Download Endocrine Vivas

ENDOCRINE VIVAS
THYROID
2009-1, 2005-1
Describe the steps in the synthesis of thyroid hormones
- Thyroid hormone are made by thyroid epithelial cells called thyrocytes
- They have 4 functions:
1. Collect and transport iodine: via Na+/I- symport (NIS), secondary active transport (Na/K ATPase)
2. Synthesise thyroglobulin and secrete it into the colloid: Contains 134 tyrosine residues
3. Fix the iodine to the thyroglobulin to generate thyroid hormones: Via thyroid peroxidase in a
multistep process w/ iodotyrosines MIT => DIT => T4 (2xDIT) and some T3 (MIT+DIT), creating a
reservoir of thyroid hormones (in the colloid), nb some (inactive) reverse T3 also made
4. Remove the thyroid hormones from the thyroglobulin and secrete then into the circulation: Colloid
internalized by endocytosis => lysosomal degradation => lysis of colloid releases hormone
- All steps TSH controlled
- T3 also made peripherally by deiodination of T4 (D1 deiodinase in periphery, kidneys, liver, thyroid)
2010-2, 2009-2 (+symtpoms), 2009-1 (T4), 2008-1, 2007-1, 2005-1
Outline the physiological effects of thyroid hormones
- The free thyroid hormones enter cells and bind to thyroid receptors in the nuclei and alter gene
expression
- T3 3-5x the affect of T4 b/c more is free and it has a higher affinity with the TR (RT 3 is inert)
Tissue
Effect
Mechanism
Heart
 -adrenergic receptors
Chronotropic
 responses to catecholamines
Inotropic
 -myosin heavy chain (higher
ATPase activity)
Adipose
 Lipolysis
Catabolic
Muscle
 Protein breakdown
Gut
 Carbohydrate absorption
Metabolic
Lipoprotein
 LDL receptors
Other metabolically active
 O2 consumption
tissues (except: testes, uterus,
 Metabolic rate (mobilize FFA,
Calorigenic
lymph nodes, spleen, anterior
increase Na/K ATPase),
pituitary)
BSL/insulin resistance
Bone
Promote normal growth and
Developmental
development (cretinism)
Nervous system
What are the effects of thyroid hormones on nervous and vascular systems? 2009-2
CNS
- Development CNS : cerebral cortex, basal ganglia, cochlea
- ↑ activity, mentation speed and agitation (via catecholamines on RAS, dopamine and direct
brain effects)
- ↑ refexes
CVS
- Heat generation => vasodilation => decreased PR => Na+ retention and expanded blood volume
- ↑HR and contractility => ↑CO
 T3 not formed in myocytes, but enters from circ and increases expression of certain
genes (drecreases other)
 Increases: -adrenergic receptors, -myosin heavy chain (higher ATPase activity),
sarcoplasmic reticulum Ca2+ ATPase, Na/K ATPase
2011-2, 2010-2,
What factors are involved in regulating thyroid hormone secretion?
- Predominant factor controlling thyroid secretion is the circulating level of TSH released from the
anterior pituitary
- TRH from hypothalamus serves to increase TSH secretion
- Negative feedback:
 T3 (and T4) block the increase in TSH secretion produced by TRH
 Thyroid hormones inhibit TSH secretion before they inhibit synthesis
- TSH receptor on thyrocytes: G-protein and activates adenylyl cyclase via Gs
- Thyrocytes also have receptors for:
 IGF-1 and EGF => promote growth
 TNF- INF- => inhibit growth (?chronic inflammation -> weight loss and cachexia)
- Other Inhibitors of TSH
 Stress
 Warmth in exp. animals (cold stimulates TSH secretion in exp animals and human infants)
 Dopamine, somatostatin and glucocorticoids (but physiological role in regulation of TSH
secretion is not known)
PANCREAS
2010-2, 2008-2, 2008-1, 2006-1, 2005-1 (describe the synthesis and receptor)
What happens when insulin binds to an insulin receptor?
