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YEAR 2 SEMESTER 2 > ENDOCRINOLOGY WEEK 1 > Flashcards

ENDOCRINOLOGY WEEK 1 Flashcards

1
Q

what are the 4 categories of hormone and give a brief description

A
  • Circulating factors which act on remote target organs
  • Endocrine
    o Source organ goes into blood and effects target tissues
  • Paracrine
    o Acts on cells in its own neighbourhood
  • Autocrine
    o Acts back on its own cells – turning off or on
  • neurotransmitters
    o peptides – adrenaline, dopamine working on synaptic cleft in brain
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2
Q

what are the main endocrine glands and what hormones do they release

A 
-	thyroid
o	thyroxine, calcitonin
-	adrenal cortex
o	cortisol, aldosterone, DHE
-	adrenal medulla
o	adrenaline, noradrenaline
-	ovary
o	oestrogen, inhibin
-	testis
o	testosterone
-	pancreas
o	insulin, glucagon
-	parathyroid
o	PTH
-	pituitary
o	ACTH, LH, FSH, GH, PRL, TSH, AVP
-	most other organs make or metabolise hormones too
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3
Q

adipose tissue - what hormones does it make and what are their effects

A
  • makes leptin, adiponectin, resistin, TNFa, IL6, cortisol, angiotensinogen, PAI-1
  • supposed to signal from fat to brain but in obesity become resistant to leptin telling brain to stop eating
  • fat generating cortisol
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4
Q

give examples of the 3 types of hormone

A

Peptides from gene products
- growth hormones, insulin, thyroxine

Amines from modified Amino acids
- adrenaline, noradrenaline

Steroids from cholesterol
- oestrogen, androgen, glucocorticoids, vitamin D

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5
Q

what are the types of receptors and give a brief description

A

Peptide and amine receptors

  • surface receptors
  • second messengers
  • multiple cellular effects

Steroids and thyroid hormones receptors

  • nuclear receptors
  • vis transcription/ translation
  • many target genes
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6
Q

what are the 3 main control centres of hormones

A

Brain (hypothalamus) -> pituitary hormones released -> glands (thyroid, adrenals, ovaries/testis) this feeds back on pituitary

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7
Q

what are the symptoms of loss of testosterone before puberty

A
  • someone who’s never gone through puberty
  • no testosterone produced
  • small penis and balls
  • feminine body shape
  • long arms and legs because these limbs require testosterone to stop growing
  • genetic disturbance
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8
Q

what are the symptoms of loss of testosterone after puberty

A
  • pituitary problem

- testicular control disappeared as an adult

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9
Q

what are the symptoms of XXY chromosome complement

A
  • small testes
  • breast enlargement
  • extra x chromosome
  • testosterone production failed halfway through puberty
  • phenotypic female
  • genetically 46 XY
  • because she has no receptors for testosterone
  • so with no sex hormones morphology is female
  • you need testosterone to masculise form and function
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10
Q

pituitary tumours effects

A
  • small pituitary tumour very common
  • 10-20% never cause illness
  • If the tumour bulges into optic chiasm it causes bitemporal hemianopia
    o Loss of outer field (temporal field) vision
    o Patients bump into things as they can’t see out laterally
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11
Q

acromegaly - how does it manifest and what is it and

A

Acromegaly is a disorder that results from excess growth hormone (GH) after the growth plates have closed. The initial symptom is typically enlargement of the hands and feet. There may also be an enlargement of the forehead, jaw, and nose.

  • A disorder that develops over many years
  • Takes time to manifest
  • Testosterone/ puberty is relevant
  • Average time of diabetes/ obesity/ high blood pressure to be reported in Cushing’s disease is 2 years
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12
Q

what’s growth hormone and how is it regulated

A
  • Pituitary peptide
  • Acromegaly in adults
  • Gigantism in children
    Regulated
  • Growth hormone releasing hormone (GHRH) released from hypothalamus
  • Stimulates pituitary to directly produce GH
  • Which then has complex cascade of control through receptor coupled with g protein
  • Drives the synthesis of GH in pituitary cell
  • GH acts on the liver, muscles and other tissues
  • Liver produces insulin and IGF1
  • 1GF1 feedbacks on the hypothalamus to inhibit GH production
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13
Q

what are reasons for growth hormones excess

A 
Genetic 
-	Mutations in Gsa (gs alpha) inside the growth hormone producing cell  
Immune
-	Antibodies stimulating GH
Tumours
-	Pituitary
-	Or tumours producing IGF1 or IGF2 from any cancer
Overstimulation
-	GHRH hypersecretion from typically benign tumours
Downstream path
-	IGF1 tumours 
Factitious/ iatrogenic 
-	Body builders/ athletes
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14
Q

