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Year 2 - Semester 2 > Endocrinology - Week 1 > Flashcards

Endocrinology - Week 1 Flashcards

1
Q

what hormones does the pituitary release?

A 
o	ACTH (Adrenocorticotropic hormone)
o	LH    (Luteinising hormone)
o	FSH  (Follicle stimulating hormone)
o	GH (Growth hormone)
o	PRL (Prolactin)
o	TSH (Thyroid stimulating hormone)
o	AVP (Arginine vasopressin)
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2
Q

what hormones does the thyroid release?

A

o Thyroxine

o calcitonin

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3
Q

what hormones does the parathyroid release?

A

o PTH

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4
Q

what hormones does the pancreas release?

A

o Insulin

o glucagon

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5
Q

what hormones does the adrenal cortex release?

A

o Cortisol
o Aldosterone
o DHEA

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6
Q

what hormones does the adrenal medulla release?

A

o Adrenaline

o Noradrenaline

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7
Q

what hormones do the testes release?

A

o Testosterone

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8
Q

what hormones do the ovaries release?

A

o Oestrogen

o Inhibin

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9
Q

what hormones does adipose tissue release?

A 
o	Leptin
o	Adiponectin
o	Resistin
o	TNFa
o	IL6
o	Cortisol
o	Angiotensinogen
o	PAl-1
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10
Q

what types of hormones are there

A

• Peptides
o Growth hormone
o Insulin
o Thyroxine

• Amines
o Adrenaline
o Noradrenaline

•	Steroids
o	Oestrogen
o	 Androgen
o	Glucocorticoids
o	Vitamin D
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11
Q

what receptors do amines have

A
  • Surface receptors
  • Secondary messengers
  • Multiple cellular effects
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12
Q

what receptors do steroids and thyroid hormones have

A
  • Nuclear receptors
  • Via transcription/translation
  • Many gene targets
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13
Q

what does an excess of GH cause and what are the causes

A

o Acromegaly in adults
o Gigantism in children

o	Causes
	Genetic – mutations in Gs-alpha
	Immune – antibodies stimulating GH
	Tumours – pituitary
	Overstimulation – GHRH hypersecretion
	Downstream path – IGF1 tumours
	Factitious/iatrogenic – body builders/ athletes
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14
Q

what to do if a hormone is in excess

A

show it can be suppressed back to normal

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15
Q

what to do if a hormone is deficient

A

replace it physiologically
• Diurnal rhythms make it hard to check hormone levels normally
• As do stress and illness

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16
Q

what makes up endocrine systems

A

at least three organs – one releases a signal, one secretes a hormone and the last responds to the hormone

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17
Q

what is the difference between endocrine and exocrine

A

Endocrine glands – do not have ducts and products secreted directly into the blood
Exocrine glands – have ducts to epithelial surfaces inside or outside the body
Some glands do both e.g. pancreas – endocrine such as insulin but also exocrine into the gut

“classical” endocrine signaling - hormone carried by blood to receptors on “target” cells

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18
Q

what are the three types of signalling other than endocrine

A

• Paracrine
o Hormone diffuses through tissue fluids
o To receptors on target cells

• Autocrine
o Hormone diffuses through tissue fluids
o To receptors on same cell

• Intracrine
o Inactive prohormone enters a cell
o Activated intracellularly
o E.g. sex steroids

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19
Q

describe peptide hormones

A

o Water soluble - circulate in blood
o Bind to surface receptors such as GPCRs or receptor kinases
o Fast acting

o Three types
• Hypothalamic-releasing hormone
• Pituitary trophic hormones
• Target organ peptide hormones

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20
Q

describe steroid hormones

A

o Transported on plasma “carrier” proteins
o Lipid soluble
o Diffuse through plasma membrane and bind to inactive cytoplasmic steroid receptors
o Activated “transcription factor” enters nucleus and binds to control regions activating gene transcription
o mRNA leaves the nucleus  new cytoplasmic protein synthesis
o this takes time – minimum 24-48 hours

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21
Q

describe amine hormones

A

o Transported on plasma “carrier” proteins

o Bind to surface receptors such as GPCRs or receptor kinases

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22
Q

describe the balance between hormone production and degradation

A 
•	Amplification:
     ‘Signalling’ hormones:
	short half-life - only a few mins
     ‘End-organ’ hormones: 
	long-lived - hours to days
•	Hormone levels in the blood 
		 balanced between:
		synthesis & secretion
	   	               vs
		degradation & excretion
•	degraded mainly in liver & kidneys
•	breakdown products excreted in urine, faeces and bile
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23
Q

what does the hypothalamus coordinate?

