Endocrinology 2 Flashcards
what are metabolic changes in pregnancy?
- increased erythropoietin, cortisol, noradrenaline
- high cardiac output
- plasma volume expansion
- high cholesterol and triglycerides
- pro thrombotic and inflammatory state
- insulin resistance
what are gestational syndromes of pregnancy?
- pre-eclampsia
- gestational diabetes
- obstetric cholestasis
- gestational thyrotoxicosis
- transient diabetes insipidus
- lipid disorders
- postnatal depression
- postpartum thyroiditis
- postnatal autoimmune disease
- paternal disease
what is the embryological development of the thyroid gland?
- fetal thyroid follicles and thyroxine synthesis occurs at 10 weeks
- axis matures at 15-20 weeks
- maternal T4 0-12 weeks regulates neurogenesis, migration and differentiation of fetal T4
what are glycoprotein hormones involved in thyroid/pregnancy?
- glycoprotein hormones contain two subunits, a common alpha subunit and a distinct beta subunit
- TSH, LH, FSH and hCG
what happens with thyroid hormone levels in the first trimester of pregnancy?
- increase in thyroxine and triiodothyronine, which results in inhibition of TSH due to a high hCG level that stimulates the TSH receptor due to partial structural similarity
- increased TBG
- increase then decrease in hCG
- increase then decrease in free T4
- decrease tehn increase in thyrotropin
what are levels of thyroid hormones like in the fetus throughout pregnancy?
increased TBG, total T4, thyrotropin, free T4, total T3, free T3 (in order of most increased to least increased levels)
what is responsible for higher thyroxine requirements in pregnancy?
- large plasma volume and thus an altered distribution of thyroid hormone
- increased thyroid hormone metabolism
- increased renal clearance of iodide
- higher levels of hepatic production of TBG in the hyperestrogenic state of pregnancy
what produces thyroxine binding globulin (TBG)?
liver
what is the incidence of hypothyroidism in pregnancy?
- 2-3%
- overt hypothyroidism 0.3-0.5% in pregnancy
- subclinical hypothyroidism 2-3%
what are symptoms of hypothyroidism in pregnancy?
weight gain, cold intolerance, poor concentration, poor sleep pattern, dry skin, constipation, tiredness
what are the ATA guidelines for TSH levels during the pregnancy?
1st trimester: 0.1-2.5mIU/L 2nd trimester: 0.2-3.0mIU/L 3rd trimester: 0.3-3.0mIU/L - 4 weekly for 20 weeks gestation - again 26-32 weeks
25-30% increase if miss period and no recent test
urgent blood test and review
ATA 2017 ULL ~4.0mIU/L
how does hypothyroidism affect pregnancy?
- inadequate treatment
- gestational hypertension
- placental abruption
- post partum haemorrhage
- low birth weight
- preterm delivery
- neonatal goitre and respiratory distress
what is the treatment for hypothyroidism in pregnancy?
- preconception counselling; ideal preconception TSH <2.5mIU/L
- increase dose by 30%
- arrange TFT early pregnancy and titrate
- women require a dose increase in their thyroxine during pregnancy
- if overt in pregnancy, aim to normalise asap
- commence at 50-100mcg, measure TFT at 4-6 weeks
when is targeted screening done for thyroid problems in pregnancy?
- age >30
- BMI >40
- miscarriage preterm labour
- personal or family history
- goitre
- anti TPO
- T1DM
- head and neck irradiation
- amiodarone, lithium or contrast use
what is the prevalence of hyperthyroidism in pregnancy? what are some causes?
0.1-0.4% prevalence
female population 2%
85-90% due to Graves’
less common causes: MNG, gestational thyrotoxicosis, toxic adenoma, trophoblastic neoplasia, TSHoma
how does hyperthyroidism affect pregnancy?
- IUGR
- low birth weight
- preeclampsia
- preterm delivery
- risk of stillbirth
- risk of miscarriage
how does pregnancy affect hyperthyroidism?
- tends to worsen in first trimester
- improves latter half of pregnancy
what is the management of hyperthyroidism in pregnancy?
- symptomatic treatment; beta blockers
- anti-thyroid medications
- PTU/carbimazole
- radioactive iodine is contraindicated
- surgical interventions; optimal timing is 2nd trimester
what are effects of carbimazole and propylthiouracil on pregnancy?
carbimazole
- increased risk of congenital abnormalities
- aplasia cutis
- choanal atresia
- intestinal anomalies
propylthiouracil
- rare hepatotoxicity
what is fetal thyrotoxicosis?
transplacental crossover of TSH-R antibodies
- 0.01% of cases
- anti-thyroid medications
what is fetal thyrotoxicosis associated with?
- IUGR
- fetal goitre
- fetal tachycardia
- fetal hydrops
- preterm delivery
- fetal demise
what are the causes of gestational thyrotoxicosis?
