flashcards
Name the 2 hormones released by the posterior pituitary gland
- Anti Diuretic Hormone (ADH) / Vasopressin
- Oxytocin
Name the 6 Hormones released by the anterior pituitary gland
FLAT PeG
- Follicle Stimulating Hormone (FSH)
- Luteinising Hormone (LH)
- Adrenocorticotrophin Hormone (ACTH)
- Thyroid Stimulating Hormone (TSH)
- Prolactin
- endorphins
- Growth Hormone (GH)
Describe the thyroid hormone axis
- Hypothalamus makes thyrotropin releasing hormone (TRH)
- Anterior pituitary makes thyrotropin/ thyroid stimulating hormone (TSH)
- Thyroid gland makes (T3) Triiodothyronine / (T4) Thyroxine
Describe the difference between T3/T4
- T4 = Thyroxine / Tetraiodothyronine
- T3 = Triiodothyronine
- Secretion T4 > T3
- T3 more biologically active
- T4 converted to T3 by deiodinase enzymes
Name some implications of hyperthyroid disease
↑ GIT glucose absorption
↑ GIT motility
↑ gluconeogenesis & glycogenolysis
↑ proteolysis & lipolysis
↑ metabolic enzymes
↑ protein synthesis
↑ BMR & Calorigenesis
- Vitamin deficiencies
Name some implications of Hypothyroidism
- *↓ protein synth**
- *↓ O2 consumption**
- *↓ BMR, Calorigenesis**
- *↓ proteolysis, lipolysis**
- *↓ LDL receptors → ↑ cholesterol**
Children - ↓ GH, ↓ bone growth
What is the pathophysiology of Hashimoto’s Thyroiditis?
Autoimmune disease involving the production of:
- Thyroid peroxidase antibodies (TPO Ab)
- Thyroglobulin antibodies (Tg Ab)
- TSH receptor-blocking antibody
Most people with Hashimoto’s have high levels of these
What are the effects of cortisol in the body?
- Promotes catabolism of proteins & fats
- Helps body adapt to stress
- Can function as anti inflammatory drug & immunosuppressive
What are some locations of thyroid hormone receptors?
- DNA/Ribosomes → Nuclear receptors that act as transcription factors, affecting regulation of gene transcription & translation
- Mitochondria/Na-K pump → 2nd messenger activation & cellular response
What are peripheral effects of thyroid hormones?
↑ Protein synthesis
↑ O2 consumption
↑ energy production and use
This increases activity of BMR via anabolic and catabolic pathways
Ie- in hyperthyroidism, an over creation and breakdown of structures and metabolites, leading to ↑↑ BMR increase and inefficiency
Name some signs & symptoms of Hyperthyroidism
- Exophthalmos
- Goitre
- Muscle weakness
- Weight loss
- Increased appetite
- Vitamin deficiencies
- Hyper-reflexia
- Restlessness, Anxiety
- Irritability, Insomnia
- Fine tremor
- Heat intolerance, sweating, superficial vasodilation
- Warm, soft skin
- Diarrhoea
- Pre-tibial myxedema
Name some signs and symptoms of Hypothyroidism
- Goiter
- Loss of appetite
- Weight gain
- Hypo-reflexia
- Poor concentration
- Impaired memory
- Cognitive dysfunction
- Constipation
- Cold intolerance
- Depression
- Coarse hair, dry skin
What are some causes of secondary Thyroid disease
- UNCOMMON
-
Hyperthyroidism
- TSH overproduction - eg due to pituitary adenoma/ hypothalamic disease
- Elevated serum T4, T3 & elevated TSH levels
-
Hypothyroidism
- Disease of Pituitary or Hypothalamus
- Reduced TSH secretion
- Reduced serum levels of T3, T4 & TSH
4 things potentially involved in treatment of Hyperthyroidism
- Beta-blockers - symptom reliever only
- Anti thyroid drugs - Carbimazole, Propylthiouracil (PTU)
- Radioiodine (I131)
- Thyroidectomy
Treatment of Hypothyroidism
- Replace thyroid hormone - levothyroxine (T4)
- About 80% of oral absorbed from GIT
- Repeat in 3-4 weeks, adjust dose every 4-8 weeks
Describe the steps of Thyroid hormone synthesis
- Iodide actively transported from blood into follicle cell (I- / Na+co-transporter). Moved to colloid space and oxidised (thyroid peroxidase).