A

central neural inputs

External environment:

sight, sound, touch, taste, smell
pain, heat, cold , fear (‘freeze, fight or flight’)

Internal physiology:
blood pressure, osmolality, blood glucose
hypoglycaemia, starvation chronic pain, fever, inflammation

Circadian biological clock:
Suprachiasmatic nucleus (SCN) rhythm generator controls daily endocrine system cycles (entrained by daily light & dark cycle)

• Stimuli from somatic & visceral sense organs
• transmitted via sensory & motor neurons from the forebrain and mid brain
• produce ‘stimulatory’ or ‘inhibitory’ neurotransmitters
(dopamine, adrenaline, noradrenaline, serotonin, acetycholine & various neuropeptides)
• Act on distinct hypothalamic ‘nuclei’
stimulate production of hypothalamic-releasing hormones

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24
Q

describe hypothalamus

A

Neuroendocrine component of the nervous system 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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25
Q

describe the pituitary gland

A 
two 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 axons
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26
Q

whats important about the vasculature between the hypothalamus and the pituitary?

A

it is easily damaged which an lead to cranial diabetes insipidus etc

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27
Q

what hormones act on which cells in the anterior pituitary

A
  • GHRH (somatoliberin) acts on Somatotrophs
  • GnRH acts on Gonadotrophs
  • CRH acts on Corticotrophs
  • TRH acts on Thyrotrophs
  • DA (dopamine), inhibits Lactotrophs
  • Somatostasin (SS) inhibits Somatotrophs & Thyrotrophs
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28
Q

what happens in the posterior pituitary

A

• Oxytocin & Vasopressin stored and released in response to neural stimulation

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29
Q

what is released from the anterior pituitary?

A
  • ACTH from Corticotrophs
  • TSH from Thyrotrophs
  • FSH & LH from Gonadotrophs
  • GH (somatotrophin) from Somatotrophs
  • PRL from Lactotrophs
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30
Q

describe HP axis feedback circuits

A

Stimulatory or inhibitory external neural inputs
Hypothalamic releasing-hormone acts on pituitary
Anterior pituitary hormone acts on target gland
Target gland hormone feeds back on Pit & Hyp
Feeds forward on tissue target/metabolism

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31
Q

what happens in target gland hormone excess

due to a target gland tumour

A

Hormone producing tumour results in:
HIGH levels of target gland hormone
increases feedback on hypothalamus & pituitary
leading to:
LOW levels of hypothalamic-releasing & anterior pituitary hormones,
all of which can be measured

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32
Q

what happens in pituitary & target gland hormone excess due to a pituitary tumour

A 
Hormone producing tumour results in:
HIGH levels of pituitary gland hormone
leading to:
HIGH levels of target gland hormones,
all of which can be measured
Pituitary tumour is unresponsive to feedback
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33
Q

what happens in target gland hormone deficiency

due to primary end organ failure

A

Failure of target gland results in:
LOW levels of target hormone,
reducing feedback on the hypothalamus & pituitary
leading to:
HIGH levels of hypothalamic releasing and anterior pituitary hormones,
all of which can be measured

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34
Q

what happens in multiple anterior pituitary hormone deficiency secondary end organ failure – due to pituitary failure

A

Failure of pituitary results in:
LOW levels of anterior pituitary & target gland hormone, reducing feedback on the hypothalamus
leading to:
HIGH levels of hypothalamic releasing hormones
all of which can be measured