- Formed in B cells as a precursor hormone w/ C peptide and stored in membrane bound granules
- t½ 5 mins => binds to receptors => endocytosed and destroyed by proteases in the endosomes
- Insulin receptor
 Tetramer: 2 and 2 glycosolated subunits
  subunits extracellular + bind insulin
  subunits span membrane, intracellular parts have tyrosine kinase activity
- Insulin binding triggers tyrosine kinase activity of  subunits → autophosphorylation of 
subunits on tyrosine residues
- Phosphorylation and de-phosphorylation of proteins
- Effectors and secondary mediators: Insulin receptor substrate (IRS-1), phosphoinositol 3kinase (PI3K)
- Once bound, insulin receptors aggregate in patches and are endocytosed => enter lysosomes =>
broken down or recycled (t½ of receptors is 7 hours)
What are the principal actions of insulin?
- Net effect: storage of CHO, protein and fat, i.e. anabolic
What is the time frame for these effects
Rapid
Seconds  transport of glucose, amino acids and K+ into insulin-sensitive cells
Intermediate Minutes  simulation synthesis  degradation of proteins
Activation of glycolysis and glycogen synthesis (enzymes)
Inhibition of gluconeogenesis (enzymes)
Delayed
Hours
Increase lipogenesis (via transcription)
2008-1
Describe the effects of insulin on various tissues
Adipose
Glucose, K+ Fatty acid and glycerol synthesis
uptake
Muscle
Glycogen and protein synthesis
Liver*
Glycogen, protein and lipid synthesis
General
Cell growth
Triglyceride deposition
Amino acids and ketone uptake
Decreases ketone production
What metabolic effects does insulin have on the liver? 2010-2*
- ↑glycogen synthesis, ↑protein synthesis, ↑lipid synthesis
- ↓ketogenesis
- ↓glucose output due to ↓gluconeogenesis and↑glycolysis
2003-1
What happens to the insulin secretion when a person is injected with 50ml of 50% Dextrose?
- It would go up
Describe the mechanism of insulin secretion
- Glucose => GLUT2 in B cells => glycolysis to pyruvate => ATP via citric acid cycle
1. Rapid phase of release (3-5mins): ATP inhibits ATP sensitive K+ channels, depolarizing the B
cell and Ca2+ enters => exocytosis of readily available secretory granules
2. Prolonged phase of release (2-3hr): metabolism of pyruvate via citric acid cycle => increased
glutamate which acts as an intracellular second messenger to release these granules
2011-2, 2009-2, 2007-1
What factors determine the plasma glucose level?
Concept: Balance between glucose entering the bloodstream and glucose leaving the bloodstream
- Dietary intake
- Cellular uptake (Esp. muscle/fat/ hepatic)
- Hepatic glucostatic activity: (glycogenisis, glycogenolysis, gluconeogenisis)
- Renal: freely filtered but PT reabsorbed to Tmax
- Hormonal effects on these
List the hormones which effect plasma glucose levels? 2009-2
BSL
- Insulin => by glucose uptake, glycogenesis, liver glucose to fat
- NSILA (nonsupressible insulin-like activity), esp. IGF 1and 2 (< activity than insulin)
BSL
- Catecholamines (NA/Adrenaline):  receptor => cAMP => glycogenolysis/gluconeogenesis
- Glucagon: cAMP => glycogenolysis/gluconeogenesis
- GH: anti-insulin effect, increases liver output
- Cortisol: permissive effect on catecholamines and glucagon, some glucogenesis
- Thyroid: absorption + glycogenolysis (esp. liver)
- Nb: -adrenergic stimulators and somatostatin inhibit insulin secretion
Explain how the blood glucose is maintained during fasting. 2011-2
Prolonged fasting:
- Glycogen depleted => increase gluconeogenesis from glycerol and amino acids in liver
- There is also increase in FFA => tissues directly and => ketones via liver
- Hormones: glucagon, cortisol and GH
What are the potential pathways for glucose metabolism in the body? 2007-1
1. Aerobic: glucose + 2ATP (or glycogen + 1ATP) + 6O2 => 6CO2 + 6H2O + 40ATP
2. Anaerobic: glucose + 2ATP (or glycogen + 1ATP) O2 => 2 lactic acid + 4ATP
3. Glycolysis: glucose => pyruvate + H+ + energy for ATP production
- Prepatory/investment phase followed by the pay-off-phase
- Can occur in aerobic and anerobic environments
- Aerobic: pyruvate ultilised via the Krebs/citric acid cycle
4. Pentose-phosphate pathway: for NADPH production
5. Glycogenesis: glucose => glycogen for storage (prevents excessive osmotic pressure)
2011-1, 2010-2, 2005-1
What are the effects of insulin deficiency?
