Endocrinology Flashcards
What is the pituitary divided into?
Anterior pituitary
Posterior pituitary
What hormones are secreted by the anterior pituitary?
FSH/LH Prolactin GH TSH ACTH
What causes a primary endocrine gland disease?
Disorder in the endocrine gland e.g. thyroid, gonads, adrenal cortex
What causes a secondary endocrine gland disease?
Disorder in the anterior pituitary
What causes a tertiary endocrine gland disease?
Disorder in the hypothalamus
Hypopituitarism
Decreased production of all anterior pituitary hormones (panhypopituitarism) OR specific hormones
Congenital (rare) or aquired
What causes congenital panhypopituitarism and what is the main symptoms it causes?
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
Congenital panhypopituitarism sufferers will be deficient in …… and at least 1 more pituitary hormone
GH
What are the MRI findings for congenital panhypopituitarism?
Hypoplastic anterior pituitary gland on MRI
What are possible causes of acquired panhypopituitarism (8)?
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)
How does panhypopituitarism/Simmond’s disease present?
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
What causes Sheehan’s syndrome?
Post-partum hypopituitarism secondary to hypotension
Because of post partum haemorrhage (PPH)-> pituitary infarction
Normally in developing countries
What happens to the anterior pituitary in pregnancy?
Enlarges
Lactotroph hyperplasia
How does Sheehan’s Syndrome present?
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
Pituitary apoplexy basis
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
Pituitary apoplexy symptoms
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)
How is hypopituitarism diagnosed (2 biochem tests and 1 radiological)?
BIOCHEMICAL
- Basal plasma concentrations of pit/target endo gland hormones
- Stimulated ‘dynamic’ pituitary function tests
RADIOLOGICAL
Pituitary MRI
How does it work and what are the limitations of the biochemical diagnosis of hypotituitarism? (METHOD 1= BASAL PLASMA CONCS)
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)
How does biochemical diagnosis of hypotituitarism work? (METHOD 2= STIMULATED ‘DYNAMIC’ PITUITARY FUNCTION TESTS)
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
What does a radiological diagnosis of hypotituitarism show? (MRI OF PITUITARY)
Pituitary MRI
May reveal specific pituitary pathology e.g. haemorrhage (apoplexy), adenoma
Empty sella- thin rim of pituitary tissue
What hormone replacements are used in therapy for hypopituitarism?
Deficient hormone-
Replacement-
Check-
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)
What happens to children and adults in GH deficiency?
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
What are the causes of short stature? (7)
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
What part of the growth axis is disrupted in Prader-Willi syndrome?
Hypothalamus
What part of the growth axis is disrupted in pituitary dwarfism?
Lack of GH
What part of the growth axis is disrupted in Laron Dwarfism?
GH receptor defect
What causes Prader-Willi syndrome?
Deficient in GH secondary to hypothalamic dysfunction
Floppy when babies, food seeking behaviour and weight problem
Achondroplasia
Mutation in fibroblast growth
Factor R 3 (FGF3)
Abnormality in growth plate chondrocytes-> impaired linear growth in limbs
Average size trunk
How do the physical features of achondroplasia and pituitary dwarfism differ?
Achondroplasia= average trunk, short limbs
Pituitary dwarfism= proportionally normal but short
Are the GH receptors working in laron dwarfism?
GH R mutations
Hypothalamus and ant pit in tact
GH can’t act on R
How can laron dwarfism be treated?
IGF-1 to increase height
How is short stature diagnosed?
Mid parental height = prediction
Then compared to curves of normal growth
What causes acquired GH deficiency in adults?
Trauma
Pituitary tumour
Pituitary surgery
Cranial radiotherapy
How is GH deficiency diagnosed?
Random GH so little use- pulsatile
Need provocative challenge (i.e. stimulation) = GH PROVOCATION TESTS
What are GH provocation tests?
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
How is GH therapy administered?
Human recombinant GH (SOMATOTROPIN)
Daily, subcutaneous injection
Monitor clinical response and adjust dose to IGF-1
How long does it take for GH therapy to reach maximal plasma concentration?
2-6h
Describe the duration of action of GH therapy
Lasts beyond clearance
Peak IGF1 levels at approx 20h
How can GH therapy benefit adults?
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
What are the problems with giving GH therapy to adults?
Increased susceptibility to cancer?
Expensive (lifelong = £42k for adult)
Hyperpituitarism
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
How does a pituitary tumour disrupt the visual field?
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
How does bitemporal hemianopia manifest?
Bumping into things
People don’t realise they’ve lost their peripheral vision
An excess of ACTH (corticotrophin)->
Cushing’s disease
An excess of TSH (thyrotrophin)->
Thyrotoxicosis
An excess of gonadotrophins (LH/FSH) in children->
Precocious puberty
An excess of prolactin->
Hyperprolactinaemiaa
An excess of GH>
Gigantism
Acromegaly
When is hyperprolactinaemia physiological and pathological?
Physiological= high when pregnant/breastfeeding
Pathological= prolactinoma (most common functioning pituitary tumour, usually <10mm diameter microadenoma)
What is the main other hormone affected when a person has a prolactinoma?
High prolactin suppresses GnRH pulsatility
What are the signs and symptoms of hyperprolactinaemia due to pituitary adenoma? (M & F)
WOMEN Galactorrhoea Secondary amernorrhoea or oligomenorrhoea Loss of libido Infertility
MEN Galactorrhoea uncommon Loss of libido Erectile dysfunction Infertility
What does an anterior pituitary lactotroph secrete?
Prolactin
How does dopamine affect prolactin secretion? (D2 R agonism)
Dopamine from hypothalamic dopaminergic neurones binds to D2 receptors on ant pit lactotroph and stops prolactin production
How is hyperprolactinaemia treated>
Medical= D2 (DA R) agonist-> decrease prolatin secretion, reduce tumour size
E.g. bromocroptine, cabergoline (oral admin)
What are the side effects of DA R agonists?
Nausea and vomiting Postural hypotension Dyskinesias Depression Pathological gambling (BNF)
How does excess GH affect children and adults?
Children- gigantism
Adults- acromegaly (can’t have increased linear growth because growth plates have fused
Usually due to benign growth hormone secreting pituitary adenoma
Why is acromegaly often diagnosed late?
Insidious in onset
Signs and symptoms progress gradually (can remain undiagnosed for years)
What are common causes of death due to acromegaly?
CV disease 60%
Respiratory complications 25%
Cancer 15%
What parts of the body grow in acromegaly?
Periosteal bone Cartilage Fibrous tissue Connective tissue Internal organs (cardiomegaly, splenomegaly, hepatomegaly etc.)
What are the clinical features of acromegaly?
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
Why is diabetes mellitus a metabolic effect of acromegaly?
Excess GH inhibits insulin signalling
- > increased insulin resistance
- > impaired glucose tolerance
- > diabetes mellitus
4 major complications of acromegaly
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)
What hormone is commonly secreted with GH in acromegaly?
Prolactin
Hyperprolactinaemia causes secondary hypogonadism
How is GH secretion regulated?
Stimulated by GHRH
Inhibited by SS
What does GH lead to in the liver?
Somatomedin production (mainly IGF1)
How does glucose-induced suppression of growth hormone show whether or not a person is acromegalic?
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
Treatment of acromegaly
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
How can somatostatin analogues be used to treat acromegaly?
Injection (sc) or monthly depot
Reduces GH secretion and tumour size
Pre-treatment before surgery to make resection easier
or
Post-operatively
What are common side effects of somatostatin analogues as treatment for acromegaly?
GI side effects
Nausea, diarrhoea, gallstones
What is the neurohypophysis?
Posterior pituitary
What is the adenohypophysis?
Anterior pituitary
What does the posterior pituitary look like on an MRI (sagittal section)?
‘Bright spot’ on pituitary MRI
Why is the posterior pituitary call the neurohypophysis and what cells are present?
Collection of axons from neuronal projections
Magnocellular- big cell bodies
What hormones are released by the post pit?
Oxytocin
Vasopressin (ADH- anti diuretic hormone)
What is diuresis?
Increase in urine production
How does ADH reduce diuresis?
Promotes retention from renal cortical and medullary collecting ducts
Via vasopressin 2 receptors (V2Rs)
Stimulates synthesis of AQP 2 (water channels)
What does aquaporin 2 do?
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
What is the net effect of the actions of ADH in the kidney?
Net effect is reabsorption of water from nephron into the plasma
What do osmoreceptors do?
Sense osmolality
Very sensitive to changes in EC osmolality (think of it as conc)
Where are osmoreceptors located and why is this area of the brain a different colour?
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)
Why does the organum vasculosum region of the brain have no BBB?