- limited to first half of the pregnancy
- raised T4, low/suppressed TSH
- absence of thyroid autoimmunity
- associated with hyperemesis gravidarum
- 5-10 cases/1000 pregnancies
- multiple gestation
- hydatidaform mole
- hyperplacentosis
- choriocarcinoma
what are the issues of gestational thyrotoxicosis?
- benefits of treating
- hyperemesis gravidum
- extreme; Wernicke’s encephalopathy
- thyrotoxicosis risks
what is the prevalence of post-partum thyroiditis?
7%
what increases the risk of post-partum thyroiditis?
T1DM, Graves’ in remission, chronic viral hepatitis, measure TSH 3 months post-partum
what is the percentage of total body water in lean body weight?
- 50-60% of lean bodyweight in men
- 45-50% in women
what is total body water in a healthy 70kg male? what compartments is this contained in?
42L
- intracellular fluid (28L, about 35% of lean bodyweight)
- extracellular; interstitial fluid that bathes the cells (9.4L, 12%)
- plasma; also extracellular (4.6L, 4-5%)
where are small amounts of water contained in, apart from intracellular and extracellular compartments?
bone, dense connective tissue and epithelial secretions, e.g. digestive secretions and CSF
what separates the compartments that body water is held in?
- intracellular and interstital fluids separated by the cell membrane
- interstitial fluid and plasma separated by the capillary wall
where does water tend to stay?
in the soluble-containing compartment because there is less free diffusion across the membrane
what is osmotic pressure?
the minimum pressure which needs to be applied to a solution to prevent the inward flow of its pure solvent across a semipermeable membrane
- measures the ability to hold water in the compartment
what is the primary determinant of the distribution of water among the three major compartments?
osmotic pressure
what is contained in the intracellular fluid?
mainly potassium (K+); most of the magnesium is bound and osmotically inactive - potassium, magnesium and phosphate/organic anions
what is contained in the ECF?
Na+ salts predominate in the interstitial fluid
- large amounts of sodium, chloride and bicarbonate ions
what is a characteristic of an osmotically active solute? what are examples?
cannot freely leave its compartment
- capillary wall is impermeable to plasma proteins
- cell membrane is impermeable to Na+ and K+ because the ATPase pump restricts Na+ to the extracellular fluid and K+ to the intracellular fluid
- Na+ freely crosses the capillary wall and achieves similar conc. in interstitium and plasma, and doesn’t contribute to fluid distribution between these compartments
- urea crosses the capillary wall and the cell membrane and is osmotically inactive
what happens when Na+ intake is increased?
- extra Na+ will initially be added to the extracellular fluid
- associated increase in extracellular osmolality causes water to move out of the cells -> extracellular volume expansion
- balance restored by excretion of excess Na+ in the urine
what is the effect of addition of 1L of water, saline 0.9% and colloid solution?
- water is distributed equally into all compartments
- saline remains in the extracellular compartment (treatment for extracellular water depletion)
- colloid stays in the vascular compartment (due to high oncotic pressure; treatment for hypovolaemia)
what does hydrostatic pressure do?
pressure of blood against the capillary wall
- tends to force fluid out of the capillaries
- due to gravity
what does oncotic pressure do?
form of osmotic pressure induced by proteins, e.g. albumin, in a blood vessels plasma
- displaces water molecules and retains fluid within the vessel
- opposes hydrostatic pressure
what is the primary determinant of renal sodium and water excretion?
EABV
what is EABV? what does it depend on?
effective arterial blood volume
- fullness of the arterial vascular compartment
- constitutes effective circulatory volume
- depends on a normal ratio between cardiac output and peripheral arterial resistance
what causes diminished EABV?
fall in cardiac output or fall in peripheral arterial resistance (increase in the holding capacity of the arterial vascular tree)
what happens when there is an increased/decreased EABV?
- expanded -> urinary Na+ excretion increased; can exceed 100mmol/L
- depleted with normal renal function -> urine free of Na_
what can lead to decreased cardiac output?
- decreased extracellular fluid volume
- low output cardiac failure
- pericardial tamponade
- constrictive pericarditis
- decreased intravascular volume secondary to diminished pressure or increased capillary permeability
what leads to peripheral arterial vasodilation?
- sepsis
- cirrhosis
- arteriovenous fistula
- pregnancy
- arterial vasodilators
what does decreased EABV lead to?
arterial underfilling -> unloading of high-pressure volume receptors -> stimulation of sympathetic nervous system -> non osmotic ADH release, increased peripheral and renal arterial vascular resistance and Na+ and H2O retention, and activation of RAAS
what does stimulation of sympathetic nervous system due to decreased EABV lead to?
- non osmotic ADH release
- activation of RAAS
- increased peripheral and renal arterial vascular resistance and Na+ and H2O retention
what does arterial underfilling due to reduced effective circulating volume lead to?
- decreased renal perfusion pressure and GFR
- increased adrenergic activity
- angiotensin II activity
-> increased proximal tubular sodium and water reabsorption -> decreased tubular sodium and water delivery
what does increased proximal tubular sodium and water reabsorption lead to?
decreased tubular sodium and water delivery
what causes impaired escape from actions of aldosterone and resistance to ANP (atrial natriuretic peptides)?
