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LCRS2- Endocrinology > Endocrinology > Flashcards

Endocrinology Flashcards

1
Q

What is the pituitary divided into?

A

Anterior pituitary

Posterior pituitary

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2
Q

What hormones are secreted by the anterior pituitary?

A 
FSH/LH
Prolactin
GH
TSH
ACTH
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3
Q

What causes a primary endocrine gland disease?

A

Disorder in the endocrine gland e.g. thyroid, gonads, adrenal cortex

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4
Q

What causes a secondary endocrine gland disease?

A

Disorder in the anterior pituitary

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5
Q

What causes a tertiary endocrine gland disease?

A

Disorder in the hypothalamus

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6
Q

Hypopituitarism

A

Decreased production of all anterior pituitary hormones (panhypopituitarism) OR specific hormones

Congenital (rare) or aquired

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7
Q

What causes congenital panhypopituitarism and what is the main symptoms it causes?

A

Rare
Usually mutations of transcription factor genes needed for normal pituitary development e.g. PROP1 mutation
Deficient in GH and at least 1 other pituitary hormone

Short stature

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8
Q

Congenital panhypopituitarism sufferers will be deficient in …… and at least 1 more pituitary hormone

A

GH

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9
Q

What are the MRI findings for congenital panhypopituitarism?

A

Hypoplastic anterior pituitary gland on MRI

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10
Q

What are possible causes of acquired panhypopituitarism (8)?

A

Tumours (hypothalamic craniopharyngiomas or pituitary adenomas/metastases/cysts)
Radiation
Infection (e.g. meningitis)
Traumatic brain injury
Infiltrative disease (often involving pit stalk)
Inflammatory (hypophysitis)
Pituitary apoplexy (haemorrhage or infarction)
Peri-partum infarction (Sheehan’s syndrome)

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11
Q

How does panhypopituitarism/Simmond’s disease present?

A

Symptoms due to deficient hormones

FSH/LH= Secondary hypogonadism
Reduced libido
Secondary amenorrhoea
Erectile dysfunction

ACTH= Secondary hypoadrenalism (cortisol deficiency)
Fatigue

TSH= Secondary hypothyroidism
Fatigue
Weight gain

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12
Q

What causes Sheehan’s syndrome?

A

Post-partum hypopituitarism secondary to hypotension

Because of post partum haemorrhage (PPH)-> pituitary infarction

Normally in developing countries

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13
Q

What happens to the anterior pituitary in pregnancy?

A

Enlarges

Lactotroph hyperplasia

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14
Q

How does Sheehan’s Syndrome present?

A

Lethargy, anorexia, weight loss- TSH/ACTH/ GH deficiency
Failure of lactation (PRL deficiency)
Failure to resume menses post-delivery
Posterior pituitary usually not affected

Often diagnosed late because many common symptoms

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15
Q

Pituitary apoplexy basis

A

Intra-pituitary haemorrhage (or less commonly infarction)
May be first presentation of a pituitary adenoma or a presentation of an existing one
Precipitated by anti-coagulants

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16
Q

Pituitary apoplexy symptoms

A

Severe sudden onset headache
Visual field defect- compressed optic chiasm (bitemporal hemianopia)
Cavernous sinus may be involved (diplopia of CN 4 and 6, ptosis of CN 3)

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17
Q

How is hypopituitarism diagnosed (2 biochem tests and 1 radiological)?

A

BIOCHEMICAL

  1. Basal plasma concentrations of pit/target endo gland hormones
  2. Stimulated ‘dynamic’ pituitary function tests

RADIOLOGICAL
Pituitary MRI

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18
Q

How does it work and what are the limitations of the biochemical diagnosis of hypotituitarism? (METHOD 1= BASAL PLASMA CONCS)

A

BIOCHEMICAL
Basal plasma concentrations of pit/target endo gland hormones

Limitations...
Cortisol fluctuates during the day
T4 (thyroxine) circulating t1/2 6 days (long half life means may start to fall)
FSH/LH depends on menstruation
GH/ACTH pulsatile (stress of blood test)
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19
Q

How does biochemical diagnosis of hypotituitarism work? (METHOD 2= STIMULATED ‘DYNAMIC’ PITUITARY FUNCTION TESTS)

A

ACTH and GH= stress hormones
Hypoglycaemia <2.2mM= stress

Insulin-induced hypoglycaemia stimulates GH release and ACTH release

TRH stimulates TSH release
GnRH stimulates FSH and LH release

Measure TSH, FSH and LH
Should increase but in a person with hypopituitarism will decrease or stay the same

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20
Q

What does a radiological diagnosis of hypotituitarism show? (MRI OF PITUITARY)

A

Pituitary MRI

May reveal specific pituitary pathology e.g. haemorrhage (apoplexy), adenoma

Empty sella- thin rim of pituitary tissue

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21
Q

What hormone replacements are used in therapy for hypopituitarism?
Deficient hormone-
Replacement-
Check-

A

Deficient hormone- ACTH
Replacement- hydrocortisone
Check- serum cortisol

Deficient hormone- TSH
Replacement- thyroxine
Check- serum free T4

Deficient hormone- women LH/FSH
Replacement- HRT (E2 plus progestagen)
Check- symptom improvement, withdrawal bleed

Deficient hormone- men LH/FSH
Replacement- testosterone
Check- symptom improvement serum testosterone

Deficient hormone- GH
Replacement- GH
Check- IGF1, growth chart (children)

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22
Q

What happens to children and adults in GH deficiency?

A

Children- short stature (=2 SDs < mean height for children of that age and sex)

Adults- less clear

  • Reduced lean mass, increased waist:hip ratio
  • Reduced muscle strength and bulk reduced exercise performance
  • Decreased plasma HDL-cholesterol and raised LDL-cholesterol
  • Impaired ‘psychological well being’ and reduced quality of life
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23
Q

What are the causes of short stature? (7)

A

Genetic= Down’s, Turner’s, Prader-Willi

Emotional deprivation= stress, absue

Systemic disease= CF, rheumatoid arthritis

Malnutrition

Malabsorption= coeliac

Endocrine disorders= Cushing’s, hypothyroidism, GH deficiency, poorly controlled T1DM

Skeletal dysplasias= achrondroplasia, osteogenesis imperfecta

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24
Q

What part of the growth axis is disrupted in Prader-Willi syndrome?

A

Hypothalamus

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25
Q

What part of the growth axis is disrupted in pituitary dwarfism?

A

Lack of GH

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26
Q

What part of the growth axis is disrupted in Laron Dwarfism?

A

GH receptor defect

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27
Q

What causes Prader-Willi syndrome?

A

Deficient in GH secondary to hypothalamic dysfunction

Floppy when babies, food seeking behaviour and weight problem

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28
Q

Achondroplasia

A

Mutation in fibroblast growth
Factor R 3 (FGF3)
Abnormality in growth plate chondrocytes-> impaired linear growth in limbs
Average size trunk

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29
Q

How do the physical features of achondroplasia and pituitary dwarfism differ?

A

Achondroplasia= average trunk, short limbs

Pituitary dwarfism= proportionally normal but short

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30
Q

Are the GH receptors working in laron dwarfism?

A

GH R mutations
Hypothalamus and ant pit in tact
GH can’t act on R

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31
Q

How can laron dwarfism be treated?

A

IGF-1 to increase height

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32
Q

How is short stature diagnosed?

A

Mid parental height = prediction

Then compared to curves of normal growth

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33
Q

What causes acquired GH deficiency in adults?

A

Trauma
Pituitary tumour
Pituitary surgery
Cranial radiotherapy

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34
Q

How is GH deficiency diagnosed?

A

Random GH so little use- pulsatile

Need provocative challenge (i.e. stimulation) = GH PROVOCATION TESTS

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35
Q

What are GH provocation tests?

A

GHRH + ARGININE (iv)
Inhibiting the inhibitor
GH flat if GH deficient
Arginine may stimulate GH release by inhibiting somatostatin release

INSULIN (iv)
Hypoglycaemia
Normal GH should rise but in GH deficiency will stay mostly flat

GLUCAGON (im)

EXERCISE

Then can measure plasma GH at specific time points to check for normal release patterns

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36
Q

How is GH therapy administered?

A

Human recombinant GH (SOMATOTROPIN)

Daily, subcutaneous injection
Monitor clinical response and adjust dose to IGF-1

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37
Q

How long does it take for GH therapy to reach maximal plasma concentration?

A

2-6h

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38
Q

Describe the duration of action of GH therapy

A

Lasts beyond clearance

Peak IGF1 levels at approx 20h

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39
Q

How can GH therapy benefit adults?

A

Improved body composition

Improved muscle strength and exercise capacity

More favourable lipid profile e.g. higher HDL-cholesterol, lower LDL-cholesterol

Increased bone mineral density

Improved psychological well being and quality of life

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40
Q

What are the problems with giving GH therapy to adults?

A

Increased susceptibility to cancer?

Expensive (lifelong = £42k for adult)

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41
Q

Hyperpituitarism

A

Symptoms associated with excess production of adenohypophysial hormones

Usually due to pituitary tumours or ectopic (non-endocrine)

Associated with visual field/CN defects and endocrine symptoms

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42
Q

How does a pituitary tumour disrupt the visual field?

A

Optic chiasm compression by growth of a suprasellar tumour
Loss of vision from outer temporal visual fields (because light from here strieks the nasal aspect of the retina)
Bitemporal hemianopia

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43
Q

How does bitemporal hemianopia manifest?

A

Bumping into things

People don’t realise they’ve lost their peripheral vision

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44
Q

An excess of ACTH (corticotrophin)->

A

Cushing’s disease

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45
Q

An excess of TSH (thyrotrophin)->

A

Thyrotoxicosis

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46
Q

An excess of gonadotrophins (LH/FSH) in children->

A

Precocious puberty

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47
Q

An excess of prolactin->

A

Hyperprolactinaemiaa

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48
Q

An excess of GH>

A

Gigantism

Acromegaly

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49
Q

When is hyperprolactinaemia physiological and pathological?

A

Physiological= high when pregnant/breastfeeding

Pathological= prolactinoma (most common functioning pituitary tumour, usually <10mm diameter microadenoma)

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50
Q

What is the main other hormone affected when a person has a prolactinoma?

A

High prolactin suppresses GnRH pulsatility

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51
Q

What are the signs and symptoms of hyperprolactinaemia due to pituitary adenoma? (M & F)

A 
WOMEN
Galactorrhoea
Secondary amernorrhoea or oligomenorrhoea
Loss of libido
Infertility
MEN
Galactorrhoea uncommon
Loss of libido
Erectile dysfunction
Infertility
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52
Q

What does an anterior pituitary lactotroph secrete?

A

Prolactin

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53
Q

How does dopamine affect prolactin secretion? (D2 R agonism)

A

Dopamine from hypothalamic dopaminergic neurones binds to D2 receptors on ant pit lactotroph and stops prolactin production

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54
Q

How is hyperprolactinaemia treated>

A

Medical= D2 (DA R) agonist-> decrease prolatin secretion, reduce tumour size
E.g. bromocroptine, cabergoline (oral admin)

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55
Q

What are the side effects of DA R agonists?

A 
Nausea and vomiting
Postural hypotension
Dyskinesias
Depression
Pathological gambling (BNF)
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56
Q

How does excess GH affect children and adults?

A

Children- gigantism
Adults- acromegaly (can’t have increased linear growth because growth plates have fused

Usually due to benign growth hormone secreting pituitary adenoma

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57
Q

Why is acromegaly often diagnosed late?

A

Insidious in onset

Signs and symptoms progress gradually (can remain undiagnosed for years)

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58
Q

What are common causes of death due to acromegaly?

A

CV disease 60%
Respiratory complications 25%
Cancer 15%

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59
Q

What parts of the body grow in acromegaly?

A 
Periosteal bone
Cartilage
Fibrous tissue
Connective tissue
Internal organs (cardiomegaly, splenomegaly, hepatomegaly etc.)
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60
Q

What are the clinical features of acromegaly?

A

Excessive sweating (hyperhidrosis)
Headache (very prevalent, hard to treat)
Enlargement of supraorbital ridges, nose, hands and feet, thickening of lips and general coarseness of features
Enlarged tongue (macroglossia)
Mandible grows causing protrusion of lower jaw (prognathism)
Carpal tunnel syndrome (median nerve compression)
Barrel chest, kyphosis
Spade shaped hands with doughy palms

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61
Q

Why is diabetes mellitus a metabolic effect of acromegaly?

A

Excess GH inhibits insulin signalling

  • > increased insulin resistance
  • > impaired glucose tolerance
  • > diabetes mellitus
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62
Q

4 major complications of acromegaly

A

Obstructive sleep apnoea (bone and soft-tissue changes surrounding upper airway-> narrowing/collapse during sleep)

Hypertension (due to GH or IGF1 on vascular tree and GH mediated renal Na reabsorption)

Cardiomyopathy (hypertension, DM, direct toxic effects of excess GH on myocardium)

Increased cancer risk (need colonoscopy- enlarged bowel)

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63
Q

What hormone is commonly secreted with GH in acromegaly?

A

Prolactin

Hyperprolactinaemia causes secondary hypogonadism

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64
Q

How is GH secretion regulated?

A

Stimulated by GHRH

Inhibited by SS

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65
Q

What does GH lead to in the liver?

A

Somatomedin production (mainly IGF1)

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66
Q

How does glucose-induced suppression of growth hormone show whether or not a person is acromegalic?

A

After 75mg oral glucose given:

Normal= decrease (trough) in GH in first 2 hours and then increase (overcorrection) in next 2 hours

Acromegaly= rise in GH in first 2 hours
AND higher start point of GH mU/l

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67
Q

Treatment of acromegaly

A

Surgery (trans-sphenoidal)

Medical= somatostatin analogues (SS inhibits GH secretion from ant pit) e.g. octreotide
= dopamine agonists (GH secreting pit tumours frequently express D2 Rs)

Radiotherapy

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68
Q

How can somatostatin analogues be used to treat acromegaly?

A

Injection (sc) or monthly depot

Reduces GH secretion and tumour size

Pre-treatment before surgery to make resection easier
or
Post-operatively

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69
Q

What are common side effects of somatostatin analogues as treatment for acromegaly?

A

GI side effects

Nausea, diarrhoea, gallstones

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70
Q

What is the neurohypophysis?

A

Posterior pituitary

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71
Q

What is the adenohypophysis?

A

Anterior pituitary

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72
Q

What does the posterior pituitary look like on an MRI (sagittal section)?

A

‘Bright spot’ on pituitary MRI

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73
Q

Why is the posterior pituitary call the neurohypophysis and what cells are present?

A

Collection of axons from neuronal projections

Magnocellular- big cell bodies

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74
Q

What hormones are released by the post pit?

A

Oxytocin

Vasopressin (ADH- anti diuretic hormone)

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75
Q

What is diuresis?

A

Increase in urine production

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76
Q

How does ADH reduce diuresis?

A

Promotes retention from renal cortical and medullary collecting ducts
Via vasopressin 2 receptors (V2Rs)
Stimulates synthesis of AQP 2 (water channels)

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77
Q

What does aquaporin 2 do?