what are causes of hormone deficiency

A
  • Genetic/ developmental failure
    o Thyroid synthetic enzyme defects
-	Autoimmune
o	Common
o	Antibodies destroy thyroid when immune system is activated by a virus
o	Failure of immune tolerance
o	Eg Hashimotos
  • Tumours/ infiltrations
    o Rarely infiltrate thyrois
  • Iatrogenic
    o Overuse of treatment
    o Carbimazole, radioiodine
  • Surgery
    o Thyroidectomy
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15
Q

what are 2 reasons for target organ resistance

A
  • Pre-receptor defects
    o Monodeiodinase defects
  • Receptor mutations
    o Thyroid resistance syndrome
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16
Q

replacement monitoring of thyroid hormone

A
  • Thyroid hormone feeds back on hypothalamus and pituitary
  • You can measure TSH
  • Thyroid hormone and TSH are stable
  • So if you want to know if you’re giving the right amount of therapy you can measure TSH
    o If it’s high not giving enough thyroid hormone
    o If it’s low give less
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17
Q

endocrine vs exocrine glands

A

ENDOCRINE GLANDS

  • Do not have ducts
  • Products secreted directly into blood
  • Eg pituitary, thyroid, adrenal, parathyroid glands, gonads (testis and ovaries)

EXOCRINE GLANDS

  • Products secreted via ducts to epithelial surfaces inside or outside the brain
  • Eg sweat, salivary, mucus, mammary, gastric, prostate gland, lover bile ducts
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18
Q

explain paracrine, autocrine and intracrine signalling

A 
PARACRINE (LOCAL) SIGNALLING
-	Hormone diffuses through tissue
-	To receptors on ‘target’ cells
AUTOCRINE (LOCAL) SIGNALLING
-	Hormone diffuses through tissue fluids
-	To receptors on the same cell
INTRACRINE
-	Inactive prohormone enters a cell
-	Activated intracellularly
-	Eg (sex steroids)
o	Eg oestrogen so that post-menopausal endometrium isn’t exposed to lots of oestrogen
o	Except this happens in steroid hormone replacement which is why there’s increased risk of cancer with it
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19
Q

what’s the composition and general mechanisms of the 3 types of hormones

A

Peptide

  • Water soluble – circulate in blood
  • Bind to cell surface receptors
  • GPCRs or receptor kinases

Amine

  • Transported on plasma ‘carrier’ proteins
  • Bind to cell surface receptors
  • GPCRs or receptor kinases

Steroid

  • Cholesterol backbone
  • Transported on plasma ‘carrier’ proteins
  • Lipid soluble – bind to intracellular receptors
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20
Q

what’s the actions of peptides and amides

A
  • Hypothalamic-releasing hormones
  • Pituitary ‘trophic’ hormones
  • Target organ peptide hormones
  • Quick acting
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21
Q

what’s the actions of steroid hormones

A
  • Hormone binds to receptor
  • Hormone-receptor complex enters nucleus
  • Complex binds to receptor sites on chromatin, activating mRNA transcription
  • mRNA leaves nucleus
  • ribosomes translate mRNA into new protein
  • takes 24-48 hrs
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22
Q

circadian biological clock in relation to hormones

A
  • suprachiasmatic nucleus (SCN0 rhythm generator controls daily endocrine system cycles (entrained by daily light and dark cycle)
  • cortisol stimulated by light which wakes you up
  • hormones peak in the morning and lower in the evening
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23
Q

hypothalamus where’s it located and whats it’s associations

A

HYPOTHALAMUS

  • neuoendocrine component of the NS within the brain
  • located at the base of the brain
  • linked via the pituitary stalk to the pituitary gland outside the brain
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24
Q

pituitary gland - what are the 2 parts and how are these differentiated

A
  • 2 glands in one
  • Anterior and posterior pituitary have different embryological origins
  • Anterior pituitary
    o Blood supply from median eminence
  • Posterior pituitary
    o Innervated by hypothalamic access
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25
Q

hypothalamus cns inputs

A
  • Stimuli from somatic and visceral sense organs
  • Transmitted via sensor and motor neurons from the forebrain and mid brain
  • Produce ‘stimulatory’ or ‘inhibitory’ neurotransmitters
    o Dopamine, adrenaline, noradrenaline, serotonin, acetylcholine, various neuopepetides
  • Act on distinct hypothalamic nuclei stimulate production of hypothalmic-releasing hormones
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26
Q

nuclei in the hypothalamus and what hormones are produced here

A

Nuclei in the hypothalamus
- Supraoptic nucleus – AVP/oxytocin
- Preoptic nucleus – GnRH
- Arcuate nucleus – GHRH/ dopamine
- Paraventricular nucleus – AVP/ oxytocin/ TRH
- Periventricular nucleus – somatostatin
There’s lots of peptide synthesis in these nuclei
Transported down the long axon fro stroage in nerve terminals