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35
Q

describe testing if a hormone is deficient

A

test if it can be stimulated normally
• SynACTHen (synthetic ACTH) stimulation test:
quantifies adrenal function or lack of function (insufficiency)
Comes in two 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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36
Q

describe testing is a hormone is in excess

A

• test if it can be suppressed normally
• Overnight Dexamethasone suppression test
synthetic glucocorticoid suppresses pituitary ACTH secretion
& cortisol production from adrenal cortex (negative feedback)
Comes in two 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

what do you need to remember when taking samples

A

• Dietary restrictions?
o Fasting- Glucose, Cholesterol and Triglycerides

• Timing

o Diurnal variation
 Cortisol
 Testosterone (males)

o TDM –
 Time from last dose (peak or trough)

o Stability?
 e.g. ACTH stable 30 minutes

o Affected by venous stasis?
 Protein bound components Increase eg Ca++

o Posture
 Renin and Aldosterone

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38
Q

what is a reference range?

A

mid 95% of normal population
Therefore 1 in 20 measurements will fall slightly out of the reference range
Using the term “normal range” is technically wrong

TSH and some other blood measurements show a skewed distribution curve with a long tail - we still discard the top and bottom 2.5%
This may be due to the inclusion of patients with occult thyroid dysfunction

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39
Q

what is the issue with there being overlap in reference ranges between healthy and diseased patients?

A

If you have a reference range which includes only diseased patients then you have
 Good clinical specificity (few false positives)
 Poor clinical sensitivity (many false negatives)
If you have a reference range which includes ALL diseased patients then you have
 Poor specificity (many false positives)
 Good sensitivity (few false negatives)

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40
Q

how do we decide on reference ranges

A

Need to know prevalence of disease in the population
Prevalence –
 Number of people in a population with the condition
When screening for rare diseases, tests of extremely high specificity and sensitivity are required

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41
Q

what errors can there be in lab testing

A 
	Pre-analytical
o	Failure to:
o	Choose the correct tests
o	 in the correct manner 
o	 on the correct patient

 Analytical
o Is the test appropriate for clinical need?
o Are there interfering factors? – systemic disease for example

 Post-analytical

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42
Q

what are the biological functions of calcium?

A

• Important to distinguish between intracellular and extracellular functions
o Intracellular Ca2+ is maintained at very low concentrations (less than 1 μmol/L).
 Reversible increases allow Ca2+ ions to bind to proteins to influence many key cell processes
o Extracellular Ca2+ is present at much higher concentration (about 1 mmol/L). 10,000x higher than intracellular
 To allow normal bone mineralization
 To maintain normal activity of excitable tissue

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43
Q

describe how extracellular calcium is measured

A 
Extracellular calcium is measured in the liquid (non-cellular) phase of blood i.e. either 
o	Serum (the liquid phase obtained after blood has clotted) OR 
o	Plasma (the liquid phase of non-clotted blood where the blood sample taken includes an anti-coagulant)
44
Q

describe serum calcium

A

• The concentration measured in plasma (or serum) is within a well-defined normal range
• This range is typically 2.1-2.6 mmol/L
• This calcium concentration 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 is the ionised Ca2+ which is actively regulated

45
Q

what is the connection between albumin and calcium

A
  • Albumin is the major Ca2+ binding protein in plasma (or serum)
  • Abnormal albumin concentration (which is quite common) will alter the Ca2+ bound
  • Measuring both albumin and total calcium is required to assess extracellular ionised Ca2+ status
46
Q

describe calcium intake and excretion

A

From our diet, half of excreted calcium is excreted through the GI tract and a proportion absorbed into the plasma to exchange into bone. Kidneys also excrete half of excreted calcium

47
Q

how does calcium balance change during life

A
  • Growth (new bone formation) requires a positive Ca2+ balance
  • Adulthood would ideally be associated with neutral balance (Ca2+ in = Ca2+ out)
  • The ageing process is associated with a slow phase of negative Ca2+ balance leading to loss of bone density (may lead to osteoporosis)
  • Bone loss accelerated after menopause
48
Q

describe bone

A

• The skeleton makes up ±17% by body weight
• Bone functions o Support of the body
o Protection of organs o Leverage system for movement
o Site for hematopoiesis
o Endocrine function (fibroblast growth factor-23; osteocalcin)
o Regulation of mineral homeostasis
• Bone morpholgy
o Trabecular Bone
o Cortical Bone

• Several day delay before osteoid mineralises
• Skeleton 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 dependent on calcitriol
o Deficiency results in failure to mineralise
o Leads to rickets in children, osteomalacia in adults
• Full mineralisation takes several months!