- increased ANP produced by heart
- decreased distal tubular sodium and water delivery
- increased aldosterone produced by angiotensin II activity
what is the neurohumoral regulation of extracellular volume?
- mediated by volume receptors that sense changes in the EABV rather than alterations in the sodium concentration
- receptors are distributed in renal and cardiovascular tissues
what do intrarenal volume receptors do?
- in walls of the afferent glomerular arterioles
- respond via the juxtaglomerular apparatus to changes in renal perfusion and control the RAAS
- sodium conc. in distal tubule and sympathetic nerve activity alters renin release
- prostaglandins I2 and E2 are generated within the kidney due to angiotensin II, and maintain GFR and sodium and water excretion
what is generated in the kidney in response to angiotensin II? what do they do?
prostaglandins I2 and E2
- maintain GFR and sodium and water excretion
- modulate the sodium-retaining effect of angiotensin II
what are mechanisms of sodium transport in the proximal tubule?
reabsorbed: 60-70%
luminal Na+ entry: Na+/H+ exchange and cotransport of Na+ with glucose, phosphate and other organic solutes
transport: angiotensin II and norepinephrine
what are mechanisms of sodium transport in the loop of Henle?
reabsorbed: 20-25%
luminal Na+ entry: Na+/K+/2Cl- cotransport
transport: flow dependent and pressure natriuresis mediated by NO
what are mechanisms of sodium transport in the distal tubule?
reabsorbed: 5%
luminal Na+ entry: Na+/Cl- cotransport
transport: flow dependent
what are mechanisms of sodium transport in the collecting ducts?
reabsorbed: 4%
luminal Na+ entry: Na+ channels
transport: aldosterone and ANP
where are extrarenal receptors for regulation of EABV located?
vascular tree in the left atrium and major thoracic veins, and in the carotid sinus body and aortic arch
what do extrarenal receptors do?
- volume receptors
- respond to a slight reduction in effective circulating volume
- result in increased sympathetic nerve activity and rise in catecholamines
- volume receptors in the cardiac atria control release of ANP from granules in the atrial walls
where are high-pressure arterial receptors located?
carotid, aortic arch, juxtaglomerular apparatus
where are low-pressure volume receptors located?
cardiac atria, right ventricle, thoracic veins, pulmonary vessels
what is responsible for day-to-day variations in Na+ excretion?
aldosterone and possibly ANP
what does a salt load lead to?
- leads to an increase in effective circulatory and extracellular volume
- raises renal perfusion pressure and atrial and arterial filling pressure
- increase in renal perfusion pressure reduces secretion of renin and then angiotensin II and aldosterone
- rise in atrial and arterial filling pressure increases release of ANP
-> reduced Na+ reabsorption in the collecting duct; promoted excretion of excess Na+
what does a low Na+ intake or volume depletion due to vomiting and diarrhoea lead to?
- decrease in effective volume enhances RAAS and reduces secretion of ANP
- enhanced Na+ reabsorption in collecting ducts -> fall in Na+ excretion
-> increases extracellular volume towards normal
what does more marked hypovolaemia lead to?
- decrease in GFR lead to increase in proximal and thin ascending limb Na+ reabsorption
- enhanced sympathetic activity acting directly on kidneys and indirectly by secretion of renin/angiotensin II and ADH
persistent hypovolaemia -> systemic hypotension and increased salt and water absorption in the proximal tubules and ascending limb of Henle
what regulates volume in oedematous conditions?
- sodium and water are retained despite increased ECV
- principal mediator of this is arterial underfilling due to reduced cardiac output or diminished peripheral arterial resistance -> reduction of pressure or stretch -> activation of SNS, RAAS and ADH -> promote salt and water retention
what are examples of oedematous conditions?
cardiac failure, hepatic cirrhosis and hypoalbuminaemia
what is a feature of Conn’s syndrome?
increased aldosterone secretion; primary hypoaldosteronism
what is the mechanism of escape from aldosterone and resistance to ANP in normal patients?
- high doses of mineralocorticoids initially increase renal sodium retention so that extracellular volume is increased by 1.5-2L
- renal sodium retention then ceases, sodium balance reestablished and no oedema
- escape is dependent on increased delivery of sodium to collecting ducts (site of action of aldosterone)
- increased distal sodium delivery is achieved by high ECV-mediated arterial overfilling
- suppresses sympathetic activity and ang. II generation, increases ANP -> increased renal perfusion pressure and GFR
-> reduced sodium absorption in proximal tubules and increased distal delivery which overwhelms sodium-retaining actions of aldosterone
is there escape from aldosterone action in patients with oedematous conditions?
