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Phase 1 SUGER > Endocrine Physiology > Flashcards

Endocrine Physiology Flashcards

1
Q

What is the embryology of the pancreas?

A

At junction of foregut and midgut 2 pancreatic buds (dorsal and ventral) are generated and eventually fuse to form pancreas
•Exocrine functions begins after birth
•Endocrine (hormone) functions from 10-15 weeks

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2
Q

What is the anatomy of the pancreas?

A

Retroperitoneal, posterior to greater curvature of stomach
•12-15cm long, head is near C-portion of duodenum

•Secretions pass into small ducts, then

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3
Q

How are the endocrine and exocrine functions of the pancrease different?

A

Formed of small clusters of glandular epithelial cells
•98-99% of cells are clusters called acini
•Exocrine activity performed by acinar cells
–Manufacture and secrete fluid and digestive enzymes, called pancreatic juice, which is released into the gut
•Endocrine activity performed by islet cells
–Manufacture and release several peptide hormones into portal vein

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4
Q

What happens at the endocrine pancreas?

A

Site of insulin and glucagon secretion at the islets of langerhan
- only 2-3% volume of total pancreas

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5
Q

How are the islets of langerhan heterogenous?

A

A-cells secrete glucagon
B-cells secrete insulin
Delta cells secrete somatostatin

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6
Q

What is the imp of the microstructure of the islets on its physiogical effects?

A

Secretes somatostatin, insulin and glucagon

paracrine ‘crosstalk’
between alpha and beta
cells is physiological,
i.e., local insulin
release inhibits glucagon

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7
Q

What peptides are secreted by the islets?

A

Insulin – polypeptide, 51 amino acids
–Reduces glucose output by liver, increases storage of glucose, fatty acids, amino acids
•Glucagon – 29 amino acid peptide
–Mobilises glucose, fatty acids and amino acids from stores
•These 2 hormones have reciprocal actions
•Somatostatin secreted from d cells – inhibitor
•Pancreatic Polypeptide – inhibit gastric emptying

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8
Q

How does insulin regulate carb metabolism?

A

Insulin
•Suppresses hepatic glucose output
– Glycogenolysis
– Gluconeogenesis
•Increases glucose uptake into insulin sensitive tissues
–Muscle – glycogen, and protein synthesis
–Fat – fatty acid synthesis
•Suppresses
–Lipolysis
–Breakdown of muscle (decreased ketogenesis)

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9
Q

How does glucagon regulate carb metabolism?

A

Glucagon - counterregulatory
•Increases hepatic glucose output
– Glycogenolysis
– Gluconeogenesis
•Reduces peripheral glucose uptake
•Stimulates peripheral release of gluconeogenic precursors (glycerol, AAs)
–Lipolysis
–Muscle glycogenolysis and breakdown

Other counterregulatory hormones (adrenaline, cortisol, growth hormone have similar
effects to glucagon and become relevant in certain disease states, including diabetes)

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10
Q

How is insulin secreted by cells?

A

KATP channel
Ca channels
Glut2 channels
ADP/ATP

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11
Q

What is proinsulin?

A

Proinsulin contains the A and B chains of insulin (21 and 30 amino acid residues respectively), joined by the C peptide.
•Disulfide bridges link a and B chains
•Presence of C peptide implies endogenous insulin production

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12
Q

What is biphasic insulin release?

A

B-cells sense rising glucose and aim to metabolise it
•First phase response is rapid release of stored product
•Second phase response is slower and as it is the release of newly synthesised hormone

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13
Q

How does insulin act in muscle and fat cells?

A

GLUT 4
Glucose enters cell

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14
Q

What is glucose homeostasis?

A

Glucose levels should remain constant
•Liver glycogen is a short-term glucose buffer

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15
Q

What is the response for low glucose?

A

Short term: split glycogen (glycogenolysis - glycogen -> glucose)

Long term: make glucose (gluconeogenesis) from amino acids/lactate

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16
Q

What is the response for high blood glucose?

A

Short term: make glycogen (glycogenesis) glucose-> glycogen

Long-term: make triglycerides (lipogenesis)

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17
Q

What is glucose sensing?

A

Primary glucose sensors are in the pancreatic islets
•Also in medulla, hypothalamus and carotid bodies
•Inputs from eyes, nose, taste buds, gut all involved in regulating food
•Sensory cells in gut wall also stimulate insulin release from pancreas - incretins

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18
Q

What are incretins?

A

Insulin response is greater following oral glucose than intravenous glucose despite similar plasma glucose concentrations
•Gut hormones stimulating insulin release are called incretins, glucagon-like peptide (GLP-1) and glucose-dependent insulinotrophic peptide(GIP)

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19
Q

What are postprandial glucose levels regulated by?

A
  1. Increase in Insulin
    Rising plasma glucose stimulates pancreatic B-cells to secrete insulin
  2. Decreasing glucagon
    Plasma glucose inhibits glucagon secretion by pancreatic a-cells
  3. Decrease in gastric emptying
    Delaying and/or slowing gastric emptying is a major determinant of postprandial glycaemic excursion
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20
Q

What cleaves GLP-1?

A

Dipeptidyl peptidase IV (DPP-IV) cleaves GLP-1

Half-life of GLP-1 ~1-2mins

DPPIV prevents hypoglycaemia

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21
Q

How is CHO metabolism regulated in the fasting stage?

A

In the fasting state, all glucose comes from liver
–Breakdown of glycogen
–Gluconeogenesis (utilises 3 carbon precursors to synthesise glucose including lactate, alanine and glycerol)
•Glucose is delivered to insulin independent tissues, brain and red blood cells
•Insulin levels are low
•Muscle uses FFA for fuel
•Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat

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22
Q

How is CHO metabolism regulated in the postprandial stage?

A

After feeding (post prandial) - physiological need to dispose of a nutrient load
•Rising glucose (5-10 min after eating) stimulates 5-10 fold increase in insulin secretion and suppresses glucagon
•40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
•Ingested glucose helps to replenish glycogen stores both in liver and muscle
•Excess glucose is converted into fats
•High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall

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23
Q

What is hypoglycaemia and hyperglycaermia?

A

Low blood glucose (hypoglycaemia) stimulates release of glucagon

High blood glucose (hyperglycaemia) stimulates release of insulin

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24
Q

How does glucagon act on liver?

A

Glucagon acts on liver to:
–Convert glycogen into glucose
–Form glucose from lactic acid and amino acids

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25
Q

What inhibits glucagon release?

A

If blood glucose continues to rise, hyperglycaemia inhibits release of glucagon

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26
Q

How does insulin act on various cells?

A

Insulin acts on various cells to:
–Accelerate facilitated diffusion of glucose into cells
–Speed conversion of glucose into glycogen
–Increase uptake of amino acids and increase protein synthesis
–Speed synthesis of fatty acids
–Slow glycogenolysis
–Slow gluconeogenesis

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27
Q

What inhibits insulin release?

A

If blood glucose continues to fall, hypoglycaemia inhibits release of insulin

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28
Q

What is diabetes mellitus?

A

A disorder of carbohydrate metabolism characterised by hyperglycaemia

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29
Q

What is the incretin effect?