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27
Q

MEDIAN EMINENCE - blood supply, capillary bed name, functional anatomy, structure of the nerve terminals

A
  • Supplied by arterial blood from superior hypophysial artery (a branch of the internal carotid artery)
  • Cappilary bed – special peithelial cells called FENESTRATED EPITHELIAL CELLS
  • Leads to direct contact with blood vessels
  • Very dense area of nerve terminals
  • Nerve terminals are on the surface of the blood vessels in this area
    o Intimate contact
    o Leading to peptides passing from nerve terminals into the blood
    o PORTAL CIRCULATION
     2 cappilary beds joined by circulation wihtout circling back through heart and lung
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28
Q

pituitary gland - size, dysfunction, DI

A

Pituitary gland about the size of a pea on the end of a wee stalk
- It can waggle about ie in car crash
- If pituitary stalk gets damaged eg whiplash
- This stops the transport of oxytocin and AVP
- Experience cranial diabetes insipidus
o Pee out 6-7 litres of urine in couple of hours
o Because lost AVP control in the kidney (recruites aquapoin in distal tubule)

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29
Q

what’s the principle blood supply of the pituitary gland

A

THE MEDIAN EMINENCE IE THE SUPERIOR HYPOPHYSIAL ARTERY

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30
Q

anterior pituitary gland - cell types and what hormones act on these

A
  • GHRH (somatoliberin) acts on somatotropha
  • GnRH acts on gonadotropha
  • CRG acts on corticotropha
  • TRH acts on thyrotrophs
  • DA, inhibits Lactotrophs
  • Somatostasin (SS) inhibits somatotrophs & thyrotrophs
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31
Q

anterior pituitary - what cell types make what hormones

A
  • ACTH from corticotrophs
  • TSH from thyrotrophs
  • FSH and LH frome gonadotrophs
  • GH (somatrophin) from somatotropha
  • PRL from lactotropha
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32
Q

posterior pituitary cell types

A
  • Oxytocin and vasopressin stored and released in response to neural stimulation
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33
Q

what does a tumour in a target gland lead to in terms of hormone levels

A
  • Produceses lots of target gland hormone
  • Ask where the problem is
    o it’s in target gland and feedback loop is still intact leading to huge feedback in the anterior pituitary gland and hypothalamus
    o leading to production of all of their hormones going down to zero – low levels of pituitary gland hormones
  • good diagnostically as have lots of target gland hormone but almost no hypothalamic or pituitary hormones
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34
Q

what does a tumour in the pituitary gland lead to in terms of hormone levels

A
  • produces lots of pituitary gland hormone
  • overstimulates target gland leading to high levels of target gland hormone
  • pituitary tumour is unresponsive to feedback
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35
Q

what does failure of a target gland (ie hormone deficiency) lead to in terms of hormone levels

A
  • target gland stops working eg injury
  • failure of target gland results in low levels of target hormone
  • reduces feedback on hypothalamus and pituitary
  • leading to high levels of hypothalamic releasing and anterior pituitary hormones which can be measured
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36
Q

suppression testing examples

A

OVERNIGHT DEXAMETHASONE SUPPRESSION TEST

  • mimics effects of cortisol
  • synthetic glucocorticoid suppresses pituitary ACTH secretion and cortisol production from adrenal cortex (negative feedback)

Comes in 2 flavours

  • low dose - suppresses pituitary ACTH secretion and cortisol production in normal individuals, but not from a pituitary adenoma
  • high dose – part-inhibits ACTH secretion from a pituitary adenoma, but not from a cortisol-producing adrenal adenoma or an ectopic ACTH-producing tumour
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37
Q

stimulation testing examples

A

SynACTHen (synthetic ACTH) stimulation test
- Quantifies adrenal function or lack of function (insufficiency)
Comes in 2 flavours
- Low dose – to measure cortisol production
- High dose – to assess total adrenal cortex function

Oral Glucose Tolerance test

  • Diagnosis of diabetes (exaggerated glucose response)
  • Diagnosis of acromegaly (GH fails to be supressed as normal)
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38
Q

hormones rarely measured in plasma (measured via petrosal sinus sampling)

A
  • Hypothalamic hormone
  • CRF
  • GnRH
  • GHRH
  • TRH
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39
Q

hormones often measured in plasma for diagnosis

A
  • Pituitary hormone
  • ACTH
  • LH/FSH (male)
  • LH/FSH (female)
  • GH
  • TSH
  • ADH/ vasopressin
  • Prolactin
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40
Q

hormones measured in plasma for diagnosis and to monitor hormone reduction or replacement