- no
- continue to retain sodium in response to aldosterone
- natriuresis when given spironolactone (blocks mineralocorticoid receptors)
- alpha-adrenergic stimulation and elevated ang. II increase sodium transport in the proximal tubule, and reduced renal perfusion and GFR increases sodium absorption
- sodium delivery to distal portion is reduced
absence of escape phenomenon is likely due to decreased sodium delivery to the collecting duct
what controls thirst and the urine concentrating/diluting functions of the kidney?
- intracellular osmoreceptors in hypothalamus
- volume receptors in capacitance vessels close to heart
- RAAS
what is the role of osmoreceptors?
- sense changes in the plasma Na+ concentration and osmolality
- influence thirst and release of ADH (vasopressin) from supraoptic and paraventricular nuclei of the anterior hypothalamus
what is the role of ADH (vasopressin)?
urinary concentration, by increasing the water permeability of normally impermeable cortical and medullary collecting ducts
what is the type of receptor for ADH (vasopressin)?
GPCR
what are the three major GPCRs for vasopressin (ADH) and where are they located?
- V1a in vascular smooth muscle cells
- V1b in anterior pituitary and throughout the brain
- V2 receptors in the principal cells of the kidney distal convoluted tubule and collecting ducts
what is the action of V1a, V1b and V2 vasopressin (ADH) receptors?
- activation of V1a receptors induces vasoconstriction
- V1b mediates the effect of ADH on the pituitary, facilitating the release of ACTH
- V2 receptors mediate the antidiuretic response as well as other functions
what is the primary step in the countercurrent mechanism? what are the two effects of it?
transport in the ascending limb of the loop of Henle; reabsorbing NaCl without water
- makes tubular fluid dilute
- medullary interstitium concentrated
what happens in the absence and presence of ADH?
absence: little water is reabsorbed in the collecting ducts, and dilute urine is excreted
presence: promotes water reabsorption in the collecting ducts down the favourable osmotic gradient between the tubular fluid and the more concentrated interstitium -> increase in urine osmolality and a decrease in urine volume
what are the types of cell in the collecting duct?
principal and intercalated cells
what is the function of principal cells?
- in the collecting duct
- 65%
- sodium and potassium channels in the apical membrane
- Na+/K+ ATPase pumps in basolateral membrane
what is the function of intercalated cells?
- do not transport NaCl
- have a role in hydrogen and bicarbonate handling and in potassium reabsorption in states of potassium depletion
what is the action of ADH on the collecting duct?
- increase in permeability occurs mainly in the principal cells
- acts on V2 receptors on the basolateral surface of principal cells -> activation of adenyl cyclase -> protein kinase activation -> aquaporin insertions
what happens to aquaporins when the ADH effect has worn off?
aggregate within clathrin-coated pits, from which they are removed from the luminal membrane by endocytosis and returned to the cytoplasm
what can lead to nephrogenic diabetes insipidus?
defect in aquaporins
- e.g. in attachment of ADH to its receptor or the function
- > resistance to action of ADH and an increase in urine output
what are the actions of the different aquaporins?
aquaporin 2 is located on the apical membrane and allows transport of water from the urine into the cell
aquaporins 3 and 4 are on the basal membrane and allow water transport into the circulation
at what osmolality is there no circulating ADH?
- plasma osmolality of <275mosmol/kg
- <135-137mmol/L
what are the mechanisms of osmoregulation?
- ingestion of water load
2. water loss
what does ingestion of a water load lead to?
- initial reduction in plasma osmolality, thus diminishing the release of ADH
- reduction in water reabsorption in the collecting ducts allows excess water to be excreted in a dilute urine
what does water loss resulting from sweating lead to?
- rise in plasma osmolality and ADH secretion, enhanced water reabsorption and excretion of small volume of concentrated urine
- minimises further water loss but does not replace the water deficit
- thirst
what happens to water load normally?
- rapidly excreted (4-6hrs) by inhibition of ADH release so there is little or no water reabsorption in collecting ducts
- volume regulation not usually affected and no change in ANP release or RAAS
- dilute urine excreted and little change in excretion of Na+
what happens with 0.9% saline administration normally?
- causes increase in volume but no change in plasma osmolality
- ANP secretion is increased, aldosterone secretion reduced and ADH secretion does not change
- net effect is the appropriate excretion of excess Na+ in isoosmotic urine
what does rise in osmolality lead to?
ADH release and thirst
what does hypervolaemia lead to?
enhances the secretion of ANP and suppresses aldosterone secretion
-> increased excretion of Na+ without water
what is SIADH?
syndrome of inappropriate ADH secretion
- impaired water excretion and hyponatraemia (dilutational) caused by persistent presence of ADH
- release of ANP and aldosterone is not impaired; Na+ handling is intact
when is ADH secreted by non-osmotic stimuli?
- stress
- reduced effective circulatory volume (e.g. cardiac failure, hepatic cirrhosis)
- psychiatric disturbance and nausea
what causes ADH release by non-osmotic stimuli?
- effects of sympathetic overactivity on supraoptic and paraventricular nuclei
- ADH release promotes water retention and vasoconstriction due to activation of V1a in smooth muscle cells
what does exposure to hypotonic solutions and cell swelling lead to?