A

GLP-1 analogues
DPPIV inhibitors

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30
Q

What is the pathogenesis of diabetes ,mellitus?

A
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31
Q

What is the pathogenesis of diabetic ketoacidosis (DKA)?

A
  1. Absent insulin secretion
  2. No hepatic insulin effect
  3. Unrestrained glucose + ketone production
  4. More glucose enters blood
  5. Hyperglycaemia and raised plasma ketones
  6. No muscle/fat insulin effect
  7. Impaired glucose clearance + muscle/fat less glucose breakdown
  8. Breakdown of tissue
  9. Glycosuria and ketonuria
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32
Q

What is endocrinology?

A

Study of hormones

A hormone is a substance secreted directly into the blood by specialised cells

Hormones are present in only minute concentrations in the blood and bind specific receptors in target cells to influence cellular reactions

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33
Q

How do hormones work?

A

Stimulus-> gland -> (hormone synthesis, release and transport) hormone A-> (binding specific receptor, cell signalling) target tissue -> action

-> Hormone B (usually -ve)-> gland

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34
Q

What are the actions of these hormones: insulin, cortisol, testosterone, oestrogen, thyroxine, adrenaline, aldosterone, progesterone, glucagon and VIP?

A
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35
Q

What are the endocrine glands?

A

Hypothalamus
Pituitary
Thyroid
Parathyroids
Adrenals
Pancreas
Ovary
Testes

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36
Q

What are the endocrine organs?

A

Heart
Liver
Fat
Kidney
Intestines - largest endocrine organ
Skin

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37
Q

What is the structure of hormones?

A

E.g. cortisol, peptides and thyroid hormones

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38
Q

What are all steroid hormones synthesised from?

A

Cholesterol

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39
Q

What are catecholamines synthesised from?

A

Tyrosine

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40
Q

What occurs in thyroid hormone synthesis?

A
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41
Q

What is the storage and secretion of hormones like?

A

Storage and secretion:

Peptides and proteins
Day
Exocytosis

Steroids and pseudo steroids
Min-hour
Diffusion

Thyroid hormones
Weeks
Proteolysis

Catecholamines
Days
Exocytosis

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42
Q

What is the binding protein, 1/2 life and time of action of hormones

A

Peptides and proteins
Some
Min-hour
Min-hour

Steroids and pseudo steroids
All
Hours
Hours-day

Thyroid hormones
Yes
Days
Day

Catecholamines
No
Sec-min
Sec

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43
Q

How do hormones exert their effect?

A

Cell surface receptors e.g. G protein coupling e.g. insulin

•Intracellular receptors e.g. cortisol

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44
Q

How are hormones modified within cells?

A
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45
Q

How do hormones affect us?

A

Pre-menstrual tension
•Pregnancy – post natal depression
•Puberty
•High dose steroids – psychosis
•Hypogonadism – poor libido
•Insulinoma - behaviour

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46
Q

What are the basic actions of thyroid, parathyroid, cortisol, aldosterone, catecholamines, oestradiol, testosterone, insulin, ANP and vitamin D hormones?

A

Thyroid - basal metabolic rate, growth
Parathyroid - Ca 2+ regulation
Cortisol - glucose regulation, inflammation
Aldosterone - BP, Na+ regulation
Catecholamines - BP, stress
Oestradiol - menstruation, femininity
Testosterone - sexual function, masculinity
Insulin - glucose regulation
ANP - Na+ regulation
Vitamin D - Ca2+ regulation

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47
Q

How are hormone concentrations measured?

A

Bioassays
Immunoassays
Mass spectrometry

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48
Q

What are the anterior pituitary hormones?

A

ACTH - regulation of adrenal cortex
TSH - thyroid hormone regulation
GH - growth, metabolism
LH/FSH - reproductive control
PRL - breast milk production

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49
Q

What are the posterior pituitary hormones?

A

ADH - water regulation
Oxytocin - breast milk expression

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50
Q

How does the feedback principle work with pituitary hormones?

A
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51
Q

What is thyrotoxicosis?

A
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52
Q

What is Cushing disease/syndrome?

A
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53
Q

What IS Acromegaly?

A
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54
Q

What are some local effects of pituitary disease?

A

Huge pituitary tumour acromegaly squashing Optic chasm and rest of pituitary

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55
Q

What is bitemporal hemianopia?

A

Visual field loss due to damage to optic chiasm

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56
Q

What is the available treatement for thyrotoxicosis?

A

•Destruction of thyroid tissue using radioiodine (131I)

•Antithyroid drugs to block hormone synthesis

•Partial surgical ablation of thyroid

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57
Q

What are some Durga to treat functioning pituitary tumour?

A

Somatostatin analogues
•Dopamine agonists
•GH receptor antagonists

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58
Q

What are some examples of too little production of glands?

A

Several hypothyroidism
Iron deficiency
- goitre - -ve consequence of -ve feedback
Adrenal insufficiency - addisons disease

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59
Q

What treatement do under active glands need?

A

Hormone replacement therapy:

Underactive thyroid – thyroxine
•Underactive adrenals – hydrocortisone(cortisol) + fludrocortisone (synthetic aldosterone analogue)
•(Premature) menopause – oestrogen replacement
•Underactive testes - testosterone

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60
Q

Is all endocrinology gland based?

A

No:

Carcinoid disease
•Small cell lung cancer
•Liver secondaries
•Flushing
•Wheezing
•Diarrhoea
•Valvular heart disease

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61
Q

What is the pituitary gland like?

A

Pea-sized
Weighs ca. 0.5 g

Secretes hormones in response to signals from hypothalamus

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62
Q

What is the blood supply of the ant. Pituitary?

A

The anterior pituitary has no arterial blood supply but receives blood through a portal venous circulation from the hypothalamus

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63
Q

What are the diff hormones In the ant. Pit vs post. Pit?

A

Anterior lobe
ACTH
TSH
GH
LH
FSH
Prolactin

Posterior lobe
Vasopressin
(AVP),
Oxytocin

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64
Q

What ate the anterior pituitary hormon types and function?

A

Pituitary Hormone - Hormone - Type Function

  1. TSH - Glycoprotein - Thyroid hormone synthesis
  2. FSH - Glycoprotein - Egg / sperm development
  3. Luteinising hormone (LH) - Glycoprotein - Sex steroid synthesis/ ovulation
  4. ACTH - adrenocorticotrophic hormone - Polypeptide - Guncragenproducton + adrenal/androgen production
  5. Growth Hormone (GH) - Polypeptide - linear growth, CHO metabolism, bone mass
  6. Prolactin - Polypeptide - Lactation
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65
Q

What is the hypothalamus?

A

Collection of brain ‘nuclei’
•Connections to almost all other areas of the brain
•Important for homeostasis
–primitive functions
–appetite, thirst, sleep, temperature regulation
•Control of autonomic function via brainstem autonomic centres
•Control of endocrine function via pituitary

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66
Q

What is the hypothalmic-hypophyseal portal system in the anterior?

A
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67
Q

What is the hypothalmic-hypophyseal portal system in the anterior?