- Thyroglobulin is synthesised and secreted (exocytosis) into colloid space
- Iodine added to tyrosines of Thyroglobulin
- Thyroglobulin returns (endocytosis) into follicle cell.
Lysosomal proteases then hydrolyse this polymer into many T3/T4 monomers - T3 & T4 diffuse into capillaries, and taken mostly (~70%) by transport proteins
Describe pathophysiology of goitre development in Grave’s disease
Describe the pathophysiology of goitre development in iodine deficient hypothyroidism
What are the 2 types of secreting cells in the Thyroid gland, and their secretions?
- Follicular cells - T3/T4
- Paracollicular C-cells - Calcitonin
How many parathyroid glands are there?
4
Parathyroid → cells, receptors, hormones
- Mostly chief cells
- Have calcium sensing receptors
- Produce parathyroid hormone when plasma calcium concentration falls
What is the “big picture” function of the Adrenal glands?
- Maintain homeostasis via affecting:
- glucose
- salt
- water
- BP
- stress response
What are the 4 adrenal zones/layers?
From outermost to innermost:
- 3x cortex regions
- Zona glomerulosa - mineralocorticoids
- zona faciculata - glucocorticoids
- zona reticularis - androgens
- Medulla
- epinephrine
- norepinephrine
- tiny amounts dopa & dopamine
Describe adrenal hormones in general
- Steroids - synth from cholesterol
- Lipid soluble - not stored in vesicles
- Diffuse into cell of target tissue - activate intracellular receptors
- Transported in blood by binding proteins
Name the 3 pathways of Aldosterone secretion
- Hypotension (RAAS)
- Hyperkalemia
- ACTH secretion
Aldosterone secretion leads to retention of which ion in particular?
Na+
Actions of Angiotensin II include:
- Generalised vasoconstriction
- ↑ Norepinephrine release from sympathetic nerves (↑ SV & HR)
- Stimulation of Na+ reabsorption kidneys (prox tubules)
- Stimulation of ADH secretion via hypothalamus receptors
- Stimulates thirst. ↑ fluid intake, thus ↑ ECF & ↑ BP
- Aldosterone secretion → adrenal cortex - Na+ reabsorption (dist tubules)
What does decreased renal perfusion pressure trigger?
- Release of Renin from juxtaglomerular cells (JGC’s)
- This converts already circulating Angiotensinogen (made in liver) to Angiotensin-I
- ACE (angiotensin-converting-enzyme - circulating and in pulmo-vasculature) then converts this to Angiotensin-II
Angiotensin II effects
↑ Thirst
↑ TPR
↑ Na+ - H+ exchange → ↑Na+ reabsorption
↑ Aldosterone - ↑Na+ reabsorption
How is non-pathological, genetic short stature determined?
Low levels of Growth Hormone Binding Protein (GHBP) is genetically predetermined
This affects circulating levels of growth hormone
How does pregnancy affect levels of triiodothyronine (T3) & thyroxine (T4)?
Elevated oestrogen stimulates production of Thyroxin Binding Globulin
This lowers free circulating levels of T3/T4
→ reduces negative feedback inhibition of TRH, TSH
thus more T3/T4 is created
Insufficient thyroid hormone in childhood leads to:
Inadequate stimulation of Growth Hormone production, which leads to
- poor bone growth
- mental retardation
with thyroxine Rx, bone growth can be largely restored but mental function cannot
What causes T1DM
An auto-immune disease caused by immune mediated destruction of insulin-producing β-cells in the pancreas
Name some theories behind development of T1DM
- Genetic susceptibility → Higher concordance rates in identical twins.
Recent genome studies have identified multiple succeptible loci for type 1 diabetes - Environmental factors → Evidence that factors such as viral infections may be involved in triggering islet cell destruction
Describe timeframe of insulin-producing β-cells destruction in T1DM
Typically after onset of symptomatic disease, β-cell destruction continues and leads to absolute insulin deficiency within 5 years
“Honeymoon phase” initial total daily requirements <0.3 units insulin/kg/day
Lifelong disease, lifelong insulin requirement
What does metabolic syndrome include?