A
  • End organ hormone
  • Cortisol
  • Testosterone
  • Oestrogen, progesterone
  • IGF1 (GH in children)
  • Thyroxine
  • Desmopressin/ DDAVP
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41
Q

what must be considered when collecting a blood sample

A

Dietary restrictions?
- Do patients need to fast
- Effects glucose, cholesterol, triglycerides
Timing
- Diurnal variation – cortisol, testosterone (male)
TDM
- Time from last dose (peak or trough)
Stability?
- Eg ACTH stable 30 mins
- Get to lab as quickly as possible
Affected by venous stasis?
- Protein bound components increase eg Ca++
Posture
- Renin and aldosterone
- Do you want them lying down for a while first

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42
Q

what are the different tubes used for collecting blood samples and in what settings are they used

A
  • Plain serum (no gel)
  • Plain serum (gel)
    o These are for clotted blood
    o Blood goes in and is allowed to clot for 30-60 mins
    o Gel provides a barrier so that in the lab it can be spun and easily separate plasma from red cells
  • Lithium heparin (anticoagulant)
    o Good for A&E
    o Advantage = don’t need to wait for blood to clot
    o Good for paediatrics bc can obtain more plasma in this sample than if bloods allowed to clot
  • Potassium EDTA (anticoagulant)
    o Used for taking full blood count
    o EDTA binds calcium
    o Stops platelets clumping to get accurate FBC
  • Tri-sodium citrate (anticoagulant)
    o Also binds calcium but more reversible than EDTA
    o Allows for clotting studies eg INR
    o For liver function tests
  • Sodium fluoride/ potassium oxalate (anticoagulant)
    o Oxalate binds calcium
    o Fluoride is an inhibitor of respiration so stops metabolism of glucose in the sample
    o Stops from giving falsely low glucose measure
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43
Q

how do we calculate the reference range

A
  • First identify a population that does not have the disease
  • Consider effects of sex and age differences
    o Eg testosterone levels between M and F
    Within reference population of at least 120 subjects plot data of these healthy (normal) individuals…
  • You usually get a gaussian symmetrical distribution

Reference range is normally mid 95% of populations study

  • So +2 or -2 standard deviations of the mean
  • 2.5% of patients have result above the reference range and 2.5% have result below it
44
Q

how many measurements will fall outside the reference range in a healthy population and what does this imply

A
  • Therefore 1/20 measurements will fall outside the reference range in a ‘healthy population’
  • Result outwith reference range isn’t necessarily abnormal – could just be an outlier
45
Q

what’s different about the reference range in thyroid stimulating hormone

A
  • Shows a sweked distribution
  • Mean is further to the right
  • Long tail on population curve
  • Exclude top and bottom 2.5% to get rr
46
Q

what are the guidelines for treating someone with high TSG

A

If TSH >10mU/L start on thyroxine

47
Q

what affects the reference range and how

A
  • Precision > how reproducible a result is
  • Accuracy > how near the true value is the result

Poor precision of a method broadens apparent reference range

An inaccurate method moves population curve

48
Q

what are 2 reasons why a test result may vary

A

o Analytic variation
 Variation in the assay itself
o Biological variation
 Physiology variation of body between days

49
Q

what are the 2 possible ‘solutions’ to the overlap int he healthy and diseased populations and what are the consequences of these

A
  • Increase the diagnostic cut off
  • Good clinical specificity (few false positives)
  • Poor clinical sensitivity (many false negatives)
  • Lots of patients that have got the disease and it’s not being diagnosed
  • If you do the opposite and lower the cut off
  • Poor sensitivity (many false positives)
  • Good sensitivity (few false negatives)
  • So lots of people who don’t have the disease are diagnosed with it wrongly
50
Q

how do screening tests differ from blood tests

A
  • Different because we’re looking at the healthy population
  • So pre-test probability is much smaller
  • So you need very highly sensitive testing to make it worth it
  • Usefulness depends on prevalence of disease in population

aka
Screening may need a choice of cut-off that leads to acceptable investigative load (95% cut-off is not relevant for screening for rare disorders)

51
Q

what are pre-analytical laboratory testing errors

A

Failure to…

  • Choose correct test
  • In the correct manner
  • On the correct patient
52
Q

what are analytical laboratory testing errors

A

the test itself goes wrong

eg interference of antibodies that leads to false positive results which isn’t picked up as a mistake

53
Q

what are post-analytical laboratory testing errors

A

Failure in…

  • Communicating the right results
  • Getting the interpretation right
54
Q

what can lead to wrong interpretation of TSH

A

changes are due to the effects of severe systemic disease – common interpretative problem

  • Stress via glucocorticoids feeds back at higher level and switch of hypothalamic drive of TSH
  • Illness via cytokines can also switch off this axis
  • Malnutrition via somatostatin can also switch this off
55
Q

what are the differences between intracellular and extracellular calcium

A
  • Intracellular Ca is maintained at very low conc. (less than 1umol/L)
    o Reversible increases show Ca2+ ions to bind to proteins to influence many key cell processes
  • Extracellular Ca2+ is present at much higher concentration (about 1mmol/L)
    o To allow normal bone mineralisation
    o To maintain normal activity of excitable tissue
56
Q

in what phase is extracellular calcium measured in - what variations of this phase exist