Contains osmoreceptors
Can communicate directly with system circulation)
How does an osmoreceptor respond to increased EC sodium?
Increased osmolality
Osmoreceptor shrinks in response (water moves out)
Stimulates osmoreceptor firing-> triggers release of ADH from hyperthalamic neurons in SON and PVN
How does an osmoreceptor respond to water deprivation?
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
What causes diabetes insipidus?
Absence or lack of circulating ADH (cranial/central)
End-organ (kidneys) resistance to ADH (nephrogenic)
What is the difference between nephrogenic and cranial DI?
Absence or lack of circulating ADH (cranial/central)
End-organ (kidneys) resistance to ADH (nephrogenic)- RARER, harder to manage
What causes acquired cranial diabetes insipidus?
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
Is acquired or congenital cranial DI more common?
Acquired
Congenital is rare
What causes congeital nephrogenic diabetes insipidus?
Rare (e.g. mutation in gene encoding V2 receptor, aquaporin 2 type water channel)
What causes acquired nephrogenic diabetes insipidus?
Drugs e.g. lithium
What are the signs and symptoms of DI?
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
What is polyuria?
Large volumes of urine
What is polydipsia?
Excessive thirst and increased drinking
How does diabetes insipidus lead to EC fluid volume expansion?
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
How does diabetes insipidus with no access to water lead to dehydration and death?
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
What is psychogenic polydipsia? What causes it?
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
How does psychogenic polydipsia occur?
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
How can you tell if someone is normal, has DI or has psychogenic polydipsia?
Numbers in mOsm/kg H2O (plasma osmolality)
DI= >290
Normal= Around 270-290
Psychogenic polydipsia= <270
What do the water deprivation test show?
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)
How do you test for DI? (incl different types of DI)
Measure urine osmolality of…
- Normal hydrated
- Water deprivation (to see DI or other cause of polydipsia)
- Give synthetic VP (DDAVP) to distinguish between cranial and nephrogenic DI
What are the biochemical features of DI?
Hypernatraemia
Raised urea
Increased plasma osmolality
Dilute (hypo-osmolar) urine - ie low urine osmolality
What are the biochemical features of pyschogenic polydipsia?
Mild hyponatraemia – excess water intake
Low plasma osmolality
Dilute (hypo-osmolar) urine - ie low urine osmolality
What is terlipressin?
A selective vasopressin receptor peptidergic agonists for V1
What is desmopressin (DDAVP)?
A selective vasopressin receptor peptidergic agonists for V2
What are the selective vasopressin receptor peptidergic agonists for VI and V2
V1 –terlipressin
V2 – desmopressin (DDAVP)
How is desmopressin administered?
Nasally (usually spray before bed)
Orally
SC
What effect does desmopressin have on cranial DI?
Reduction in urine volume and concentration in cranial DI
CAN’T DRINK AS MUCH AS NORMAL-> risk of hyponatraemia
How can nephrogenic diabetes insipidus be treated?
Thiazides e.g. bendroflumethiazide
What is the possible mechanism of thiazide to treat nephrogenic diabetes insipidus?
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
What happens if there is excess ADH?
Syndrome of Inappropriate ADH (SIADH)
Make too much ADH
Plasma vasopressin concentration is inappropriately high for the existing plasma osmolality
How does SIADH lead to euvolaemia and hyponatraemia?
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
What is euvolaemia?
Normal circulating volume
Maintained because of collecting ducts and ANP
What are the signs of SIADH?
Raised urine osmolality, decreased urine volume (initially)
Decreased p[Na+] (HYPONATRAEMIA) mainly due to increased water reabsorption
Feel unwell but can be symptomless
What happens if you are hyponatraemic?
Normal plasma conc of Na= 120mM
<120mM-> generalised weakness, poor mental function, nausea
<110mM-> confusion, coma, death
What are the causes of SIADH? (5 groups)
CNS= SAH, stroke, tumour, TBI Pulmonary disease= Pneumonia, bronchiectasis Malignancy= Lung (small cell) Drug-related= Carbamazepine, SSRI Idiopathic
How is SIADH treated?
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)
What does demeclocycline do?
Induce nephrogenic DI (in a SIADH patient) ie reduce renal water reabsorption
What to V2 receptor antagonists (VAPTANS) do?
Inhibit action of ADH
Non-competitve V2 R antagonists
Inhibit AQP2 synthesis-> promote water loss rather than losing water and sodium
What causes primary hypothyroidism (myxoedema)?
Autoimmune damage to thyroid
Leads to decline in thyroxine (low T4) levels
TSH levels climb
What are common symptoms of hyothyroidism?
Weight gain Cold intolerance Voice deepens Bradycardia-> hypertension Constipation Depression and tiredness Oedema Dry hair
Eventual myxoedema coma
What does a healthy adult thyroid gland secrete?
T4 (less active) and T3 (more active metabolite)
Why is T4 (thyroxine) a prohormone?
T4 converted by deiodinase enzyme activity into tri-iodothyronine (T3)
T3= active metabolite that provides almost all thyroid hormone activity to target cells
How much T3 is from deiodination of T4 and how much is from direct thyroidal secretion?
80% from deiodination of T4
20% from direct thyroidal secretion
What is TRE?
Thyroid response element
What happens to T4 and T3 in the target cell?
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
What thyroid hormone replacement therapy exists?
Levothyroxine sodium (THYROXINE=T4)= more commonly used
Liothyronine sodium (TRIIODOTHYRONINE=T3)= less commonly used
What are the clinical uses of levothyroxine sodium (synthetic thyroxine)?
Autoimmune primary hypothyroidism
OR
Iatrogenic primary hypothyroidism – e.g. post-thyroidectomy, post-radioactive iodine
OR
Secondary hypothyroidism (problem with pituitary not gland)
How is levothyroxine sodium administered for primary hypothyroidism? (incl. how to guide dose)
Oral administration
TSH used as guidance for thyroxine dose - aim to suppress TSH into the reference range
What does levothyroxine sodium aim to do?
Negative feedback
Reduce production of TSH (ant pit)
How is levothyroxine sodium administered for primary hypothyroidism? (incl. how to guide dose)
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
When is liothyronine (synthetic trio-iodothyronine) used? How is it administered?
Myxoedema coma - a VERY RARE complication of hypothyroidism
iv initially – as onset of action faster than T4 then oral when possible
What is combined thyroid hormone replacement?
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
What happens in thyroid hormone over-replacement? (4 groups)
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
What is the half life of levothyroxine (T4) and liothyronine (T3)
Levothyroxine (T4) plasma half life= 6 days
Liothyronine (T3) plasma half life= 2.5 days
How much circulating T4 and T3 is bound to plasma proteins (mainly TBG)?
Approx 99.97% of circulating T4
Approx 99.7% of circulating T3
Bound to plasma proteins, mainly thyroxine binding globulin (TBG)
Is bound thyroid hormone available to tissues?
No
Only free (unbound) thyroid hormones are available to tissues
What can increase or decrease plasma binding proteins? (I.e. TBG)
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)
How much T4 is there compared to T3 (in the plasma)?
10x more T4
How long does it take free and conjugated T3 and T4 to be secreted in the urine?
T3 is cleared in hours
T4 is cleared in about 6 days
What drugs are used in treatment of hyperthyroidism? (4 groups)
The thionamides (thiourylenes; anti-thyroid drugs)
Potassium Iodide
Radioiodine
β-blockers
Which hyperthyroid drugs are aimed at blocking thyroxine synthesis
The thionamides
Potassium Iodide
Radioiodine
What is the aim of beta blockers in treatment of hyperthyroidism?
Relieves symptoms
Give 2 examples of thionamides
Propylthiouracil (PTU)
Carbimazole (CBZ)
How can thionamides (PTU and CBZ) be used clinically? (3 ways)
Daily treatment of hyperthyroid conditions e.g. Graves
Treatment prior to surgery
Reduction of symptoms while waiting for radioactive iodine to act
What are hyperthyroid conditions which may require daily treatment with thionamides?
Graves
Toxic thyroid nodule/toxic multinodular goitre
How are thyroid hormones synthesised?
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
What enzymes are used in thyroid hormone synthesis to get thyroid hormone in and out of the cell?
Into cell= peroxidase transaminase
Out of cell= thyroperoxidase and H202
How do thionamides interfere with thyroid hormone synthesis?
Inhibit thyroperoxidase (and hence T3 and T4 synthesis and secretion)
How long does it take biochemically and clinically to have an effect from thionamides?
Biochemical effect= hours
Clinical effect= weeks
Why might treatment with thionamides often include proranolol?