49
Q

describe bone cells

A

Osteoblasts: cells that make bone
Osteoclasts: cells that resorb bone
Osteocytes: most abundant cell type in bone Function: mechanosensor cell?

50
Q

what is the connection between alkaline phosphatase (ALP) and mineralisation

A

• Expressed on surface of differentiated osteoblasts; also released into extracellular fluid and circulation (bone formation marker)
• Releases inorganic phosphate ions (PO4 3- ) from diverse molecules (hydrolysis)
• ALP promotes mineralisation (i.e., precipitation of calcium phosphate/ hydroxyapatite) in 2 ways:
o by increasing the local concentration of inorganic phosphate ions
o by hydrolysing pyrophosphate, a key inhibitor of mineralisation

51
Q

describe bone resorption

A

• Osteoclasts
o Multinucleate, motile bone-resorbing cells
o Formed by fusion of promonocytic precursors present in marrow and circulation
o “Ruffled border” adjacent to bone surface secretes H+ and enzymes
o Express high levels of carbonic anhydrase II required for H+ generation
osteoblast also have RANK ligand

52
Q

describe osteopetrosis

A
  • Also known as: ‘Marble bone disease’
  • Inherited bone disease
  • Increased bone mass
  • Caused by dysfunctional osteoclasts
  • Pits caused by osteoclasts are squished instead of wide and round
  • 10 genes are implicated in this
53
Q

describe bone turnover

A

we need bone metabolism
o To grow
o Respond to altered mechanical requirements
o Repair damage (macro / micro fractures)
o Maintenance (failure prevention)
o Calcium deficit

  • Skeleton is renewed every ± 7 years
  • In health, bone formation and resorption are balanced
  • For bone growth, formation exceeds resorption

• Pathological imbalance between formation and resorption leads to disease
• Most common bone diseases reflect this imbalance
o Osteoporosis
 Most common cause: low oestrogen after menopause
 Main cause of bone loss: increased bone resorption
o Paget’s disease
 Due to overactive osteoclasts

54
Q

How is ionised Ca2+ regulated?

A
  • This regulation is endocrine, requiring the participation of 2 key hormones called parathyroid hormone (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 (vitamin D)
  • The principal organs involved are gut, bone and kidney
55
Q

describe PTH

A
  • A peptide hormone required for the minute-by-minute regulation of ionised calcium levels 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 suppresses PTH secretion (negative feedback loop)
  • PTH secretion is tightly regulated to maintain Ca2+ in physiological range
  • Calcium receptors on cell sense Ca2+ levels to regulate PTH secretion
  • G-protein coupled receptor is activated by binding of calcium
56
Q

what are the actions of PTH

A

o Stimulates efflux of Ca2+ from bone
o Stimulates renal tubular reabsorption of Ca2+ (distal tubule)
o Stimulates formation of calcitriol (indirectly) promoting intestinal absorption of Ca2+
o Promotes phosphate and bicarbonate loss from the kidney (proximal tubule)

57
Q

describe 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 (e.g. neither total thyroidectomy nor calcitonin-secreting tumours alter calcium homeostasis)
  • May be used therapeutically to treat high serum calcium levels
  • Also serves as a ‘tumour marker’ (certain thyroid tumours; some breast cancers)
58
Q

describe vitamin D

A
  • Cholecalciferol
  • Fat soluble vitamin
  • Steroid structure
  • Produced endogenously by the action of UV light on skin precursor, 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 at many sites
  • vitamin D is distinct from other “classical” vitamins, such as vitamin C, B vitamins, etc., which act as cofactors in biochemical reactions
  • Calcitriol is required for the longer-term maintenance of calcium (and phosphate) levels and is required for normal bone growth and mineralisation
59
Q

describe vitamin D synthesis

A
  • The precursor for vitamin D synthesis is a sterol in the cholesterol biosynthetic pathway, 7- dehydrocholesterol which is found in skin
  • Ultraviolet light (UVB) 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 vitamin D adequacy
  • 25(OH)vitamin D circulates to the kidneys where it is hydroxylated by 1α-hydroxylase to 1,25(OH)2 vitamin D (calcitriol) = ‘active’ vitamin D
  • Renal 1α-hydroxylase is regulated by PTH which stimulates its activity. PTH is the principle physiologic regulator, although calcium can affect the activity
  • Other hydroxylations possible (e.g. at the 24- position)
60
Q

what are the mechanisms of calcitriol action

A

• Calcitriol binds to a single vitamin D receptor (VDR)