A

Water channels (to allow water passage through membrane)

Bags of AQP2 are inserted into apical membrane of the collecting duct

When there is an osmotic gradient across the cell then water flows in through aquaporin (into collecting duct cell) then across to BL membrane through AQP3 and AQP4 into plasma

Net effect is reabsorption of water from nephron into the plasma

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78
Q

What is the net effect of the actions of ADH in the kidney?

A

Net effect is reabsorption of water from nephron into the plasma

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79
Q

What do osmoreceptors do?

A

Sense osmolality

Very sensitive to changes in EC osmolality (think of it as conc)

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80
Q

Where are osmoreceptors located and why is this area of the brain a different colour?

A

Organum vasculosum
Project to hypothalamic PVN and SON (where there are vasopressinergic nuclei)

Different colour because no BBB (so can communicate directly with system circulation)

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81
Q

Why does the organum vasculosum region of the brain have no BBB?

A

Contains osmoreceptors

Can communicate directly with system circulation)

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82
Q

How does an osmoreceptor respond to increased EC sodium?

A

Increased osmolality
Osmoreceptor shrinks in response (water moves out)
Stimulates osmoreceptor firing-> triggers release of ADH from hyperthalamic neurons in SON and PVN

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83
Q

How does an osmoreceptor respond to water deprivation?

A

Increased serum osmolality (dehydrated)
Stimulation of osmoreceptors-> thirst and increased VP release

Increased water reabsorption from renal collecting ducts

Reduced urine volume, increase in urine osmolality
AND
Reduced serum osmolality

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84
Q

What causes diabetes insipidus?

A

Absence or lack of circulating ADH (cranial/central)

End-organ (kidneys) resistance to ADH (nephrogenic)

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85
Q

What is the difference between nephrogenic and cranial DI?

A

Absence or lack of circulating ADH (cranial/central)

End-organ (kidneys) resistance to ADH (nephrogenic)- RARER, harder to manage

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86
Q

What causes acquired cranial diabetes insipidus?

A

Damage to Neurohypophysial system

E.g.
Traumatic brain injury
Pituitary surgery (damage to stalk)
Pituitary tumours, craniopharyngioma
Metastasis to the pituitary gland e.g. breast
Granulomatous infiltration of median eminence eg TB, sarcoidosis

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87
Q

Is acquired or congenital cranial DI more common?

A

Acquired

Congenital is rare

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88
Q

What causes congeital nephrogenic diabetes insipidus?

A

Rare (e.g. mutation in gene encoding V2 receptor, aquaporin 2 type water channel)

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89
Q

What causes acquired nephrogenic diabetes insipidus?

A

Drugs e.g. lithium

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90
Q

What are the signs and symptoms of DI?

A

Large volumes of urine (polyuria)
Urine very dilute (hypo-osmolar)
Thirst and increased drinking (polydipsia)
Dehydration (and consequences) if fluid intake not maintained - can lead to DEATH
Possible disruption to sleep with associated problems

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91
Q

What is polyuria?

A

Large volumes of urine

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92
Q

What is polydipsia?

A

Excessive thirst and increased drinking

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93
Q

How does diabetes insipidus lead to EC fluid volume expansion?

A 
Inadequate production of/response to ADH
Large volumes of dilute (hypotonic) urine
Increase in plasma osmolality (and Na)
Reduction in EC fluid volume
Thirst- polydipsia
EC fluid volume expansion
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94
Q

How does diabetes insipidus with no access to water lead to dehydration and death?

A 
Inadequate production of/response to ADH
Large volumes of dilute (hypotonic) urine
Increase in plasma osmolality (and Na)
Reduction in EC fluid volume
NO ACCESS TO WATER
Dehydration and death
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95
Q

What is psychogenic polydipsia? What causes it?

A

Most frequently seen in psychiatric patients – aetiology unclear, may reflect anti-cholinergic effects of medication – ‘dry mouth’
Can be in patients told to ‘drink plenty’ by healthcare professionals
Excess fluid intake (polydipsia) and excess urine output (polyuria) – BUT unlike DI, ability to secrete vasopressin in response to osmotic stimuli is preserved

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96
Q

How does psychogenic polydipsia occur?

A

Increased drinking (polydipsia)
Expansion of EC fluid volume, reduction in plasma osmolality
Less VP secreted by posterior pituitary
Large volumes of dilute (hypotonic) urine
EC fluid volume returns to normal
Increased drinking (polysipsia)… REPEAT

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97
Q

How can you tell if someone is normal, has DI or has psychogenic polydipsia?

A

Numbers in mOsm/kg H2O (plasma osmolality)

DI= >290
Normal= Around 270-290
Psychogenic polydipsia= <270

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98
Q

What do the water deprivation test show?

A

Determines whether the patient has diabetes insipidus as opposed to other causes of polydipsia (a condition of excessive thirst that causes an excessive intake of water)

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99
Q

How do you test for DI? (incl different types of DI)

A

Measure urine osmolality of…

  1. Normal hydrated
  2. Water deprivation (to see DI or other cause of polydipsia)
  3. Give synthetic VP (DDAVP) to distinguish between cranial and nephrogenic DI
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100
Q

What are the biochemical features of DI?

A

Hypernatraemia
Raised urea
Increased plasma osmolality
Dilute (hypo-osmolar) urine - ie low urine osmolality

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101
Q

What are the biochemical features of pyschogenic polydipsia?

A

Mild hyponatraemia – excess water intake
Low plasma osmolality
Dilute (hypo-osmolar) urine - ie low urine osmolality

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102
Q

What is terlipressin?

A

A selective vasopressin receptor peptidergic agonists for V1

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103
Q

What is desmopressin (DDAVP)?

A

A selective vasopressin receptor peptidergic agonists for V2

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104
Q

What are the selective vasopressin receptor peptidergic agonists for VI and V2

A

V1 –terlipressin

V2 – desmopressin (DDAVP)

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105
Q

How is desmopressin administered?

A

Nasally (usually spray before bed)
Orally
SC

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106
Q

What effect does desmopressin have on cranial DI?

A

Reduction in urine volume and concentration in cranial DI

CAN’T DRINK AS MUCH AS NORMAL-> risk of hyponatraemia

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107
Q

How can nephrogenic diabetes insipidus be treated?

A

Thiazides e.g. bendroflumethiazide

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108
Q

What is the possible mechanism of thiazide to treat nephrogenic diabetes insipidus?

A

Inhibits Na+/Cl- transport in distal convoluted tubule (-> diuretic effect)
Volume depletion
Compensatory increase in Na+ reabsorption from the proximal tubule (plus small decrease in GFR, etc.)
Increased proximal water reabsorption
Decreased fluid reaches collecting duct
Reduced urine volume

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109
Q

What happens if there is excess ADH?

A

Syndrome of Inappropriate ADH (SIADH)

Make too much ADH

Plasma vasopressin concentration is inappropriately high for the existing plasma osmolality

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110
Q

How does SIADH lead to euvolaemia and hyponatraemia?

A

Increased ADH
Increased H2O reabsorption from renal collecting ducts
Expansion of ECF volume

-> Hyponatraemia

OR

-> Atrial natriuretic peptide (stretch sensitive) from right atrium
Natriuresis
-> Euvolaemia OR hyponatraemia

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111
Q

What is euvolaemia?

A

Normal circulating volume

Maintained because of collecting ducts and ANP

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112
Q

What are the signs of SIADH?

A

Raised urine osmolality, decreased urine volume (initially)

Decreased p[Na+] (HYPONATRAEMIA) mainly due to increased water reabsorption

Feel unwell but can be symptomless

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113
Q

What happens if you are hyponatraemic?

A

Normal plasma conc of Na= 120mM

<120mM-> generalised weakness, poor mental function, nausea

<110mM-> confusion, coma, death

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114
Q

What are the causes of SIADH? (5 groups)

A 
CNS= SAH, stroke, tumour, TBI
Pulmonary disease= Pneumonia, bronchiectasis
Malignancy= Lung (small cell)
Drug-related= Carbamazepine, SSRI
Idiopathic
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115
Q

How is SIADH treated?

A

Surgery for tumour/radiotherapy if there is one

If there is severe hyponatraemia

  • Fluid restriction first
  • Drugs to prevent VP action in kidneys (to induce nephrogenic DI to reduce renal water reabsorption)
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116
Q

What does demeclocycline do?

A

Induce nephrogenic DI (in a SIADH patient) ie reduce renal water reabsorption

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117
Q

What to V2 receptor antagonists (VAPTANS) do?

A

Inhibit action of ADH
Non-competitve V2 R antagonists

Inhibit AQP2 synthesis-> promote water loss rather than losing water and sodium

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118
Q

What causes primary hypothyroidism (myxoedema)?

A

Autoimmune damage to thyroid
Leads to decline in thyroxine (low T4) levels
TSH levels climb

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119
Q

What are common symptoms of hyothyroidism?

A 
Weight gain
Cold intolerance 
Voice deepens
Bradycardia-> hypertension
Constipation
Depression and tiredness
Oedema
Dry hair

Eventual myxoedema coma

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120
Q

What does a healthy adult thyroid gland secrete?

A

T4 (less active) and T3 (more active metabolite)

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121
Q

Why is T4 (thyroxine) a prohormone?

A

T4 converted by deiodinase enzyme activity into tri-iodothyronine (T3)
T3= active metabolite that provides almost all thyroid hormone activity to target cells

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122
Q

How much T3 is from deiodination of T4 and how much is from direct thyroidal secretion?

A

80% from deiodination of T4

20% from direct thyroidal secretion

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123
Q

What is TRE?

A

Thyroid response element

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124
Q

What happens to T4 and T3 in the target cell?

A

Enter target cell
T4 converted to T3

T3 transported into cell nucleus

Binds to heterodimer:
T3 binds to thyroid receptor and RXR (retinoid x receptor) and TRE-> alters gene expression

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125
Q

What thyroid hormone replacement therapy exists?

A

Levothyroxine sodium (THYROXINE=T4)= more commonly used

Liothyronine sodium (TRIIODOTHYRONINE=T3)= less commonly used

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126
Q

What are the clinical uses of levothyroxine sodium (synthetic thyroxine)?

A

Autoimmune primary hypothyroidism

OR

Iatrogenic primary hypothyroidism – e.g. post-thyroidectomy, post-radioactive iodine

OR

Secondary hypothyroidism (problem with pituitary not gland)

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127
Q

How is levothyroxine sodium administered for primary hypothyroidism? (incl. how to guide dose)

A

Oral administration

TSH used as guidance for thyroxine dose - aim to suppress TSH into the reference range

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128
Q

What does levothyroxine sodium aim to do?

A

Negative feedback

Reduce production of TSH (ant pit)

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129
Q

How is levothyroxine sodium administered for primary hypothyroidism? (incl. how to guide dose)

A

Oral administration.

TSH low due to anterior pituitary failure, so can’t use TSH as a guide to dose

Aim for fT4 middle of reference range

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130
Q

When is liothyronine (synthetic trio-iodothyronine) used? How is it administered?

A

Myxoedema coma - a VERY RARE complication of hypothyroidism

iv initially – as onset of action faster than T4 then oral when possible

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131
Q

What is combined thyroid hormone replacement?

A

Combo of T4 and T3= some reported improvement in well-being

Not advised because T3 effects so potent e.g. symptoms of ‘toxicity’ (palpitations, tremor, anxiety)

Also, often combination treatment suppresses TSH

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132
Q

What happens in thyroid hormone over-replacement? (4 groups)

A

Usually associated with low/suppressed TSH

Skeletal- increased bone turnover, reduction in bone mineral density, risk of osteoporosis

Cardiac– tachycardia, risk of dysrhythmia, particularly atrial fibrillation

Metabolism– increased energy expenditure, weight loss

Increased β-adrenergic sensitivite tremor, nervousness

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133
Q

What is the half life of levothyroxine (T4) and liothyronine (T3)

A

Levothyroxine (T4) plasma half life= 6 days

Liothyronine (T3) plasma half life= 2.5 days

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134
Q

How much circulating T4 and T3 is bound to plasma proteins (mainly TBG)?

A

Approx 99.97% of circulating T4
Approx 99.7% of circulating T3

Bound to plasma proteins, mainly thyroxine binding globulin (TBG)

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135
Q

Is bound thyroid hormone available to tissues?

A

No

Only free (unbound) thyroid hormones are available to tissues

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136
Q

What can increase or decrease plasma binding proteins? (I.e. TBG)

A

Plasma binding proteins increase in pregnancy and on prolonged treatment with oestrogens and phenothiazines

TBG falls with malnutrition, liver disease, certain drug treatments (e.g. co-administered drugs incl. phenytoin/salicylates compete for protein binding sites)

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137
Q

How much T4 is there compared to T3 (in the plasma)?

A

10x more T4

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138
Q

How long does it take free and conjugated T3 and T4 to be secreted in the urine?

A

T3 is cleared in hours

T4 is cleared in about 6 days

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139
Q

What drugs are used in treatment of hyperthyroidism? (4 groups)

A

The thionamides (thiourylenes; anti-thyroid drugs)
Potassium Iodide
Radioiodine
β-blockers

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140
Q

Which hyperthyroid drugs are aimed at blocking thyroxine synthesis

A

The thionamides
Potassium Iodide
Radioiodine

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141
Q

What is the aim of beta blockers in treatment of hyperthyroidism?

A

Relieves symptoms

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142
Q

Give 2 examples of thionamides

A

Propylthiouracil (PTU)

Carbimazole (CBZ)

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143
Q

How can thionamides (PTU and CBZ) be used clinically? (3 ways)

A

Daily treatment of hyperthyroid conditions e.g. Graves

Treatment prior to surgery

Reduction of symptoms while waiting for radioactive iodine to act

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144
Q

What are hyperthyroid conditions which may require daily treatment with thionamides?

A

Graves

Toxic thyroid nodule/toxic multinodular goitre

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145
Q

How are thyroid hormones synthesised?

A

Uptake of iodide by active transport

Iodination= iodide converted to iodine

Condensed onto tyrosine residues along the polypeptide backbone of thyroglobulin

Coupling reaction= storage in colloid

Endocytosis and secretion

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146
Q

What enzymes are used in thyroid hormone synthesis to get thyroid hormone in and out of the cell?

A

Into cell= peroxidase transaminase

Out of cell= thyroperoxidase and H202

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147
Q

How do thionamides interfere with thyroid hormone synthesis?

A

Inhibit thyroperoxidase (and hence T3 and T4 synthesis and secretion)

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148
Q

How long does it take biochemically and clinically to have an effect from thionamides?

A

Biochemical effect= hours

Clinical effect= weeks

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149
Q

Why might treatment with thionamides often include proranolol?

A

Rapidly reduces tremor and tachycardia

-olol= beta blocker

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150
Q

How does thionamide lead to improvements in patients with hyperthyroidism? (2 ways)

A

May suppress antibody production in Graves’ disease

Reduces conversion of T4 to T3 in peripheral tissues (PTU)
Lots of T3 made by iodination but want to try and reduce this manufacture

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151
Q

What unwanted actions does thionamide cause?