A
  • Extracellular Ca is measured in the lipid (non-cellular) phase of blood ie either…
    o Serum (the liquis phase ontained after blood has clotted)
    OR
    o Plasma (the liquid phase of non-clotted blood where the blood sample taken includes an anti-coagulant)
57
Q

plasma (or serum) calcium - what’s the normal range, what are the components

A
  • The concentration measured in the plasma (or serum) is within a well defined normal range
    o 2.1-2.6mmol/L
  • The ca conc. Is made up of 2 components
    o Ionised Ca2+ which is physiologically active
    o Ca2+ which is ‘bound’ mainly to albumin and is not physiologically active
  • It’s the ionised Ca2+ which is actively regulated
58
Q

what’s the relationship between albumin and calcium

A
  • Albumin is the major Ca2+ binding protein in plasma (or serum)
  • Abnormal albumin conc. (which is quite common) will alter the Ca2+ bound
  • Measuring both albumin and total calcium is required to assess extracellular ionised Ca2+ status
59
Q

how does albumin effect interpretation of plasma calcium

A
  • People with less albumin may appear hypocalcaemic but they’re not as ionised calcium is at a normal level
60
Q

how is dietary calcium used up int he body

A 
-	Diet 25mmoles
o	10mmoles absorbed in gut
o	5mmoles excreted through GI tract
o	5mmol absorbed into bones
o	5mmol excreted by kidneys into urine
61
Q

how does the calcium balance alter throughout life

A
  • Growth (new bone formation) requires positives Ca balance
  • Adulthood – assoc. with neutral balance
  • Ageing process assoc. with neg. phase leading to loss of bone density (may lead to osteoporosis)
    o Hormonally influenced by oestrogen – women more affected
  • Bone loss accelerated after menopause
62
Q

what are the functions and morphology of bone

A 
Bone functions
-	Support body
-	Protects organs
-	Leverage system for movement
-	Site of meatopoiesis
-	Endocrine function (fibroblast growth factor-23; osteocalcin)
-	Regulation of mineral homeostasis
Bone morphology
-	Trabecular bone
-	Cortical bone
63
Q

what are the main bone cells and what do they do

A

Osteoblasts – cells that make bone
Osteoclasts – cells that resorb bone
Osteocytes – most abundant cell type in bone
- Function – mechanosensor cell – sense stress in the bone eg during high intensity exercise / fracture
- Send out chemical signals to attract osteoblasts to lay down new matrix
Osteoid – uncalcified bone matrix

64
Q

explain bone matrix mineralisation

A
  • Several days before osteoid mineralises
  • Skelenton contains ~98% of body calcium
  • Mineral component is hydroxyapatite – Ca10(PO4)6(OH)2
    o Tiny crystals surround collagen fibres
    o Provides rigidity, resistance to compression
  • Mineralisation of osteoid dependant on calcitrol (to do with vit D)
    o Deficiency results in failure to mineralise
    o Leads to rickers in children, osteomalacia in adults
65
Q

alkaline phosphatase and mineralisation - how can we interpret elevated levels, what cells express it, what does it release, how does it promote mineralisation

A
  • Also linked to liver
    o If ALP and Gamma-GT both high = liver problem
    o If ALP high and gamma-Gt low = bone problem
  • Expressed on surface of differentiated osteoblasts – also releases into extracellular fluid and circulation (bone formation marker)
  • Releases inorganic phosphate ions (PO43-) from diverse molecules hydrolysis
  • ALP promotes mineralisation (ie precipitation of calcium phosphate/ hydroxyapatite) in 2 ways
    o By increasing the local conc. Og inorganic phosphate ions
    o By hydrolysing pyrophosphate, a key inhibitor of mineralisation
     Pyrophosphate inhibits mineralisation brekaing it up stops this and provides phosphate
66
Q

describe the process of bone resorption

A
  • Multinucleate, motile bine-resorbing cells
  • Formed by fusion of promonocytic precursors present in marrow and circulation]
  • ‘ruffled border’ adjacent to bone surface secretes H+ and enzymes
  • Express high level of carbonic anydrase II required for H+ generation
67
Q

role of RANK/RANKL in osteoclast biology and function

A
  • Mature osteoclats needs to become activated
  • RANKL attaches to RANK receptor on osteoclats to these cells to make them osteoclast precursor cells
    o RANKL is expressed by various stromal cells
    o Osteoblasts also have RANKL
     So also have a role in reabsorption
68
Q

bone remodelling cycle

A

1) Period of quiescence
2) Osteoclasts come along to repair damsge – normal wear and tear
3) Osteoblasts lay down new osteoid to build bone backup
4) Formation of new bone as osteoid is mineralised
a. Takes about 3 months
Whole duration takes aout 7 months