-
Intracellular glucose deficiency w/
extracellular excess
Derangement of the glucostatic function of the liver
Hyperglycaemia with no decrease in
gluconeogenesis
Secondary osmotic diuresis with dehydration
Electrolyte and calorie loss
Catabolism of protein and fat
Ketosis => acidosis
2011-1
Please name the principal Ketone bodies.
- Acetoacetate, β hydroxybutyrate, Acetone
How are the Ketone bodies produced and how are they metabolised?
- Fatty acids (β oxidation) => acetyl-CoA => citric acid cycle => high output of energy (c.f. CHOs)
- Occurs in the mitochondria in the liver and other tissues
- Acetyl-CoA will condense => acetoacetyl-CoA (and aceyl-CoA + acetoacetyl-CoA = HMG-CoA)
- In the liver from these (via deacyclase and HMG-CoA) acetoacetate <=> β hydroxybutyrate
(irreversible, the enzyme for acetoacetate => acetyl-CoA is not found in liver cells)
- These products are water soluble (unlike fatty acids and triglycerides) and are exported from the
liver to extraheaptic tissues (esp. brain, skeletal and cardiac muscle) for ultilisation
- They convert the β-HB => acetoacetate => acetoacetyl-CoA => acetyl-CoA for ulilisation
- The acetone is formed from the spontaneous decarboxylation of acetoacetate cannot be
converted back to acetyl-CoA and is excreted in urine and the lungs
In which clinical situations do they accumulate in the body?
- Insulin inhibits and glucagon stimulates there production
- This pathway is most active during extended periods of fasting
- A rise is seen during sleep, starvation, high fat/low carb diet
- Also seen in diabetes when there is insulin deficiency and glucagon excess
- Also alcoholic ketosis can occur: alcohol blocks the first step of gluconeogenesis
- Normally the levels of β-HB and acetoacetate will be much higher than acetone, but still very low
due to utilization in the tissues
What are the physiological and clinical consequences of excess ketones?
- When production exceeds ultilisation (and excretion of acetone) there is a buildup (ketosis)
- Acetoacetate and β-HB are acids: normally buffered, but when the mechanisms are exceeded a
metabolic acidosis develops
- The kidneys and lungs initially compensate
- The acidosis is exacerbated by the hyperglycaemia in DKA causing dehydration
2010-2
What are the physiologic actions of glucagon?
- Acts on Gs protein receptors => cAMP => Protein kinase A
- Also acts of different receptors to activate phospholipid C => Ca2+
- These lead to:
 Glycogenolysis in liver (not muscle)
 Gluconeogenesis from amino acids (only at very high levels)
 Lipolysis
 Ketogenesis
 +ve inotropic effect on heart (used in β-blocker OD b/c different receptor)
 Inc blood flow to kidneys
 Stimulates secretion of GH, insulin and somatostatin
What factors affect glucagon secretion?