Rapidly reduces tremor and tachycardia
-olol= beta blocker
How does thionamide lead to improvements in patients with hyperthyroidism? (2 ways)
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
What unwanted actions does thionamide cause?
Agranulocytosis/granulocytopenia reduced/absent granular leukocytes (RARE and reversible on withdrawal of drug)
Rashes (relatively common)
Outline the pharmacokinetics of thionamides? PTU and CBZ
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
How long is anti-thyroid drug treatment usually for?
18 months
Period reviews including thyroid function tests for remission/relapse
What is the role of β blockers in thyrotoxicosis?
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
When is iodide (usually KI) used for hyperthyroidism?
Preparation of hyperthyroid patients for surgery
Severe thyrotoxic crisis (thyroid storm)
KI doses= 30x average daily requirement
How does KI treat hyperthyroidism (2 ways)?
Inhibits iodination of thyroglobulin
Inhibits H202 generation
Time taken for:
Hyperthyroid symptoms to reduce
Vascularity and size of gland to reduce
Hyperthyroid symptoms to reduce= 1-2 days
Vascularity and size of gland to reduce= 10-14 days
What is the Wolff-Chaikoff effect?
Reduction in thyroid hormone levels caused by ingestion of a large amount of iodine
Presumed autoregulatory
(KI hyperthyroidism)
What are the unwanted actions of KI treatment of hyperthyroidism?
Allergic reaction e.g. rashes, fever, angio-oedema
Pharmacokinetic features of KI treatment of hyperthyroidism?
Given orally (Lugol’s solution; aqueous iodine) Maximum effects after 10 days’ continuous administration
How does high dose radioiodine treat hyperthyroidism (2 ways)?
Accumulates in colloid
Emits B particles
Destroys follicular cells
Pharmacokinetic features of radioiodine treatment of hyperthyroidism?
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
What are the single oral radioiodine doses administered for Graves and thyroid cancer?
Graves’ disease: approx 500 MBq
Thyroid cancer: circa 3,000 MBq
Who can’t receive radioiodine to treat hyperthryoidism?
Pregnant women
Breast feeding women
NB. Avoid close contact with small children for several weeks after receiving radioiodine
What is 131^I?
Radioiodine for treatment of hyperthyroidism
What is the use of radioiodine (131^I or technetium 99 pertechnetate) in very low, tracer doses?
To test thyroid gland pathology e.g. toxic nodule, thyroiditis vs Graves’
Administer IV
Negligible cytotoxicity
What diseases are caused by hypersecretion of adrenal hormones?
Cushing’s syndrome (cortisol)
Conn’s syndrome (aldosterone)
What inhibits steroid biosynthesis in Cushing’s syndrome?
Metyrapone
Ketoconazole
What is an MR antagonist in Conn’s syndrome?
Spironolactone
Epleronone
How does metyrapone act to relieve Cushing’s syndrome?
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
What are the main arms of steroid biosynthetic pathways?
Cholesterol->
Mineralocorticoid arm
Glucocorticoid arm
Adrenocorticoid arm
SEE DIAGRAM
What is the principal glucocorticoid in humans?
Cortisol
In which layers of the adrenal cortex are the following found?
Mineralocorticoid arm
Glucocorticoid arm
Adrenocorticoid arm
Mineralocorticoid arm= z. glomerulosa
Glucocorticoid arm= z. fasciculata
Adrenocorticoid arm= z. reticularis
How is metyrapone used to treat Cushing’s syndrome? (2 times)
Control of Cushing’s before surgery
Control of Cushing’s syndrome after radiotherapy (slow to work)
Why does metyrapone help control Cushing’s before surgery?
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)
Why can metyrapone cause hypertension?
Deoxycorticosterone accumulates in z. glomerulosa
Has aldosterone-like (mineralocorticoid) activity, leading to salt retention and hypertension
Why can metyrapone cause hirsutism?
Precursors accumulate (may go to different arm)
Increased adrenal androgen production hirsutism
in women
What are the unwanted actions of metyrapone?
Hypertension (on long-term admin)
Hirsutism
How was ketoconazole originally intended to be used (before Cushing’s)? How did it become off-label treatment for Cushing’s?
Antifungal agent
Withdrawn due to hepatotoxicity risk
Higher conc-> inhibits steroidogenesis (needs careful monitoring but useful for Cushing’s)
How does ketoconazole help Cushing’s syndrome patients?
Block production of glucocorticoids, mineralocorticoid and sex steroids
Many steps blocked, stops production of cortisol (amongst other features)
How is ketoconazole used?
For Cushing’s patients
Treatment and control of symptoms prior to surgery
Orally active
What are the unwanted actions of ketoconazole?
Liver damage (possibly fatal) So monitor liver function weekly, clinically and biochemically
What is spironolactone used for?
Primary hyperaldosteronism (Conn’s syndrome)
How does spironolactone treat Conn’s syndrome?
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)
What is canrenone? What is it converted from?
Converted from spironolactone
Canrenone= competitive antagonist of the mineralocorticoid receptor (MR)
Pharmacokinetics of canrenone?
Orally active
Highly protein bound and metabolised in the liver
What are the unwanted effects of spironolactone? Why do these occur?
Menstrual irregularities (+ progesterone receptor) Gynaecomastia (- androgen receptor)
How does epleronone treat Conn’s syndrome?
Mineralocorticoid receptor (MR) antagonist
Similar affinity to the MR compared to the MR compared to spironolactone
Less binding to androgen and progesterone, better tolerated
What is CRH?
Corticotrophin releasing hormone
What is ACTH?
Adrenocorticotrophic hormone= corticotrophin
How many carbons are in cholesterol?
C27
CHOLESTEROL SYNTHESIS. What are the hydroxylase enzymes in the cholesterol synthesis pathway?
CHOLESTEROL SYNTHESIS Learn the numbers from diagram
What are the main causes of adrenocortical failure?
Tuberculous Addison’s disease (most common worldwide)
Autoimmune Addison’s disease (commonest UK)
Congenital adrenal hyperplasia
What happens in congenital adrenal hyperplasia?
Missing 2nd enzyme
Adrenal glands are enormous but not functioning properly
95% cases= lack 21-hydroxylase
List symptoms of Addison’s
Tan Buckle pigmentation (teeth, eyes) Pigmented scar Weak- proximal myopathy Losing weight Vitiligo- predisposition to thyroid disease (autoimmune) Hypotensive (postural hypotension)
What are the consequences of of adrenocortical failure?
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
Why does high CTH lead to increased pigmentation?
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
What is MSH and why does it cause a tanned appearance?
Melanocyte stimulating hormone
Stimulates melanocytes to make melanin
What should the cortisol and ACTH be in an Addison’s patient at 9am in a blood test?
Cortisol= low ACTH= high
What specific test is used for Addison’s?
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
What is the most common cause of congenital adrenal hyperplasia?
21-hydroxylase deficiency
Complete or partial
What hormones are totally absent or in excess in complete 21-hydroxylase deficiency?
Totally absent= aldosterone and cortisol
Excess= sex steroids and testosterone
No cortisol production, so ACTH rises (no -ve fb)-> drives further adrenal androgen production
When a baby has congenital adrenal hyperplasia, how do they present?
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
What hormones are deficient or in excess in partial 21-hydroxylase deficiency?
Deficient= cortisol and aldosterone Excess= sex steroids and testosterone
What age do people with partial 21-hydroxylase deficiency patients present? What is the main problem with the deficiency?
Any age
They survive
Main problem in later life is hirsutism and virilisation in girls and precocious puberty in boys due to adrenal testosterone
How does 11 deoxycorticosterone behave?
Like aldosterone
What happens if there is excess 11 deoxycorticosterone?
Hypertension
Hypokalaemia
What hormones are deficient or in excess in 11-hydroxylase deficiency?
Deficient= cortisol and aldosterone Excess= sex steroids, testosterone and 11-deoxycorticosterone
What are the problems of 11-hydroxylase deficiency?
Essentially becomes a problem of too much mineralocorticoid
This means virilisation, hypertension and low K
What hormones are deficient or in excess in 17-hydroxylase deficiency?
Deficient= cortisol and sex steroids Excess= 11-deoxycorticosterone and aldosterone (mineralocorticoids)
What are the problems of 17-hydroxylase deficiency?
Hypertension, low K, sex steroid deficiency and glucocorticoid deficiency (low glucose)
What are the functions of cortisol, aldosterone and androgens/oestrogens?
Cortisol= essential for life Aldosterone= promotes Na+ retention and K+ loss Androgens/oestrogens= different sexual/reproductive functions (from gonads)
What are the main two types of corticosteroid receptors?