69
Q

why do we need bone metabolism

A
  • To grow
  • Respond to latered mechanical requirements
  • Repair damage (macro/micro fractures)
  • Maintenance (failure prevention)
  • Calcium deficit = to release calcium
70
Q

what causes paget’s disease

A
  • Due to overactive osteoclasts
71
Q

what are the 2 molecules involved in the hormonal regulation of calcium, and what are the priniciple organs involved

A

PTH and calcitriol which show typical endocrine feedback loops
- PTH is a peptide hormone
- Calcitriol is a steroid hormone which is synthesised from dietary factor (Vit D)
The prinicpal organs involved are the gut, bone and kidney

72
Q

PTH physiology - speed of regulation, what causes/suppresses it’s secretion

A
  • A peptide hormone required for the minute-by-minute regulation of ionised calcium level in blood
  • PTH is secreted as a single chain polypeptide (84 amino acids) from the parathyroid glands
  • PTH secretion is increased in response to falling Ca2+ and its actions are directed at restoring Ca2+ levels
  • Rising Ca2+ feeds back to the parathyroid glands and suppressed PTH secretion (negative feedback loop)
73
Q

PTH actions

A
  • Stimulates efflux of Ca2+ from bone
  • Stimulates renal tubular resorption of Ca2+ (distal tubule)
  • Stimulates formation of calcitriol (indirectly) promoting intestinal absorption of Ca2+
  • Promotes phosphate and bicarbonate loss from the kidney (proximal tubule)
74
Q

calcitonin

A

Not to be confused with calcitriol

  • 32 amino acid polypeptide secreted in response to rising Ca2+ from parafollicular or C -cells of the thyroid gland
  • Principal action is to reduce osteoclast activity
  • No clear role in calcium homeostasis (eg neither total thyroidectomy nor calcitonin-secreting tumours alter calcium homeostasis)
  • May be used therapeutically to treat high serum calcium levles
  • Also serves as a ‘tumour marker’ (certain thyroid tumours, some breast cancers)
75
Q

vitamin D - structure, how’s it produced, wheres it activated, where’s calcitrol synthesised from it

A
  • Cholecalciferol
  • Fat soluble vitamin
  • Steroid structure
  • Produced endogenous by the action of UV light on skin precursoer, 7-dehydrocholesterol
  • Dietary sources include oily fish, eggs, butter, margarine (fortified)
  • Cholecalciferol requires activation by liver and kidney to produce the active hormone, calcitriol
  • calcitriol is a hormone, it is synthesised in one location (kidney) and acts on many sites
76
Q

Vitamin D synthesis

A
  • The precurosr for Vitamin D is a sterol in the cholesterol biosynthetic pathway, 7-dehydrocholesterol whch is found in skin
  • UV light transforms 7-dehydrocholesterol to vitamin D3 (cholecalciferol)
  • Vitamin D3 circulates to the liver, where the microsomal enzyme 25-hydroxylase hydroxylates it to 25-hydroxy vitamin D (25(OH)vitamin D)
  • 25-hydroxylase functions constitutively without input from blood calcium status or PTH
  • 25(OH)vitamin D is the best screening test for vit D deficiency
  • 25(OH)vitamin D circulates to the kidneys where it is hydroxylated by 1a-hydroxylase to 1,25(OH)2vitamin D (calcitriol) = active vitamin D
  • Renal 1a-hydroxylase is regulated by PTH which stimulates its activity.
    o PTH is the principle physiologic regulator, although calcium can affect the activity
  • Other hydroxylations possible (eg at the 24-position deactivates vit D)
77
Q

mechanism of calcitriol actions

A
  • Calcitriol binds to a single vit D receptor (VDR)
  • The VDR-calcitriol complex acts through a vit-D responsive element (new protein synthesis)
    o In intestine, a clacium-binding protein (calbindin D9k) is synthesised which promotes absorption of both calcium and phosphate
    o In bone, stimulates osteoblast differentiation and osteoclast activation via RANK ligand formation in osteoblasts
78
Q

calcitriol vs PTH

A
  • Both maintain ionised Ca2+
  • PTH responsible for minute-to min reg.
  • Calcitriol for long term reg.
  • PTH tends to decrease plasma phosphate and calcitriol raises it
79
Q

interactions between PTH and calcitriol - co-operativity and limitation

A

Co-operativity
- PTH promotes 1a-hysroxylase activity
- PTH and calcitriol both required in vivo for osteoclast activation and distal tubular Ca2+ reabsorption
- Calcitriol deficiency may impair PTH action
Limitation of cation
- Calcitriol stimulates 24-hydroxylase (promotes its own inactivation)
- Calcitriol can switch off PTH gene transcription via VDR in PTH cells, limiting PTH action