- increase in plasma membrane potassium and chloride conductance in the cell -> efflux
- other intracellular osmolytes, e.g. taurine and other amino acids are transported out of the cell
- regulatory volume decrease
- vice versa for hypertonic solutions
how do tubular cells at the tip of renal papillae maintain their cell volume?
- constantly exposed to a hypertonic extracellular mileu
- take up smaller molecules, e.g. betaine, taurine and myoinositol
- synthesise more sorbitol and glycerophosphocholine
what does distribution depend on, according to Starling principles?
- venous tone, which determines the capacitance of the blood compartment and thus hydrostatic pressure
- capillary permeability
- oncotic pressure; mainly dependent on serum albumin
- lymphatic drainage
what is the action of ADH (vasopressin)?
- kidney is the predominant site of action of ADH at normal concentrations
- stimulates V2 receptors -> collecting ducts to become permeable to water via migration of aquaporins
- permits reabsorptionof hypotonic luminal fluid
- reduces diuresis and results in overall retention of water
- at high concentrations it causes vasoconstriction via V1 receptors in vascular tissue
what level is vasopressin secretion suppressed at?
below 280mOsm/kg
what is the upper limit of normal vasopressin levels?
295mOsm/kg
how do vasopressin levels vary in normal levels?
- above 280mOsm/kg, plasma vasopressin levels increase in direct proportion to plasma osmolality
- at 295mOsm/kg, maximum antidiuresis is achieved
when is thirst experienced?
at 298mOsm/kg of vasopressin
what are some disorders of vasopressin secretion or activity?
- deficiency due to hypothalamic disease (cranial diabetes insipidus)
- inappropriate excess of the hormone
- nephrogenic insipidus; renal tubules are insensitive to vasopressin
what are causes of cranial diabetes insipidus?
- familial (e.g. DIDMOAD)
- idiopathic (often autoimmune)
- tumours
- infections (TB, meningitis, cerebral abscess)
- infiltrations (sarcoidosis, Langerhans’ cell histiocytosis)
- inflammatory (hypophysitis)
- post-surgical (transfrontal, transsphenoidal)
- post-radiotherapy
- vascular (haemorrhage/thrombosis, Sheehan’s syndrome/aneurysm)
- trauma (head injury)
what tumours can cause cranial diabetes insipidus?
- craniopharyngioma
- hypothalamic tumour e.g. glioma, germinoma
- metastases, esp. breast
- lymphoma/leukaemia
- pituitary with suprasellar extension
what are causes of nephrogenic diabetes insipidus?
- familial (vasopressin receptor gene, aquaporin-2 gene defect)
- idiopathic
- renal disease (e.g. renal tubular acidosis)
- hypokalaemia
- hypercalcaemia
- drugs (e.g. lithium, demeclocycline, glibenclamide)
- sickle cell disease
- mild temporary nephrogenic DI after prolonged polyuria
what is vasopressin (ADH) increased by?
- increased osmolality
- hypovolaemia
- hypotension
- nausea
- hypothyroidism
- angiotensin II
- adrenaline
- cortisol
- nicotine
- antidepressants
what is vasopressin (ADH) secretion decreased by?
- decreased osmolality
- hypervolaemia
- hypertension
- ethanol
- alpha-adrenergic stimulation
what are the clinical features of diabetes insipidus?
- polyuria, nocturia and compensatory polydipsia
- daily urine output may reach as much as 10-15L
- dehydration, may be severe if thirst mechanisms or conciousness is impaired or patient is denied fluid
- may be masked by cortisol deficiency
- MR scanning may show an absent or poorly developed posterior pituitary
what are genetic features of diabetes insipidus?
- familial isolated vasopressin deficiency causes DI from early childhood and is dominantly inherited, caused by mutation in AVP-NPII gene
- DIDMOAD (Wolfram) syndrome
what is DIDMOAD syndrome?
- Wolfram syndrome
- rare autosomal recessive disorder
- comprises diabetes insipidus, diabetes mellitus, optic atrophy and deafness
- mutations in WFS1 gene on chromosome 4
what is the biochemistry of diabetes insipidus?
- high or high-normal plasma osmolality with low urine osmolality (in primary polydipsia plasma osmolality tends to be low)
- resultant high or high-normal plasma sodium (hypernatraemia)
- high 24-hr urine volumes (less than 2L excludes need for further investigation)
- failure of urinary concentration with fluid deprivation
- restoration of urinary concentration with vasopressin/analogue
what tests are used to detect diabetes insipidus?