• The VDR-calcitriol complex acts through a vitamin D-responsive element (new protein synthesis)
o In the intestine, a calcium-binding protein (calbindinD9k) is synthesised which promotes absorption of both calcium and phosphate
o In bone, stimulates osteoblast differentiation and osteoclast activation via RANK ligand (RANKL) formation in osteoblasts

61
Q

what are the actions of calcitriol

A
  • Calcitriol promotes gut absorption of calcium and phosphate (requires new protein synthesis)
  • Calcitriol, in concert with PTH, stimulates osteoclasts and efflux of Ca2+ from bone
  • Calcitriol, in concert with PTH, increases renal Ca2+ reabsorption
  • Maintenance of both calcium and phosphate levels essential for hydroxyapatite formation and normal bone mineralisation
  • Calcitriol deficiency has major effects on bone mineralisation (low calcitriol, high PTH)
62
Q

describe Calcitriol vs PTH

A
  • Both maintain ionised Ca2+
  • PTH responsible for minute-by-minute plasma Ca2+ regulation
  • Calcitriol responsible for longer term plasma Ca2+ regulation
  • PTH tends to decrease plasma phosphate
  • Calcitriol raises plasma phosphate
63
Q

what are some interactions between PTH & calcitriol

A

• Co-operativity
o PTH promotes 1α-hydroxylase activity
o PTH and calcitriol both required in vivo for osteoclast activation and distal tubular Ca2+ reabsorption
o Calcitriol deficiency may impair PTH action

• Limitation of action – Calcitriol stimulates 24-hydroxlase (promotes its own inactivation) – Calcitriol can switch off PTH gene transcription via VDR in parathyroid cells, limiting PTH action

64
Q

how does PTH regulate ionised calcium

A

• Fall in Ca2+ stimulates parathyroid hormone (PTH)

• PTH restores Ca2+ by:
o increasing bone release of Ca2+
o increasing renal reabsorption of Ca2+
o stimulating formation of calcitriol

  • Rising Ca2+ suppresses PTH
  • Calcitonin non-essential role
65
Q

what are the sources of vitamin D3

A

70% of vitamin D3 from sunlight on the skin

30% from dietary sources

66
Q

what are the clinical manifestations of hypercalcaemia

A
  • ‘Stones, bones, abdominal moans and psychic groans’ - also thrones as using toilet a lot – dehydration from urinating a lot
  • Muscle weakness (striated and smooth); possible competition with inward Na+ movement
  • Central effects (anorexia, nausea, mood change, depression)
  • Renal effects (impaired water concentration; renal stone formation)
  • Bone involvement (cause-dependent)
  • Abdominal pain
  • ECG changes (shortened QT interval)
67
Q

what are the causes of factitious hypercalcaemia (non-pathological)

A

• Raised [calcium] due to high plasma [albumin] e.g.
o Venous stasis
o Dehydration
o IV albumin

68
Q

describe primary hyperparathyroidism epidemiology and aetiology

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)
69
Q

describe 1y vs 2y vs 3y hyperparathyroidism

A
  • 1y hyperparathyroidism is an autonomous and inappropriate overproduction of PTH leading to hypercalcaemia
  • 2y hyperparathyroidism is an appropriate increase in PTH in response to hypocalcaemia
  • 3y hyperparathyroidism is rare but refers to the situation where a 2y overactive gland becomes overactive (can be in chronic renal failure)
70
Q

how do you diagnose 1y hyperparathyroidism

A
  • Raised Ca2+ with inappropriately increased PTH
  • Phosphate and bicarbonate tend to be low in serum (increased renal excretion)
  • Alkaline phosphatase normal or moderately increased in more severe disease

• Further investigations:
o Parathyroid imaging scan (Sestamibi, 99mTc-MIBI)