80
Q

clinical manifestations of high blood calcium

A

“stones, bones, abdominal moans and psychic groans’

  • Muscle weakness (striated and smooth), possible competition with inward Na+ movement
  • Central effects (anorexia, nasuea, mood change, depression)
  • Renal effects (impaired water concentration, renal stone formation)
  • Bone involvement (cause-dependant)
  • Abdominal pain
  • ECG changes (shortened QT interval)
81
Q

what causes factitious hypercalcaemia (non-pathological)

A
  • Raised calcium due to high plasma albumin eg
    o Venous stasis
    o Dehydration
    o IV albumin
82
Q

primary hyperparathyroidism as a cause of hypercalcaemia

A
  • 1 in 500 to 1 in 1000
  • Most common in 6th decade
  • Most common aetiology in outpatients
  • Women > men 3:2 ratio
  • Many patients found on routine screening with minimal symptoms
  • 90% solitary adenoma; hyperplasia; carcinoma (rare)
83
Q

explain 1y vs 2y vs 3y hyperparathyrdoidism

A

1y
- An autonomous and inapproproate overproduction of PTH leading to hypercalcaemia
2y
- An appropriate increase in PTH in response to hypocalcaemia
3y
- Rare but refers to the situation where a 2y overactve gland becomes overactive

84
Q

what is found on investigation that leads to diagnosis of 1y hyperparathyroidism

A
  • Phosphate and bicarbonate tend to be low in serum (increased renal excretion)
  • Alkaline phosphatase normal or moderatelt increased in more severe disease
  • Further investigations
    o Parathyroid imaging scan
85
Q

what is the treatment for 1y hyperparathyroidism

A
  • Acutely, patient may need treatment of their high ionised calcium
    o Re-hydration
    o Drugs
  • Defintiive treatment is removal of parathyroid gland or adenoma
  • Mild cases may be managed by repeated follow-up of serum calcium/PTH
  • Where surgery may be difficult (eg poor operative risk) drugs to lower calcium levels may be required
86
Q

drugs to treat hypercalcaemia

A

Available drugs
- Bisphophonates (inhibit osteoclast action and bone resorption), after re-hydration this is key drug for long-term control
- Furosemide (inhibits distal Ca2+ reabsorption, requires care and patient must be hydrated first)
- Calcitonin (inhibites osteaoclast action), tolerance may develop but useful for immediate, short-term management
- Glucocorticoids (inhibit vit D conversion to calcitriol, can prolong calcitonin action)
Newer Drugs
- Calcimimetic drugs which bind to Ca2+ sensor and inhibit PTH release, restricted use (eg Parathyroid carcinomas)

87
Q

malignant disease as a cause of hypercalcaemia

A
  • Commonest cause of hypercalcaemia In hospitalised patients
  • Up to 20-30% cancer patients may develop hypercalcaemia during course of illness
  • 2 broad reasons
    o Endocrine factors secreted by malignant cells acting on bone
    o Metastatic tumour deposits in bone locally stimulating bone resorption via osteoclast activation
88
Q

endocrine factors in malignant hypercalcaemia

A
  • Solid tumours may secrete PTH-related peptide (or PTHrP) (eg breast; squamous tumours of lung, head and neck)
  • PTHrP shows structural homology to PTH and shares similar actions but is distinct (PTH itself is suppressed)
  • Where PTHrP is the cause this is known as humoral hypercalcaemia or maliganancy
  • Some tumours (esp. Hodgkin’s lymphoma) possess 1-OHase activity and synthesise calcitriol
89
Q

malignant hypercalcaemia assoc. with bony metastases

A
  • Approx. 20% of malignant hypercalcaemia
  • Most commonly assoc. with breast and lung cancers, multiple myeloma
  • Secretion of osteoclast activating cytokine or other factors into te bone micro-environment is key element
  • Metastatic breast tumour may locally produce PTHrP
  • Myeloma cells produe cytokine that activate osteoclasts (RANKL, IL-3, IL-6)
90
Q

diagnosis of multiple myeloma

A
  • Bone marrow biopsy shows an increase in plasma cells
  • From pelvis
  • Look at serum and so protein electrophoresis
91
Q

general clinical signs of malignancy

A
  • Rasied calcium with supressed PTH
  • Phosphate tends to be high
  • Alkaline phosphatase may be very high (liver or bone metastases)
  • Often clear from prev. histpry of malignant disease
92
Q

whats the treatment of malignant hypercalcaemia

A
  • Re-hydrate the patient
  • If required, use drugs which lower calcium in the blood
  • Treat underlying malignancy
93
Q

less common causes of hypercalcaemia

A
  • Granulomatous disease eg sarcoidosis
  • Exogenous vit D excess
  • Familial hypocalciuric hypercalcemia
  • Drugs (eg Li, thiazide diuretics)
  • Some endocrine diseases (thyrotoxicosis, Addison’s disease)
  • Immobilization
94
Q