Insulin resistance
Hypertension
Cholesterol abnormalities
Increased risk of clotting
Often overweight or obese, but uncommonly symptoms may occur in patients with normal body weight
Signs and symptoms of metabolic syndrome include:
- Fasting hyperglycaemia
- Hypertension
- Elevated triglycerides
- Decreased HDL cholesterol
- Central obesity → waist circ > 102cm men, 88cm women
Risk factors metabolic syndrome
Central obesity
Physical inactivity
Over 50y
Prolonged stress → HPA (hypothalamic-pituitary-adrenal) axis imbalance leading to high blood cortisol, and thus high blood glucose and insulin
How to diagnose T2DM
Random blood glucose >11mmol/L
Fasting blood glucose > 7 mmol/L
Causes of type 2 diabetes (think micro)
- Decreased sensitivity to insulin - decreased response of insulin sensitive tissues
- Dysfunctional insulin secretion - Insulin secretion is impaired, and unable to compensate for resistance in peripheral tissues
Insulin resistance is defined as:
The failure of target tissues to respond normally to insulin
“Incretins” are:
Gut hormones that stimulate insulin release -
Eg: glucagon like peptide (GLP-1)
Responsible for increased insulin release that occurs post meal - vs IV glucose inj
Other professionals to refer to for management of diabetes
Dietitian
Exercise Physiologist
Opthamologist or optometrist
Podiatrist
Dentist
Rx algorithm for T2 diabetes
Begin at the top, if not working, add the next
- Lifestyle modification - diet, weight, physical activity
- Metformin (1st line Rx)
- Add one of →
SGLT-2 inhibitors - (Dr Jack Big Fan - other extraglycaemic benefits renal, cardiac) OR
GLP-1 Therapies (Dr Jack Big Fan - other extraglycaemic benefits weight loss)OR
- Sulphonylurea - (DR Jack not a fan - oldschool, high hypo risk)
Acarbose OR
Glitazone OR - Insulin → last resort really
Give an example of a Biguanide, its MOA and some side effects
Metformin:
MOA:
- Decreases hepatic gluconeogenesis
- Increases peripheral insulin sensitivity
Side effects:
- Lactic acidosis
- GIT discomfort or diarrhoea
What hormones are secreted by pancreatic islets?
Describe composition of pancreatic islets - (endocrine cells or islets of langerhans)
What prompts glucagon release
Decreased blood glucose (major)
Increased intake of amino acids (minor - think keto)
Cortisol, exercise, infections (stressors - minor)
CCK, Gastrin (enteric endocrin)
GLUT 2 transporters are low affinity, which means:
They only transport glucose into the cell when concentrations are high
Primary targets of glucagon are:
Liver and adipose tissue
In liver, glucagons actions are
Gluconeogenesis (prodn of glucose)
Glycogenolysis (breakdown of glycogen)
In adipose tissue, glucagon:
Activates hormone sensitive lipase → fat catabolism
Release of FFAs
Activation of ketogenesis → metabolism of FFAs
2 major sites for insulin action
Hepatocytes - remember, it passes through portal circulation to here first!
Skeletal muscle
Describe metabolic effects of insulin
Describe the main effects of glucagon
Glucagon’s primary targets are:
Liver (major)
Adipose tissue - tiny bit
Insulin receptor down regulation occurs with:
Chronically high insulin levels
Obesity
Excess growth hormone
(decreased insulin sensitivity)
Insulin receptor up regulation occurs with:
Exercise
Starvation
(increased insulin sensitivity)
Early, Intermediate and Late effects of Insulin:
Early:
- Absorption of glucose from blood
Intermediate:
- Modulation of enzymes (phosporylation) → metabolic processes
Late:
- Proliferation, growth, differentiation
Describe Insulin effects on blood levels of key metabolites
↓Glucose
↓Fatty acids
↓Keto acids
↓Amino acids
Describe glucagon effects on blood levels of key metabolites
↑Glucose
↑Fatty acids
↑Keto acids
No effect amino acids
How do insulin and glucagon effect Glycogenolysis?