71
Q

how do you treat 1y hyperparathyroidism

A

• Acutely, patients may need treatment of their high ionised calcium:
o re-hydration
o drugs

  • Definitive treatment is removal of parathyroid adenoma (surgery)
  • Mild cases may be managed by repeated follow-up of serum calcium/PTH
  • Where surgery may be difficult (e.g. poor operative risk) drugs to lower calcium levels may be required
72
Q

describe drugs to treat hypercalcaemia

A 
•	Available drugs: 
o	Bisphosphonates (inhibit osteoclast action and bone resorption); after re-hydration this is key drug for longerterm control 
o	Furosemide (inhibits distal Ca2+ reabsorption; requires care and patient must be hydrated first) 
o	Calcitonin (inhibits osteoclast action); tolerance may develop but useful for immediate, short-term management 
o	Glucocorticoids (inhibit vitamin D conversion to calcitriol; can prolong calcitonin action)

• Newer drugs:
o Calcimimetic drugs which bind to Ca2+ sensor and inhibit PTH release. Restricted use (e.g. parathyroid carcinomas)

73
Q

what is the connection between malignant disease and hypercalcaemia

A
  • Commonest cause of hypercalcaemia in hospitalised patients
  • Up to 20-30% cancer patients may develop hypercalcaemia during course of illness

• Two 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

74
Q

what are the endocrine factors in malignant hypercalcaemia

A
  • Solid tumours may secrete PTH-related peptide (or PTHrP) (e.g. 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 of malignancy
  • Some tumours (esp. Hodgkin’s lymphoma) possess 1-OHase activity and synthesise calcitriol
75
Q

describe malignant hypercalcaemia associated with bony metastases

A
  • Approx. 20% cases malignant hypercalcaemia
  • Most commonly associated with breast and lung cancers, multiple myeloma
  • Secretion of osteoclast activating cytokines or other factors into the bone micro-environment is key element
  • Metastatic breast tumour may locally produce PTHrP
  • Myeloma cells produce cytokines that activate osteoclasts (RANKL, IL-3, IL-6) - causes “pepperpot skull with distinctive pits in the skull
76
Q

how do you diagnose malignant hypercalcaemia

A

• Raised Ca2+ with suppressed PTH
o Phosphate tends to be high
o Alkaline phosphatase may be very high (liver or bone metastases)
o Often clear from previous history of malignant disease

77
Q

how do you treat malignant hypercalcaemia

A
  • Re-hydrate the patient
  • If required, use drugs which lower calcium in the blood (as discussed earlier)
  • Treat underlying malignancy (surgery, chemotherapy)
78
Q

what are some “other” causes of hypercalcaemia

A
  • Granulomatous disease e.g. sarcoidosis
  • Exogenous vitamin D excess
  • Familial hypocalciuric hypercalcemia
  • Drugs (e.g. Li, thiazide diuretics)
  • Some endocrine diseases (thyrotoxicosis, Addison’s disease)
  • Immobilization
79
Q

describe sarcoidosis

A
  • Granulomatous disease
  • Usually affects lung (90%) and skin (10%)
  • ↑[calcium] with n[PTH]
  • Hydroxylation of vit D in granulomas
80
Q

describe familial hypocalciuric hypercalcaemia (FHH)

A
  • Rare but interesting
  • Ca2+ sensor on parathyroid glands less sensitive to Ca2+ suppression of PTH
  • Altered ‘set-point’ for PTH/Ca2+ interaction
  • PTH levels tend to be high normal or slightly raised
  • Plasma ionised calcium increased (mild)
  • PTUrine Ca2+ excretion low (relative to plasma Ca2+)
81
Q

describe the clinical manifestations of hypocalcaemia

A

• Predominantly due to an increase in neuromuscular excitability (increased inward Na+ movement?)