Glucocorticoid receptors
Mineralocorticoid receptors
What are the differences between glucocorticoid Rs and mineralocorticoid Rs?
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
How does 11B-hydroxysteroid dehydrogenase (11BHSD) protect mineralocorticoid receptors from cortisol?
11BHSD inactivates cortisol-> cortisone (inactive)
Stops aldosterone receptors being overly activated by cortisol
What happens in Cushing’s syndrome that leads to hypertension?
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
What kind of corticosteroid receptors do the following drugs act on? Hydrocortisone Prednisolone Fludrocortisone Dexamethasone
Hydrocortisone= acts on GR/MR Prednisolone= acts on GR/weak MR Fludrocortisone= acts on MR Dexamethasone= acts on GR
What kind of drug is fludrocortisone?
Aldosterone analogue
Used as an aldosterone substitute
Corticosteroid drug
How are corticosteroids administered?
Oral= hydrocortisone, prednisolone, dxamethasone, fludrocortisone
Parental (IV or IM)= hydrocortisone, dexamethasone
How are corticosteroids distributed?
Bind to plasma proteins (cortisol binding globulin CBG and albumin) as circulating cortisol does
How long do corticosteroids last?
Hydrocortisone= duration 8h Prednisolone= duration 12h Dexamethasone= duration 40h
What hormones do Addison’s patients lack?
Cortisol and aldosterone
Primary adrenocortical failure
What hormones do patients of secondary adrenocortical failure lack?
Cortisol but not aldosterone
ACTH deficiency
How is secondary adrenocortical failure treated?
Oral hydrocortisone
What is an acute adrenocortical failure?
Addisonian crisis (severe hypotension occurs)
How is a patient undergoing a Addisonian crisis treated?
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
How is congenital adrenal hyperplasia treated?
Dexamethasone 1/day pm
OR
Hydrocortisone 2-3/day, high dose pm
= to replace cortisol
Fludrocortisone= to replace aldosterone
What are aims for the therapy of congenital adrenal hyperplasia?
Replace cortisol and aldosterone
Why is it important to monitor/optimise corticosteroid replacement therapy by measuring?
Measure 17 OH progesterone (precursor)
Clinical assessment:
- Cushingoid if GC dose too high
- Hirsutism if GC dose too low (hence ACTH risen)
Why do you increase glucocorticoid dosage when patients are vulnerable to stress?
17 OH progesterone
Cortisol (normally= 20mg/day but in stress 200-300mg/day)
When is glucocorticoid dosage increased?
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
Outline the male HPG axis
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
How many days is the female menstrual cycle? What are the phases?
28
Follicular phase, ovulation, luteal phase
Outline the female HPG axis (not in ovulation)
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
Outline the female HPG axis (in ovulation)
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
What happens if implantation doesn’t occur in the luteal phase?
Endometrium is shed (menstruation)
Define: infertility
Inability to conceive after 1 year of regular unprotected sex
1:6 couples
What percentage of infertility is caused by abnormalities of M and F?
Males- 30%
Females- 45%
Unknown- 25%
How is the HPG axis affected in primary gonadal failure?
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.
How is the HPG axis affected in hypothalamic/pituitary disease
Low LH/FSH
Low testosterone/oestradiol
Low inhibin
What are the clinical features of male hypogonadism?
Loss of libido = sexual interest / desire Impotence Small testes Decrease muscle bulk Osteoporosis
What are the causes of male hypogonadism?
Hypothalamic-pituitary disease (pituitary not working, low testosterone)
Primary gonadal disease
Hyperprolactinaemia
Androgen receptor deficiency
What are the symptoms of Kallmans syndrome?
Anosmia
Low GnRH
Testes orignally undesecended
Stature low-normal
What are examples of hypothalamic-pituitary disease that cause male hypogonadism?
Hypopituitarism
Kallmans syndrome
Illness/underweight
What are examples of primary gonadal disease that cause male hypogonadism?
Congenital: Klinefelters syndrome (XXY)
Acquired: Testicular torsion, chemotherapy
How can you investigate male hypogonadism?
LH, FSH, testosterone (if all low-> MRI pituitary)
Prolactin
Sperm count
Chromosomal analysis (Klinefelters XXY)
Define: azospermia
Absence of sperm in ejaculate
Define: oligospermia
Reduced numbers of sperm in ejaculate
How is male hypogonadism treated?
Replacement testosterone for all patients
For fertility: if hypo/pit disease subcutaenous gonadotrophins (LH/FSH)
Hyperprolactinaemia- DA agonist
What are the endogenous sites of production of androgens?
Interstitial Leydig cells of the testes
Adrenal cortex (males and females)
Ovaries
Placenta
Tumours
What are the 4 main actions of testosterone?
Development of the male genital tract Maintains fertility in adulthood Control of secondary sexual characteristics Anabolic effects (muscle, bone)
How much testosterone is bound to protein?
98%
What can testosterone be converted in to? What enzymes does this involve?
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
What receptors do the actions of DHT/E2 depend on?
Nuclear receptors
What are the clinical uses of testosterone?
Testosterone in adulthood will increase: Lean body mass Muscle size and strength Bone formation and bone mass (in young men) Libido and potency
Can testosterone restore fertility?
Will not restore fertility alone
Requires treatment with gonadotrophins to restore normal spermatogenesis
What are gonadal disorders in the female?
Amenorrhoea
Polycystic ovarian syndrome (PCOS)
Hyperprolactinaemia
What is amenorrhoea? Primary? Secondary?
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
What is oligomenorrhoea?
Irregular long cycles
What causes amenorrhoea?
Pregnancy
Lactation
Ovarian failure (premature ovarian failure, ovariectomy/chemo, ovarian dysgenesis)
Gonadtrophin failure
Hyperprolactinaemia
Androgen excess: gonadal tumour
What is ovarian dysgenesis?
In Turners (45 XO) Lacking one chromosome
What are common features of Turners syndrome?
Short stature
Cubitus valgus (wide carrying angle)
Gonadal dysgenesis
1:5000 live births
What can cause a gonadotrophin failure in women?
Hypo/pit disease
Kallmann’s syndrome
Low BMI
Post pill amernorrhoea
What investigations would be carried out on a patient with amernorrhoea? (7)
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
How is amenorrhoea treated?
Treat the cause e.g. low weight
Primary ovarian failure- infertile, HRT
Hypothalamic/pit disease (HRT for oestrogen replacement and gonadotrophins in IVF)
What is PCOS?
Polycystic ovarian syndrome
Incidence: 1 in 12 women of reproductive age
Associated with increased cardiovascular risk and insulin resistance (>diabetes)
How is PCOS diagnosed?
2 of:
Polycystic ovaries on US
Oligoovulation/anovulation
Clinical/biochemical androgen excess
What are the clinical features of PCOS?
Hirsuitism
Menstrual cycle disturbance
Increased BMI
What fertility drugs are given to treat PCOS?
Metformin
Clomiphene
Gonadotrophic therapy as part of IVF
What is clomiphene? How does it work?
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
Outline prolactin secretion control
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
What causes hyperprolactinaemia? (7)
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
How does stalk compression cause hyperprolactinaemia?
Stops/reduces affect of DA and TRH on pituitary
Imbalance in - and +
Increased prolactin secretion
What are the clinical features of hyperprolactinaemia?
Galactorrhoea
Reduced GnRH secretion/LH action-> hypogonadism
Prolactinoma-> headache, visual field defect
What are the treatments for hyperprolactinaemia?
Treat cause e.g. stop anti-emetics
DA agonist (e.g. bromocriptine, cabergoline)
Prolactinoma rarely needs pituitary surgery
A male presents to endocrine clinic who has had bilateral orchidectomy (removal of testes). What would you expect his blood results to show:
- Low LH, Low FSH, Low Testosterone
- Low LH, high FSH, Low Testosterone
- high LH, high FSH, Low Testosterone
- high LH, high FSH, high Testosterone
- high LH, high FSH, Low Testosterone
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:
- Low LH, Low FSH, Low oestradiol
- Low LH, high FSH, Low oestradiol
- high LH, high FSH, Low oestradiol
- high LH, high FSH, high oestradiol
- Low LH, Low FSH, Low oestradiol
What is dyspareunia?
Painful sex
Which of the following is a common symptom of menopause? Sleep disturbance Headache Chest pain Leg swelling
Sleep disturbance
Why may menopause affect the bones?
Low oestrogen-> osteoporosis and fracture
What risks are related to HRT?
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
What is menopause?
Permanent cessation of menstruation
Loss of ovarian follicular activity
Climacteric (period of transition period)
What’s the average age of menopause?
Average age 51 (range 45-55)
What are the symptoms of menopause?