A
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68
Q

What are the hypothalamic hormones?

A
  1. Hormone released (pituitary): / 2. releasing hormone (hypothalamus):
  2. Thyroid stimulating hormone (TSH) - Thyrotropin releasing hormone (TRH)
  3. Adrenocorticotrophic hormone (ACTH) - Corticotropin releasing hormone (CRH)
  4. Follicle Stimulating hormone (FSH) - Gonadotropin releasing hormone (GnRH or LHRH)
  5. Luteinising hormone (LH) - Gonadotropin releasing hormone (GnRH or LHRH)
  6. Growth Hormone (GH) - GH releasing hormone (GHRH)
    (Somatostatin – inhibitory)
  7. Prolactin - Dopamine (inhibitory)
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69
Q

What is the importance of negative feedback?

A

ACTH/cortisol

Stress, cytokines diurnal rhythms -> hypothalamus (CRH+)->pituitary (ACTH+) -> adrenal -> cortisol -> tissue action

Back to ——> pituitary and hypothalamus

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70
Q

What is the only anterior pituitary hormone that doesn’t have negative feedback?

A

Prolactin

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71
Q

What are the effects of ACTH on adrenal size?

A

Deficiency - smaller emdulla and cortex

Excess - larger medulla and cortex

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72
Q

What does ACTH regulate?

A

ACTH regulates glucocorticoid synthesis:

•Acutely stimulates cortisol release

•Stimulates corticosteroid synthesis (and capacity)

•CRH stimulates ACTH release

•Negative feedback of cortisol on CRH and ACTH production

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73
Q

How are glucocorticoid levels regulated?

A
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74
Q

What is the diurnal rhythm of circulating cortisol?

A
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75
Q

What is the cortisol circadian rhythm?

A

Released throughout life

Pulsatile

Stimulated by low glucose, exercise, sleep

Suppressed by hyperglycaemia

Effects mediated by GH and IGF1

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76
Q

What is the GH like?

A

Released throughout life

Pulsatile

Stimulated by low glucose, exercise, sleep

Suppressed by hyperglycaemia

Effects mediated by GH and IGF1

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77
Q

What are the actions of the GH?

A

Linear growth in children
•Acquisition of bone mass
•Stimulates:
•protein synthesis
•lipolysis (fat breakdown)
•glucose metabolism
•Regulation of body composition
•Psychological well-being

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78
Q

How are thyroid hormone levels regulated?

A

Negative feedback loop between TSH and thyroxine

In pituitary failure both TSH and thyroxine are low

(in a case of underactive thyroid, where thyroid and not pituitary is problem, thyroxine is low and TSH rises to stimulate thyroid)

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79
Q

What is the female HPG axis?

A
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80
Q

What are the LH/FSH importance?

A

Essential for reproductive cycle
•LH stimulates sex hormone secretion
•FSH stimulates development of follicles
•Absence leads to infertility and hypogonadism

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81
Q

What is the male HPG axis?

A
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82
Q

What is the control of prolactin?

A

Synthesised in lactotrophs
•Regulation of PRL different to other anterior pituitary homones
•Negative regulation by tonic release in inhibiting factor - dopamine

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83
Q

What is the imp of prolactin?

A

Essential for lactation

•Levels increase dramatically in pregnancy and during breast-feeding – do not test at these times

•Inhibits gonadal activity through central suppression of GnRH (and thus decreased LH/FSH)

•Mainly causes disease when present in excess

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84
Q

What is hyperprolactinaemia like physiologically?

A

Physical or psychological stress
•Post seizure
•Greater in women
•Rarely exceeds 850 – 1000 mU/L
•PRL has circadian rhythm with peak during sleep

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85
Q

What are the clinical features of hyperprolactaemia ?

A

Usually easy to recognise in pre-menopausal women
•Less apparent in men & post-menopausal women
•Pre-menopausal women
○Hypogonadism
●Oligo/amennorrhoea
●Oestrogen deficiency
○Galactorrhoea – spontaneous/ expressible
•Post-menopausal women
○Due to hypogonadal status – none of the above

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86
Q

What is the pathology of hyperprolactinaemia?

A

PRL-secreting pituitary tumours – prolactinomas
○Microadenoma (< 1 cm diameter)
○Macroadenoma (≥1 cm diameter)
Loss of inhibitory effect hypothalamic DA
○Pituitary stalk compression/ pituitary disconection
Drugs – DA antagonists
○Phenothiazines, metoclopramide, TCAs, verapamil
Hypothyrodism

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87
Q

What are the diseases of the pituitary?

A

Benign pituitary adenoma
•Craniopharygioma
•Trauma
•Apoplexy / Sheehans
•Sarcoid / TB

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88
Q

What is craniopharyngioma?

A
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89
Q

How does the pituitary develop?

A
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90
Q

What can tumours cause?

A

Tumours cause:
1.Pressure on local structure e.g. optic nerves
●Bitemporal hemianopia
2.Pressure on normal pituitary
●hypopituitarism
3.Functioning tumour
●Prolactinoma
●Acromegaly

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91
Q

What are the local effects of the pituitary tumour?

A

Chiasmatic compression - cranial nerve damage, hypothalamic damage

Bony invasion - pain, CSF leaks

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92
Q

Why may a patient be unaware they have bitemporal hemianopia?

A

Patient can adjust for this by moving head more from side to
side to compensate, may not be aware of deficit

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93
Q

What does excess of pituitary hormones lead to?

A

ACTH – Leads to increased cortisol levels (Cushing’s disease)

•GH – Leads to increased GH and IGF-1 levels (Acromegaly)

•LH or FSH – Very rare! Might stop periods (Gonadotrophinoma)

•TSH – Leads to thyrotoxicosis. Very rare cause!

•Prolactin – Leads to galactorrhoea and amenorrhoea
•(Prolactinoma)

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94
Q

What does excess of pituitary hormones lead to?

A

ACTH – Leads to increased cortisol levels (Cushing’s disease)

•GH – Leads to increased GH and IGF-1 levels (Acromegaly)

•LH or FSH – Very rare! Might stop periods (Gonadotrophinoma)

•TSH – Leads to thyrotoxicosis. Very rare cause!

•Prolactin – Leads to galactorrhoea and amenorrhoea
•(Prolactinoma)

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95
Q

What is prolactin microadenoma?

A
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96
Q

What is prolactin microadenoma?

A
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97
Q

What are prolcatinomas?

A

More common in women
•Present with galactorrhoea / amenorrhoea / infertility
•Loss of libido
•Visual field defect

•Treatment dopamine agonist eg Cabergoline or bromocriptine.

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98
Q

What is an acromegaly?

A

GH excess

•Leads to increased Insulin-like Growth Factor-1 production in the liver

•Both GH and IGF1 increase growth of a range of soft and hard tissues

•>98% due to a pituitary tumour, often large

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99
Q

What are the symptoms of acromegaly?

A

Symptoms:
Sweating
Headaches
Aching (osteoarthritis)
Snoring/sleep apnoea
Those of hypopituitarism

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100
Q

What are the clinical features of acromegaly?