•	Neuromuscular 
o	Numbness and paraesthesiae (‘tingling’) in fingertips, toes, around mouth 
o	Anxiety and fatigue 
o	Muscle cramps, carpo-pedal spasm, bronchial or laryngeal spasm 
o	Seizures 
•	Mental state 
o	Personality change 
o	Mental confusion, psychoneurosis 
o	Impaired intellectual ability 
•	ECG changes, eye problems
82
Q

describe factitious hypocalcaemia

A

Consequence of low plasma [albumin] e.g.:
• Acute phase response (low albumin)
• Malnutrition or malabsorption (protein deficiency in diet)
• Liver disease (reduced liver synthesis albumin)
• Nephrotic syndrome (albumin lost in urine)

83
Q

what are causes of deficient 1,25 Vit D amount or action

A
  • Lack of sunlight
  • Inadequate dietary source
  • Malabsorption
  • Chronic renal disease (relatively common)
  • Chronic liver disease (rare)
  • Defective 1-OHase (v. rare)
  • Defective 1,25- D3 receptor (v.rare)
84
Q

what are risk factors for vitamin D deficiency

A

o Those confined indoors (e.g. elderly)
o Dark skinned individuals at high latitudes
o Lack of sunlight exposure through dress, high factor sunscreen etc.

85
Q

what are the biochemical and clinical features of vitamin D deficiency

A
  • Symptoms related to low Ca2+
  • Osteomalacia (bone pain, fractures, disordered growth in children as a consequence of defective mineralisation)
  • Low 25-D3 and 1,25-D3 (usually)
  • Low Ca2+ (may be normal in early stages)
  • High PTH (2y hyperparathyroidism)
  • Phosphate tends to be low
  • Often raised ALP
86
Q

describe osteomalacia (Rickets’ in children)

A
  • Pathological bone problem classically associated with vitamin D deficiency
  • Osteoid laid down by osteoblasts is not adequately calcified
  • Osteoid content in bone increases at the expense of normal calcified osteoid (bone matrix)
  • Bones are softened, weak and susceptible to fracture
87
Q

what are some inherited causes of osteomalacia/Rickets

A
  • Deficient 1-hydroxylase (vitamin D-resistant rickets type 1, VDRR type 1)
  • Defective receptor for calcitriol (Vitamin Dresistant rickets type 2, VDRR type 2)

• Other inherited causes of rickets:

o	Hypophosphataemic rickets 
	Low serum phosphate 
	Impaired mineralisation 
	Excessive urine phosphate loss 
	Phosphaturic hormone (FGF23)/PHEX mutations

o Hypophosphatasia (low alkaline phosphatase)

88
Q

what are some causes of hypoparathyroidism

A

• Acquired
o Surgical damage or removal (relatively common; usually transient)
o Suppressed secretion (e.g. low Mg2+, maternal hypercalcaemia)

• Inherited
o Developmental parathyroid problems
o Genetic/familial disorders e.g. DiGeorge
syndrome

• Biochemistry
o Low Ca2+
o Inappropriately low PTH
o Phosphate may be increased

89
Q

how do you treat hypocalcaemia

A
  • In acute situations IV calcium may be required
  • Normally oral calcium and vitamin D are given (Mg sometimes)

• Vitamin D may be given in various forms:
o By injection (IM) if malabsorption is present or stores require to be repleted more quickly
o As the 1OH form if renal function is impaired

• Close monitoring of plasma calcium concentration necessary

90
Q

describe osteoporosis

A
  • Commonest bone disease (up to 30% women and 12% men)
  • Reduced bone mineral density; disruption of microarchitecture
  • Increased risk of fracture

• Routine biochemistry unaffected
o Calcium levels in blood are typically unaffected

91
Q

describe osteoporosis vs osteomalacia

A
  • Osteoporosis:
  • Loss of calcified matrix and reduced bone density
  • ‘Less’ bone but histologically normal
  • Susceptibility to fracture
  • Essentially normal biochemistry
  • Defined by bone densitometry (less than 2.5 SD than bone from a young adult)
  • Osteomalacia:
  • Abnormal histology with wide seams of uncalcified osteoid
  • Loss of calcified matrix and reduced bone density
  • Susceptibility to fracture
  • Abnormal biochemistry
92
Q

how does calcium enter a cell

A

The influx of calcium is usually initiated by depolarisation of the cell membrane, which activates voltage-gated calcium channels. Calcium diffuses into the cytosol down the large concentration gradient established by the high extracellular and low intracellular calcium concentrations.
This reversible influx of calcium is required for a number of important cellular processes.