Stimulators
Glucogenic amino acids
CCK, gastrin
Cortisol
Exercise, starvation, stress, protein meal
Infection
Theophylline
Vagal stimulation (acetylcholine)
Inhibitors
Glucose
Insulin
Somatostatin
Secretin
FFAs, ketones
Phenytoin
α-adrenergic, GABA
Additional
Insulin secretion
Glucose => GLUT2 in B cells => glycolysis to pyruvate => ATP via citric acid cycle
3. Rapid phase of release: ATP inhibits ATP sensitive K+ channels, depolarizing the B cell and Ca2+
enters => exocytosis of readily available secretory granules
4. Prolonged phase of release: metabolism of pyruvate via citric acid cycle => increased glutamate
which acts as an intracellular second messenger to release these granules by exocytosis
Stimulators
Glucose, mannose
Glucagon, GIP (gastrin,secretin,CCK), ACh
Amino acids, b-keto acids
β-adrenergic stimulation
Theophylline, sulphonureas
Inhibitors
K+ depletion
Somatostatin, insulin
2-deoxyglucose, mannoheptose
α-adrenergic stimulation
Phenytoin, thiazides, diazoxide
ADRENAL
2010-1, 2008-1, 2005-2
What are the physiological effects of glucocorticoids?
1. Metabolic (Intermediary metabolism of carbohydrate, protein, fat)
- Increased protein catabolism
- Elevate blood glucose:  hepatic glycogenesis and (permissive effect on) gluconeogenesis
- Raise peripheral tissue insulin resistance
- Make DM worse, and Cushings -> IGT in 80%, and DM in 20%
- If deficient then hypoglycaemia (if fasting)
2. Permissive effects on other reactions
- Are required for catecholamines to produce calorigenic and lipolytic effects, pressor
responses (vascular reactivity) and bronchodilation
3. Inhibit ACTH secretion (feedback)
4. Allow water excretion (mechanism unclear)
5. Blood and lymphatics:
- lymphocytes, lymph glands and eosiniphils
- RBC, neutophils and platelets
6. Required for stress response
7. CNS w/ effects on EEG waveforms (mild personality,
irritable, poor concentration, apprehensive)
How is glucocorticoid secretion regulated?
- Basal secretion and stress response both dependent on
ACTH
- Other substances may stimulate adrenal directly but no evidence of role in physiologic regulation
- Free glucocorticoids produce negative feedback on ACTH secretion at both hypothalamic and
pituitary levels (effect mediated by action on DNA)
- Stress response ACTH secretion mediated almost exclusively via hypothalamic release of
corticotrophin releasing hormone
- Circadian rhythm: ACTH released in irregular bursts throughout day but much more common in
early morning. 75% of cortisol secreted at this time
How are they metabolised 2005-2
- Cortisol is metabolised in the liver
- Congugated to glucuronic acid
- Excreted in the urine (15% in stool, via enterohepatic circulation)
2010-2, 2009-2, 2008-2, 2007-1
What is the physiological role of aldosterone
- Causes retention of Na+ (and therefore H2O) expanding the ECF
- Increases absorption of Na+ from urine, sweat, saliva and colon
- On kidney is acts on principal cells in CD ->  ENaC (rapid insertion & slower synthesis)
- The  Na+ will be exchanged for H+ and K+ -> K+ diuresis and acidification of the urine
- By expansion of the ECF -> increased renal perfusion -> negative feedback on rennin production
- Aldosterone is only one of the mechanisms for defense of ECF volume
What conditions increase aldosterone secretion
Primary adrenal disease
- 70% bilateral adrenal hyperplasia (idiopathic)
- Adrenal adenoma (Conn syndrome)
Secondary hyperaldosteronism
- Overactivity of the RAS
- eg. CCF, cirrhosis & nephrosis
- Renal artery constriction
Describe the typical serum / urine effects in hyperaldosteronism
1. Na/Cl mild ↑, fluid retention (follows Na),
2. ↓K, alkalosis (alkalaemia only if K+ depletes)
3. Urine K+/ H↑
Clinical picture: usually without edema (due to escape phenomenom b/c ANP) , but weakness,
hypertension, tetany, polyuria and hypokalemic alkalosis
List the stimuli that increase aldosterone secretion
1. Renin from kidney via angiotensin II (diaglycerol and protein kinase C)
2. ACTH from anterior pituitary (cAMP, protein kinase A)
3. Stimulatory effect of rise in plasma K+ conc. on adrenal cortex (Ca2+ via voltage gated channels)
4. Clinical causes: Surgery, haemorrhage, standing, anxiety, physical trauma, high K intake, low
Na+ intake, constriction of IVC in thorax, hyperaldosteronism (eg CCF, cirrhosis, nephrosis)
Describe the feedback regulation of aldosterone secretion
1. Fall in ECF / blood volume -> reflex  in renal nerve discharge &  in renal artery pressure
2. Increase in renin secretion -> increase -> in angiotensin II -> increase in aldosterone secretion
3. Na+ & water retention -> expanded ECF volume -> decrease in stimulus that initiated renin
secretion
2006-1
What hormones are secreted by the adrenal medulla
- The catecholamines: Adrenaline, noradrenaline and dopamine
What are the major effects of these hormones?