A

Clinical Features:
Leonine facies, broad nose, thick lips
Spade like hands
Increase in ring, hat and shoe size
Skin thickening
Hypertension
Diabetes

101
Q

What are the features of Cushing disease?

A

Fat tissue: Central obesity, moon face, ‘buffalo hump”
Collagen/protein: Thin skin, striae, easy bruising, myopathy, osteoporosis
Androgen excess: Acne, hirsutism, amenorrhoea
Other: Hypertension, depression, diabetes, immunosuppression

102
Q

How is Cushings disease diagnosed?

A

Diagnosed by:
high cortisol production
loss diurnal rhythm of cortisol
loss of negative feedback of glucocorticoids on the pituitary

With pituitary origin ACTH levels will be high or inappropriately normal for the high cortisol levels

ACTH levels will be high in the blood draining from the pituitary

Treatment is by transsphenoidal surgery

103
Q

What are the causes of Cushing’s syndrome?

A
104
Q

What is hypopituitarism?

A

GH deficiency causes reduced linear growth in childhood. Symptoms less obvious in adulthood

•LH/FSH deficiency causes hypogonadism

•ACTH deficiency causes adrenal insufficiency

•TSH deficiency causes hypothyroidism

•Associated with increased morbidity & mortality

105
Q

What are some causes/ Clinical features of hypopituitarism?

A

Common causes:
Pituitary tumours (often non-functioning)
Pituitary surgery / radiotherapy / infarction
Congenital
Moderate-severe Head injuries

Clinical Features:
Depend on hormones deficient
Usual sequence of failure:
GH, LH/FSH, ACTH, TSH +/- AVP

106
Q

Where does the posterior pituitary originate from?

A

Originates from Neuro tissue – large numbers of Glial-type cells

107
Q

What hormones are secreted by the posterior pituitary?

A

Two hormones secreted
–Vasopressin (Antidiuretic hormone – controls water secretion into urine)
•Primarily from supraoptic nuclei
–Oxytocin – expression of milk from the glands of the breasts to the nipples; promotes onset of labour.
•Primarily from paraventricular nuclei

108
Q

What are the chemical characteristics of vasopressin and oxytocin?

A

Arginine vasopressin
- neurohypophyseal binding protein

Oxytocin
- neurophysin 1 - oestrogen stimulated

109
Q

What is the production transport and secretion of vasopressin?

A
110
Q

What is the production transport and secretion of vasopressin?

A
111
Q

How much of the human body is fluid?

A

60% of the human body is fluid
• 70kg man

Extracellular
33% TBW = 14L
- intravascular - 3.5L
- interstitial - 10.5L

Intracellular
- 66% TBW - 28L

Total body water = 42L

112
Q

How is water balance regulated?

A
113
Q

What is the relationship between plasma osmolality,urine osmolality and plasma vasopressin?

A
114
Q

What is the relationship between plasma osmolality,urine osmolality and plasma vasopressin?

A
115
Q

What is the urine concentration in the nephron?

A
116
Q

What is the mechanism of action for vasopressin?

A
  1. Vasopressin binds to membrane
    receptor.
  2. Receptor activates CAMP second
    messenger system.
  3. Cell Inserts AGP2 water pores into
    apical membrane.
  4. Water is absorbed by osmosis into
    the blood.
117
Q

What is vasopressin action in the renal tubule?

A
118
Q

What is the role of aquaporin water channels?

A
119
Q

What is the localisation and function of V1a receptor?

A

Localisation - Vascular smooth muscle
Platelets
Hepatocytes
Myometrium

Function - Vasoconstriction, myocardial hypertrophy
Platelet aggregation
Glycogenolysis
Uterine contraction

120
Q

What is the localisation and function of V1b (V3)?

A

Localisation. - Anterior pituitary
Function - ACTH release

121
Q

What is the localisation and function of receptor V2?

A

Localisation - Basolateral membrane collecting tubule

Function - Insertion of AQP-2 water channels into apical membrane, induction of AQP-2 synthesis

122
Q

What is the localisation and function of receptor V2?

A

Localisation - Basolateral membrane collecting tubule

Function - Insertion of AQP-2 water channels into apical membrane, induction of AQP-2 synthesis

123
Q

How do oamoreceptors and baroreceptors regulate ADH release?

A
124
Q

How do oamoreceptors and baroreceptors regulate ADH release?

A
125
Q

What controls vasopressin release and its actions?

A
126
Q

What other hormones are involved in salt and water physiology?

A

Interplay between AVP and salt and water physiology – other hormones e.g.

Angiotensin
Renin
Aldosterone etc

127
Q

What happens during dehydration?

A
  1. Loss of body water
  2. Increase in plasma osmolality
  3. -> increase in AVP neurone firing
  4. -> release of AVP
  5. -> AVP at V2R
  6. -> water reabsorption

7./5. Restoration of osmolality
and circulating sodium concentration

Or another pathway

  1. Increases in thirst
  2. Increase in fluid intake
128
Q

What is osmolality?

A

Concentration of particles per kilo of fluid

• size of particle not important, number is important - i.e one
molecule of larger protein albumin same effect as Na+

• sodium, potassium, chloride, bicarbonate, urea and glucose
present at high enough concentrations to affect osmolality

• alcohol, methanol, polyethylene glycol or mannitol -
exogenous solutes that may affect osmolality

129
Q

How can plasma osmolality be calculated at the bedside?

A

(2XNa) + glucose + urea
All in mmol/L

130
Q

What is the osmotic control of AVP like?

A

280-285 mmol/kg or 135 mEq of sodium per litre
Secretion stopped when below 135 mEq
Increase in EC fluid - increase in AVP release

131
Q

What is the relationship of plasma AVP concentration and urine concentration?

A

Increase in AVP = increase in urine osmolality

More thirst - more plasma osmolality - more AVP - more urine concentration

132
Q

When is there a loss in relationship between plasma osmolality and vasopressin?

A

Drinking rapidly suppresses vasopressin release and thirst.

•In pregnancy osmotic threshold for VP release and thirst is decreased.

•Plasma VP concentrations increase with age (also thirst blunting, decreased renal concentrating ability, decreased fluid intake).

133
Q

What is vasopressin deficiency/ resistance like?

A

Literally - insipid tasting urine

Large volumes of urine - polyuria
Large volumes of drinking - polydypsia
No glycosuria?

Vasopressin Deficiency – Cranial
lack of vasopressin (ADH)

Vasopressin Resistance – Nephrogenic
resistance to vasopressin

134
Q

What is normal urine volume, concentration and plasma osmolality?

A

800-2000 millilitres - 0.8-2L
Les than 300 mOsm/Kg?
285-295 mmol/L

135
Q

What is normonatraemia and hypernatraemia?

A

normonatraemia - normal plasma sodium concentration
- 135-145 mEq/L
hypernatraemia - high conc of sodium in blood

136
Q

What is glycosuria, hypercalcaemia or hypokalaemia?

A

Glycosuria - glucose or sugar in urine (caused by diabetes)

Hypercalcaemia - high calcium levels in blood

Hypokalaemia - deficiency of potassium in bloodstream

137
Q

What is glycosuria, hypercalcaemia or hypokalaemia?