93
Q

what is total serum calcium

A

what is measured in blood tests

Free, ionised calcium (~50% of total) (physiologically active form of calcium)

Protein-bound calcium (~40% of total)

Inorganic ion-bound calcium (~10% of total)

94
Q

Which forms of extracellular calcium can be filtered at the kidney

A

Both free and inorganic ion-bound calcium (about 60% of total serum calcium) can be filtered at the kidney. Protein-bound calcium cannot be filtered at the kidney and therefore remains in the bloodstream

95
Q

whats important about albumin and calcium

A

it acts as a buffer for free, ionised calcium.
keeps protein bound calcium at ~40% of the total.
main binding protein for calcium

in hypoalbuminaemia, total calcium is also low
However, changes in albumin do not usually affect the concentration of free, ionised calcium, because this is tightly controlled by hormones. So the patient may have a low total serum calcium, but no symptoms of hypocalcaemia.

96
Q

what is corrected calcium

A

Calculating a corrected calcium value involves adding 0.02 mmol/L to the patient’s measured total serum calcium for every 1 g/L the albumin is below 40 g/L.

Thus, corrected [Ca2+] = measured [Ca2+] + (40 - [albumin] * 0.02)

97
Q

what are some causes of total serum calcium not representing ionised calcium

A

Hypoalbuminaemia

acid-base balance disorders can affect the binding of calcium to albumin and inorganic ions. In acidosis, albumin becomes protonated which prevents it from binding calcium as effectively, therefore unbound calcium increases. On the other hand, in alkalosis albumin can bind calcium more easily, resulting in a reduction in unbound calcium.

98
Q

what are some causes of positive and negative calcium balance

A

Certain situations require positive calcium balance, e.g. in childhood it is necessary for growth.

Later in life, we tend towards a state of negative calcium balance – this is especially the case in females after menopause.

99
Q

how is calcium absorbed from the gut

A

passive transport paracellularly

active transport transcellularly

100
Q

where is calcium reabsorbed in the kidney

A

60% in proximal tubule
25% in ascending limb
10% in distal tubule which can be modified by hormones

101
Q

describe calcitriol

A

Calcitriol is the active form of Vitamin D3 that regulates calcium homeostasis. As a steroid hormone, calcitriol can cross the cell membrane to act by altering levels of gene transcription. It binds to the Vitamin D Receptor (VDR), a nuclear receptor. Vitamin D receptors are expressed in a wide range of tissues: skin, bone, immune system, muscle (both skeletal and cardiac) and endocrine tissues.
Like PTH, calcitriol acts to increase serum calcium concentrations

102
Q

what molecule is measured when measuring Vitamin D levels

A

calcidiol, the inactive version which is turned into calcitriol, as it has a much more stable concentration in the body than calcitriol

103
Q

what is the biochemical profile of osteomalacia

A 
Low calcium
High PTH
Low calcitriol
Low phosphate
High alkaline phosphatase
104
Q

what is the biochemical profile of pagets

A

normal everything other than

High ALP

105
Q

what is Chvostek Sign

A

The Chvostek sign involves tapping the face to agitate the facial nerve. This may induce a twitch on the same side of the face in patients with hypocalcaemia.
The Chvostek sign has a low sensitivity and specificity.
(Tip: Chvostek – think ‘cheek’)

106
Q

what is Trousseau’s sign

A

involves blocking blood flow from the brachial artery using a blood pressure cuff. This may induce carpo-pedal spasm which involves a distinctive wrist flexion, flexion of MCP joints, extension of IP joints and adduction of the thumb. This can be seen even in patients who have not yet developed other hypocalcaemia symptoms.
Trousseau’s sign is more specific than the Chvostek sign, but patients may find carpo-pedal spasm extremely uncomfortable.

107
Q

what are some causes of hypoalbuminaemia

A

Acute phase response (innate body defence mechanism in response to inflammation which alters the concentration of certain serum proteins - seen during acute illness)
Malnutrition or malabsorption
Protein-losing enteropathy e.g. inflammatory bowel disease (IBD)
Liver disease (decreased liver production of albumin)
Nephrotic syndrome (loss of albumin in the urine)

Year 2 - Semester 2 (8 decks)

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