A

Agranulocytosis/granulocytopenia reduced/absent granular leukocytes (RARE and reversible on withdrawal of drug)

Rashes (relatively common)

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152
Q

Outline the pharmacokinetics of thionamides? PTU and CBZ

A

PTU
Orally active
Plasma half life 6-15h
Crosses placenta and secreted in breastmilk (less than in CBZ)
Metabolised in liver and secreted in urine

CBZ
Orally active
Carbimazole= pro-drug (first converted to methimazole)
Plasma half life 6-15h
Crosses placenta and secreted in breastmilk (more than in PTU)
Metabolised in liver and secreted in urine

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153
Q

How long is anti-thyroid drug treatment usually for?

A

18 months

Period reviews including thyroid function tests for remission/relapse

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154
Q

What is the role of β blockers in thyrotoxicosis?

A

Anti-thyroid drugs don’t have clinical effects for 2 weeks

B blockers lead to reduced tremor, slower heart rate, less anxiety

Non-selective (i.e. B1 and B2) B blocker e.g. propanolol are more effective than selective B1 blockers e.g. atenolol for this

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155
Q

When is iodide (usually KI) used for hyperthyroidism?

A

Preparation of hyperthyroid patients for surgery
Severe thyrotoxic crisis (thyroid storm)
KI doses= 30x average daily requirement

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156
Q

How does KI treat hyperthyroidism (2 ways)?

A

Inhibits iodination of thyroglobulin

Inhibits H202 generation

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157
Q

Time taken for:
Hyperthyroid symptoms to reduce
Vascularity and size of gland to reduce

A

Hyperthyroid symptoms to reduce= 1-2 days

Vascularity and size of gland to reduce= 10-14 days

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158
Q

What is the Wolff-Chaikoff effect?

A

Reduction in thyroid hormone levels caused by ingestion of a large amount of iodine

Presumed autoregulatory

(KI hyperthyroidism)

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159
Q

What are the unwanted actions of KI treatment of hyperthyroidism?

A

Allergic reaction e.g. rashes, fever, angio-oedema

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160
Q

Pharmacokinetic features of KI treatment of hyperthyroidism?

A 
Given orally (Lugol’s solution; aqueous iodine)
Maximum effects after 10 days’ continuous administration
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161
Q

How does high dose radioiodine treat hyperthyroidism (2 ways)?

A

Accumulates in colloid
Emits B particles
Destroys follicular cells

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162
Q

Pharmacokinetic features of radioiodine treatment of hyperthyroidism?

A

Discontinue ATDs 7-10 days before radioiodine treatment

Administer as a single oral dose

Radioactive half life of 8 days

Radioactivity negligible after 2 months

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163
Q

What are the single oral radioiodine doses administered for Graves and thyroid cancer?

A

Graves’ disease: approx 500 MBq

Thyroid cancer: circa 3,000 MBq

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164
Q

Who can’t receive radioiodine to treat hyperthryoidism?

A

Pregnant women
Breast feeding women

NB. Avoid close contact with small children for several weeks after receiving radioiodine

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165
Q

What is 131^I?

A

Radioiodine for treatment of hyperthyroidism

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166
Q

What is the use of radioiodine (131^I or technetium 99 pertechnetate) in very low, tracer doses?

A

To test thyroid gland pathology e.g. toxic nodule, thyroiditis vs Graves’
Administer IV
Negligible cytotoxicity

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167
Q

What diseases are caused by hypersecretion of adrenal hormones?

A

Cushing’s syndrome (cortisol)

Conn’s syndrome (aldosterone)

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168
Q

What inhibits steroid biosynthesis in Cushing’s syndrome?

A

Metyrapone

Ketoconazole

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169
Q

What is an MR antagonist in Conn’s syndrome?

A

Spironolactone

Epleronone

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170
Q

How does metyrapone act to relieve Cushing’s syndrome?

A

Inhibition of 11β-hydroxylase

-> Stops cortisol synthesis
= Steroid synth in z. fasc (and z.retic) are arrested at the 11-deoxycortisol stage

-> ACTH secretion increased

-> Plasma deoxycortisol increases
=There is no negative fb effect on the hypothalamus and pituitary gland by 11-deoxycortisol

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171
Q

What are the main arms of steroid biosynthetic pathways?

A

Cholesterol->

Mineralocorticoid arm
Glucocorticoid arm
Adrenocorticoid arm

SEE DIAGRAM

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172
Q

What is the principal glucocorticoid in humans?

A

Cortisol

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173
Q

In which layers of the adrenal cortex are the following found?
Mineralocorticoid arm
Glucocorticoid arm
Adrenocorticoid arm

A

Mineralocorticoid arm= z. glomerulosa
Glucocorticoid arm= z. fasciculata
Adrenocorticoid arm= z. reticularis

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174
Q

How is metyrapone used to treat Cushing’s syndrome? (2 times)

A

Control of Cushing’s before surgery

Control of Cushing’s syndrome after radiotherapy (slow to work)

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175
Q

Why does metyrapone help control Cushing’s before surgery?

A

Adjust dose (oral) according to cortisol (aim for mean serum cortisol 150-300 nmol/L)

Improves patient’s symptoms and promotes better post-op recovery (better wound healing, less infection etc)

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176
Q

Why can metyrapone cause hypertension?

A

Deoxycorticosterone accumulates in z. glomerulosa

Has aldosterone-like (mineralocorticoid) activity, leading to salt retention and hypertension

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177
Q

Why can metyrapone cause hirsutism?

A

Precursors accumulate (may go to different arm)
Increased adrenal androgen production hirsutism
in women

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178
Q

What are the unwanted actions of metyrapone?

A

Hypertension (on long-term admin)

Hirsutism

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179
Q

How was ketoconazole originally intended to be used (before Cushing’s)? How did it become off-label treatment for Cushing’s?

A

Antifungal agent
Withdrawn due to hepatotoxicity risk
Higher conc-> inhibits steroidogenesis (needs careful monitoring but useful for Cushing’s)

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180
Q

How does ketoconazole help Cushing’s syndrome patients?

A

Block production of glucocorticoids, mineralocorticoid and sex steroids
Many steps blocked, stops production of cortisol (amongst other features)

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181
Q

How is ketoconazole used?

A

For Cushing’s patients
Treatment and control of symptoms prior to surgery

Orally active

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182
Q

What are the unwanted actions of ketoconazole?

A 
Liver damage (possibly fatal)
So monitor liver function weekly, clinically and biochemically
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183
Q

What is spironolactone used for?

A

Primary hyperaldosteronism (Conn’s syndrome)

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184
Q

How does spironolactone treat Conn’s syndrome?

A

Converted to several active metabolites including canrenone
Canrenone= competitive antagonist of the mineralocorticoid receptor (MR)
Blocks Na+ resorption and K+ excretion in the kidney tubules (K sparing diuretic)

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185
Q

What is canrenone? What is it converted from?

A

Converted from spironolactone

Canrenone= competitive antagonist of the mineralocorticoid receptor (MR)

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186
Q

Pharmacokinetics of canrenone?

A

Orally active

Highly protein bound and metabolised in the liver

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187
Q

What are the unwanted effects of spironolactone? Why do these occur?

A 
Menstrual irregularities (+ progesterone receptor)
Gynaecomastia (- androgen receptor)
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188
Q

How does epleronone treat Conn’s syndrome?

A

Mineralocorticoid receptor (MR) antagonist
Similar affinity to the MR compared to the MR compared to spironolactone
Less binding to androgen and progesterone, better tolerated

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189
Q

What is CRH?

A

Corticotrophin releasing hormone

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190
Q

What is ACTH?

A

Adrenocorticotrophic hormone= corticotrophin

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191
Q

How many carbons are in cholesterol?

A

C27

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192
Q

CHOLESTEROL SYNTHESIS. What are the hydroxylase enzymes in the cholesterol synthesis pathway?

A

CHOLESTEROL SYNTHESIS Learn the numbers from diagram

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193
Q

What are the main causes of adrenocortical failure?

A

Tuberculous Addison’s disease (most common worldwide)
Autoimmune Addison’s disease (commonest UK)
Congenital adrenal hyperplasia

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194
Q

What happens in congenital adrenal hyperplasia?

A

Missing 2nd enzyme
Adrenal glands are enormous but not functioning properly
95% cases= lack 21-hydroxylase

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195
Q

List symptoms of Addison’s

A 
Tan
Buckle pigmentation (teeth, eyes)
Pigmented scar
Weak- proximal myopathy
Losing weight
Vitiligo- predisposition to thyroid disease (autoimmune)
Hypotensive (postural hypotension)
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196
Q

What are the consequences of of adrenocortical failure?

A

Can’t make aldosterone
Fall in BP
Loss of salt in urine-> hypotension
Increased plasma potassium (hyperkalaemia)
Fall in glucose due to glucocorticoid deficiency
High ACTH resulting in increased pigmentation
Eventual death due to severe hypotension if not treated

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197
Q

Why does high CTH lead to increased pigmentation?

A

Damage to adrenal gland-> less cortisol so no negative feedback
Make more ACTH from the precursor POMC
Synthesised in pituitary and broken down to ACTH and MSH (and endorphins, enkephalins, other peptides)
MSH-> look tanned

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198
Q

What is MSH and why does it cause a tanned appearance?

A

Melanocyte stimulating hormone

Stimulates melanocytes to make melanin

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199
Q

What should the cortisol and ACTH be in an Addison’s patient at 9am in a blood test?

A 
Cortisol= low
ACTH= high
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200
Q

What specific test is used for Addison’s?

A

Short synacthen test (synACTHen= synthetic ACTH)
Give 250ug synacthen IM so should make lots of IM
Measure cortisol response

Normal person= cortisol goes up
Addisons patient= very small/no rise

Then imaging studies to find source e.g. adrenal or pituitary tumour

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201
Q

What is the most common cause of congenital adrenal hyperplasia?

A

21-hydroxylase deficiency

Complete or partial

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202
Q

What hormones are totally absent or in excess in complete 21-hydroxylase deficiency?

A

Totally absent= aldosterone and cortisol
Excess= sex steroids and testosterone

No cortisol production, so ACTH rises (no -ve fb)-> drives further adrenal androgen production

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203
Q

When a baby has congenital adrenal hyperplasia, how do they present?

A

Usually by 1 week old
As a neonate with a salt losing Addisonian crisis
Some girls may have ambiguous genitalia (virilised by adrenal testosterone)

NB. In utero, foetus gets steroids across placenta

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204
Q

What hormones are deficient or in excess in partial 21-hydroxylase deficiency?

A 
Deficient= cortisol and aldosterone
Excess= sex steroids and testosterone
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205
Q

What age do people with partial 21-hydroxylase deficiency patients present? What is the main problem with the deficiency?

A

Any age
They survive

Main problem in later life is hirsutism and virilisation in girls and precocious puberty in boys due to adrenal testosterone

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206
Q

How does 11 deoxycorticosterone behave?

A

Like aldosterone

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207
Q

What happens if there is excess 11 deoxycorticosterone?

A

Hypertension

Hypokalaemia

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208
Q

What hormones are deficient or in excess in 11-hydroxylase deficiency?

A 
Deficient= cortisol and aldosterone
Excess= sex steroids, testosterone and 11-deoxycorticosterone
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209
Q

What are the problems of 11-hydroxylase deficiency?

A

Essentially becomes a problem of too much mineralocorticoid

This means virilisation, hypertension and low K

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210
Q

What hormones are deficient or in excess in 17-hydroxylase deficiency?

A 
Deficient= cortisol and sex steroids
Excess= 11-deoxycorticosterone and aldosterone (mineralocorticoids)
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211
Q

What are the problems of 17-hydroxylase deficiency?

A

Hypertension, low K, sex steroid deficiency and glucocorticoid deficiency (low glucose)

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212
Q

What are the functions of cortisol, aldosterone and androgens/oestrogens?

A 
Cortisol= essential for life
Aldosterone= promotes Na+ retention and K+ loss
Androgens/oestrogens= different sexual/reproductive functions (from gonads)
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213
Q

What are the main two types of corticosteroid receptors?

A

Glucocorticoid receptors

Mineralocorticoid receptors

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214
Q

What are the differences between glucocorticoid Rs and mineralocorticoid Rs?

A

GR
Wide distribution
Selective for glucocorticoids
Low affinity for cortisol

MR
Discrete distribution (kidney)
Don’t distinguish between aldosterone and cortisol
High affinity for cortisol

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215
Q

How does 11B-hydroxysteroid dehydrogenase (11BHSD) protect mineralocorticoid receptors from cortisol?

A

11BHSD inactivates cortisol-> cortisone (inactive)

Stops aldosterone receptors being overly activated by cortisol

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216
Q

What happens in Cushing’s syndrome that leads to hypertension?

A

Cushings-> making too much cortisol but 11BHSD enzyme can’t do it all so some cortisol not converted to cortisone (inactive) and instead binds to MR aldosterone receptors

Excess cortisol binds to MR-> hypokalamia, hypernatreamia so HYPERTENSIVE

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217
Q 
What kind of corticosteroid receptors do the following drugs act on?
Hydrocortisone
Prednisolone
Fludrocortisone
Dexamethasone
A 
Hydrocortisone= acts on GR/MR
Prednisolone= acts on GR/weak MR
Fludrocortisone= acts on MR
Dexamethasone= acts on GR
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218
Q

What kind of drug is fludrocortisone?

A

Aldosterone analogue
Used as an aldosterone substitute
Corticosteroid drug

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219
Q

How are corticosteroids administered?

A

Oral= hydrocortisone, prednisolone, dxamethasone, fludrocortisone

Parental (IV or IM)= hydrocortisone, dexamethasone

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220
Q

How are corticosteroids distributed?

A

Bind to plasma proteins (cortisol binding globulin CBG and albumin) as circulating cortisol does

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221
Q

How long do corticosteroids last?

A 
Hydrocortisone= duration 8h
Prednisolone= duration 12h
Dexamethasone= duration 40h
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222
Q

What hormones do Addison’s patients lack?

A

Cortisol and aldosterone

Primary adrenocortical failure

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223
Q

What hormones do patients of secondary adrenocortical failure lack?

A

Cortisol but not aldosterone

ACTH deficiency

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224
Q

How is secondary adrenocortical failure treated?

A

Oral hydrocortisone

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225
Q

What is an acute adrenocortical failure?

A

Addisonian crisis (severe hypotension occurs)

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226
Q

How is a patient undergoing a Addisonian crisis treated?

A

IV saline (0.9% sodium chloride) to rehydrate patient

High dose hydrocortisone (IV infusion or IM every 6h, mineralocorticoid effect at high dose-11BHSD overwhelmed)

5% dextrose if hypoglycaemia

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227
Q

How is congenital adrenal hyperplasia treated?

A

Dexamethasone 1/day pm
OR
Hydrocortisone 2-3/day, high dose pm
= to replace cortisol

Fludrocortisone= to replace aldosterone

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228
Q

What are aims for the therapy of congenital adrenal hyperplasia?

A

Replace cortisol and aldosterone

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229
Q

Why is it important to monitor/optimise corticosteroid replacement therapy by measuring?

A

Measure 17 OH progesterone (precursor)
Clinical assessment:
- Cushingoid if GC dose too high
- Hirsutism if GC dose too low (hence ACTH risen)

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230
Q

Why do you increase glucocorticoid dosage when patients are vulnerable to stress?

A

17 OH progesterone

Cortisol (normally= 20mg/day but in stress 200-300mg/day)

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231
Q

When is glucocorticoid dosage increased?