A

Glycosuria - glucose or sugar in urine (caused by diabetes)

Hypercalcaemia - high calcium levels in blood

Hypokalaemia - deficiency of potassium in bloodstream

138
Q

What is polyuria and polydypsia?

A

Polyuria - Body makes too much urine - pee a lot
Polydypsia - excessive thirst - reaction to fluid loss in body

139
Q

What are the causes of AVP deficiency?

A

Destruction of hypothalamus

•Interruption of the connection
of hypothalamus to pituitary

140
Q

How can AVP deficiency be acquired vs familia?

A

Acquired

•Idiopathic
•Tumours - craniopharyngioma, germinoma, metastases
•Trauma
•Infections - TB
•Vascular - neurosarcoidosis, Langerhans’s histiocytosis
•Granuloma

Familial - very rare -
mutations in the neurophysin part of pro-AVP

•Autosomal dominant
•Rarely autosomal recessive

141
Q

How is AVP-R - (AVP- resistance) acquired vs familial?

A

Acquired
- osmotic diuresis (diabetes mellitus)
- drugs (lithium, demeclocycline, tetracycline)
- chronic renal failure
- post-obstructive uropathy
- metabolic (hypercalcaemia, hypokalaemia)
- infiltrative (amyloid)

Familial:
- x-linked (V2 receptor defect)
- autosomal recessive (aquaporin 2 defect)

142
Q

What is the investigation of AVP - D/R(VD/VR)?

A

VD = Water deprivation test
VD/VR - hypertonic saline stimulation test

How?

143
Q

What is the management of AVP-D?

A

treat any underlying condition

• desmopressin
•tablets 100-600 micrograms/day
•nasal spray 10-20 micrograms/day
•injection 1-2 micrograms/day

144
Q

What is the management of AVP-R?

A

try and avoid precipitating drugs

• congenital DI - very difficult
• free access to water
• very high dose desmopressin
• hydrochlorothiazide or indomethacin

145
Q

What is SIADH - syndrome of antidiuretic hormone secretion?

A

Common in clinical practice

• Too much AVP, when it should not be being secreted
• Causes low blood concentration - low osmolality
• Urine is inappropriately concentrated
• Plasma sodium is low
• Euvolaemia

146
Q

What are the essential criteria for the diagnosis of SIADH?

A

Hyponatraemia < 135 mmol/L
•Plasma hypo-osmolality < 275 mOsm/Kg
•Urine osmolality > 100 mOsm/Kg
•Clinical euvolaemia
•No clinical signs of hypovolaemia (orthostatic decreases in blood pressure, tachycardia, decreased skin turgor, dry mucous membranes)
•No clinical signs of hypervolaemia (oedema, ascites)
•Increased urinary sodium excretion > 30 mmol/L with normal salt and water intake
•Exclude recent diuretic use, renal disease, hypothyroidism, and hypocortisolism

147
Q

What is the plasma AVP levels in SIADH?

A

Inappropriately elevated in most

148
Q

Causes of SIADH?

A

CNS disorders
Resp causes
Tumours
Drugs
Long list…

149
Q

How is SIADH managed?

A

treat underlying condition
•fluid restriction <1L/24 hour

•sometimes demeclocycline

•‘Vaptans’ – V2 receptor antagonists

•if Na+ low AND fitting hypertonic N/Saline on ITU

•<12mmol/l increase in Na+ per 24 hour

•Potential risk of central pontine myelinolysis

150
Q

How is SIADH managed?

A

treat underlying condition
•fluid restriction <1L/24 hour

•sometimes demeclocycline

•‘Vaptans’ – V2 receptor antagonists

•if Na+ low AND fitting hypertonic N/Saline on ITU

•<12mmol/l increase in Na+ per 24 hour

•Potential risk of central pontine myelinolysis

151
Q

What is the Treatment of Hyponatraemia secondary to SIADH?

A

Hyponatraemia -> acute (24-48hrs) -> 3% saline if symptomatic; if asymptomatic fluid restriction

-> slow onset (more than 48hrs) -> mild/severe symptoms

Mild/asymptomatic: fluid restriction and vaptans
Severe symptoms - 3% saline

152
Q

What should you remember when treating Hyponatraemia?

A

Hypertonic saline should raise sodium by 1 to 2 mmol/l/hour; monitor sodium every 2 hours

•Hypertonic saline should be stopped when asymptomatic or serum sodium >120mmol/l

•One should increase sodium around 8 – 12 mmol/l in 24 hours or 16 – 24 mmol/l in 48 hours to avoid osmotic demyelination

•Aim for a safe range as opposed to a normal range

153
Q

What is oxytocin?

A

release stimulated by milk suckling
• Action
– stimulates milk let down
– stimulates contraction of myometrium (100X more potent that AVP)
– 200X less active at the V2 receptor compared to AVP

154
Q

How does oxytocin act?

A
155
Q

What is the posterior pituitary directly connected to?

A

Hypothalamus

156
Q

What are hormones transported down?

A

Hormones transported down nerve axons

157
Q

What does Vasopressin cause?

A

Vasopressin (ADH) causes antidiuresis - water reabsorption in DCT and CD

158
Q

Is AVP and ADH the same?

A

Yesss

159
Q

What causes AVP-D and R?

A

AVP-D results from lack of ADH and AVP-R resistance to ADH

160
Q

What is a common disorder of the posterior pit?

A

SIADH is common

161
Q

What are the functions of the adrenal gland?

A

Endocrine physio -
Histology -
Pathology -
Cardio physio -
Renal -
Pharmacology/ therapeutics -

162
Q

What is the anatomy of the adrenal gland?

A

Outer = right and left - on top of kidneys and separated by…
Inside = Cortex and medulla

163
Q

What is the histological zonation of the adrenal?

A

Outer capsule: mineralocorticoids - aldosterone
Zona glomerulosa

Cortex: glucorticoids - cortisol
Androgens - DHEA, androstenedione
Zona fasciulata

Medulla: catecholamine synthesis
Zona reticularis

Corticosteroid synthesis in all areas!

164
Q

What is the adrenal of the neonate?

A
165
Q

How does the fetal vs adult adrenal differ?

A

Fetal:
Capsul
Definitive zone
Transitional zone
Fetal zone
Developing medulla

Adult:
Capsul
Zona glomerulosa
Zona fasiculata
Zona reticularis
Medulla

166
Q

How does the adrenal develop?

A

Prenatal life Adrenal

  1. Urogenital ridge - 4 weeks
  2. Adrenogonadal primordium - 8 weeks
  3. Adrenal primordium
  4. Fetal adrenal - 9 weeks/ 24/28 weeks - medulla, DZ and FZ

Birth

Postnatal life:

  1. Adrenal - 6 months - ZG/ZF
  2. Adrenal from 2-3 yrs ZG/ZF/ZR islets
  3. Adrenal after adrenache 6-8 years - ZG/ZF/ZR
167
Q

What is the structure of corticosteroids?