(Think hormones)
How do insulin and glucagon effect Gluconeogenesis?
How do insulin and glucagon effect Glycolysis?
Define Gestational Diabetes Mellitus (GDM)
Inability to compensate for pregnancy metabolic needs
Insulin resistance in pregnancy
Glucose transporters and their location
GLUT 1 - RBCs → work without insulin
GLUT 2 - Liver, Kidneys (2 way) → Phosphorylation of glucose in hepatocyte by hexokinease maintains glucose gradient as more glucose enters cell
GLUT 3 - Neurones - in brain, work without insulin
GLUT 4 - Skeletal muscles, Adipose tissue (1 way) → Insulin dependent
Diabetes type 2 pathophysiology leads to both:
Decrease in responsiveness of peripheral cells to insulin
Inadequate responsiveness of B-cells to glucose
In type 2 diabetes, what causes hyperglycaemia?
- In response to a glucose load, ~70% less glucose is secreted than nondiabetic patients
- Pattern of insulin affected - no post intake spike (smaller, slower, erratic)
- ALSO → excessive hepatic glucose production, compounding higher levels of fasting glucose
- Sustained hyperglycaemia impedes insulin signalling and β cell function
Risk factors for GDM (Gestational Diabetes Mellitus)
- Genetic predisposition (ethnic groups)
- History of macrosomia (birth weight >4500 g or >90th centile)
- Polycystic ovary syndrome
- Essential or pregnancy-related hypertension
- History of spontaneous abortions/unexplained still births
- Family history of diabetes/history of GDM
- Obesity (pre pregnancy BMI >30)
- Medications - corticosteroids, antipsychotics
Complications of GDM (Gestational Diabetes Mellitus) - Mother & Foetus
Maternal risks:
- Increased risk of UTIs
- Preeclampsia
- Caesarean delivery/delivery of large baby
Foetal Risks
- Hypoglycaemia
- Macrosomia (birth weight >4000g)
- Shoulder dystocia/brachial plexus injury
- Stillbirth
Explain HbA1c - Glycated Haemoglobin
Haemoglobin with a glucose molecule attached
Indicated excessive blood glucose
Measurement is a general indicator of a 3 month average of blood glucose (remember 120 day average RBC lifespan)
Higher amounts of HbA1c in patients indicates poorer glucose control
Describe the production of insulin.
Also, what is it and where does the magic happen?
Insulin is a protein, made in pancreatic β cells:
- mRNA encodes Proinsulin
- Proinsulin enters ER, packaged to Golgi
- In the golgi, proteases break down proinsulin to make:
- Insulin and C-peptide
- Both are secreted via exocytosis
Explain C-peptide - a byproduct of insulin creation - and advantages of measuring it
- No known physiological functions
But, it can be measured as an indicator of β cell function because:
- Created in equal amounts with insulin
- Longer plasma half life than insulin
- Excreted unchanged in urine
Steps in the secretion of insulin
Pancreatic β cells have GLUT-2 transporters, which have low glucose affinity
Ie, a significant increase in blood glucose leads to an increase in Insulin secretion
- Glucose enters β cell via GLUT-2 transporter,
- Glucose phosphorylated by glucokinase to glucose-6-phosphate (remember glycolysis)
- G-6-P metabolised to produce ATP
- ↑ ATP inhibits ATP sensitive K+ channels
- → β cell depolarises
- Depolarisation opens voltage sensitive Ca2+ channels
- → Influx of Ca2+
- High intracellular Ca2+ leads to exocytosis of vesicles w insulin & c-peptide
How do increased plasma levels of amino acids lead to secretion of insulin?