Hot flushes (head, neck, upper chest) Urogenital atrophy and dyspareunia Sleep disturbance Depression Decreased libido Joint pain
Symptoms usually diminish/disappear with time
How do the hormonal changes during menopause affect the HPG axis?
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
Why does menopause lead to osteoporosis?
Oestrogen deficiency
Loss of bone matrix
10-fold increased risk of fracture
Why does menopause lead to cardiovascular disease?
Protected against CVD because the menopause
Have the same risk as men by the age of 70
What is the main purpose of HRT?
Control vasomotor symptoms (hot flushes)
What drug is prescribed as HRT?
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)
Why isn’t oestrogen usually used in HRT alone in patients without a hysterectomy?
Risk of endometrial carcinoma
What are HRT formulations?
Cyclical (oestrogen every day and progesterone for the last 12 days)
Continuous combined
Oestrogen preparations
What are the different oestrogen preparations in HRT?
Oral estradiol (1mg)
Oral conjugated equine oestrogen (0.625mg)
Transdermal (patch) oestradiol (50ug/day)
Intravaginal
What are the different kinds of oestrogen?
Estradiol Estrone sulphate (conjugated) Ethinyl estradiol (semi-synthetic)
Why is estradiol not that useful in HRT?
Well absorbed Low bioavailability (first pass metabolism)
Why is ethinyl estradiol useful in HRT?
Ethinyl group protects the molecule from first pass metabolism
What does it mean that ‘timing of exposure’ is importnant in HRT when considering CHD risk?
No excess risk in younger menopausal women (50-59) or women <10 years since menopause
What is tibolone?
Synthetic prohormone
Oestrogenic, progestogenic and weak androgenic actions
Rarely used
What affect does tibolone have on risks related to HRT?
Reduces fracture risk
Increased risk of stroke
Unknown risk of breast cancer
What is Raloxifene?
Selective oestrogen receptor modulator
SERM
What affect does raloxifene have on risks related to HRT?
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
What is premature ovarian insufficiency?
Menopause occurring before age 40
1% of women
What causes premature ovarian insufficiency?
Autoimmune
Surgery
Chemotherapy
Radiation
What is in combined oral contraceptives?
Oestrogen (ethinyl oestradiol) and progestogen (e.g. levonorgestrel or norethisterone)
How do combined oral contraceptives work?
Suppress ovulation
- E and P-> -ve fb actions at hypothalamus/pit
- P thickens cervical mucus
Taken 21 days, stop for 7
What is the progesterone only contraceptive? When is it used?
P only
When oestrogens contra-indicated e.g. patient ?35 with migraines
When must progesterone only contraceptives be taken? Why?
Same time every day
Short duration of action
Short half-life
NB. Long acting preparations may be given via an intra-uterine
What are the available types of emergency (post-coital) contraception? When can they be used?
Copper IUD
Levonorgestrel (within 72hrs)
Ulipristal (up to 120h after intercourse)
What is a copper IUD? How does it work?
Intrauterine contraceptive device
Affects sperm viability and function
What is ulipristal?
Emergency contraception
Anti-progestin activity
Delay ovulation by as much as 5 days
Impairs implantation
Describe the male reproductive organ
Testis- with seminiferous tubules (spermatozoa surrounded by sertoli cells, in interstitia have leydig cells)
Prostate
Seminal
Efferent ductis (from testis to epididymus)
What does oestrogen control in the male reproductive organ?
Tubular fluid reabsorption
What does androgen control in the male reproductive organ?
Nutrients and glycoprotein secretion into epididymal fluid
How far does spermatozoan travel from testic to oviduct?
100,000 x its length
What proportion of sparmatozoa reach the ovum?
<1/10^6
What is ejaculate comprised of?
Spermatozoa= 15-120 x 10^6/ ml
Seminal fluid= 2-5ml
Leucocytes
NB. Potentially viruses e.g. hep V, HIV
What percent of the spermatozoa in ejaculate enter the cervix?
1%
Where is seminal fluid from?
Small contribution from epididymis/testis
Mainly from accessory sex glands
- Seminal vesicle
- Prostate
- Bulbourethral glands
What needs to happen for a sperm to achieve fertilizing capability in the female reproductive tract?
Maturation/capacitation
Outline maturation/capacitation of sperm
- Loss of glycoprotein coat
- Change in surface membrane characteristics
- Whiplash movements of tail
What does capacitation of sperm depend on?
Oestrogen-dependent
Takes place in ionic and proteolytic environment of the Fallopian tube
Ca dependent
What is the acrosome reaction?
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
What hormone is involved in Ca influx into sperm in the acrosome reaction?
Progesterone
Where does fertilisation occur?
Within the fallopian tubes
What does fertilization trigger?
Triggers cortical reaction
What is the cortical reaction triggered by fertilization? What does this do?
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)
What are polar bodies (relate to fertilization)?
Unequal division of cytoplasm
Leaves polar bodies
What happens to the fertilised egg as it moves down the Fallopian tube?
Moves to uterus and continues to divide (3-4 days)
Receives nutrients from uterine secretions
Free-living phase can last for 9-10 days
How does the fertilised egg become a blastocyst?
Fertilised egg
2-cell conceptus
4-cell conceptus
8-cell conceptus
COMPACTION
Morula
Blastocyst
What can be found in a blastocyst?
Blastocoelic cavity
Inner cell mass
Trophoblast cells
What are the phases of implantation? What do they require?
Attachment phase
Decidualization
Requires progesterone domination in the presence of oestrogen
What happens in the attachment phase of implantation?
Outer trophoblast cells contact uterine surface epithelium
What happens in decidualization of implantation?
Decidualization of underlying uterine stromal tissue (within a few hours)
What is released from secretory glands in endometrial lining in implantation? What do they do?
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
What is LIF?
Leukaemia inhibitory factor from endometrial secretory glands
Stimulates adhesion of blastocyst to endometrial cells
What does IL11 do in implantation?
Interleukin-11 from endometrial cells
Released into uterine fluid
What is decidualisation?
Endometrial changes due to progesterone
What happens in decidualisation?
Endometrium changes due to progesterone
Glandular eipthelial secretion
Glycogen accumulation in stromal cell cytoplasm
Growth of capillaries
Increased vascular permeability (oedema)
What factors are involved in decidualisation?
IL11
Histamine
Certain prostaglandins
TGF beta (which promotes angiogenesis)
What are the main hormonal changes during pregnancy?
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
What is hCG?
Human chorionic gonadotrophin
Produced by developing implanting blastocysts (syncytiotrophoblast)
How do the oestrogens of pregnancy change?
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
How does the placenta make oestradiol/oestrone?
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
What maternal hormones increase and decreases in pregnancy?
INCREASE ACTH Prolactin Iodothyronines Adrenal steroids PTHrp (lactation)
DECREASE
Gonadotrophins
TSH
hCH (decreases as the placental hCH variant increases)
Where is PTHrp secreted from?
Breast
Important for lactation
What happens endocrinologically in parturition?
Oxytocin
Raised calcium
Contraction
Fetal hypothalamus makes CRH
Pituitary makes corticotrophin
Adrenals make cortisol
What happens endocrinologically in lactation?
Suckling (stimulus)-> neural pathways stimulate hyopathlamus-> pituitary
Neurohypophysis-> oxytocin-> milk ejection
Adenohypophysis-> prolactin-> milk synthesis
What percentage of the body’s calcium is stored in bone?
> 95%
What are the main components of bone? What percentage of bone mass is it?
Inorganic mineral component (65%)
- Calcium hydroxyapatite crystals fill the space between collagen fibrils
Organic components (osteoid- unmineralised bone) (35%) - Type 1 collagen fibres (95%)
Why is bone remodelling called a dynamic process?
Osteoblasts= bone deposition
Osteoclasts=bone resorption
What do osteoblasts do?
Synthesise osteoid and participate in mineralisation/ calcification
of osteoid
BONE DEPOSITION
What do osteoclasts do?
Release lysosomal enzymes which break down bone
BONE RESORPTION
What do osteocytes do?
Make type 1 collage and other EC matrix components
Outline osteoclast differentiation
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)
What does RANKL do?
Activates osteoclast differentiation
What does osteoprotegerin (OPG) do?
Inhibits osteoclast differentiation
How is bone remodelling regulated?
Osteoblasts synthesis new bone
Express Rs for PTH and calcitriol
What are PTH and calcitriol the key hormones for?
Regulating bone remodelling and calcium balance
What is the active form of vitamin D?
Calcitriol
1, 25 (OH2D)
1, 25 dihydroxy vitamin D
What is the inactive form of vitamin D?