A

Cholesterol precursor for all adrenal steroidogenesis
cyclopentanoperhydrophenanthrene structure
three cyclohexane rings (A, B, and C)
single cyclopentane ring (D)

168
Q

How is cortisol made? (+structure)

A
169
Q

What are corticosteroids like?

A

Lipid soluble - can pass through biological membranes
●Bind to specific intracellular receptors
●Alter gene transcription directly or indirectly
●Exact action depends on structure, ability to bind specific receptors (and recruit cofactors)

170
Q

What is the action of glucocorticoid?

A
171
Q

What are the classifications of steroids?

A
  1. Pregnane derivatives
    21 carbons e.g. Progesterone, Corticoids
  2. Androstane derivatives
    19 carbons e.g. Androgens
  3. Estrane derivatives
    18 carbons e.g. Oestrogens

Small structural modifications can substantially alter specificity for steroid receptors

172
Q

How is aldosterone made?

A

Cholesterol -(StAR/CYP11A1)—> Pregnenolone
-(HSD3B2)—> Progesterone —(CYP21A2)->
11-deoxy-corticosterone —CYP11B2/CYP11B2–>
Corticosterone —(CYP11B2)—> Aldosterone -> MR

Zona mineralcorticoids - salt - made here

173
Q

How is cortisol made?

A

2 pathways:

  1. Cholesterol -(StAR/CYP11A1)—> Pregnenolone
    —(CYP17A1)-> 17-hydroxypregenolone
    —(HSD3B2)—> 17-hydroxyprogesterone —(CYP21A2)->
    11-deoxy-cortisol —(CYP11B1)—> cortisol
  2. Cholesterol -(StAR/CYP11A1)—> Pregnenolone
    -(HSD3B2)—> Progesterone -(CYP17A1)—>
    17-hydroxy-progesterone —(CYP21A2)—>
    11-deoxy-cortisol —(CYP11B1)—> cortisol

Made in Zona Fasciulata - glucocorticoids - sugar, stress

174
Q

How are androgens made?

A

Two pathways:

  1. Cholesterol -(StAR/CYP11A1)—> Pregnenolone
    —(CYP17A1)-> 17-hydroxypregenolone —(CYP17A1)->
    DHEA —(HSD3B2)-> Androsteronedione —(HSD17B)->
    Testosterone —> AR
  2. Cholesterol -(StAR/CYP11A1)—> Pregnenolone
    -(HSD3B2)—> Progesterone -(CYP17A1)—>
    17-hydroxy-progesterone —(CYP17A1) —>
    Androstenedione —(HSD17B)—> Testosterone -> AR

Made in the Zona reticularis - androgens - sex

175
Q

What is the importance of ACTH for corticosteroids synthesis?

A
176
Q

What is the effect of ACTH on adrenal size?

A

Deficiency - smaller cortex and medulla (adrenal)
Excess - larger

177
Q

What do glucocorticoids do?

A

Actions
Transport
Regulation

178
Q

What are glucocorticoids steroids like?

A

Synthesised in zona fasciculata and reticularis
•Essential to life
•Have actions on most tissues
•Many actions “permissive” (do not directly initiate but allow to occur in presence of other factors), e.g. the effects of catecholamines on vascular tone
•“Permissive” actions only apparent with deficiency
•Important in homeostasis e.g. conditioning body’s response to stress

179
Q

What are the effects of glucocorticoid steroids on body tissues and systems?

A
  1. Brain/CNS:
    - Depression
    - Psychosis
  2. Carbohydrate/lipid metabolism:
    ­ - hepatic glycogen deposition
    ­ - peripheral insulin resistance
    ­ - gluconeogenesis
  3. Eye:
    - Glaucoma
  4. Endocrine system:
    ¯ LH, FSH release
    ¯ TSH release
  5. GI tract:
    Peptic ulcerations
  6. Adipose tissue distribution:
    - Promotes visceral obesity
  7. Cardiovascular/Renal:
    - Salt and water retention
    - Hypertension
  8. Skin/muscle/connective tissue:
    - Protein catabolism/collagen breakdown
    - Skin thinning
    - Muscular atrophy
  9. Bone and calcium metabolism:
    ¯ bone formation
    ¯ bone mass and osteoporosis
  10. Growth and Development:
    ¯ linear growth
  11. Immune system:
    - Anti-inflammatory action
    - Immunosuppression
180
Q

What are the actions of glucocorticoids?

A

Increase glucose mobilisation
Augment gluconeogenesis
Amino acid generation
Increased lipolysis

Important during “stress”
Maintenance of circulation
Vascular tone
Salt and water balance

Immunomodulation
Dampen immune response

Important during stress

181
Q

How are glucocorticoids transported?

A

In the circulation glucocorticoids are heavily bound to proteins
–90% bound to Corticosteroid-Binding Globulin (CBG)
–5% bound to albumin
–5% “free”
•Only “free” glucocorticoids bioavailable
•In clinical practice “total” rather than “free”

182
Q

What is cortisol binding like in non-stressed state and also in sepsis?

A
183
Q

How is glucocorticoid synthesis regulated?

A

ACTH (and CRH) action
Diurnal rhythm
Stress
Illness

184
Q

How does ACTH regulate glucocorticoid synthesis?

A

ACTH regulates glucocorticoid synthesis:

•Acutely stimulates cortisol release

•Stimulates corticosteroid synthesis (and capacity)

•CRH stimulates ACTH release

•Negative feedback of cortisol on CRH and ACTH production

185
Q

How is MC2R and the MCR involved?

A

Protein folding & translocation across ER
•Escorting MC2R to cell surface
•Stabilising of MC2R at cell surface
•Ligand specificity

In Zona fasiculata across to nucleus

186
Q

What is stress?

A

The sum of the bodies responses to adverse stimuli”

187
Q

What are the causes/effects of stress?

A

• Infection
• Trauma
• Haemorrhage
• Medical illness
• Psychological
• Exercise/exhaustion

188
Q

What are the effects of surgery on cortisol levels?

A

Serum cortisol increases initially after surgery
Returns to lower levels due to loss of diurnal variation
Returns to normal levels when diurnal rhythm returns

189
Q

What are the effects of sepsis and multiple trauma on serum cortisol levels?

A

Increases exponentially X5/6 as much a s normal levels
- fluctuate slightly - criss crossing

190
Q

What is the normal HPA-Axis function?

A
191
Q

What is the HPA- Axis function during acute illness?

A
192
Q

What are mineralcorticoids?

A

Synthesised in zona glomerulosa
Aldosterone synthase present in this region
•Main mineralocorticoids are aldosterone and DOC
•DOC has 3% mineralocorticoid activity of aldosterone
•Essential to life
•Critical to salt and water balance in
–Kidney
–Colon
–Pancreas
–Salivary glands
–Sweat glands

193
Q

Where is the site of aldosterone action?

A

Kidney - DCT and CDs

194
Q

What is the cause of endocrine salt loss?

A

Plasma: sodium low, potassium high
Urine: sodium high, potassium low

195
Q

What are the primary adrenal insufficiency?

A
  • CAH
    -Aldosterone synthase deficiency
    -inborn AI
  • autoimmune AI
  • X-linked adrenoleukodystrophy
196
Q

What is not in secondary adrenal insufficiency?