- Amino acids are absorbed by pancreatic β cell
- Converted to energy in Kreb cycle via pyruvate & Acetyl CoA
- ⇑ Cellular ATP → closure of ATP sensitive K+ channels
- Cell depol, opening of voltage sensitive Ca2+ channels → Ca2+ influx
- High intracellular Ca 2+ leads to exocytosis of insulin & c-peptide vesicles
Describe ANS (Autonomic nervous system) impact on insulin release
Parasympathetic (feeding) → Ach → ⇡ Insulin release
Sympathetic (fight or flight) → NE → ⇣ Insulin release
Describe the actions of Glucagon
- Promote Gluconeogenesis
- Promote Glycogenolysis
- Promote release of FFAs from adipose tissue (activates hormone sensitive lipase)
- Promote Ketogenesis - metabolism of FFAs
Describe the actions of Insulin
- Triggers GLUT-4 translocation to cell surface of SKM - ⇡ glucose absorption
- Triggers GLUT-2 translocation to cell surface of Hepatocytes - ⇡ glucose absorption
- Promotes glycogenesis
- Inhibits proteolysis
- Promotes fat synthesis
- Inhibits hormone sensitive lipase
Number of available insulin receptors is affected by
- Exercise
- Diet
- Insulin and other hormones (pancreatic polypeptide)
Insulin receptor up regulation occurs with
- Exercise
- Starvation
Insulin receptor down regulation occurs with
- Chronically high insulin levels
- Obesity
- Excess growth hormone
Glucagon-like-peptide 1 (GLP-1) is a potent stimulant for?
Insulin release from pancreatic B cells
Describe Ghrelin - Where it comes from, triggers for release and what it does
- Ghrelin comes from pancreatic E cells (ε) and the stomach
- It is secreted in response to negative energy balance - important regulator of hunger
- Secretion of Ghrelin has an inhibitory effect on:
- Insulin
- Leptin (stimulates satiety)
- CCK
- GLP-1 (glucagon-like peptide1)
Describe Pancreatic Polypeptide (PP) -
Where it comes from, what it does
- Secreted from F cells in pancreatic islets
- Thought to slow absorption of food by inhibiting:
- bile secretion
- gall bladder contraction
- secretion by exocrine pancreas
- Also reduces expression of GLUT-2 receptors in liver ⇢ more glucose passes liver and is available in peripheries
Common distribution of diabetic ulcers
Glove and stocking
Microvascular complications of diabetes
- Retinopathy
- Nephropathy
- Neuropathy
Macrovascular complications of diabetes
- IHD (ischaemic heart disease)
- Stroke - Cerebrovascular Disease
- PVD (Peripheral vascular disease)
What immunosensitivity reaction causes T1DM
Type 4 - T cell mediated
Name the 3 antibodies involved in T1DM
- Anti - B cell antibodies
- Anti insulin antibodies
- Anti GAD antibodies (Glucuronic Acid Decarboxylase) → enzyme involved in B cell Glycolysis
Dx of diabetes
Fasting BGL > 7mmol/L
Incidental BGL > 11.1 mmol/L
HbA1c > 6.5% or >48mmol/L
Antibody testing (B cell, anti insulin, anti GAD antibodies) - T1
Glucose sensitivity test
Biometric testing for metabolic syndrome
Describe mechanisms of hyperglycaemia
- Glucose can deposit on cell walls causing thickening
- Glucose has osmotic drive causing fluid extravasation (oedema)
- ⇡ Glucose metabolised by different pathway to normal glycolysis → produces sorbitol
- Sorbitol has higher osmotic deposition preference → deposits around vessels which supply neurones → neuropathy
- ⇡ Fatty acids → ⇡ Atherosclerosis
LOOK THESE BADBOIS UP
- ⇡ Hyalin deposits (glucose breakdown product) → hyalinsclerosis?
- ⇡ Amyloid → coats cells and thickens membranes → amyloidosis?
6 I’s of DKA (diabetic ketoacidosis) and HHS (hyperglycaemic hyperosmolar syndrome)
- Insulin → insufficient - either undiagnosed or poorly managed
- Infections → ⇡ metabolic demand
- Inflammation → ⇡ metabolic demand
- Intoxication → alcohol, cocaine, amphetamines
- Infarction → AMI, CVA
- Iatrogenic → corticosteroids, surgery (wound healing)
How do norepinephrine, cortisol, glucagon and insulin affect free fatty acid (FFA) release?