 and  effects
- Cardiovascular as per table and diagram
- Increase in blood glucose via:
1. Glycogenolysis in liver ( effect)
2. Stimulation of B cells  Insulin, glucagon ( effect)
- Increased lipolyis (FA and TGs) via 3
- Hypokalaemia (K+ into cells) via 2
- Metabolic acidosis
- Increased metabolism
- Increase alertness
- Bronchodilation 2
- Mydriasis 
- Increased rennin
- Leucocytosis
- Gastric, uterine, bladder SMC relaxation
Noradrenaline
Adrenaline
Dopamine
1=2, 1>>2
1=2, 1=2
D1=D2>>>>
Vasoconstricts, positive inotrope (minimal chronotropy), CO
Vasoconstricts except skeletal m, positive inotrope/chronotrope
Vasodilation of renal and mesentery, vasoconstriction
elsewhere (?NA release), inotropic (CO)
CALCIUM
2010-2, 2009-1, 2006-1, 2004-2
What hormones are involved in serum calcium regulation.
Hormone
Secreted from
Main actions
PTH
Parathyroid
 Ca2+, mobiles from bone, urinary reabsorption in
DT, urinary excretion of PO43-,
1,25 DHCC
Sun/skin/GI – liver/kidneys
 Ca2+, increases GI absorption, urinary reabsorption
in PT
Calcitonin
Thyroid (parafollicular cells)  Ca2+, inhibits bone resorption, urinary excretion
2011-2, 2010-2, 2009-2, 2009-1, 2006-1, 2004-2
Describe the role of parathyroid hormone in calcium metabolism.
1. Bone:
- Directly increases bone resorption and mobilises Ca2+ causing increased serum calcium
- Over longer timeframe will stimulate osteoblast and oseteoclast activity
2. Kidney:
- Directly increases Ca2+ reabsorption by the distal renal tubules although increased filtered
Ca2+ may cause increased excretion (overwhelms absorbtion)
- Also causes increase PO43- excretion in PT (NaPi-IIa) i.e. phosphaturic
3. GI:
- Indirectly increases gut absorption of Ca2+ by increasing formation of calcitriol
How is parathyroid hormone secretion regulated?
- Serum Ca2+ exerts negative feedback on PTH secretion via a membrane Ca 2+ receptor
- Calcitriol exerts negative feedback by reducing preproPTH mRNA
- Serum PO43- stimulates PTH secretion by decreasing Ca2+ and inhibiting calcitriol formation
- Mg2+ is required for PTH secretion
PTrH
- Parathyroid related hormone
- Probable role in fetal cartilage growth, teeth, breast, skin and placental Ca2+ transport
- Hypercalcaemia in cancer caused by it 80% of the time
- (20% by bone destruction – local osteolytic hypercalcaemia)
- Secreted by cancers of the breast, renal, ovary and skin
2008-1, 2006-1, 2004-2
What are the actions of vitamin D?
- Increased absorption of calcium from the intestine by induction of calbindin-D proteins
- Increased reabsorption of calcium in the kidneys
- Increased osteoblast activity (w/ secondary osteoclastic activity)
- Aids calcification of bone matrix
- Note it also stimulates the uptake of PO43- from the GI (-ve FB on itself)
How is the synthesis of vitamin D regulated?