A
197
Q

What are end organ resistances that cause endocrine salt loss?

A

-mineralocorticoid receptor defects
- ENaC defects
- Other deficiencies in the collecting tubule pathway

198
Q

What is the role and structure of the juxtaglomerular apparatus?

A
199
Q

What occurs in RAAS? And role of renin? CHECK

A

Liver -> angiotensinogen (renin from kidneys acts here)
-> Angiotesnin 1
-> lungs (ACE)
-> angiotensin 2
-> adrenal glands ()
-> aldosterone
-> kidney - ANP/Dopamine act on kidney? Results in: - EC volumes, renal blood presssure, Na+ (water) retention, K+ excretion
Leads to -> Decrease in ECF (K+) (goes back to adrenal glands-full circle)

Decrease in renal blood pressure, B-adrenergic action and prostaglandins trigger renin to release from kidney?

200
Q

What are the other actions of mineralcorticoids?

A

Effects on pancreas
•Sweat glands
•Salivary glands —> sodium reabsorption (decreased Na+)
•Colon

Non-classical effects:
- myocardial collagen production
- role in cardiac fibrosis/remodelling

201
Q

What is the specificity of mineralcorticoids receptors?

A

MR - aldosterone And MR - cortisol ——> gene transcription, Apical Na channel, Na/KATPase

202
Q

Why isn’t the MR swamped by cortisol?

A

MR trans activation in pre-receptor regulation of kidney

F-cortisol/E-cortisol - 11B-HSD2?

AME, liquorice ingestion

203
Q

What are adrenal androgens?

A

Weak androgens generated in adrenal gland
•Dehydroepiandrosterone (DHEA) most abundant adrenal steroid but very weak androgen
•Androstenedione more androgenic but only 1/10th that of testosterone
•Major source of androgens in women
•Oestrogen precursors in postmenopausal women
•Production regulated by ACTH rather than gonadotrophins

204
Q

What occurs in adrenal steroid genesis?

A
205
Q

What is the adrenal medulla like?

A

Part of autonomic nervous system
•Specialised ganglia supplied by sympathetic preganglionic neurones (ACh as transmitter)
•Synthesises catecholamines
•Main site for adrenaline synthesis
•(Phenylethanolamine-N-methyl transferase present)
•Not essential for life

206
Q

What occurs in catecholamine synthesis?

A

Tyrosine -(tyrosine hydroxylase)—> DOPA
(L-Dopa decarboxylase)—-> dopamine
(Dopamine B-hydroxylase)—> noradrenaline (Phenylethanolamine N-methytransferase)—> adrenaline

Cortisol induction at thyroxine hydroxylase and Phenyl etc
sympathetic stimulation at tyrosine hydroxylase and dopamine b-hydroxylase

207
Q

What is catecholamine synthesis like?

A

Relative production of catecholamines
80% adrenaline, 20% noradrenaline
Dopamine in small amounts
•Normal catecholamine synthesis dependent on high local cortisol levels (permissive effect)

208
Q

When are catecholamines released?

A

•Catecholamines released during “flight or fight”
–­gluconeogenesis in liver and muscle
–­lipolysis in adipose tissue
–Tachycardia and ­ cardiac contractility

209
Q

What occurs in adrenal cortex synthesis?

A

Glucocorticoids, mineralocorticoids, androgens
Regulation of each is distinct (ACTH, ATII etc.)

For glucocorticoids and mineralocorticoids
negative feedback important

210
Q

What occurs in adrenal medulla synthesis?

A

Catecholamines (mostly adrenaline)
Under sympathetic control

211
Q

What is trophies, diurnal variation, permissive actions?

A
212
Q

What structures is the thyroid gland related to?

A

Investing fascia
Pretracheal fascia
• Anterior jugular vein
Sternocleidomastoid
Sternohyoid
- Sternothyroid
Omohyoid - External jugular
vein Carotid sheath (containing common carotid artery, internal jugular vein, and vagus nerve) with
sympathetic chain behind
Pre-vertebral fascia

213
Q

What is the blood supply of the thyroid gland?

A

External carotid artery
Superior thyroid artery
Internal jugular vein
Middle thyroid vein
Inferior thyroid artery
Thyrocervical trunk
Subclavian artery
Inferior thyroid vein
Left brachiocephalic (innominate) vein

214
Q

What is the decent of the thyroid gland like during development?

A

Lingual thyroid Suprahyoid thyroglossal
cyst •Track of thyroid descent and of a
thyroglossal fistula
Thyroglossal cyst or ectopic thyroid
Pyramidal lobe
Retrosternal goitre

Possible sites of
ectopic thyroid tissue, thyroglossal cysts and pyramidal lobe

215
Q

What is the thyroid glands anatomy?

A

Located in neck
•Brownish-red
•25-30 g
•Thin fibrous capsule of connective tissue
•Right and left lobes united by a narrow isthmus

216
Q

What is the thyroid glands anatomy?

A

Located in neck
•Brownish-red
•25-30 g
•Thin fibrous capsule of connective tissue
•Right and left lobes united by a narrow isthmus

217
Q

What are the cell types in the thyroid gland?

A

C-cell
Colloid
Thyroid epithelial/follicular cell -> follicle

218
Q

What is the role of the thyroid hormone?

A

Control of metabolism:
energy generation and use

●Regulation of growth

●Multiple roles in development

219
Q

What controls thrypoid hormone secretion?

A

Hypothalamus-> pituitary -> thyroid -> target tissue

TR, TS,T3/4

220
Q

How is the thyroid hormone synthesised?

A
  1. TSH bonds to TSHR on the base lateral membrane (where?)
  2. I- uptake by NIS - Na/I symporter
  3. Iodination of Tg tyrosyl residues by TPO (thyro-peroxidase)
  4. Coupling of iodotyrosol residues by TPO (on apical membrane)
  5. Export of mature Tg to colloid where it is stored

Thyroglobulins?

221
Q

Give an example of thyroid hormone synthesis

A

Thyroglobulin, tyrosine -(thyroid peroxidase)—>
Diiodotyrosine (TPO)—-> Thyroxine

222
Q

What are the key steps for a thyroid hormone?

A
223
Q

What are thyroid hormones like?

A

T3 is biologically active hormone
•Produced by mono-deiodination of T4 which most abundant
•Deiodinase (D1, D2, D3) enzymes in peripheral tissues

224
Q

Describe thyroid hormone synthesis?

A

Produced by follicular thyroid cells
•Synthesised from the thyroglobulin precursor
•Iodine is absorbed from bloodstream and concentrated in follicles
•Thyroperoxidase binds iodine to tyrosine residues in thyroglobulin molecules to form MIT + DIT
•MIT + DIT = T3
•DIT + DIT = T4

225
Q

What are the thyroid hormone binding proteins?

A

T4 —deiodination—-> T3

T4 - TBG, transthyretin, albumin

T3 - TBG, trasnthyretin and albumin

TBG = thyroxine binding globulin

Free T4 = 0.03%
Free T3 = 0.3%

226
Q

How is the thyroid hormone transported in the CNS?