Calcidiol
Inactive, stored
25 hydroxyide vitamin D
What regulates the production of the active form of vitamin D?
PTH
How do changes in EC Ca affect nerve and skeletal muscle excitability?
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
What are the signs and symptoms of hypocalcaemia?
PACT (or CATs go numb)
Parasthesia (hands, mouth, feet, lips)
Arrhythmias
Convulsions
Tetany
Because excitable tissues are sensitised
What is Chvostek’s sign?
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)
What is Trousseau’s sign?
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
What can cause hypocalcaemia?
Vit D deficiency
Low PTH levels= hypoparathyroidism (surgical or auto-immune)
PTH resistance e.g. pseudohypoparathyroidism
Renal failure
Why does renal failure lead to hypocalcaemia?
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
What is the normal range for calcium?
2.2-2.6 mmol/L
What are the signs and symptoms of hypercalcaemia?
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)
What causes hypercalcaemia?
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)
How are Ca and PTH release related normally?
PTH released in response to falling serum calcium
Then-> negative feedback
What happens in primary hyperparathyroidism?
RAISED CALCIUM
RAISED (UNSUPPRESSED) PTH
NO negative feedback
Autonomous PTH secretion DESPITE hypercalcaemia
What regulates the production of the active form of vitamin D?
PTH
How do changes in EC Ca affect nerve and skeletal muscle excitability?
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
What are the effects of the bioactive form of vitamin D?
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)
What is Chvostek’s sign?
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)
What is Trousseau’s sign?
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
What can cause hypocalcaemia?
Vit D deficiency
Low PTH levels= hypoparathyroidism (surgical or auto-immune)
PTH resistance e.g. pseudohypoparathyroidism
Renal failure
Why does renal failure lead to hypocalcaemia?
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
What is the normal range for calcium?
2.2-2.6 mmol/L
What can cause vitamin D deficiency?
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)
What causes hypercalcaemia?
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)
How are Ca and PTH release related normally?
PTH released in response to falling serum calcium
Then-> negative feedback
What happens in primary hyperparathyroidism?
RAISED CALCIUM
RAISED (UNSUPPRESSED) PTH
NO negative feedback
Autonomous PTH secretion DESPITE hypercalcaemia
What happens in hypercalcaemia of malignancy?
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)
How is vitamin D deficiency treated in patients with normal renal function?
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
What is FGF23?
Hormone produced by bone which increases urine PO4^3- excretion
What happens if there is a lack of vitamin d?
Lack of mineralisation in bone-> ‘softening’ of bone, bone deformities, bone pain, severe proximal myopathy
Children= rickets Adults= osteomalacia
Where does vitamin D come from?
UVB light (reacts with skin 7-dehydrocholesterol (precursor))- vitamin D3
Vitamin D2 from diet
What is osteoporosis?
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)
What does calcitriol do?
Ca absorption in gut
Ca maintenance in bone
renal effects
Negative feedback on PTH
What happens in secondary hyperparathyroidism?
PTH increases to try to normalise serum calcium (which has fallen from vitamin D deficiency)
How do you diagnose vitamin D deficiency?
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
How does renal dysfunction lead to bone disease?
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
What are brown tumours?
Radiolucent bone lesions (not actually tumours)
Reflect excessive osteoclastic bone resorption secondary to high PTH
How is vitamin D deficiency treated in patients with renal failure?
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
What happens if someone has excess vitamin D (intoxication)?
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
What granulomatous diseases can lead to vitamin D excess? Why do they do this?
Sarcoidosis
Leprosy
TB
Macrophages in the granuloma produce 1a hydroxylase to convert from inactive to active vit D
Why do women with an intact uterus need additional progestogen with HRT oestrogen?
Prevent endometrial hyperplasia/cancer
Will give withdrawal bleed- patients not pleased as they had stopped periods
What conditions pre-dispose patients for osteoporosis?
Postmenopausal oestrogen deficiency Age-related deficiency in bone homeostasis Hypogonadism in young women and in men Endocrine conditions Iatrogenic
How does postmenopausal oestrogen deficiency predispose a patient to osteoporosis?
Oestrogen deficiency leads to a loss of bone matrix
Subsequent increased risk of fracture
How does age increasing predispose a patient to osteoporosis?
Ostoblast senescence
Why are bisphosphonates used to treat osteoporosis?
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
What can bisphosponates be used to treat?
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)
What are the treatment options of osteoporosis?
Oestrogen/Selective Oestrogen Receptor Modulators (SERM)
Bisphosphonates
Denosumab
Teriparatide
How does HRT (oestrogen) treat osteoporosis? Why is it limited?
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
What is denosumab?
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
What is teriparatide?
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
What is Paget’s disease of bone?
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
How do tissue selective ER agonists work and how is this useful in osteoporosis?
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
What are the pharmacokinetics of bisphosphonates?
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
What are the clinical features of Paget’s disease?
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
How do you diagnose Paget/s disease?
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
What causes Paget’s disease?
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
How is body weight homeostasis regulated by the hypothalamus?
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
What are the hypothalamus subregions determined by?
Nuclei differentiated by anatomy/function
Paraventricular nucleus
Lateral hypo
Ventromedial hypo
Arcuate nucleus
What is the arcuate nucleus?
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
What do NPY/Agrp neurons in the arcuate nucleus do?
Increase appetite
What do POMC neurons in the arcuate nucleus do?
Decrease appetite
How do POMC and Agrp from the arcuate nucleus affect the paraventricular nucleus MC4R?
POMC-> a-MSH-> activates MC4R-> suppresses food intake
Agrp-> Agrp-> inhibits MC4R-> increases food intake
Why haven’t NPY or Agrp mutations associated with appetite been identified?
Maybe brain rewires
Maybe just don’t study thin people
What do POMC deficiency and MC4R mutations cause?
Morbid obesity
Useful to explain signalling
What are the features of the ob/ob mouse?
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
What is leptin?
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
What can leptin resistance cause?
Obesity due to leptin resistance- hormone is present but doesn’t signal effectively
Don’t realise how much leptin you have
What happens in the absence of leptin?
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
Why can leptin be used for children?
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)
Why can leptin be used in women with amenorrhea?
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
How does insulin affect food intake?
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
What are gut hormones important for?
GI tract= >20 different regulatory peptide hormones
Influence processes including gut motility, secretion of other hormones, appetite
What regulates gut hormones?
Gut nutrient content
What are the major GI hormones?
Cholecystokinin Secretin GIP Motilin Ghrelin Gastrin Insulin Glucagon Pancreatic polypeptide Amylin GLP-1 GLP-1 Oxymtomodulin PYY3-36
What is cholecystokinin involved in?
Gall bladder contraction
GI motility
Pancreatic exocrine secretion
What is secretin involved in?
Pancreatic exocrine secretion
What is GIP involved in?
Incretin activity
What is motilin involved in?
GI motility
What is ghrelin involved in? how?
Hunger
Growth hormone release
Directly modulates neurones in the arcuate nucleus
- > stimulates NPY/Agrp neurones
- > inhibits POMC neurons
- > increases appetite
What is gastrin involved in?
28AA gastrin hormone
Acid secretion
What are insulin and glucagon involved in?
Glucose homeostasis
What is pancreatic polypeptide involved in?
Gastric motility
Satiation
What is amylin involved in?
Glucose homeostasis
Gastric motility
What is GLP-1 (glucagon- like peptide 1) involved in? What codes for it?
Incretin activity (involved in stimulating glucose-stimulated insulin release) Satiation-> reduced food intake
Coded for by the preproglucagon gene and released post-prandially
What is GLP-2 involved in?
GI motility and growth
What is oxymtomodulin involved in?
Satiation
Acid secretion
What is PYY3-36 involved in? How?
Satiation
Secreted post-prandially
Directly modulates neurons in the arcuate nucleus
- > inhibits NPY release
- > stimulates POMC neurones
- > decreases appetite
What happens if peripheral GLP-1 is given to rodents/humans?
Inhibits food intake
GLP-1 agonists have been FDA approved (and DPP-4 inhibitors)
What happens to pro-glucagon in intestinal L-cells after a meal?
Processing of pro-glucagon
Prohormone convertase 1-> active agonist
Very short half life (regulated by inactivation)
What is Saxenda?
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)
Why is PYY3-36 limited as a drug target?
Narrow therapeutic window (effective area)
ABOVE= nausea BELOW= no effect
What comorbidies are associated with obesity?
Depression Stroke Sleep apnoea Myocardial infarction Hypertension Diabetes Bowel cancer Osteoarthritis Peripheral vascular disease Gout
How do twin studies show genetic involvement of obesity?