A

Under stress
In minor illness (2x normal dose)
In surgery- hydrocortisone IM with pre-med and at 6-8h intervals, oral once eating and drinking

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232
Q

Outline the male HPG axis

A 
GnRH released from hypothalamus
Stimulatory effect on pituitary
Leads to release of LH and FSH
Stimulatory effect on testis
Production of testosterone

Inhibin released by sertoli cells
With increasing testosterone-> inhibits release of FSH and LH from pit gland and inhibits hypothalamus

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233
Q

How many days is the female menstrual cycle? What are the phases?

A

28

Follicular phase, ovulation, luteal phase

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234
Q

Outline the female HPG axis (not in ovulation)

A 
GnRH released from hypothalamus
Stimulatory effect on pituitary
Leads to release of LH and FSH
Stimulatory effect on ovary
Production of oestradiol and progesterone

Inhibin released
With increasing testosterone-> inhibits release of FSH and LH from pit gland and inhibits hypothalamus

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235
Q

Outline the female HPG axis (in ovulation)

A 
GnRH released from hypothalamus
Stimulatory effect on pituitary
Leads to release of LH and FSH
Stimulatory effect on ovary
Production of oestradiol

Positive feedback leads to increased GnRH and LH/FSH surge which triggers ovulation

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236
Q

What happens if implantation doesn’t occur in the luteal phase?

A

Endometrium is shed (menstruation)

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237
Q

Define: infertility

A

Inability to conceive after 1 year of regular unprotected sex

1:6 couples

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238
Q

What percentage of infertility is caused by abnormalities of M and F?

A

Males- 30%
Females- 45%
Unknown- 25%

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239
Q

How is the HPG axis affected in primary gonadal failure?

A

GnRH released from hypothalamus (HIGH)
LARGE stimulatory effect on pituitary
Leads to HIGH release of LH and FSH
But problem in testes/ovary-> LOW testosterone/oestradiol
LOW inhibin so not appropriate -ve feedback

…. high GnRH etc.

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240
Q

How is the HPG axis affected in hypothalamic/pituitary disease

A

Low LH/FSH
Low testosterone/oestradiol
Low inhibin

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241
Q

What are the clinical features of male hypogonadism?

A 
Loss of libido = sexual interest / desire
Impotence 
Small testes
Decrease muscle bulk
Osteoporosis
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242
Q

What are the causes of male hypogonadism?

A

Hypothalamic-pituitary disease (pituitary not working, low testosterone)

Primary gonadal disease

Hyperprolactinaemia

Androgen receptor deficiency

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243
Q

What are the symptoms of Kallmans syndrome?

A

Anosmia
Low GnRH
Testes orignally undesecended
Stature low-normal

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244
Q

What are examples of hypothalamic-pituitary disease that cause male hypogonadism?

A

Hypopituitarism
Kallmans syndrome
Illness/underweight

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245
Q

What are examples of primary gonadal disease that cause male hypogonadism?

A

Congenital: Klinefelters syndrome (XXY)
Acquired: Testicular torsion, chemotherapy

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246
Q

How can you investigate male hypogonadism?

A

LH, FSH, testosterone (if all low-> MRI pituitary)

Prolactin

Sperm count

Chromosomal analysis (Klinefelters XXY)

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247
Q

Define: azospermia

A

Absence of sperm in ejaculate

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248
Q

Define: oligospermia

A

Reduced numbers of sperm in ejaculate

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249
Q

How is male hypogonadism treated?

A

Replacement testosterone for all patients

For fertility: if hypo/pit disease subcutaenous gonadotrophins (LH/FSH)

Hyperprolactinaemia- DA agonist

250
Q

What are the endogenous sites of production of androgens?

A

Interstitial Leydig cells of the testes

Adrenal cortex (males and females)

Ovaries

Placenta

Tumours

251
Q

What are the 4 main actions of testosterone?

A 
Development of the male genital tract
Maintains fertility in adulthood
Control of secondary sexual characteristics
Anabolic effects (muscle, bone)
252
Q

How much testosterone is bound to protein?

A

98%

253
Q

What can testosterone be converted in to? What enzymes does this involve?

A

Tissue specific processing

Dihydrotestosterone
(DHT) acts via the androgen
receptor (AR)
Converted with 5a-reductase

17β-Oestradiol
(E2) acts via the oestrogen
receptor (ER)
e.g. brain and adipose tissue
Converted with aromatase
254
Q

What receptors do the actions of DHT/E2 depend on?

A

Nuclear receptors

255
Q

What are the clinical uses of testosterone?

A 
Testosterone in adulthood will increase:
Lean body mass
Muscle size and strength
Bone formation and bone mass (in young men)
Libido and potency
256
Q

Can testosterone restore fertility?

A

Will not restore fertility alone

Requires treatment with gonadotrophins to restore normal spermatogenesis

257
Q

What are gonadal disorders in the female?

A

Amenorrhoea
Polycystic ovarian syndrome (PCOS)
Hyperprolactinaemia

258
Q

What is amenorrhoea? Primary? Secondary?

A

Amenorrhoea= absence of periods
1 amenorrhoea= failure to being spontaneous menstruation by age 16 years
2 amenorrhoea= absence of menstruation for 3 months in a woman who has previously had cycles

259
Q

What is oligomenorrhoea?

A

Irregular long cycles

260
Q

What causes amenorrhoea?

A

Pregnancy

Lactation

Ovarian failure (premature ovarian failure, ovariectomy/chemo, ovarian dysgenesis)

Gonadtrophin failure

Hyperprolactinaemia

Androgen excess: gonadal tumour

261
Q

What is ovarian dysgenesis?

A 
In Turners (45 XO)
Lacking one chromosome
262
Q

What are common features of Turners syndrome?

A

Short stature
Cubitus valgus (wide carrying angle)
Gonadal dysgenesis
1:5000 live births

263
Q

What can cause a gonadotrophin failure in women?

A

Hypo/pit disease
Kallmann’s syndrome
Low BMI
Post pill amernorrhoea

264
Q

What investigations would be carried out on a patient with amernorrhoea? (7)

A 
Pregnancy test
LH, FSH, oestradiol
Day 21 progesterone
Prolactin, thyroid function tests
Androgens (testosterone, androstenedione, DHEAS) 
Chromosomal analysis (Turners 45 XO)
Ultrasound scan ovaries / uterus
265
Q

How is amenorrhoea treated?

A

Treat the cause e.g. low weight
Primary ovarian failure- infertile, HRT
Hypothalamic/pit disease (HRT for oestrogen replacement and gonadotrophins in IVF)

266
Q

What is PCOS?

A

Polycystic ovarian syndrome

Incidence: 1 in 12 women of reproductive age

Associated with increased cardiovascular risk and insulin resistance (>diabetes)

267
Q

How is PCOS diagnosed?

A

2 of:
Polycystic ovaries on US
Oligoovulation/anovulation
Clinical/biochemical androgen excess

268
Q

What are the clinical features of PCOS?

A

Hirsuitism
Menstrual cycle disturbance
Increased BMI

269
Q

What fertility drugs are given to treat PCOS?

A

Metformin
Clomiphene
Gonadotrophic therapy as part of IVF

270
Q

What is clomiphene? How does it work?

A

Fertility drug
Anti-oestrogenic in the hypothalamo-pituitary axis

Bind to oestrogen Rs in hypothalamus-> blocks normal negative feedback-> increased secretion of GnRH and gonadotrophins

271
Q

Outline prolactin secretion control

A

Hypothalamus releases TRH (+) and DA (-) which act on pituitary

Leads to release of prolactin

Prolactin-> lactation
AND
Prolactin-> inhibits LH actions on ovary/testis and inhibits GnRH pulsatility

272
Q

What causes hyperprolactinaemia? (7)

A

DA antagonists (e.g. anti-emetics like metoclopramide and anti-psychotics like phenothiazines)

Prolactinoma

Stalk compression due to pituitary adenoma

PCOS

Hypothyroidism (TSH stimulates PL)

Oestrogens (OCP), pregnancy, lactation

Idiopathic

273
Q

How does stalk compression cause hyperprolactinaemia?

A

Stops/reduces affect of DA and TRH on pituitary
Imbalance in - and +
Increased prolactin secretion

274
Q

What are the clinical features of hyperprolactinaemia?

A

Galactorrhoea
Reduced GnRH secretion/LH action-> hypogonadism
Prolactinoma-> headache, visual field defect

275
Q

What are the treatments for hyperprolactinaemia?

A

Treat cause e.g. stop anti-emetics
DA agonist (e.g. bromocriptine, cabergoline)
Prolactinoma rarely needs pituitary surgery

276
Q

A male presents to endocrine clinic who has had bilateral orchidectomy (removal of testes). What would you expect his blood results to show:

  1. Low LH, Low FSH, Low Testosterone
  2. Low LH, high FSH, Low Testosterone
  3. high LH, high FSH, Low Testosterone
  4. high LH, high FSH, high Testosterone
A
  1. high LH, high FSH, Low Testosterone
277
Q

A young woman presents to endocrine clinic who complains of secondary amenorrhea and galactorrhea. Her GP measured her prolactin at 4500 (high). What would you expect her blood results to show:

  1. Low LH, Low FSH, Low oestradiol
  2. Low LH, high FSH, Low oestradiol
  3. high LH, high FSH, Low oestradiol
  4. high LH, high FSH, high oestradiol
A
  1. Low LH, Low FSH, Low oestradiol
278
Q

What is dyspareunia?

A

Painful sex

279
Q 
Which of the following is a common symptom of menopause?
Sleep disturbance 
Headache
Chest pain
Leg swelling
A

Sleep disturbance

280
Q

Why may menopause affect the bones?

A

Low oestrogen-> osteoporosis and fracture

281
Q

What risks are related to HRT?

A 
Blood clots
Strokes
Breast cancer
Heart attacks
Gallstones

Absolute risk of complications for healthy symptomatic postmenopausal woman in their 50s taking HRT for 5 years is very low

282
Q

What is menopause?

A

Permanent cessation of menstruation
Loss of ovarian follicular activity
Climacteric (period of transition period)

283
Q

What’s the average age of menopause?

A

Average age 51 (range 45-55)

284
Q

What are the symptoms of menopause?

A 
Hot flushes (head, neck, upper chest)
Urogenital atrophy and dyspareunia
Sleep disturbance
Depression
Decreased libido
Joint pain

Symptoms usually diminish/disappear with time

285
Q

How do the hormonal changes during menopause affect the HPG axis?

A

Hypothalamus releases GnRH
Causes increased LH and FSH (either or both)
Ovaries are not producing oestradiol or inhibin B
No negative feedback
Increases LH and FSH further

286
Q

Why does menopause lead to osteoporosis?

A

Oestrogen deficiency
Loss of bone matrix
10-fold increased risk of fracture

287
Q

Why does menopause lead to cardiovascular disease?

A

Protected against CVD because the menopause

Have the same risk as men by the age of 70

288
Q

What is the main purpose of HRT?

A

Control vasomotor symptoms (hot flushes)

289
Q

What drug is prescribed as HRT?

A

HRT= E (oestrogen) and P (progesterone) to prevent endometrial hyperplasia

If a woman has had a hysterectomy- E only (don’t need to worry about endometrial proliferation)

290
Q

Why isn’t oestrogen usually used in HRT alone in patients without a hysterectomy?

A

Risk of endometrial carcinoma

291
Q

What are HRT formulations?

A

Cyclical (oestrogen every day and progesterone for the last 12 days)

Continuous combined

Oestrogen preparations

292
Q

What are the different oestrogen preparations in HRT?

A

Oral estradiol (1mg)
Oral conjugated equine oestrogen (0.625mg)
Transdermal (patch) oestradiol (50ug/day)
Intravaginal

293
Q

What are the different kinds of oestrogen?

A 
Estradiol 
Estrone sulphate (conjugated)
Ethinyl estradiol (semi-synthetic)
294
Q

Why is estradiol not that useful in HRT?

A 
Well absorbed
Low bioavailability (first pass metabolism)
295
Q

Why is ethinyl estradiol useful in HRT?

A

Ethinyl group protects the molecule from first pass metabolism

296
Q

What does it mean that ‘timing of exposure’ is importnant in HRT when considering CHD risk?

A

No excess risk in younger menopausal women (50-59) or women <10 years since menopause

297
Q

What is tibolone?

A

Synthetic prohormone
Oestrogenic, progestogenic and weak androgenic actions
Rarely used

298
Q

What affect does tibolone have on risks related to HRT?

A

Reduces fracture risk
Increased risk of stroke
Unknown risk of breast cancer

299
Q

What is Raloxifene?

A

Selective oestrogen receptor modulator

SERM

300
Q

What affect does raloxifene have on risks related to HRT?

A

Ostrogenic in bone- reduces risk of vertebral fractures
Anti-oestrogenic in breast and uterus- reduces breast cancer risk
Increases risk of VTE and fatal stroke

301
Q

What is premature ovarian insufficiency?

A

Menopause occurring before age 40

1% of women

302
Q

What causes premature ovarian insufficiency?

A

Autoimmune
Surgery
Chemotherapy
Radiation

303
Q

What is in combined oral contraceptives?

A

Oestrogen (ethinyl oestradiol) and progestogen (e.g. levonorgestrel or norethisterone)

304
Q

How do combined oral contraceptives work?

A

Suppress ovulation

  • E and P-> -ve fb actions at hypothalamus/pit
  • P thickens cervical mucus

Taken 21 days, stop for 7

305
Q

What is the progesterone only contraceptive? When is it used?

A

P only

When oestrogens contra-indicated e.g. patient ?35 with migraines

306
Q

When must progesterone only contraceptives be taken? Why?

A

Same time every day
Short duration of action
Short half-life

NB. Long acting preparations may be given via an intra-uterine

307
Q

What are the available types of emergency (post-coital) contraception? When can they be used?

A

Copper IUD
Levonorgestrel (within 72hrs)
Ulipristal (up to 120h after intercourse)

308
Q

What is a copper IUD? How does it work?

A

Intrauterine contraceptive device

Affects sperm viability and function

309
Q

What is ulipristal?

A

Emergency contraception
Anti-progestin activity
Delay ovulation by as much as 5 days
Impairs implantation

310
Q

Describe the male reproductive organ

A

Testis- with seminiferous tubules (spermatozoa surrounded by sertoli cells, in interstitia have leydig cells)
Prostate
Seminal
Efferent ductis (from testis to epididymus)

311
Q

What does oestrogen control in the male reproductive organ?

A

Tubular fluid reabsorption

312
Q

What does androgen control in the male reproductive organ?

A

Nutrients and glycoprotein secretion into epididymal fluid

313
Q

How far does spermatozoan travel from testic to oviduct?

A

100,000 x its length

314
Q

What proportion of sparmatozoa reach the ovum?

A

<1/10^6

315
Q

What is ejaculate comprised of?

A

Spermatozoa= 15-120 x 10^6/ ml
Seminal fluid= 2-5ml
Leucocytes

NB. Potentially viruses e.g. hep V, HIV

316
Q

What percent of the spermatozoa in ejaculate enter the cervix?

A

1%

317
Q

Where is seminal fluid from?