- Sunlight or ingestion: VitD3 (cholecalciferol) => P450 in liver 25(OH)D (25-hydroxycholecalciferol
= calciferol) => PT cells in kidney to active 1,25 (OH)2D (1,25-dihydroxycholecalciferol = calcitriol)
- Not closely regulated
-  Ca2+ leads to  PTH secretion => (via 1 hydroxylase) =>  calcitriol is produced
-  Ca2+ inhibits PTH and the kidneys produce inactive metabolites (24,25DHCC)
- PO43- directly inhibits the 1 hydroxylase =>  calcitriol production
- Calcitriol itself also inhibits the 1 hydroxylase and the release of PTH
2008-1
What factors influence the level of free calcium in plasma?
- Protein binding: Mainly to albumin, depends on plasma protein level and pH (less bound if acid)
- Total body calcium: 99% bound in bone w/ some bone readily exchangeable vs slowly
exchangeable (resorption/deposition)
- Mobilisation from bone (PTH, calcitriol and calcitonin)
- Intake and subsequent GI absorption under influence of calcitriol
- Renal absorption by PTH (DT) and calcitriol (PT) and PO43- levels (decreases calcitriol)
How does bone resorption occur?
- Osteoclasts are monocytes that develop from stromal cells under influence of RANKL
- Attach to bone via integrins in sealing zone of the membrane.
- Hydrogen dependent proton pumps move into cell and acidify the area
- Acid dissolves hydroxyapatite and collagen
- Products move across osteoclast into interstitial fluid
2004-2
What are the secondary hormones involved in calcium metabolism?
- GH: increases gut absorption
- Glucocorticoids: increases bone reabsorption
- Oestrogens: inhibits osteoclasts
PITUITARY
2006-2
Describe the changes in ACTH secretion that occur in response to stress
- Increased ACTH secretion
- Mediated through hypothalamus by CRH
- CRH produced in paraventricular nuclei, secreted in medial
eminence and transported in portal hyperphysical vessels to
anterior pituitary
- Multiple nerve endings converge on paraventricular nuclei
- Destruction of median eminence means stress response is
blocked
What are the physiological consequences of sudden
cessation of steroid therapy after prolonged treatment?
- Low glucorticoid levels with inability to increase
- Normally a drop in resting corticoid levels stimulate ACTH
secretion (feedback loop)
- Prolonged exogenous glucocorticoid inhibits ACTH
- Adrenal atrophic and unresponsive
- Inhibitory effect pituitary and hypothalamus due action on DNA
- Degree of pituitary inhibition proportional to glucocorticoid
level
- ACTH inhibiting activity parallels glucocorticoid potency
- Pituitary unable to secrete normal amounts of ACTH for one
month, probably secondary to decreased ACTH synthesis
- After one month a slow rise in ACTH levels to supranormal
levels, stimulates adrenal with increased glucocorticoid output
- Feedback inhibition causes a gradual decrease in ACTH
levels to normal
- Avoid by tapering dose over long period (or short dosing if
possible)
s
Acid
Basophil
2005-1
What hormones are produced by the pituitary?
Anterior pituitary (adenohypophysis):
Hormone Cell-type
Associated syndrome
F
FSH
Hypogonadism (lethargy, loss of libido, amenorrhoea),
Gonadotroph
mass effect and hypopituitarism
L
LH
A
ACTH
Corticotroph
Cushing’s syndrome
T
TSH
Thyrotroph
Hyperthyroid
P
Prolactin Lactotroph
Amenorrhea, galactorrhea, loss of libido, and infertility
I
Ignore
Mammosomatotroph Combined features of GH and prolactin excess
G
GH
Somatotroph
Giantism (children), acromegaly (adults)
Posterior pituitatry (neurohypophysis) – remember: Point-of-view => posterior has oxytocin and
vasopressin.
What are the physiologic effects of vasopressin
1. Antidiuretic: renal retention of water in excess of solute reducing body fluid osmolality insertion of
aquaporins in CD
2. Pressor: increases peripheral vascular resistance => BP