sarcoidosis

A
  • Granulomatous disease
  • Usually affects lungs (90%) or skin (10%)
  • Inc. calcium with normal PTH
  • Hydroxylation of vit D in granulomas
95
Q

familial hypocalciuric hypercalcaemia

A
  • Rare but interesting
  • Ca2+ sensor on PT glands less sensitive to Ca suppression of PTH
  • Altered set point for PTH/Ca interaction
  • PTH levels tend to be high normal or slightly raised
  • Plasma ionised calcium increased (mild)
  • Urine Ca excretion low (relative to plasma Ca)
96
Q

clinical manifestations of low blood calcium

A

Neuromuscular

  • Numbness and paraesthesiae (tingling) in fingertips, toes and mouth
  • Anxiety and fatigue
  • Muscle cramps, carpo-pedal spasm, bronchial or laryngeal spasm
  • Seizure

Mental states

  • Personality change
  • Mental confusion, psychoneurosis
  • Impaired intellectual ability

ECG changes and eye problems

97
Q

factitious hypocalcaemia causes

A

Consequences of low plasma (albumin) eg

  • Acute phase response (low albumin)
  • Malnutrition or malabsorpion (protein deficinecy in diet)
  • Liver disease (reduced liver synthesis albumin)
  • Nephrotic syndrome (albumin lost in urine)
98
Q

vitamin D deficiency

A
  • Lack of sunloght
  • Inadequet dietary source
  • Malabsorption
  • Chronic renal disease
  • Chronic liver disease
  • Defective 1-OHase
  • Defective 1,25-D3 receptor
99
Q

risk factors where supplementation may be required

A
  • Those confined indoors eg elderly
  • Dark skinned individuals at high latitudes
  • Lack of sunlight exposure through dress, high factor sunscreen etc
100
Q

deficient 1,25-D3 as a cause of vit D deficiency and clinical factors of this deficiency

A
  • Symptoms related to low Ca
  • Osteomalacia (bone pain, fractures, disordered growth in children as a consequence of defective mineralisation)

Factors

  • Low 25-D3 and 1,25-D3 (usually)
  • Low Ca2+ (may be normal in early stages)
  • High PTH (2y hyperparathyroidim)
  • Phosphate tends to be low
  • Often raised ALP
101
Q

osteomalacia/ rickets

A
  • Pathological bone problem classically assoc. with vit D deficiency
  • Osteoid laid down by osteoblasts is not adequtely calcified
  • Osteoid content in bone increases at expense of normal calcified osteoid
  • Bones softened, weak and fracture easy
102
Q

inherited causes of osteomalacia/ rickets

A
  • Deficient 1-hydroxylase (vit D resistant rickets, type 1
  • Defective recpetor for calcitriol (vit D resistant rickets type 2)
  • Other inhertief causes of rickets
    o Hypophosphataemic rickets
     Low serum phosphate
     Impaired mineralisation
     Excessive urine phosphate loss
     Phosphaturic hormone (FGF23) mutations
103
Q

hypoparathyroidism as a cause of hypocalcaemia - acquired vs inherited

A
  • Acquired
    o Surgical damage or removal (relatively common, usually transient)
    o Suppressed secretion (eg low Mg2+, maternal hypercalcaemia)
  • Inherited
    o Developmental parathyroid problems
    o Genetics/familial disorders eg DiGeorge syndrome
104
Q

biochemistry of hypoparathyroidism - 3 factors

A
  • Low Ca2+
  • Inappropriately low PTH
  • Phosphate may be increased
105
Q

treatment of hypocalcaemia

A
  • Acutely give IV calcium
  • Normally oral calcium and vit D are given (Mg sometime too)
  • Vitamin D may be gicen in various forms
    o By injection into muscle if malabsorption is presnt or stores require to be repleted more quickly
    o As the 1OH form if renal function is impaired
  • Close monitoring
106
Q

osteoporosis and how it’s diagnosed

A
  • Commonest bone disease (up to 30% women, 12% men)
  • Reduced bone mineral density, disruption of microarchitecture
  • Increased risk of fracture
  • Routine biochemistry unaffected
    Diagnosed…
  • Via imagine – dual energy X-ray absorptiometry (DEXA)
  • Assesses bone mineral density (BMD)
107
Q

comparison of osteoporosis vs osteomalacia

A

Osteoporosis
- Loss of calcified matrix and reduced bone density
- ‘less’ bone but histologically normal
- Susceptible to fracture
- Essentially normal biochemistry
- Defined by DEXA scan
Osteomalacia
- Abnormal histology with wide seams of uncalcified osteoid
- Loss of calcifed matrix and reduced bone density
- Suspetibilty to fracture
- Abnormal biochemistry

YEAR 2 SEMESTER 2 (14 decks)

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