A

Small contribution from epididymis/testis

Mainly from accessory sex glands

  • Seminal vesicle
  • Prostate
  • Bulbourethral glands
318
Q

What needs to happen for a sperm to achieve fertilizing capability in the female reproductive tract?

A

Maturation/capacitation

319
Q

Outline maturation/capacitation of sperm

A
  1. Loss of glycoprotein coat
  2. Change in surface membrane characteristics
  3. Whiplash movements of tail
320
Q

What does capacitation of sperm depend on?

A

Oestrogen-dependent
Takes place in ionic and proteolytic environment of the Fallopian tube
Ca dependent

321
Q

What is the acrosome reaction?

A

RELEASE ENZYMES FROM ACROSOME TO ALLOW SPERM TO ENTER THE OVUM

Proteolytic digestive enzymes in capacitated sperm bind to ZP3 (R) glycoprotein coating on zona pellucida of ovum

Ca influx into sperm stimulated by progesterone

Release of hyaluronidase and proteolytic enzymes

Spermatozoon penetrates the zona pellucida

322
Q

What hormone is involved in Ca influx into sperm in the acrosome reaction?

A

Progesterone

323
Q

Where does fertilisation occur?

A

Within the fallopian tubes

324
Q

What does fertilization trigger?

A

Triggers cortical reaction

325
Q

What is the cortical reaction triggered by fertilization? What does this do?

A

Cortical granules release molecules which degrade zona pellucida

Prevent binding of another sperm

Diploidy is achieved (2 sets of chromosomes= 1 from ovum, 1 from sperm)

326
Q

What are polar bodies (relate to fertilization)?

A

Unequal division of cytoplasm

Leaves polar bodies

327
Q

What happens to the fertilised egg as it moves down the Fallopian tube?

A

Moves to uterus and continues to divide (3-4 days)

Receives nutrients from uterine secretions

Free-living phase can last for 9-10 days

328
Q

How does the fertilised egg become a blastocyst?

A

Fertilised egg
2-cell conceptus
4-cell conceptus
8-cell conceptus

COMPACTION

Morula

Blastocyst

329
Q

What can be found in a blastocyst?

A

Blastocoelic cavity
Inner cell mass
Trophoblast cells

330
Q

What are the phases of implantation? What do they require?

A

Attachment phase
Decidualization

Requires progesterone domination in the presence of oestrogen

331
Q

What happens in the attachment phase of implantation?

A

Outer trophoblast cells contact uterine surface epithelium

332
Q

What happens in decidualization of implantation?

A

Decidualization of underlying uterine stromal tissue (within a few hours)

333
Q

What is released from secretory glands in endometrial lining in implantation? What do they do?

A

ADHESION
Leukaemia-inhibitory factor and IL11 promote attachment of trophoblast cells (of inner cell mass) to endometrial lining
Many other molecules involved in process (e.g. HB-EGF)
Blastocyst attachment by adhesion

DECIDUALISATION
IL11 also leads to trophoblast migration, decidualisation

334
Q

What is LIF?

A

Leukaemia inhibitory factor from endometrial secretory glands
Stimulates adhesion of blastocyst to endometrial cells

335
Q

What does IL11 do in implantation?

A

Interleukin-11 from endometrial cells

Released into uterine fluid

336
Q

What is decidualisation?

A

Endometrial changes due to progesterone

337
Q

What happens in decidualisation?

A

Endometrium changes due to progesterone

Glandular eipthelial secretion
Glycogen accumulation in stromal cell cytoplasm
Growth of capillaries
Increased vascular permeability (oedema)

338
Q

What factors are involved in decidualisation?

A

IL11
Histamine
Certain prostaglandins
TGF beta (which promotes angiogenesis)

339
Q

What are the main hormonal changes during pregnancy?

A

First 10 weeks= Peak HCG (produced by placenta) which gradually falls

Oestrogen and progesterone increase

Human placental lactogen increases

Very low LH and low FSH

340
Q

What is hCG?

A

Human chorionic gonadotrophin

Produced by developing implanting blastocysts (syncytiotrophoblast)

341
Q

How do the oestrogens of pregnancy change?

A

5-6 weeks

  • Maternal ovaries (corpus luteum)
  • Rising circulating progesterone and oestradiol
  • Essential for developing fetoplacental unit
  • Inhibit maternal LH and FSH (-ve feedback)

Then taken over by hCG

  • Produced by developing implanting blastocyst
  • Later takes over stimulatory role of gonadotrophins on corpus luteum

From day 40
- Fetoplacental unit takes over

342
Q

How does the placenta make oestradiol/oestrone?

A

Mother produces cholesterol, DHEA and pregnenolone (which -> progesterone that acts on fetal adrenals)

Fetus produces DHEAS (in adrenals)

Cholesterol from mother acts in placenta to convert DHEAS to oestradiol and oestrone
Also cholesterol-> pregnenolone

SEE DIAGRAM IN NOTES

343
Q

What maternal hormones increase and decreases in pregnancy?

A 
INCREASE
ACTH
Prolactin
Iodothyronines
Adrenal steroids
PTHrp (lactation)

DECREASE
Gonadotrophins
TSH
hCH (decreases as the placental hCH variant increases)

344
Q

Where is PTHrp secreted from?

A

Breast

Important for lactation

345
Q

What happens endocrinologically in parturition?

A

Oxytocin
Raised calcium
Contraction

Fetal hypothalamus makes CRH
Pituitary makes corticotrophin
Adrenals make cortisol

346
Q

What happens endocrinologically in lactation?

A

Suckling (stimulus)-> neural pathways stimulate hyopathlamus-> pituitary

Neurohypophysis-> oxytocin-> milk ejection

Adenohypophysis-> prolactin-> milk synthesis

347
Q

What percentage of the body’s calcium is stored in bone?

A

> 95%

348
Q

What are the main components of bone? What percentage of bone mass is it?

A

Inorganic mineral component (65%)
- Calcium hydroxyapatite crystals fill the space between collagen fibrils

Organic components (osteoid- unmineralised bone) (35%) 
- Type 1 collagen fibres (95%)
349
Q

Why is bone remodelling called a dynamic process?

A

Osteoblasts= bone deposition

Osteoclasts=bone resorption

350
Q

What do osteoblasts do?

A

Synthesise osteoid and participate in mineralisation/ calcification
of osteoid

BONE DEPOSITION

351
Q

What do osteoclasts do?

A

Release lysosomal enzymes which break down bone

BONE RESORPTION

352
Q

What do osteocytes do?

A

Make type 1 collage and other EC matrix components

353
Q

Outline osteoclast differentiation

A

RANKL expressed on osteoblast surface

RANKL binds to RANK-R on osteoclast precursor to stimulate osteoclast formation and activity

-> Activated osteoclast

Can be inhibited by OPG (decoy receptor for RANKL)

354
Q

What does RANKL do?

A

Activates osteoclast differentiation

355
Q

What does osteoprotegerin (OPG) do?

A

Inhibits osteoclast differentiation

356
Q

How is bone remodelling regulated?

A

Osteoblasts synthesis new bone

Express Rs for PTH and calcitriol

357
Q

What are PTH and calcitriol the key hormones for?

A

Regulating bone remodelling and calcium balance

358
Q

What is the active form of vitamin D?

A

Calcitriol

1, 25 (OH2D)
1, 25 dihydroxy vitamin D

359
Q

What is the inactive form of vitamin D?

A

Calcidiol

Inactive, stored
25 hydroxyide vitamin D

360
Q

What regulates the production of the active form of vitamin D?

A

PTH

361
Q

How do changes in EC Ca affect nerve and skeletal muscle excitability?

A

Na influx across cell membrane required for generating AP in nerves/skeletal muscle

High EC Ca (hypercalcaemia)= Ca blocks Na influx, less membrane excitability

Low EC Ca (hypocalcaemia)= greater Na influx allowed, more membrane excitability

362
Q

What are the signs and symptoms of hypocalcaemia?

A

PACT (or CATs go numb)

Parasthesia (hands, mouth, feet, lips)
Arrhythmias
Convulsions
Tetany

Because excitable tissues are sensitised

363
Q

What is Chvostek’s sign?

A

Tap facial nerve just below zygomatic arch
Positive response = twitching of facial muscles
Indicates neuromuscular irritability due to hypocalcaemia

Important after surgery which may have affected parathyroid glands (PTH may have been affected)

364
Q

What is Trousseau’s sign?

A

Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia

Spasm is painful, like tetany (can’t relax) so don’t repeat too often

365
Q

What can cause hypocalcaemia?

A

Vit D deficiency

Low PTH levels= hypoparathyroidism (surgical or auto-immune)

PTH resistance e.g. pseudohypoparathyroidism

Renal failure

366
Q

Why does renal failure lead to hypocalcaemia?

A

Impaired 1α hydroxylation -> decreased production of 1,25(OH)2D3

If you’re not making that enzyme, then you’re not doing second hydroxylation step which is very important

367
Q

What is the normal range for calcium?

A

2.2-2.6 mmol/L

368
Q

What are the signs and symptoms of hypercalcaemia?

A

Reduced neuronal excitability-> atonal muscles

‘Stones RENAL, abdominal GI moans and psychic CNS groans’

RENAL EFFECTS
Polyuria and thirst
Nephrocalcinosis (can cause stones), renal colic, chronic renal failure (if prolonged exposure, rare)

GI EFFECTS
Anorexia, nausea, dyspepsia, constipation, pancreatitis

CNS EFFECTS
Fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L)

369
Q

What causes hypercalcaemia?

A

Primary hyperparathyroidism
Malignancy- tumours/metastases often secrete a PTH-like peptide
Conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone- immobilised patient)
Vitamin D excess (rare)

370
Q

How are Ca and PTH release related normally?

A

PTH released in response to falling serum calcium

Then-> negative feedback

371
Q

What happens in primary hyperparathyroidism?

A

RAISED CALCIUM
RAISED (UNSUPPRESSED) PTH

NO negative feedback
Autonomous PTH secretion DESPITE hypercalcaemia

372
Q

What regulates the production of the active form of vitamin D?

A

PTH

373
Q

How do changes in EC Ca affect nerve and skeletal muscle excitability?

A

Na influx across cell membrane required for generating AP in nerves/skeletal muscle

High EC Ca (hypercalcaemia)= Ca blocks Na influx, less membrane excitability

Low EC Ca (hypocalcaemia)= greater Na influx allowed, more membrane excitability

374
Q

What are the effects of the bioactive form of vitamin D?

A

Bioactive form= 1,25 (OH2)D3, calcitriol

Stimulate intestinal absorption of Ca2+ (and Mg2+) and PO4^3-
-> provides ions necessary for normal bone mineralisation

Regulates osteoblast differentiation

Has renal effects (increased Ca2+ reabsorption, decreased PO4^3- reabsorption via FGF23)

375
Q

What is Chvostek’s sign?

A

Tap facial nerve just below zygomatic arch
Positive response = twitching of facial muscles
Indicates neuromuscular irritability due to hypocalcaemia

Important after surgery which may have affected parathyroid glands (PTH may have been affected)

376
Q

What is Trousseau’s sign?

A

Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia

Spasm is painful, like tetany (can’t relax) so don’t repeat too often

377
Q

What can cause hypocalcaemia?

A

Vit D deficiency

Low PTH levels= hypoparathyroidism (surgical or auto-immune)

PTH resistance e.g. pseudohypoparathyroidism

Renal failure

378
Q

Why does renal failure lead to hypocalcaemia?

A

Impaired 1α hydroxylation -> decreased production of 1,25(OH)2D3

If you’re not making that enzyme, then you’re not doing second hydroxylation step which is very important

379
Q

What is the normal range for calcium?

A

2.2-2.6 mmol/L

380
Q

What can cause vitamin D deficiency?

A

No sunlight (e.g. elderly/ overprotected child/ non-Caucasian)

Malabsorption or dietary insufficiency (GI e.g. coeliac disease, IBD)

Liver disease

Renal disease

Receptor defects (N.B. very rare)

381
Q

What causes hypercalcaemia?

A

Primary hyperparathyroidism
Malignancy- tumours/metastases often secrete a PTH-like peptide
Conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone- immobilised patient)
Vitamin D excess (rare)

382
Q

How are Ca and PTH release related normally?

A

PTH released in response to falling serum calcium

Then-> negative feedback

383
Q

What happens in primary hyperparathyroidism?

A

RAISED CALCIUM
RAISED (UNSUPPRESSED) PTH

NO negative feedback
Autonomous PTH secretion DESPITE hypercalcaemia

384
Q

What happens in hypercalcaemia of malignancy?

A

RAISED CALCIUM
SUPPRESSED PTH

Not an abnormal parathyroid gland
Caused by metastatic cancer deposits in bone
There is still negative feedback (PTH turned off by increasing Ca)

385
Q

How is vitamin D deficiency treated in patients with normal renal function?

A

Give 25 hydroxy vit D (25 (OH) D)
Patient can convert this to 1,25 dihydroxy vit D via 1a hydroxlyase in kidney

Ergocalciferol= 25 hydroxy vitamin D2
Cholecalciferol= 25 hydroxy vitamin D3
386
Q

What is FGF23?

A

Hormone produced by bone which increases urine PO4^3- excretion

387
Q

What happens if there is a lack of vitamin d?

A

Lack of mineralisation in bone-> ‘softening’ of bone, bone deformities, bone pain, severe proximal myopathy

Children= rickets
Adults= osteomalacia
388
Q

Where does vitamin D come from?

A

UVB light (reacts with skin 7-dehydrocholesterol (precursor))- vitamin D3

Vitamin D2 from diet

389
Q

What is osteoporosis?

A

Condition of reduced bone mass and a distortion of bone microarchitecture which predisposes to fracture after minimal trauma

Bone mineral density (BMD) 2.5 SDs below the average value from young healthy adults (T-score of -2.5 or lower)

390
Q

What does calcitriol do?

A

Ca absorption in gut
Ca maintenance in bone
renal effects
Negative feedback on PTH

391
Q

What happens in secondary hyperparathyroidism?

A

PTH increases to try to normalise serum calcium (which has fallen from vitamin D deficiency)

392
Q

How do you diagnose vitamin D deficiency?

A

Low inactive vit D (calcidiol)- NB don’t measure active because assay difficult

Low plasma Ca conc (may be normal if secondary hyperparathyroidism has developed)

Low plasma phosphate conc

High PTH (secondary hyperparathyroidism)

Radiological findings e.g. widened osteroid seams

393
Q

How does renal dysfunction lead to bone disease?

A

Decreased renal function

1a) -> Decreased calcitriol
Decreased Ca absorption
Hypocalcaemia

AND/OR

1b) -> Decreased phosphate excretion
Increased plasma phosphate
Hypocalcaemia

2a) Decreased bone mineralization
Osteitis fibrosa cystica

AND/OR

2b) Increased PTH concentration
Increased bone resorption
Osteitis fibrosa cystica

NB. Increased phosphate-> extra-skeletal calcification

394
Q

What are brown tumours?

A

Radiolucent bone lesions (not actually tumours)

Reflect excessive osteoclastic bone resorption secondary to high PTH

395
Q

How is vitamin D deficiency treated in patients with renal failure?