- Norepinephrine, cortisol and glucagon all activate Hormone Sensitive Lipase (HSL) - which promotes FFA release
- Insulin inhibits Hormone Sensitive Lipase (HSL) - which decreases FFA release
Ca2+ released from sarcoplasmic reticulum (SR) causes translocation of Glut-4 receptors (as well as facilitating actin & myosin interaction)
How does diabetes mess shite up?
Non enzymatic glycosylation of proteins → damages proteins
In eyes, kidneys and neural tissue there is a lack of Sorbitol Dehydrogenase which is a 2ndary metabolism pathway.
Lack of this enzyme particularly in these cells increases intracellular osmotic gradient, which can cause lysis or damage of surrounding structures
Compare and contrast the half-lives and temporal effects of ADH and cortisol
ADH
- Short ½ life (15-30 minutes) → soluble in plasma, exposed to degrading enzymes
- Rapid effects - seconds -minutes → receptor binding affects existing proteins in collecting duct
CORTISOL
- Longer ½ life → protein bound in plasma (steroid hormone), protected from enzymatic destruction
- Nuclear or cytosolic (intracellular) receptors - take longer to work as promote protein production
Describe the nervous system components of the stress response
Sympathetic NS
Postganglionic neurons release norepinephrine
Some preganglionic neurons synapse at adrenal medulla, release epinephrine
Both act at adrenoreceptors
Describe endocrine component of stress response
- Hypothalamus releases CRH (corticotrophin-releasing hormone)
- Pituitary releases ACTH (adreno corticotrophic hormone)
- Adrenal zona faciculata releases cortisol (a glucocorticoid)
- Cortisol increases production of adrenaline - increasing adrenal medulla response
- Major role of cortisol is to
- make glucose available in the blood
- conversion of amino acids to glucose
- muscle catabolism
How does the stress response affect immune function?
Cortisol → inhibits release Arachadonic acid →
Reduction of prostaglandins and leukotrienes that are important inflammatory mediators
Further, inhibits release of Histamine and serotonin
Describe “growth hormone binding protien”
Circulating levels are genetically determined → influences attained adult height
It extends ½ life of GH by keeping it from being excreted
Describe key hormones in puberty
Where they come from, and how pattern changes at puberty?
GnRH from Hypothalamus
LH & FSH from anterior pituitary
In puberty, increase in amplitude and frequency of release pulses, which normally start during sleep
Describe sex hormone binding globulin
Glycoprotein that binds to androgens and oestrogens
Created in sertoli cells in seminiferous tubules of testes
AKA androgen binding protein in this case
Describe the HPA axis
3 key centres
3 key hormones
Hypothalamus (Paraventricular nucleus @ median eminence spec.) - CRH
Anterior Pituitary - ACTH
Zona Faciculata - Cortisol (Has a negative feedback cycle on first 2)
- CRH = Corticotrophin Releasing Hormone
- ACTH = AdrenoCorticoTrophic Hormone
Main release triggers of cortisol (via HPA axis)
CRH->ACTH->Cortisol
- Diurnal cycle
- Stress
- Hypoglycaemia
Main effects of Cortisol
Think - energy, immune, bone
- Stimulates Gluconeogenesis (liver)
- Decrease peripheral tissue insulin sensitivity
- Works indirectly with adrenaline to promote glycogenolysis
- Promotes lypolysis
- Prolonged high levels can lead to proteolysis (to provide glucogenic amino acids for gluconeogenesis)
- Reduces B-cell mediated antibody response (save energy for fighting/fleeing)
- Reduces bone formation (a/a)
- Raises free serum amino-acids - inhibiting collagen formation and reducing muscle amino acid uptake
What is the mechanism that cortisol and adrenaline affect glycogenolysis
Activation of glycogen phosporylase (which is a rate limiting step in glycogenolysis)
Pathophysiology of Graves Disease
- Auto-immune response
- Creation of Thyroid Stimulating Immunoglobulins - mainly IgG
- These act like TSH - but to an excessive amount, and chronically stimulate follicular cells to create T3 & T4 - However, as it is not truely TSH stimulating the follicular cells, the normal TPA axis negative feedback loop does not work