Monozygotic twins= 0.66 correlation
Dizygotic twins= 0.26 correlation
Outline the thrifty gene hypothesis
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)
Outline the adaptive drift (drifty gene) hypothesis
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
What is the main difference between T1DM and T2DM?
T1= lacking insulin T2= insulin resistance
What are the ambiguous features of diabetes T1/T2?
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)
What is LADA?
Latent autoimmune Diabetes in Adults
Autoimmune T1 diabetes= leading to insulin deficiency can present in later decades
What is MODY?
Monogenic diabetes can be type 1 or type 2
Mitochondrial diabetes
Treat with sulfonylureas not insulin
Approximate number of people with T2DM and T1DM in UK?
T1= 0.5 mil
T2= 6% population, going up
What causes hyperglycaemia in T1DM?
Environmental trigger and genetics
Autoimmune destruction of islet cells
Insulin deficiency
Hyperglycaemia
What causes hyperglycaemia in T2DM?
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
Outline the pathogenesis of type 1 diabetes
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
What is the honeymoon phase in T1DM?
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
Why is the immune basis of T1DM important?
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
What happens to beta cells in the pancreas when there is an increased amount of inflammatory cells?
In T1DM, beta cells destroyed
What has a larger genetic basis, T1 or T2DM?
Type 2
What are the HLA-DR alleles that cause a significant risk of T1DM?
DR3 and D4
What seasonal, environmental factors have been identified in T1DM?
Environmental influence > genetic influence
T1DM patients normally present in winter/autumn (maybe an infectious process)
When are markers (antibodies) used for diabetic patients?
Measure antibodies in blood stream to see T1DM when unsure if patient T1 or T2
Not needed for most patients
What markers are used for differentiating between T1DM and T2DM?
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
What are the symptoms and signs in T1DM?
SYMPTOMS Polyuria Nocturia Polydipsia Blurring of vision Thrush Weight loss
SIGNS Dehydration Cachexia Hyperventilation Sme;l of ketones Glycosuria Ketonuria
Why does metabolic acidosis lead to hyperventilation?
Excess CO2 exhalation
Heavy breathing
Hyperventilation to expel excess CO2
What happens in T1DM (when there is no insulin)?
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
What are the aims of treatment in T1DM?
Reduce early mortality
Avoid acute metabolic decompensation
T1DM need exogenous insulin to preserve life
Prevent long term complications= retinopathy, nephropathy, neuropathy, vascular disease
What is the recommended diet in type 1 diabetes?
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
How was insulin discovered?
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
What kinds of insulin treatment are there?
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)
How were insulin analogues developed?
Genetic engineering to alter absorption, distribution, metabolism and excretion
What is b.d. insulin?
Twice a day
What is t.b.s. insulin?
3x a day insulin
With every meal
If someone eats erratic amounts, how is their dose of insulin affected?
Need to give different doses throughout the day
What is an insulin pump?
Continuous insulin delivery (attached to lower abdomen)
Preprogrammed basal rates and bolus for meals
Doesn’t measure glucose- no completion of feedback loop
How does an islet cell transplant work? What are the advantages and limitations?
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
How can you monitor blood glucose?
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
What is the benefit of the capillary monitoring over time?
Can ask retrospectively what they were doing then
Tailor insulin and dietary regime to resolve
When is HbA1c false?
In patient has something affecting RBCs
= hamoglobinopathy (e.g. SCA, thal)
Also rate of glycation is faster in some individuals
What kind of binding is glucose to HbA1c?
Irreversible, non-covalent
What happens if you lower HbA1c?
Lower risk of complication particularly microvascular complication
What is ketoacidosis?
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
What kind of diabetes has diabetic ketoacidosis?
Normally type 1
But can be type 2
What happens when a patient has a ‘hypo’?
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
At what mmol/l are impaired mental processes and consciousness/death likely?
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’
Who is most at risk of hypos?
Main risk factor is quality of glycaemic control
More frequent in patients with low HbA1c
When can hypos commonly occur?
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
What are the symptoms and signs of hypoglycaemia?
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
How can you treat hypoglycaemia?
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)
What is diabetes mellitus?
State of chronic hyperglycaemia sufficient to cause long term damage to specific tissues (especially retina, kidney, nerves and arteries)
What are key features of T2DM?
Not ketosis prone
Not mild
Often involves weight, lipids and blood pressure
What does a fasting glucose <6 mean?
Normal
What does a fasting glucose 6 -7mean?
Impaired fasting glucose
What does a fasting glucose >7 mean?
Diabetes
What does a 2 hour glucose <7.8 mean?
Normal
What does a 2 hour glucose 7.8-11.1 mean?
Impaired glucose tolerance
What does a 2 hour glucose >11.1 mean?
Diabetes
What does a random glucose <11.1 mean?
Normal
What does a random glucose >11.1 mean?
Diabetes
Outline the epidemiology of T2DM
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
Outline the pathophysiology of T2DM
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)
What causes maturity onset diabetes of the young (MODY)?
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
How do genes lead to macrovascular and microvascular complications?
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
What is the correlation in identical and non-identical twins for T1DM and T2DM?
T1
Identical= 35%
Nonidentical= 10%
T2
Identical= 70%
Nonidentical= 40%
How does insulin resistance relate to B cells?
Decreasing B cell reserve with increasing insulin resistance
How do people with T2DM usually present?
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
What does a hyperglycaemic clamp show?
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
What factors contribute to increased fasting plasma glucose in T2DM?
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)
Where does glycogen->glucose (gluconeogenesis)?
Liver
Where does glucose->glycogen?
Muscle
Where are TG->glycerol and NEFA (lipolysis)?
Adipocytes
Particularly from omental fat
NB. fat cells are profoundly important endocrine tissue (not just a store)
How is obesity involved in T2DM?
More than a precipitant Fatty acids and adipocytokines important Central and omental obesity= worse 80% T2DM are obese Weight reduction useful signs
How do gut microbiota contribute to T2DM?
Host and inflammation signaling
Bacterial lipopolysaccharides fermentation to short chain FA, bacterial modulation bile acids
Most studies show correlation between microbiota and T2DM
What diabetes treatments lead to weight gain?
TZDs especially
SUs
Meglitinides
NB. Metformin doesn’t so combo treatment help
What are the major complications of T2DM?
MICROVASCULAR
Retinopathy
Nephropathy
Neuropathy
MACROVASCULAR Ischaemia heart disease Cerebrovascular Renal artery stenosis PVD
METABOLIC
Lactic acidosis
DKA
Hyperosmolar
TREATMENT
Hypoglycaemia
What is the basis of management of T2DM?
Education
Diet
Pharmacological treatment
Complication screening
MONITOR- weight, glycaemia, blood pressure, dyslipidaemia
Why should T2DM be treated?
Symptoms
Reduce chance of acute metabolic complications
Reduce chance of long term complications
Education
What is the recommended diet for T2DM?
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)
What are the main drugs for T2DM?
LIVER
Metformin
ABDOMEN and MUSCLES
Thiazolidinediones
INTESTINES
a glucosidase inhibitor
PANCREAS
Sulphonylureas and metaglinidies
Glucagon like peptide
DPP4 inhibitor
How does metformin work? When is it used/not used? SEs?
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
How does sulphonylurea work? When is it used/not used? SEs?
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
How does acarbose work? SEs?
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
What is flatus?
Gas in or from the stomach or intestines, produced by swallowing air or by bacterial fermentation
How do thiazolidinediones work? SEs?
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
What increases secretion of incretins? What do these do?
Increased in response to presence of food in GI tract
Incretins are additional factors which stimulates insulin secretion after oral glucose ingestion
What is GLP-1?
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)
What does GLP-1 do?
Used in T2DM
E.g. Exenatide, liraglutide Injectable Long acting GLP-1 agonist Decrease glucagon conc Decrease glucose conc Weight loss
What are gliptins?
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
What is empagliflozin?
For T2DM
Inhibits Na-Glu transported, increases glycosuria
Lowers mortality especially CV mortality e.g. from heart failure
What happens to the B cell function with intervention in T2DM?
B-cell function continues to decline regardless of intervention in T2DM
As well as hyperglycaemia, what is important to control in T2DM?