A

Inadequate 1α hydroxylation, so can’t activate 25 hydroxyl vitamin D preparations

Give active form which is quite potent (has to be prescribed)

Alfacalcidol= 1α hydroxycholecalciferol

396
Q

What happens if someone has excess vitamin D (intoxication)?

A

Can lead to hypercalaemia and hypercalciuria due to increased intestinal absorption of calcium

Can occur as a result of:

  • Excessive treatment with active metabolites of vit D
  • Granulomatous diseases
397
Q

What granulomatous diseases can lead to vitamin D excess? Why do they do this?

A

Sarcoidosis
Leprosy
TB

Macrophages in the granuloma produce 1a hydroxylase to convert from inactive to active vit D

398
Q

Why do women with an intact uterus need additional progestogen with HRT oestrogen?

A

Prevent endometrial hyperplasia/cancer

Will give withdrawal bleed- patients not pleased as they had stopped periods

399
Q

What conditions pre-dispose patients for osteoporosis?

A 
Postmenopausal oestrogen deficiency
Age-related deficiency in bone homeostasis 
Hypogonadism in young women and in men
Endocrine conditions
Iatrogenic
400
Q

How does postmenopausal oestrogen deficiency predispose a patient to osteoporosis?

A

Oestrogen deficiency leads to a loss of bone matrix

Subsequent increased risk of fracture

401
Q

How does age increasing predispose a patient to osteoporosis?

A

Ostoblast senescence

402
Q

Why are bisphosphonates used to treat osteoporosis?

A

Bind avidly to hydroxyapatite and ingested by osteoclasts-> impair ability of osteoclasts to reabsorb bone

Decrease osteoclast progenitor development and recruitment

Promote osteoclast apoptosis (programmed cell death)

Net result = reduced bone turnover

403
Q

What can bisphosponates be used to treat?

A

Net result= reduced bone turnover

Osteoporosis (first line treatment)

Malignancy (associated hypercalcaemia and reduced bone pain from metastases)

Paget’s disease (reduce bony pain)

Severe hypercalcaemic emergency (IV, after rehydration to dilute Ca)

404
Q

What are the treatment options of osteoporosis?

A

Oestrogen/Selective Oestrogen Receptor Modulators (SERM)
Bisphosphonates
Denosumab
Teriparatide

405
Q

How does HRT (oestrogen) treat osteoporosis? Why is it limited?

A

Given to post-menopausal women (pharmacological doses of oestrogen)
Prevents bone loss and has anti-resorptive effects on the skeleton

Women with intact uterus need progestogen too

LIMITED
Increased risk of breast cancer
Venous thromboembolism

406
Q

What is denosumab?

A

Human monoclonal antibody

Binds RANKL-> inhibits osteoclast formation and activity

-> Inhibits osteoclast-mediated bone resorption

Given as SC injection every 6 months

2nd line to bisphosphonates

407
Q

What is teriparatide?

A

Recombinant PTH fragment (amino-terminal 34 AAs of native PTH)

Increases bone formation and bone resorption but formation outweighs resorption

3rd line treatment for osteoporosis

Daily SC injection

408
Q

What is Paget’s disease of bone?

A

Accelerated, localised but disorganised bone remodelling

Excessive bone resorption (ostoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts)

Leads to formation of woven bone (structurally disorganised) which is weaker than normal adult lamellar bone

-> bone frailty and bone hypertrophy/ deformity

CHARACTERISED BY abnormal, large osteoclasts- excessive in number

409
Q

How do tissue selective ER agonists work and how is this useful in osteoporosis?

A

Oestrogenic activity in bone
Anti-oestrogenic at breast and uterus
Risks include venous thromboembolism, stroke

NB. Raloxfene has been further developed for its selectivity on bone

410
Q

What are the pharmacokinetics of bisphosphonates?

A

Orally active but poorly absorbed (take on empty stomach, not with milk which reduces drug absorption)

Accumulates at site of bone mineralisation and remains part of bone until it’s resorbed

411
Q

What are the clinical features of Paget’s disease?

A 
Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected
Arthritis
Fracture
Pain
Bone deformity
Increased vascularity (warmth over affected bone) 
Deafness- cochlear involvement
Radiculopathy- due to nerve compression
412
Q

How do you diagnose Paget/s disease?

A

Normal plasma Ca conc
Increased plasma alkaline phosphatase

Plain X-rays (lytic lesions= early THEN deformed, enlarged, thickened bones= later)

Radionuclide bone scan demonstrates extent and locations of skeletal involvement

413
Q

What causes Paget’s disease?

A

Possibly genetic (family history)

Viral origin?

Men and women equal

Usually >50y

Prevalence

  • Highest in UK, N America, Australia and NZ
  • Lowest in Asian and Scandinavia
414
Q

How is body weight homeostasis regulated by the hypothalamus?

A

INPUTS TO HYPOTHALAMUS
Ghrelin, PYY and other gut hormones
Leptin
Neural input from the periphery and other bran regions

INTEGRATED IN HYPOTHALAMUS

HYPOTHALMUS THEN DETERMINES….
Food intake
Energy expenditure

415
Q

What are the hypothalamus subregions determined by?

A

Nuclei differentiated by anatomy/function

Paraventricular nucleus
Lateral hypo
Ventromedial hypo
Arcuate nucleus

416
Q

What is the arcuate nucleus?

A

Key brain area involved in food intake regulation

Incomplete BBB so has access to peripheral hormones (can integrate peripheral and central feeding signals)

Has stimulatory neuronal populations (NPY/Agrp neurons) and inhibitory neuronal populations (POMC neurons)

These neurons extend to other hypothalamic and extra-hypothalamic regions

417
Q

What do NPY/Agrp neurons in the arcuate nucleus do?

A

Increase appetite

418
Q

What do POMC neurons in the arcuate nucleus do?

A

Decrease appetite

419
Q

How do POMC and Agrp from the arcuate nucleus affect the paraventricular nucleus MC4R?

A

POMC-> a-MSH-> activates MC4R-> suppresses food intake

Agrp-> Agrp-> inhibits MC4R-> increases food intake

420
Q

Why haven’t NPY or Agrp mutations associated with appetite been identified?

A

Maybe brain rewires

Maybe just don’t study thin people

421
Q

What do POMC deficiency and MC4R mutations cause?

A

Morbid obesity

Useful to explain signalling

422
Q

What are the features of the ob/ob mouse?

A

MISSING LEPTIN

Recessive mutation
Profoundly obese
Diabetic
Infertile
Stunted linear growth
Decreased body temperature
Decreased energy expenditure
Decreased immune function
Similar abnormalities to starved animals
423
Q

What is leptin?

A

Anti-starvation hormone (rather than anti-obesity hormone)

Codes for 167 AA hormone
Missing in ob/ob mouse

Low when low body fat (high when high)
Central or peripheral admin-> decreased food intake and increased thermogenesis

Activates POMC and inhibits NPY/Agrp neurones

424
Q

What can leptin resistance cause?

A

Obesity due to leptin resistance- hormone is present but doesn’t signal effectively

Don’t realise how much leptin you have

425
Q

What happens in the absence of leptin?

A

Profound effects e.g. hyperphagia, lowered energy expenditure, sterility

Presence of leptin tells the brain that one has sufficient fat reserves for normal functioning- but high leptin has little effect

426
Q

Why can leptin be used for children?

A

Suppresses food intake-> brings body weight down

They haven’t been exposed to it in the past

Reproductive process can be restored (kids don’t go through puberty- body switches off fertility)

427
Q

Why can leptin be used in women with amenorrhea?

A

If they have low body fat leptin can fool their brain that they have fat reserves

Restores LH pulsatility

Preferable to put on some weight

428
Q

How does insulin affect food intake?

A

Insulin also circulates at levels proportional to body fat

Receptors in the hypothalamus

Central administration reduces food intake

May co-ordinate glucose and energy homeostasis-> regulates blood glucose and body adiposity

429
Q

What are gut hormones important for?

A

GI tract= >20 different regulatory peptide hormones

Influence processes including gut motility, secretion of other hormones, appetite

430
Q

What regulates gut hormones?

A

Gut nutrient content

431
Q

What are the major GI hormones?

A 
Cholecystokinin
Secretin
GIP
Motilin
Ghrelin
Gastrin
Insulin
Glucagon
Pancreatic polypeptide
Amylin
GLP-1
GLP-1
Oxymtomodulin
PYY3-36
432
Q

What is cholecystokinin involved in?

A

Gall bladder contraction
GI motility
Pancreatic exocrine secretion

433
Q

What is secretin involved in?

A

Pancreatic exocrine secretion

434
Q

What is GIP involved in?

A

Incretin activity

435
Q

What is motilin involved in?

A

GI motility

436
Q

What is ghrelin involved in? how?

A

Hunger
Growth hormone release

Directly modulates neurones in the arcuate nucleus

  • > stimulates NPY/Agrp neurones
  • > inhibits POMC neurons
  • > increases appetite
437
Q

What is gastrin involved in?

A

28AA gastrin hormone

Acid secretion

438
Q

What are insulin and glucagon involved in?

A

Glucose homeostasis

439
Q

What is pancreatic polypeptide involved in?

A

Gastric motility

Satiation

440
Q

What is amylin involved in?

A

Glucose homeostasis

Gastric motility

441
Q

What is GLP-1 (glucagon- like peptide 1) involved in? What codes for it?

A 
Incretin activity (involved in stimulating glucose-stimulated insulin release)
Satiation-> reduced food intake

Coded for by the preproglucagon gene and released post-prandially

442
Q

What is GLP-2 involved in?

A

GI motility and growth

443
Q

What is oxymtomodulin involved in?

A

Satiation

Acid secretion

444
Q

What is PYY3-36 involved in? How?

A

Satiation

Secreted post-prandially

Directly modulates neurons in the arcuate nucleus

  • > inhibits NPY release
  • > stimulates POMC neurones
  • > decreases appetite
445
Q

What happens if peripheral GLP-1 is given to rodents/humans?

A

Inhibits food intake

GLP-1 agonists have been FDA approved (and DPP-4 inhibitors)

446
Q

What happens to pro-glucagon in intestinal L-cells after a meal?

A

Processing of pro-glucagon

Prohormone convertase 1-> active agonist

Very short half life (regulated by inactivation)

447
Q

What is Saxenda?

A

Long-acting GLP-1 R agonist (liraglutide)

Used originally for T2DM but people using it released they’d lost weight-> FDA approval for weight loss (EMEA soon)

448
Q

Why is PYY3-36 limited as a drug target?

A

Narrow therapeutic window (effective area)

ABOVE= nausea
BELOW= no effect
449
Q

What comorbidies are associated with obesity?

A 
Depression
Stroke
Sleep apnoea
Myocardial infarction
Hypertension
Diabetes
Bowel cancer
Osteoarthritis
Peripheral vascular disease
Gout
450
Q

How do twin studies show genetic involvement of obesity?

A

Monozygotic twins= 0.66 correlation

Dizygotic twins= 0.26 correlation

451
Q

Outline the thrifty gene hypothesis

A

Specific genes selected for to increase metabolic efficiency and fat storage

Now we have plentiful food and do little exercise these genes predispose their carriers to obesity and diabetes

Evolutionarily sensible to put on weight

Supported because the most likely to be come obese are those exposed to Western diet and sedentary life-style after being historically prone to starvation (e.g. Pima Indians, Pacific Islanders)

452
Q

Outline the adaptive drift (drifty gene) hypothesis

A

Normal distribution of body weight: the fat are eaten, the thin starve

Humans defend against predators

Obesity not selected against

Body fat then became neutral change

453
Q

What is the main difference between T1DM and T2DM?

A 
T1= lacking insulin
T2= insulin resistance
454
Q

What are the ambiguous features of diabetes T1/T2?

A

Autoimmune T1 diabetes= leading to insulin deficiency can present in later decades (LADA= Latent autoimmune Diabetes in Adults)

T2DM may present in childhood

Diabetic ketoacidosis can occur in T2DM (particularly afro-caribbean patients)

Monogenic diabetes can be type 1 or type 2 (MODY= mitochondrial diabetes)

455
Q

What is LADA?

A

Latent autoimmune Diabetes in Adults

Autoimmune T1 diabetes= leading to insulin deficiency can present in later decades

456
Q

What is MODY?

A

Monogenic diabetes can be type 1 or type 2

Mitochondrial diabetes

Treat with sulfonylureas not insulin

457
Q

Approximate number of people with T2DM and T1DM in UK?

A

T1= 0.5 mil

T2= 6% population, going up

458
Q

What causes hyperglycaemia in T1DM?

A

Environmental trigger and genetics

Autoimmune destruction of islet cells

Insulin deficiency

Hyperglycaemia

459
Q

What causes hyperglycaemia in T2DM?

A

Obesity and genetics

Insulin resistance

Pancreas will start to fail when it’s making too much insulin over long time-> leads to B cell failure

Hyperglycaemia

460
Q

Outline the pathogenesis of type 1 diabetes

A

PREDIABETES (decrease in B cell mass)

  • Interactions between genes imparting susceptibility and resistance
  • Variable insulitis B-cell sensitivity to injury

OVERT
Very low B cell mass
Glucose intolerance develops

C peptide below detection

Depending on type of immune insult, can happen quickly or over years

461
Q

What is the honeymoon phase in T1DM?

A

When pancreas produces last of insulin and then suddenly beta cells fail

Could be due to imbalance of T cells

Because T1DM is relapsing-remitting disease

462
Q

Why is the immune basis of T1DM important?

A

Increased prevalence of other autoimmune disease

Risk of autoimmunity in relatives (e.g. family could have pernicious anaemia with B12 deficiency)

More complete destruction of B cells

Auto antibodies can be used clinically

Immune modulation offers the possibility of novel treatments

463
Q

What happens to beta cells in the pancreas when there is an increased amount of inflammatory cells?

A

In T1DM, beta cells destroyed

464
Q

What has a larger genetic basis, T1 or T2DM?

A

Type 2

465
Q

What are the HLA-DR alleles that cause a significant risk of T1DM?

A

DR3 and D4

466
Q

What seasonal, environmental factors have been identified in T1DM?

A

Environmental influence > genetic influence

T1DM patients normally present in winter/autumn (maybe an infectious process)

467
Q

When are markers (antibodies) used for diabetic patients?

A

Measure antibodies in blood stream to see T1DM when unsure if patient T1 or T2

Not needed for most patients

468
Q

What markers are used for differentiating between T1DM and T2DM?

A

Islet cell antibodies (ICA)- group O human pancreas

Insulin antibodies (IAA)

Glutamic acid decarboxylase (GADA)- widespread neurotransmitter

Insulinoma-associated-2 autoantibodies (IA-2A)-receptor like family

469
Q

What are the symptoms and signs in T1DM?

A 
SYMPTOMS
Polyuria
Nocturia
Polydipsia
Blurring of vision
Thrush
Weight loss
SIGNS
Dehydration
Cachexia
Hyperventilation
Sme;l of ketones
Glycosuria
Ketonuria
470
Q

Why does metabolic acidosis lead to hyperventilation?

A

Excess CO2 exhalation
Heavy breathing
Hyperventilation to expel excess CO2

471
Q

What happens in T1DM (when there is no insulin)?