- water deprivation test
- measurement of plasma vasopressin during hypertonic saline infusion
what is the treatment of choice for diabetes insipidus? what is the dose? what is the main problem?
synthetic vasopressin (ADH) analogue: desmopressin
- longer duration of action
- no vasoconstrictive effects
- given intranasally as a spray 10-40ug OD/BD or
- orally 100-200ug TDS or
- IM 2-4ug OD
- fluid input/output and plasma osmolality measurements
- avoiding water overload and hyponatraemia
what are alternative agents used for diabetes insipidus?
mild DI, probably working by sensitising the renal tubules to endogenous vasopressin
- thiazide diuretics
- carbamazepine 200-400mg OD
- chlorpropamide 200-350mg daily
what is indication for a water deprivation test?
diagnosis or exclusion of diabetes insipidus
what is the procedure for a water deprivation test?
- fasting and no fluids from 0730 (or overnight if only mild DI expected and polyuria modest)
- monitor serum and urine osmolality, urine volume and weight hourly for up to 8 hours
- abandon fluid deprivation if weight >3% occurs
- if serum osmolality >300mOsm/kg and/or urine osmolality <600mOsm/kg give desmopressin 2ug IM at end of test
- allow free fluid but measure urine osmolality for 2-4hrs
what is the interpretation of water deprivation tests?
- normal response: serum osmolality remains within normal range (275-295mOsm/kg). urine osmolality rises to >600mOsm/kg
- DI: serum osmolality rises above normal w/out adequate conc. of urine osmolality
- nephrogenic DI: desmopressin doesn’t concentrate urine
- cranial DI: urine osmolality rises by >50% after desmopressin
what indicates normal response to a water deprivation test?
serum osmolality remains within normal range (275-295mOsm/kg). urine osmolality rises to >600mOsm/kg
what indicates diabetes insipidus from a water deprivation test?
serum osmolality rises above normal w/out adequate conc. of urine osmolality
- i.e. serum osmolality >300mOsm/kg; urine osmolality <600mOsm/kg
what indicates nephrogenic DI from a water deprivation test?
desmopressin doesn’t concentrate urine
what indicates cranial DI from a water deprivation test?
urine osmolality rises by >50% after desmopressin
what is cranial DI?
deficiency of vasopressin (ADH) due to hypothalamic disease
what is nephrogenic diabetes insipidus? what is it caused by?
- renal tubules are resistant to normal or high levels of plasma vasopressin (ADH)
- may be inherited as a rare sex-linked recessive, with abnormality in V2 receptor
- may be inherited as an autosomal post-receptor defect in aquaporin-2
- may be due to renal disease, sickle cell disease, drug ingestion (e.g. lithium), hypercalcaemia or hypokalaemia
what are other causes of polyuria and polydipsia?
- diabetes mellitus
- hypokalaemia
- hypercalcaemia
- primary polydipsia
what is polyuria caused by in diabetes mellitus?
osmotic diuresis secondary to glycosuria which leads to dehydration and increased perception of thirst due to hypertonicity of ECF
what is primary polydipsia?
- common cause of thirst and polyuria
- is a psychiatric disturbance characterised by excessive intake of water
- plasma sodium and osmolality fall and urine is dilute
- vasopressin levels become undetectable
- may lead to renal medullary washout, with fall in concentrating ability of the kidney
how is primary polydipsia?
water deprivation test
- low plasma osmolality is usual at start of test
- urine becomes concentrated as vasopressin secretion and action can be stimulated
- initially low urine osmolality increases with duration of water deprivation
what are tumours that cause SIADH?
- small-cell carcinoma of the lung
- prostate
- thymus
- pancreas
- lymphomas
- leukaemia
- sarcoma
- mesothelioma
what are pulmonary lesions that cause SIADH?
- pneumonia
- TB
- lung abscess
- severe asthma
- pneumothorax
- positive-pressure ventilation
- emphysema
what are CNS causes of SIADH?
- meningitis
- tumours
- head injury
- subdural haematoma
- cerebral abscess
- SLE
- vasculitis
- encephalitis
- haemhorrage/thrombosis
- Guillain Barre syndrome
- acute intermittent porphyria
what are metabolic causes of SIADH?
- alcohol withdrawl
- porphyria
what are drug causes of SIADH?
- chlorproamide
- carbamazepine
- cyclophosphamide
- vincristine
- phenothizines
- clofibrate
- thiazides
- MAO inhibitors
- cyclotoxics
- desmopressin
- vasopressin
- oxytocin
- SSRIs
- PPIs
what are clinical features of SIADH?
- retention of water and hyponatraemia
- vague presentation
- confusion, nausea, irritability and later, fits and coma
- no oedema
- elderly may show symptoms with milder abnormalities
what are sodium levels like in SIADH?
- mild symptoms occur with levels below 125mmol/L
- serious manifestations occur below 115mmol/L
what must SIADH be distinguished from?
dilutational hyponatraemia due to excess infusion of glucose/water solutions or diuretic administrations (thiazides or amiloride)
what are the usual features of SIADH?