Blood pressure
Diabetic dyslipidaemia (increased LDL, decreased LDL)
Outline the prevalence of T1DM and T2DM
Type 1= 0.25%
Type 2= 4-7%
Outline the geography of T1DM and T2DM
Type 1= Europids
Type 2= Less europids
Outline the typical age of T1DM and T2DM
Type 1= Child, adolescent
Type 2= Middle-age +
Outline the onset of T1DM and T2DM
Type 1= Acute
Type 2= Gradual
Outline the habitus of T1DM and T2DM
Type 1= Lean
Type 2= Obese
Outline the family history T1DM and T2DM
Type 1= Uncommon
Type 2= Common
Outline the weight loss in T1DM and T2DM
Type 1= Usual
Type 2= Uncommon
Outline the ketosis in T1DM and T2DM
Type 1= Yes
Type 2= No
Outline the serum insulin in T1DM and T2DM
Type 1= Low/absent
Type 2= Variable
Outline the HLA association in T1DM and T2DM
Type 1= DR3, DR4
Type 2= None
Outline the islet B cells in T1DM and T2DM
Type 1= Destroyed
Type 2= Function
Outline the islet cells antibodies in T1DM and T2DM
Type 1= Present
Type 2= Absent
Why does diabetes lead to micro and macrovascular complications?
Diabetes damages blood vessels
Where are the main sites of microvascular complications?
Retinal arteries Glomerular arterioles (kidney) Vasa nervorum (tiny blood vessels that supply nerves)
What are the main microvascular complications?
Severity of hyperglycaemia Hypertension Genetic Hyperglycaemic memory Tissue damage through originally reversible and later irreversible alterations in proteins
What is the challenge of hyperglycaemic memory?
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
How does severity of hyperglycaemia relate to microvascular complication?
Complications are reduced if HbA1c is low (i.e. not severe)
How does hypertension relate to microvascular complications?
Vessels that control BP can be affected
Higher bP-> more likely to get systolic disease
What are the mechanisms of glucose damage?
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
What is diabetic retinopathy?
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
What is background diabetic retinopathy? 3 common features
Happens to majority of patients
3 common features:
Hard exudates (cheese colour, lipid)
Microaneurysms (“dots”)
Blot haemorrhages
What is pre-proliferative diabetic retinopathy?
Progression from background diabetic retinopathy (if untreated)
Cotton wool spots also called soft exudates (fluffy)
Represent retinal ischaemia-. various parts become ischaemic
What is proliferative retinopathy?
Visible new vessels on disk or elsewhere in retina
What is maculopathy?
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
What is the progression of retinopathy?
Background
Pre-proliferative
Proliferative
NB. Could have maculopathy
How is diabetic retinopathy managed?
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
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
Maculopathy can threaten direct vision
What is the pathophysiology of diabetic nephropathy?
Hypertension
Progressively increasing proteinuria
Progressively deteriorating kidney function
Classic histological features
Why is it important to understanding kidney disease with diabetes?
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
What are the histological features of diabetic nephropathy?
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
What is the epidemiology of diabetic nephropathy?
Type 1 DM= 20-40% after 30-40 years
Type 2 DM= Probably equivalent but compounding factors
What factors can affect the epidemiology of nephropathy in T2DM?
Age at development of disease Racial factors Age at presentation May have been asymptomatic but still glucose unregulated Loss due to cardiovascular morbidity
What are the clinical features of diabetic nephropathy?
Progressive proteinuria
Increased BP
Deranged renal function
What are the ranges for proteinuria?
See degree of protein being expelled
Normal range
<30mg/24hrs
Microalbuminuric range
20-200mg/24hrs
Asymptomatic range
300-3000mg/24hrs
Nephrotic range
>3000mg/24hr
What are the strategies for intervention of diabetic nephropathy?
Diabetic control (decreasing HbA1c-> reduced microvascular complications)
Inhibition of activity of RAS system
Blood pressure control (e.g. ACE inhibitors)
Stopping smoking
What drugs affect angiotensin 2?
ACE inhibitors
What effects does angiotensin 2 have?
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
Which microvascular complication of diabetes do ACE inhibitors prevent?
Diabetic nephropathy
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
Progressively increasing proteinuria
What is diabetic neuropathy?
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
What kinds of diabetic neuropathy are there?
Peripheral polyneuropathy Mononeuropathy Mononeuritis multiplex Radiculopathy Autonomic neuropathy Diabetic amyotrophy Sensory and motor
How does diabetic neuropathy progress?
Initiating event (genetics and inflammation contribute)- from insult or chronic disorders
Glycation
Epigenetic
Function and progressive pathological changes
What is peripheral neuropathy?
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)
Who is peripheral neuropathy most likely to occur in?
Who is it most likely to occur in?
What is a monofilament exam?
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
What is mononeuropathy?
Usually sudden motor loss
Wrist drop, foot drop
Cranial nerve palsy (double vision due to 3rd nerve palsy)
What is pupil sparing third nerve palsy?
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)
How can an aneurysm cause third nerve palsy?
Press on parasympathetic fibres first causing fixed dilated pupil
Pupil not spared (so can tell it’s not diabetic)
What is mononeuritis multiplex?
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
What is radiculopathy?
Pain over spinal nerves, usually affecting a dermatome on the abdomen or chest wall
Nerves that are connected
What is the difference between mononeuritis multiplex and radiculopathy?
Mononeuritis= random combo of peripheral nerve lesions Radiculopathy= nerves that are connected
What is autonomic neuropathy?
Loss of sympathetic and parasympathetic nerves to GI tract, bladder, cardiovascular system
How does autonomic neuropathy affect the GI tract?
Difficulty swallowing
Delayed gastric emptying
Constipation/ nocturnal diarrhoea
How does autonomic neuropathy affect the postural hypotension?
Can be disabling e.g. collapsing on standing
How can you measure cardiac autonomic supply in diabetic autonomic neuropathy?
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
What are the main types of macrovascular disease in diabetes?
Early widespread atherosclerosis
Ischaemic heart disease
Cerebrovascular disease
Peripheral vascular disease
How are atheromas formed? (Macrovascular disease and the metabolic syndrome_
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
What risk factors contribute to atheromas?
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)
How is life expectancy affected by hyperglycaemia?
Hyperglycaemia is associated with significantly reduced life expectancy
True or false: macrovascular conditions occur in people with diabetes only
FALSE
Occurs in people with or without diabetes
How do microvascular and macrovascular diseases affect morbidity and mortality?
Microvascular disease causes morbidity
Macrovascular disease causes morbidity and mortality
How does diabetes mortality change with known CVD?
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
How does macrovascular disease affect ischaemic heart disease, cardiovascular disease, peripheral vascular disease and renal artery stenosis?
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
Is controlling blood sugar more important for microvascular or macrovascular conditions of diabetes?
Microvascular
What is adiponectin?
Mechanism possibly responsible to T2DM
Normally decreases insulin resistance
How should macrovascular diseases be managed?
Aggressive management of multiple risk factors (modifiable and non-modifiable)
Intensive therapy over conventional
What are the risk factors for macrovascular disease?
NON-MODIFIABLE Age Sex Birth weight FH/Genes
MODIFIABLE Dyslipidaemia High blood pressure Smoking Diabetes
What are the treatment goals in T2DM?
Lower blood glucose
Treat BP
Manage blood lipids
What complications of diabetes predispose the patient to foot disease?
Neuropathy- sensory, motor and autonomic
Peripheral vascular disease
What is the prevalence of current or past foot ulceration in diabetes?
5-7%
Risk of amputation 60x in diabetes
What is the pathway to foot ulceration?
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)
What happens in sensory neuropathy that leads to foot ulceration?
Loss of touch (don’t notice stone in shoe/sore feet)
Loss of vibration
Loss of temp sensation (hot bath)
What happens in motor neuropathy that leads to foot ulceration?
Clawing of toes and flattening of arch of foot
-> abnormal neuropathy
What happens in autonomic neuropathy that leads to foot ulceration?
Lack of sweating
How does limited joint mobility lead to foot ulceration?
Abnormal pressure on parts of feet
How does reduced resistance to infection lead to foot ulceration?
White cells don’t work as well in hyperglycaemia
What will a magnetic resonance angiography for peripheral vessel disease show?
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)
What are the features of the neuropathic foot, ischaemic foot and neuro-ischaemic foot?
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
Why may someone with a diabetic ulcer have a black toe?
Peripheral vascular disease
End artery has occluded-> gangrene of toe
Where are common sites for foot ulcers?
Dorsum of toes
Ball of foot
What should be considered when you assess the foot of a diabetic patient?
Appearance= deformity? callus?
Feel= hot? cold? dry?
Foot pulses= dorsalis pedis? posterior tibial pulse?
Neuropathy= vibration sensation, temp, ankle jerk reflex, fine touch sensation
How can you prevent foot ulcers?
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
How are diabetic foot ulcers managed?
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
What features of diabetic feet may lead to osteomyelitis?
Patient with Charcot neuro-osteoarthropathy and a rocker-bottom foot
Will have osteomyelitis on cuboid bone
How can you differentiate between osteomyelitis and active charcot?
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