A

Fats broken down in adipocytes and lipolysis

Increased HGO and glucose in liver

Decreased glucose uptake into muscles and destruction of muscle tissues
Increased proteolysis

Fatty acids converted to ketone bodies in liver -> ketone bodies in the blood and in urine

472
Q

What are the aims of treatment in T1DM?

A

Reduce early mortality

Avoid acute metabolic decompensation

T1DM need exogenous insulin to preserve life

Prevent long term complications= retinopathy, nephropathy, neuropathy, vascular disease

473
Q

What is the recommended diet in type 1 diabetes?

A

Reduces calories as fat
Reduce calories as refined carbs
Increase calories as complex carbs
Increase soluble fibre

Balanced distribution of food over course of day with regular meals and snacks

474
Q

How was insulin discovered?

A

If you took out pancreas of dogs, they’d develop T1DM and die eventually

But you could make dog survive by giving dog without a pancreas an injection of pancreatic cells (including insulin) from another dog

Now have insulin analogues

475
Q

What kinds of insulin treatment are there?

A

WITH MEALS
Short acting
Human insulin
Insulin analogue (Lispro, Aspart, Glulisine)

BACKGROUND
Long acting
Non-c bound to zinc or protamine
Insulin analogue (Glargine, Determir, Degludec)

476
Q

How were insulin analogues developed?

A

Genetic engineering to alter absorption, distribution, metabolism and excretion

477
Q

What is b.d. insulin?

A

Twice a day

478
Q

What is t.b.s. insulin?

A

3x a day insulin

With every meal

479
Q

If someone eats erratic amounts, how is their dose of insulin affected?

A

Need to give different doses throughout the day

480
Q

What is an insulin pump?

A

Continuous insulin delivery (attached to lower abdomen)
Preprogrammed basal rates and bolus for meals
Doesn’t measure glucose- no completion of feedback loop

481
Q

How does an islet cell transplant work? What are the advantages and limitations?

A

Islet cells from patients who have just died
Inject these into another individual
Then cells travel through portal system and start producing insulin

ADVANTAGES
Glucose control better than with injections/insulin pump

LIMITATIONS
Only for patients who struggle with control because limited number of cells available
Will need immunosuppressive agents

482
Q

How can you monitor blood glucose?

A

CAPILLARY MONITORING
Patients prick finger
Check blood on meter (tell you glucose level)

ABDOMEN MONITORING
Monitor on abdomen-> continuous reading (last up to 2 weeks)- not as sensitive as capillary sugars but give an indicate of patients control without them pricking

483
Q

What is the benefit of the capillary monitoring over time?

A

Can ask retrospectively what they were doing then

Tailor insulin and dietary regime to resolve

484
Q

When is HbA1c false?

A

In patient has something affecting RBCs
= hamoglobinopathy (e.g. SCA, thal)

Also rate of glycation is faster in some individuals

485
Q

What kind of binding is glucose to HbA1c?

A

Irreversible, non-covalent

486
Q

What happens if you lower HbA1c?

A

Lower risk of complication particularly microvascular complication

487
Q

What is ketoacidosis?

A

Rapid decompensation of type 1 diabetes

Hyperglycaemia= reduced tissue glucose utilisation AND increased HGO

Metabolic acidosis= circulating acetoacetate and hydroxybutyrate AND osmotic dehydration and poor tissue perfusion

488
Q

What kind of diabetes has diabetic ketoacidosis?

A

Normally type 1

But can be type 2

489
Q

What happens when a patient has a ‘hypo’?

A

Hypoglycaemic episode

Plasma glucose of < 3.6 mmol / l

(Severe hypoglycaemia - any hypo requiring help of another person to treat)

Occasional hypos Inevitable as a result of treating diabetes
major cause of anxiety in patients and families
Source of major misconceptions in media

490
Q

At what mmol/l are impaired mental processes and consciousness/death likely?

A

Most mental processes impaired at <3 mmol/l
consciousness Impaired at <2 mmol/l
Severe hypoglycaemia may contribute to arrhythmia and sudden death

May have long-term effects on the brain (-> cognitive impairment)

Recurrent hypos result in loss of warnings

‘Hypoglycaemia unawareness’

491
Q

Who is most at risk of hypos?

A

Main risk factor is quality of glycaemic control

More frequent in patients with low HbA1c

492
Q

When can hypos commonly occur?

A

Can occur at anytime but often a clear pattern

Pre-lunch hypos common

Nocturnal hypos very common and often not recognised

WHY?
Unaccustomed exercise
Missed meals
Inadequate snacks
alcohol
Inappropriate insulin regime
493
Q

What are the symptoms and signs of hypoglycaemia?

A 
DUE TO INCREASED AUTONOMIC ACITIVATION
Palpitations (tachycardia) 
Tremor
Sweating
Pallor/cold extremities
Anxiety
DUE TO IMPAIRED CNS FUNCTION
Drowsiness
Confusion
Altered behaviour
Focal neurology
Coma
494
Q

How can you treat hypoglycaemia?

A 
ORAL= feed the patient
Glucose (rapidly absorbed as solution or tablets)
Complex CHO (to maintain blood glucose after initial treatment)

PARENTERAL= give if consciousness impaired
IV dextrose e.g. 10% glucose infusion
1mg glucagon IM
Avoid concentration solutions if poss (e.g. 50% glucose)

495
Q

What is diabetes mellitus?

A

State of chronic hyperglycaemia sufficient to cause long term damage to specific tissues (especially retina, kidney, nerves and arteries)

496
Q

What are key features of T2DM?

A

Not ketosis prone
Not mild
Often involves weight, lipids and blood pressure

497
Q

What does a fasting glucose <6 mean?

A

Normal

498
Q

What does a fasting glucose 6 -7mean?

A

Impaired fasting glucose

499
Q

What does a fasting glucose >7 mean?

A

Diabetes

500
Q

What does a 2 hour glucose <7.8 mean?

A

Normal

501
Q

What does a 2 hour glucose 7.8-11.1 mean?

A

Impaired glucose tolerance

502
Q

What does a 2 hour glucose >11.1 mean?

A

Diabetes

503
Q

What does a random glucose <11.1 mean?

A

Normal

504
Q

What does a random glucose >11.1 mean?

A

Diabetes

505
Q

Outline the epidemiology of T2DM

A

Diabetes is prevalent
Mostly T2DM
Increasing age, but now in children (moving younger but typically from middle ages)
Increasing prevalence
Greatest in ethnic groups that move from rural to urban lifestyle

506
Q

Outline the pathophysiology of T2DM

A

Genes and intrauterine environment (low birth weight-> T2DM predisposition) combine with adult environment

Inulin resistance and insulin secretion defects

Fatty acids important

(Can be MODY- monogenic, mitochrondrial)

507
Q

What causes maturity onset diabetes of the young (MODY)?

A

GENETIC MUTATIONS- monogenic

Several hereditary forms (1-8)
Autosomal dominant
Ineffective pancreatic B cell insulin production
Mutations of transcription factor genes, glucokinase gene
Positive FH, no obesity

508
Q

How do genes lead to macrovascular and microvascular complications?

A

1) Genes-> IUGR

2) Genes-> Obesity/FA-> insulin resistance and adipocytokines
a)-> mitogenic-> MACROVASCULAR
B) -> metabolic dyslipidaemia-> MACROVASCULAR

3) Genes-> B cell failure
a) -> insulin requirement
b) -> hyperglycaemia-> MICROVASCULAR
c) -> metabolic dyslipidaemia-> MACROVASCULAR

509
Q

What is the correlation in identical and non-identical twins for T1DM and T2DM?

A

T1
Identical= 35%
Nonidentical= 10%

T2
Identical= 70%
Nonidentical= 40%

510
Q

How does insulin resistance relate to B cells?

A

Decreasing B cell reserve with increasing insulin resistance

511
Q

How do people with T2DM usually present?

A 
Obesity
Hyperglycaemia and dyslipidaemia
Actue and chronic complications
Osmotic symptoms
Infections
With a complication (acute= hyperosmolar coma AND chronic= ischaemic heart disease adn retinopathy)

Insulin resistance and insulin secretion deficit

512
Q

What does a hyperglycaemic clamp show?

A

Starts with intravenous bolus, followed by glucose infusion to maintain steady blood glucose levels

Look at plasma glucose and plasma insulin

Quantifies insulin resistance and secretion

513
Q

What factors contribute to increased fasting plasma glucose in T2DM?

A

Impaired glucose disposal (e.g. from diminished ability to store glucose)

Increased hepatic glucose production

Inadequate insulin action

Inappropriate glucagon secretion induces continued glucose production by stimulating glycogenolysis (release of glucose from glycogen) and gluconeogenesis (glucose synthesis)

514
Q

Where does glycogen->glucose (gluconeogenesis)?

A

Liver

515
Q

Where does glucose->glycogen?

A

Muscle

516
Q

Where are TG->glycerol and NEFA (lipolysis)?

A

Adipocytes
Particularly from omental fat

NB. fat cells are profoundly important endocrine tissue (not just a store)

517
Q

How is obesity involved in T2DM?

A 
More than a precipitant
Fatty acids and adipocytokines important
Central and omental obesity= worse
80% T2DM are obese
Weight reduction useful signs
518
Q

How do gut microbiota contribute to T2DM?

A

Host and inflammation signaling

Bacterial lipopolysaccharides fermentation to short chain FA, bacterial modulation bile acids

Most studies show correlation between microbiota and T2DM

519
Q

What diabetes treatments lead to weight gain?

A

TZDs especially
SUs
Meglitinides

NB. Metformin doesn’t so combo treatment help

520
Q

What are the major complications of T2DM?

A

MICROVASCULAR
Retinopathy
Nephropathy
Neuropathy

MACROVASCULAR
Ischaemia heart disease
Cerebrovascular
Renal artery stenosis
PVD

METABOLIC
Lactic acidosis
DKA
Hyperosmolar

TREATMENT
Hypoglycaemia

521
Q

What is the basis of management of T2DM?

A

Education
Diet
Pharmacological treatment
Complication screening

MONITOR- weight, glycaemia, blood pressure, dyslipidaemia

522
Q

Why should T2DM be treated?

A

Symptoms
Reduce chance of acute metabolic complications
Reduce chance of long term complications
Education

523
Q

What is the recommended diet for T2DM?

A

Control total calories/increase exercise (weight)
Reduce refined carbohydrate (less sugar)
Increase complex carbohydrate (more rice etc)
reduce fat as proportion of calories (less IR)
Increase unsaturated fat as proportion of fat (IHD)
Increase soluble fibre (longer to absorb CHO)

524
Q

What are the main drugs for T2DM?

A

LIVER
Metformin

ABDOMEN and MUSCLES
Thiazolidinediones

INTESTINES
a glucosidase inhibitor

PANCREAS
Sulphonylureas and metaglinidies
Glucagon like peptide
DPP4 inhibitor

525
Q

How does metformin work? When is it used/not used? SEs?

A

Biguanide, insulin sensitiser
Reduces insulin resistance
Reduces hepatic glucose output
Increases peripheral glucose disposal

USED FOR
Overweight patient with T2DM where diet alone has not succeeded

NOT USED
If severe liver, severe cardiac or mild renal failure

SEs
GI

526
Q

How does sulphonylurea work? When is it used/not used? SEs?

A

Used in T2DM

Glibenclamide, insulin secretagogue

Act by increasing insulin release from the beta cells in the pancreas

USED FOR
Lean patients with type 2 diabetes where diet alone has not succeeded

SEs
Hypoglycaemia, weight gain

527
Q

How does acarbose work? SEs?

A

Used in T2DM

Alpha glucosidase inhibitor
Prolongs absorption of oligosaccharides
Allows insulin secretion to cope, following defective first phase insulin

As effective as metformin

SEs
Flatus

528
Q

What is flatus?

A

Gas in or from the stomach or intestines, produced by swallowing air or by bacterial fermentation

529
Q

How do thiazolidinediones work? SEs?

A

Peroxisome proliferator-activated receptor agonists (PPAR-γ)

E.g. Pioglitazone

Insulin sensitizer, mainly peripheral
Adipocyte differentiation modified, weight gain but peripheral not central
Improvement in glycaemia and lipids
Important for vascular system

SEs
Older types hepatitis
Heart failure

530
Q

What increases secretion of incretins? What do these do?

A

Increased in response to presence of food in GI tract

Incretins are additional factors which stimulates insulin secretion after oral glucose ingestion

531
Q

What is GLP-1?

A

Glucagon ike peptide-1

Used in T2DM

Secreted in response to nutrients in gut
Transcription product of proglucagon gene, mostly from L cell
Stimulates insulin, suppresses glucagon
Increases satiety
Restores B cell glucose sensitivity
Short half life, rapid degredation from enzyme dipeptidyl peptidase-4 (DPPG-4 inhibitor)

532
Q

What does GLP-1 do?

A

Used in T2DM

E.g. Exenatide, liraglutide
Injectable
Long acting GLP-1 agonist
Decrease glucagon conc
Decrease glucose conc
Weight loss
533
Q

What are gliptins?

A

DPPG-4 inhibitor (used in T2DM)

Increase half life of exogenous GLP-1
Increase GLP-1 conc
Decrease glucagon conc
Decrease glucose conc
Neutral on weight
534
Q

What is empagliflozin?

A

For T2DM

Inhibits Na-Glu transported, increases glycosuria

Lowers mortality especially CV mortality e.g. from heart failure

535
Q

What happens to the B cell function with intervention in T2DM?

A

B-cell function continues to decline regardless of intervention in T2DM

536
Q

As well as hyperglycaemia, what is important to control in T2DM?

A

Blood pressure

Diabetic dyslipidaemia (increased LDL, decreased LDL)

537
Q

Outline the prevalence of T1DM and T2DM

A

Type 1= 0.25%

Type 2= 4-7%

538
Q

Outline the geography of T1DM and T2DM

A

Type 1= Europids

Type 2= Less europids

539
Q

Outline the typical age of T1DM and T2DM

A

Type 1= Child, adolescent

Type 2= Middle-age +

540
Q

Outline the onset of T1DM and T2DM

A

Type 1= Acute

Type 2= Gradual

541
Q

Outline the habitus of T1DM and T2DM

A

Type 1= Lean

Type 2= Obese

542
Q

Outline the family history T1DM and T2DM

A

Type 1= Uncommon

Type 2= Common

543
Q

Outline the weight loss in T1DM and T2DM

A

Type 1= Usual

Type 2= Uncommon

544
Q

Outline the ketosis in T1DM and T2DM

A

Type 1= Yes

Type 2= No

545
Q

Outline the serum insulin in T1DM and T2DM

A

Type 1= Low/absent

Type 2= Variable

546
Q

Outline the HLA association in T1DM and T2DM

A

Type 1= DR3, DR4

Type 2= None

547
Q

Outline the islet B cells in T1DM and T2DM

A

Type 1= Destroyed

Type 2= Function

548
Q

Outline the islet cells antibodies in T1DM and T2DM

A

Type 1= Present

Type 2= Absent

549
Q

Why does diabetes lead to micro and macrovascular complications?

A

Diabetes damages blood vessels

550
Q

Where are the main sites of microvascular complications?

A 
Retinal arteries
Glomerular arterioles (kidney)
Vasa nervorum (tiny blood vessels that supply nerves)
551
Q

What are the main microvascular complications?