- dilutational hyponatraemia due to excessive water retention
- euvolaemia (in contrast to hypovolaemia of sodium and water depletion states)
- low plasma osmolality with inappropriate urine osmolality >100mOsm/kg
- continued urinary sodium excretion >30mmol/L (lower levels suggest sodium depletion)
- absence of hypokalaemia or hypotension
- normal renal and adrenal and thyroid function
- too much AVP
- hyponatraemia
- urine inappropriately concentrated
- water retention
- increased GFR; less Na reabsorption
- Na >30mmol/l
normal circulating volume
no oedema
how is saline used to distinguish between SIADH and hyponatraemia?
trial infusion of 1-2L of 0.9% saline is given
- SIADH will not respond (but will excrete sodium and water load effectively)
- sodium depletion will respond
- ACTH gives similar biochemical picture to SIADH, so check HPA axis is intact
what is the treatment used for SIADH to give symptomatic relief?
- fluid intake restricted to 500-1000mL daily
- plasma osmolality, serum sodium and body weight measured frequently
- demeclocycline 600-1200mg daily is given; inhibits action of vasopressin on kidney, causing a reversible form of nephrogenic DI
- hypertonic saline (in severe cases; can be dangerous)
- V2 antagonists e.g. tolvaptan 15mg daily
- diagnose and treat underlying condition
- <8-10mmol/l increase in Na+ per 24hrs if chronic
- potential risk of central pontine myelinolysis
why are disorders of sodium concentration considered disorders of body water content?
- sodium content regulated by volume receptors
- water content is adjusted to maintain (in health) a normal osmolality and in absence of abnormal osmotically active solutes, a normal sodium concentration
- disturbances of sodium concentration are caused by disturbances of water balance
what is hyponatraemia?
Na+ <135mmol/L
- hyponatraemia with hypovolaemia
- hyponatraemia with euvolaemia
- hyponatraemia with hypervolaemia
what is pseudo-hyponatraemia?
- occurs in hyperlipidaemia or hyperproteinaemia where there is low measured sodium concentration
- sodium confined to aqueous phase and its concentration is expressed in terms of total volume of plasma
- plasma abnormality is normal and treatment is unnecessary
what is artefactual hyponatraemia caused by?
taking blood from the limb into which fluid of low sodium concentration is being infused
what are extrarenal and renal causes of hyponatraemia with hypovolaemia?
salt loss in excess of water loss
extrarenal (urinary sodium <20mmol/L)
- vomiting
- diarrhoea
- haemorrhage
- burns
- pancreatitis
kidney (urinary sodium >20mmol/L)
- osmotic diuresis
- diuretics
- adrenocortical insufficiency
- tubulo-interstitial renal disease
- unilateral renal artery stenosis
- recovery phase of acute tubular necrosis
what are causes of hyponatraemia with euvolaemia?
- abnormal ADH release
- SIADH
- major psychiatric illness
- increased sensitivity to ADH
- ADH-like substances (desmopressin)
- unmeasured osmotically active substances stimulating osmotic ADH release
what causes abnormal ADH release (in hyponatraemia with euvolaemia)?
- vagal neuropathy (failure of inhibition of ADH release)
- deficiency of ACTH or glucocorticoids (Addison’s disease)
- hypothyroidism
- severe potassium depletion
what are major psychiatric illnesses that can cause hyponatraemia with euvolaemia?
- psychogenic polydipsia
- non-osmotic ADH release
- antidepressant therapy
what drugs cause increased sensitivity to ADH?
- clorpropamide
- tolbutamide
what are unmeasured osmotically active substances that stimulate osmotic ADH release?
- glucose
- chronic alcohol abuse
- mannitol
- sick-cell syndrome (leakage of intracellular ions)
what are causes of hyponatraemia with hypervolaemia?
- heart failure
- liver failure
- oliguric kidney injury
- hypoalbuminaemia
- CCF
- cirrhosis of liver
what is the mechanism of hyponatraemia with hypovolaemia?
- salt loss in excess of water loss
- ADH secretion is initially suppressed via the hypothalamic osmoreceptors, but as fluid volume is lost, volume receptors override osmoreceptors and stimulate thirst and release of ADH
what makes up the ECF?
intravascular fluid (1/4, 3.5L) interstitial fluid (3/4, 10.5L)
what is the feedback loop response to water excess?
increased cellular hydration -> decreased thirst and decreased vasopressin secretion -> decreased water intake and increased urine excretion -> decreased total body of water -> ingestion of water -> decreased plasma osmolality and increased cellular hydration
what is the feedback loop response to water deficit?
decreased cellular hydration -> increased thirst and vasopressin secretion -> increased water intake and decreased urine water excretion -> increased total body water -> water loss -> increased plasma osmolaltiy and decreased cellular hydration
what controls release of vasopressin (ADH)?
osmoreceptors in hypothalamus - day to day
baroreceptors in brainstem and great vessels - emergency
where does fixed water excretion occur?
- stool (0.1 L/day)
- sweat (0.1 L/day)
- pulmonary (0.3 L/day)
total insensible losses: 0.5L/day
where does variable water excretion occur?
kidneys
- 180L filtrate/day
- total urine output 1-1.5 L/day
what affects osmolality?