A

In/through blood brain barrier
Uses astrocyte
T3 responsive gene

D2/3

MCT8
OATP1C1

227
Q

What are the tests for thyroid function?

A

Serum TSH
Serum free T4
Serum free T3

Hyperthyroidism:

Decreased TSH
Increased Serum free T4
Increased serum free T3

228
Q

What do tests show for hypothyroidism?

A

Increased serum TSH
Decreased serum free T4
Decreased serum free T3

229
Q

Prevelance of thyroid disease? Necessary?

A
230
Q

What are the signs and symptoms of hyperthyroidism?

A

Cardiovascular
●Tachycardia (rapid heart rate)
●AF (atrial fibrillation)
●Shortness of breath
●Ankle swelling

Neurological
●Tremor
●Myopathy (muscle weakness)
●Anxiety

Gastrointestinal
●Weight loss
●Diarrhoea
●Increased appetite

Eyes/skin
●Sore, gritty eyes
●Double vision
●Staring eyes
●Pruritus (itching)

231
Q

What is the aetiology of hyperthyroidism?

A

●Aetiology:
- Graves’ hyperthyroidism
- Toxic nodular goitre (single or multinodular)
- Thyroiditis (silent, subacute): inflammation
- Exogenous iodine
- Factitious (taking excess thyroid hormone)
- TSH secreting pituitary adenoma
- Neonatal hyperthyroidism

232
Q

What is the aetiology of hypothyroidism?

A

●Aetiology:
•Autoimmune – Hashimoto’s thyroiditis (TPO and Tg antibodies - genetic predisposition)
•After treatment for hyperthyroidism
•Subacute/silent thyroiditis
•Iodine deficiency
•Congenital (thyroid agenesis/enzyme defects)

233
Q

What are the signs and symptoms of hypothyroidism?

A

Cardiovascular
●Bradycardia (slow heart rate)
●Heart failure
●Pericardial effusion
Gastrointestinal
●Weight gain
●Constipation

Skin
●Myxoedema
●Erythema ab igne
●Vitiligo

Neurological
●Depression
●Psychosis
●Carpal tunnel syndrome

234
Q

What is the structure of the parathyroid gland?

A

Thyroid
Cricoid cartilage
Superior parathyroid gland
Inferior thyroid artery entering posterior capsule
Inferior parathyroid gland

Trachea
Oesophagus
Recurrent laryngeal nerve

235
Q

What are the functions of the parathyroid gland?

A

Regulate calcium and
phosphate levels

Secrete parathyroid hormone
(PTH) in response to:
Low calcium or
High phosphate

Actions of PTH:
Increases calcium reabsorption in renal distal tubule
Increases intestinal calcium absorption (via activation of vitamin D)
Increases calcium release from bone (stimulates osteoclast activity)

Decrease phosphate reabsorption

236
Q

What do bone and calcium homeostasis involve?

A
  1. Protect vital organs
  2. Support muscles
  3. Reservoir of calcium
  4. Excitable tissue
  5. Muscle/nerves
  6. Cell adhesion
237
Q

What hormones are involved in bone and calcium homeostasis?

A

Bone turnover and soluble calcium overlap

> 99% Steroid hormones, calcitonin and PTH, Vitamin D <1%

238
Q

What do bone and calcium homeostasis involve?

A

Endocrine control of extracellular calcium homeostasis
•Parathyroid hormone
•Vitamin D
•Calcitonin, FGF23

Bone and control of bone homeostasis
•Mineral phase (Calcium/phosphate)
•Protein phase (Collagen and non-collagenous proteins)
•Bone cells
•Bone ‘turnover’ and remodelling units

Bone diseases
•Hyperparathyroidism
•Osteomalacia andosteoporosis

239
Q

What is the calcium in blood like?

A

50% of serum calcium ‘free’ (ionised)
50% bound to albumin (so cannot diffuse into cells)

240
Q

What hormones act/affect serum calcium?

A

GI tract - vitamin D
Kidney - PTH,vit d, FGF23
Bone - PTH, vit d

241
Q

Where does calcium like in the body?

A

Bone (1kg) <-0.5g/day
-> 0.5g/day to serum Ca2+

Serum Ca2+

Intestine - (1.0g/day in)
-> 0.2g/day serum Ca2+
-> 0.8g/day out

Kidney Ca2+
-> to serum Ca2+ 9.8g/day
-> from serum Ca2+ 10g/day
-> Ca2+ 0.2g/day urinary excretion

242
Q

What increases serum calcium?

A

Hypocalcaemia -> parathyroid glands
Increases PTH secretion
-> bone - increases bone resorption
-> kidney - increases urinary phosphate, decreases urinary calcium, increases 1,25D3 production (acts on bone and intestine)
-> intestine - increases calcium absorption, increases phosphate absorption

Actions all tend to increase serum calcium

243
Q

How does -ve feedback affect hypocalcemia?

A

After all actions, an increase in serum calcium reaches pparathyroid glands

244
Q

How does -ve feedback affect hypocalcemia?

A

After all actions, an increase in serum calcium reaches pparathyroid glands

245
Q

What is the parathyroid hormone like?

A

84 amino acid peptide but biological activity in first 34 amino acids (PTH 1-34), half-life 8 mins
•Cleaved to smaller peptides
•Assayed by two site assay (to avoid detecting fragments)
•Still detects some inactive fragments e.g. in renal failure
•Normal adult reference range = 1.6 - 6.9 pmol/L

246
Q

What is the action of the PTH in kidney?

A

In kidney:
PTH increases distal tubular reabsorption of calcium
(+ inhibition of PO4 reabsorption)
PTH also stimulates production of the active form of vitamin D, 1,25(OH)2D

PTH enhances bone resorption by stimulating osteoclasts

Negative feedback:
PTH transcription (mRNA production) is inhibited by 1,25D3

PTH translation (mRNA to protein synthesis) is inhibited by increased serum calcium

247
Q

What are the levels of hyperparathyroidism?

A

Raised serum PTH
•Primary HPT
–parathyroid tumour (usually benign adenoma)
–Causes hypercalcaemia and low serum phosphate
–Loss of negative feedback from hypercalcaemia
–(Treatment is surgery)

•Secondary HPT
–renal disease (increased phosphate, decreased activation of vitamin D)
–(Treatment with phosphate binders or vitamin D analogues)

•Tertiary HPT
– long-standing secondary HPT leads to irreversible parathyroid hyperplasia. Usually seen when renal disease corrected e.g. by transplantation
–(Treatment is surgery)

248
Q

What is calcitonin like?

A

Produced by thyroid c-cells (parafollicular)
•Calcitonin released in hypercalcaemia, inhibits bone resorption (by direct effect on osteoclasts)
•Not essential to life (post thyroidectomy no calcium problems)
•Two calcitonin genes products from a single gene and primary RNA transcript

249
Q

What is the prevalence of hyperthyroidism, hypoparathyroidism and hyperparathyroidism in males and females?

A

Females - 20/1000
Males - 2/1000

Hypoparathyroidism - 40/1000 females

Hyperparathyroidism - 1 to 4 per 1000 in general population In UK

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