A 
Severity of hyperglycaemia 
Hypertension 
Genetic
Hyperglycaemic memory
Tissue damage through originally reversible and later irreversible alterations in proteins
552
Q

What is the challenge of hyperglycaemic memory?

A

Have epigenetic ‘reminiscence’ of altered metabolic state

Challenge= lots of patients carry on with normal lifestyle

Then wait for complication and then consider changing lifestyle but TOO LATE

553
Q

How does severity of hyperglycaemia relate to microvascular complication?

A

Complications are reduced if HbA1c is low (i.e. not severe)

554
Q

How does hypertension relate to microvascular complications?

A

Vessels that control BP can be affected

Higher bP-> more likely to get systolic disease

555
Q

What are the mechanisms of glucose damage?

A

Hyperglycaemic and hyperlipidaemia

  • > AGE-RAGE (advanced glycation end-product), oxidative stress, hypoxia
  • > inflammatory signaling cascades
  • > local activation of pro-inflammatory cytokine
  • > inflammation
  • > nephropathy, retinopathy, neuropathy
556
Q

What is diabetic retinopathy?

A

Complication of diabetes, caused by high blood sugar levels damaging the back of the eye (retina)

Main cause of visual loss in people with diabetes and the main cause of blindness in people of working age

557
Q

What is background diabetic retinopathy? 3 common features

A

Happens to majority of patients

3 common features:
Hard exudates (cheese colour, lipid)
Microaneurysms (“dots”)
Blot haemorrhages

558
Q

What is pre-proliferative diabetic retinopathy?

A

Progression from background diabetic retinopathy (if untreated)

Cotton wool spots also called soft exudates (fluffy)
Represent retinal ischaemia-. various parts become ischaemic

559
Q

What is proliferative retinopathy?

A

Visible new vessels on disk or elsewhere in retina

560
Q

What is maculopathy?

A

Hard exudates near the macula
Same disease as background but happens to be near macula
Can threaten direct vision
May also have cotton wool spots

561
Q

What is the progression of retinopathy?

A

Background
Pre-proliferative
Proliferative

NB. Could have maculopathy

562
Q

How is diabetic retinopathy managed?

A

Need to improve control of blood glucose (warn patient that warning signs are present)

Pan retinal photocoagulation for pre-proliferative and proliferative
(Round circles where eye laser beam fired into eye-> prevents new ischaemic patches forming)

Treat maculopathy with GRID of photocoagulation (GRID laser therapy) NOT PAN RETINAL because problem only around macula

563
Q

Which of the following statement is true regarding diabetic retinopathy?

Progression is unrelated to glycaemic control

Cotton wool spots are a feature of background retinopathy

Hard exudates are always treated with pan retinal photocoagulation

Maculopathy can threaten direct vision

Proliferative changes are best left untreated

A

Maculopathy can threaten direct vision

564
Q

What is the pathophysiology of diabetic nephropathy?

A

Hypertension
Progressively increasing proteinuria
Progressively deteriorating kidney function
Classic histological features

565
Q

Why is it important to understanding kidney disease with diabetes?

A

Diabetes and kidney disease-> increased risk of CHF (chronic heart failure), AMI (acute MI), CVA/TIA (stroke), PVD (periph vasc disease) , death
-> ASSOCIATED MORBIDITY AND MORTALITY

Health care burden

566
Q

What are the histological features of diabetic nephropathy?

A

GLOMEULAR
Mesangial expansion
Basement membrane thickening
Glomerulosclerosis

VASCULAR

TUBULOINTERSTITIAL

Essentially in diabetic nephropathy, metabolic and haemodynamic factors-> over production of matrix leading to mesangial expansion and to basement membrane thickening
As this progresses you get sclerosis of the glomerulus and secondary effects in the tubulointerstitium

567
Q

What is the epidemiology of diabetic nephropathy?

A

Type 1 DM= 20-40% after 30-40 years

Type 2 DM= Probably equivalent but compounding factors

568
Q

What factors can affect the epidemiology of nephropathy in T2DM?

A 
Age at development of disease 
Racial factors
Age at presentation
May have been asymptomatic but still glucose unregulated 
Loss due to cardiovascular morbidity
569
Q

What are the clinical features of diabetic nephropathy?

A

Progressive proteinuria
Increased BP
Deranged renal function

570
Q

What are the ranges for proteinuria?

A

See degree of protein being expelled

Normal range
<30mg/24hrs

Microalbuminuric range
20-200mg/24hrs

Asymptomatic range
300-3000mg/24hrs

Nephrotic range
>3000mg/24hr

571
Q

What are the strategies for intervention of diabetic nephropathy?

A

Diabetic control (decreasing HbA1c-> reduced microvascular complications)

Inhibition of activity of RAS system

Blood pressure control (e.g. ACE inhibitors)

Stopping smoking

572
Q

What drugs affect angiotensin 2?

A

ACE inhibitors

573
Q

What effects does angiotensin 2 have?

A 
Vasoactive effects
Mediation of glomerular hyperfiltration
Increased tubular uptake of proteins
Induction of pro fibrotic cytokines
Stimulation of glomerular and tubular growth
Podocyte effects
Induction of pro inflammatory cytokines
Generation of ROS and NF-kB
Stimulates fibroblast proliferation
Up regulation of adhesion molecules on endothelial cells
Up regulation of lipoprotein receptors
574
Q

Which microvascular complication of diabetes do ACE inhibitors prevent?

A

Diabetic nephropathy

575
Q

Which of the following are features of diabetic nephropathy?

Affects all patients with diabetes over time
Associated with decreased blood pressure
Progressively increasing proteinuria
Unrelated to glycaemic control
Associated with a low risk of cardiovascular events

A

Progressively increasing proteinuria

576
Q

What is diabetic neuropathy?

A

Diabetic neuropathies are a family of nerve disorders caused by diabetes

Blocking of small vessels supplying nerves (vasa nervorum)

Some people with nerve damage have no symptoms

Others may have symptoms such as pain, tingling or numbness in the hands, arms, feet, and legs

577
Q

What kinds of diabetic neuropathy are there?

A 
Peripheral polyneuropathy
Mononeuropathy
Mononeuritis multiplex
Radiculopathy
Autonomic neuropathy
Diabetic amyotrophy
Sensory and motor
578
Q

How does diabetic neuropathy progress?

A

Initiating event (genetics and inflammation contribute)- from insult or chronic disorders

Glycation

Epigenetic

Function and progressive pathological changes

579
Q

What is peripheral neuropathy?

A

Longest nerves supply feet

Loss of sensation, ankle jerks, vibration sense (tuning fork)

Danger is that patients will not sense an injury to the foot (e.g. stepping on nail)

May repeatedly injure but not notice-> multiple fractures on foot X-ray (Charcot’s joint)

580
Q

Who is peripheral neuropathy most likely to occur in?

A

Who is it most likely to occur in?

581
Q

What is a monofilament exam?

A 
Test for peripheral neuropathy
Metal object (nylon filament) has predefined pressure (when it bends = 10g of pressure applied to skin)
Ask patient to say when they can feel the pressure point on their foot

Predicts neuropathy and ulceration

582
Q

What is mononeuropathy?

A

Usually sudden motor loss
Wrist drop, foot drop
Cranial nerve palsy (double vision due to 3rd nerve palsy)

583
Q

What is pupil sparing third nerve palsy?

A

Eye is usually down and out
6th nerve pulls eye out
and 4th nerve pulls it down

Pupil does respond to light (because parasympathetic fibres on outside don’t easily lose blood supply in diabetes)

584
Q

How can an aneurysm cause third nerve palsy?

A

Press on parasympathetic fibres first causing fixed dilated pupil
Pupil not spared (so can tell it’s not diabetic)

585
Q

What is mononeuritis multiplex?

A

Random combo of peripheral nerve lesions
Can occur in different ways
E.g. optic nerve and radial nerve can be affected despite not being linked

586
Q

What is radiculopathy?

A

Pain over spinal nerves, usually affecting a dermatome on the abdomen or chest wall
Nerves that are connected

587
Q

What is the difference between mononeuritis multiplex and radiculopathy?

A 
Mononeuritis= random combo of peripheral nerve lesions
Radiculopathy= nerves that are connected
588
Q

What is autonomic neuropathy?

A

Loss of sympathetic and parasympathetic nerves to GI tract, bladder, cardiovascular system

589
Q

How does autonomic neuropathy affect the GI tract?

A

Difficulty swallowing
Delayed gastric emptying
Constipation/ nocturnal diarrhoea

590
Q

How does autonomic neuropathy affect the postural hypotension?

A

Can be disabling e.g. collapsing on standing

591
Q

How can you measure cardiac autonomic supply in diabetic autonomic neuropathy?

A

Measure changes in heart rate in response to Valsalva manoevre (blow into syringe-> pressure-> affect HR, patients with autonomic neuropathy may not do as well)
Normally there is a change in heart rate
Look at ECG and compare R-R intervals

592
Q

What are the main types of macrovascular disease in diabetes?

A

Early widespread atherosclerosis
Ischaemic heart disease
Cerebrovascular disease
Peripheral vascular disease

593
Q

How are atheromas formed? (Macrovascular disease and the metabolic syndrome_

A

SILENT CLINICALLY
Initial lesion (grows with IR lipid BP)
Fatty streak (IR lipid BP)
Intermediate (IR lipid BP)

OVERT CLINICALLY
Atheroma (smooth muscle IR)
Fibroatheroma
Complicated (thrombosis)

*IR= insulin resistance

594
Q

What risk factors contribute to atheromas?

A

Atheroma= macrovascular complication of diabetes

Fasting glucose (>6mmol/l)

HDL (<1 for men or <1.3 women)

Hypertension (BP >135/80)

Insulin resistance, inflammation, adipocytokines, urine microalbumin

Waist circumference (>102 in men and >88 in women)

595
Q

How is life expectancy affected by hyperglycaemia?

A

Hyperglycaemia is associated with significantly reduced life expectancy

596
Q

True or false: macrovascular conditions occur in people with diabetes only

A

FALSE

Occurs in people with or without diabetes

597
Q

How do microvascular and macrovascular diseases affect morbidity and mortality?

A

Microvascular disease causes morbidity

Macrovascular disease causes morbidity and mortality

598
Q

How does diabetes mortality change with known CVD?

A

Mortality increased in MI if you have diabetes

Mortality similar if someone has diabetes and no MI AND someone who has no diabetes but has had MI

Harder to treat patients with co-morbidities

599
Q

How does macrovascular disease affect ischaemic heart disease, cardiovascular disease, peripheral vascular disease and renal artery stenosis?

A

IHD
The major cause of morbidity and mortality in diabetes
The mechanisms are similar with and without diabetes

CVD
Earlier than without diabetes
More widespread

PVD
Contributes to diabetic foot problems with neuropathy

RAS
May contribute to hypertension and renal failure

600
Q

Is controlling blood sugar more important for microvascular or macrovascular conditions of diabetes?

A

Microvascular

601
Q

What is adiponectin?

A

Mechanism possibly responsible to T2DM

Normally decreases insulin resistance

602
Q

How should macrovascular diseases be managed?

A

Aggressive management of multiple risk factors (modifiable and non-modifiable)

Intensive therapy over conventional

603
Q

What are the risk factors for macrovascular disease?

A 
NON-MODIFIABLE
Age
Sex
Birth weight
FH/Genes
MODIFIABLE
Dyslipidaemia
High blood pressure
Smoking
Diabetes
604
Q

What are the treatment goals in T2DM?

A

Lower blood glucose
Treat BP
Manage blood lipids

605
Q

What complications of diabetes predispose the patient to foot disease?

A

Neuropathy- sensory, motor and autonomic

Peripheral vascular disease

606
Q

What is the prevalence of current or past foot ulceration in diabetes?

A

5-7%

Risk of amputation 60x in diabetes

607
Q

What is the pathway to foot ulceration?

A 
Sensory/motor/autonomic neuropathy 
Limited joint mobility
Peripheral vascular disease
Trauma
Reduced resistance to infection
Diabetic complications e.g. retinopathy (can't see things-> stub toe)
608
Q

What happens in sensory neuropathy that leads to foot ulceration?

A

Loss of touch (don’t notice stone in shoe/sore feet)
Loss of vibration
Loss of temp sensation (hot bath)

609
Q

What happens in motor neuropathy that leads to foot ulceration?

A

Clawing of toes and flattening of arch of foot

-> abnormal neuropathy

610
Q

What happens in autonomic neuropathy that leads to foot ulceration?

A

Lack of sweating

611
Q

How does limited joint mobility lead to foot ulceration?

A

Abnormal pressure on parts of feet

612
Q

How does reduced resistance to infection lead to foot ulceration?

A

White cells don’t work as well in hyperglycaemia

613
Q

What will a magnetic resonance angiography for peripheral vessel disease show?

A

Major stenoses (e.g. at the origin of left external iliac artery) and occlusion (e.g. in proximal segment of the right superficial femoral artery)

614
Q

What are the features of the neuropathic foot, ischaemic foot and neuro-ischaemic foot?

A

NEUROPATHIC FOOT= numb, warm, dry, palpable foot pulses, ulcers at points of high pressure loading.

ISCHAEMIC FOOT= cold, pulseless, ulcers at the foot margins.

NEURO-ISCHAEMIC FOOT= numb, cold, dry, pulseless, ulcers at points of high pressure loading and at foot margins

615
Q

Why may someone with a diabetic ulcer have a black toe?

A

Peripheral vascular disease

End artery has occluded-> gangrene of toe

616
Q

Where are common sites for foot ulcers?

A

Dorsum of toes

Ball of foot

617
Q

What should be considered when you assess the foot of a diabetic patient?

A

Appearance= deformity? callus?
Feel= hot? cold? dry?
Foot pulses= dorsalis pedis? posterior tibial pulse?
Neuropathy= vibration sensation, temp, ankle jerk reflex, fine touch sensation

618
Q

How can you prevent foot ulcers?

A 
PREVENTATIVE
Inspect feet daily
Have feet measured when buying shoes
Buy shoes with laces and square toe box
Inspect inside of shoes for foreign objects
attend chiropodist
Cut nails straight across
Care with heat
Never walk barefoot
DIABETES CONTROL
Hyperglycaemia
Hypertension
Dyslipidaemia
Stop smoking
Education
619
Q

How are diabetic foot ulcers managed?

A 
Relief of pressure
bed rest (risk of DVT, heel ulceration, redistribution of pressure/total contact cast)

Antibiotics, possibly long term

Debridement

Revascularization (angioplasty, arterial bypass surgery)

Amputation

620
Q

What features of diabetic feet may lead to osteomyelitis?

A

Patient with Charcot neuro-osteoarthropathy and a rocker-bottom foot

Will have osteomyelitis on cuboid bone

621
Q

How can you differentiate between osteomyelitis and active charcot?

A

OSTEOMYELITIS
Hot red foot with ulcer
X ray= normal first weeks
MRI= marrow oedema in forefoot and hindfoot near ulcer

ACTIVE CHARCOT
Hot red foot, no ulcer
Midfood subarticular
X ray= normal first weeks
MRI= marrow oedema in midfoot subcondral

LCRS2- Endocrinology (1 decks)

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