- sodium, potassium, chloride, bicarbonate, urea and glucose
- alcohol, methanol, polyethylene glycol or manitol (exogenous)
how is normal plasma osmolality with normal serum sodium calculated?
Na+: 137 x 2
glucose: 4.5
urea: 6
total = 284.5mmol/L
- 2 x Na+ accounts for anions associated with Na+
- 0-10mOsmo/kg gap between measured and calculated; higher usually due to alcohol
what are normal osmolality levels?
282-295mOsmol/kg
how is plasma osmolality in hyponatraemia calculated?
Na+: 125 x 2
glucose: 4.5
urea: 6
total = 260.5mmol/L
what are acquired causes of cranial DI (lack of vasopressin)?
- idiopathic
- tumours: craniopharyngioma, germinoma, metastases, never anterior pituitary tumour
- trauma
- infections: TB, encephalitis, meningitis
- vascular: aneurysm, infarction, Sheenan’s, sickle cell
- inflammatory: neurosarcoidosis, Langerhans’s histiocytosis, Guillain Barre, granuloma
what are primary causes of cranial DI (lack of vasopressin)?
genetic
- DIDMOAD (Wolfram syndrome)
- autosomal dominant
- rarely autosomal recessive
developmental
- septo-optic dysplasia
what are acquired causes of nephrogenic DI (resistance to vasopressin action)?
- osmotic diuresis (DM)
- drugs (lithium, demeclocycline, tetracycline)
- chronic renal failure
- postobstructive uropathy
- metabolic (hypercalcaemia, hypokalaemia)
- infiltrative (amyloid)
what are familial causes of nephrogenic DI (resistance to vasopressin action)?
- X linked (V2 receptor defect)
- autosomal recessive (aquaporin 2 defect)
what is management of nephrogenic DI?
- try and avoid precipitating drugs
- congenital DI: free access to water, high dose desmopressin, hydrochlorothiazide or indomethacin
what is the definition of hyponatraemia? what are severe levels? what are normal levels?
definition: serum sodium <135mmol/l
severe: serum sodium <125mmol/l
normal serum sodium: 137-144mmol/l
what are signs and symptoms of hyponatraemia at 130-135mmol/l?
asymptomatic/headache
what are signs and symptoms of hyponatraemia at 125-130mmol/l?
- lethargy
- anorexia and abdominal pain
- weakness
- confusion/hallucinations
what are signs and symptoms of hyponatraemia at <125mmol/l?
- agitation
- decreased conscious level
what are signs and symptoms of hyponatraemia at <115mmol/l?
- fitting
- coma
what kind of volume adaptation does the brain go through in response to gradual-onset hyponatraemia?
normal brain (normal osmolaltiy) -> immediate effect of hypotonic state -> water gain (low osmolality) > rapid adaption -> loss of sodium, potassium and chloride and water -> slow adaption -> loss of organic osmolytes (low osmolality) -> improper therapy (rapid correction of hypotonic state) leads to osmotic demyelination or proper therapy (slow correction) leads to normal brain and normal osmolality
what does proper and improper therapy for low osmolality in the brain caused by hyponatraemia?
proper therapy (slow correction of hypotonic state) -> normal brain and normal osmolaltiy
improper therapy (rapid correction of hypotonic state) -> osmotic demyelination
what is acute vs chronic hyponatraemia?
acute: 48 hours
- rapid correction safer and may be necessary
chronic hyponatraemia: CNS adapts
- correction must be slow; <8mmol/24hours
what are tests to do when hyponatraemia presents?
- plasma osmolality
- urine osmolality
- plasma glucose
- urine sodium
- urine diptest for protein
- TSH
- cortisol
- short synacthen if cortisol <500nmol/l
- consider alcohol
what are the treatment goals of SIADH?
- ensure correct diagnosis
- allow increase in serum Na+
- treat any underlying condition
- identify and stop any causative drug
- in acute setting, daily U+E/hospital
- chronic setting; weekly to monthly U+E/hospital/GP
- frequent comorbidity
- Na>130mmol/l; usually no need for urgent intervention
what are drawbacks to current managements for SIADH?
- compliance with fluid restriction difficult
- nursing and other staff find enforcement of fluid restriction a challenge
- demeclocycline can cause skin rash/photosensitivity
- lithium is not often effective, has side effects
- management of chronic SIADH is challenging
how and when is hypertonic saline administered?
- symptomatic hyponatraemia
- administer 1.8% N Saline 300mls over 20mins
- repeat sodium after 20mins
- consider repeating bolus of hypertonic saline
- avoid increasing sodium by more than 10mmol/L in first 24hrs and 18mmol/L over 48hrs
what are examples of vaptans?
tolvaptan and conivaptan
what is tolvaptan?
selective V2 receptor oral antagonist
- competitive antagonist to AVP
- causes aquaresis
- no effect on 30 day mortality in heart failure, but increased body weight/likelihood for readmission after cessation
- licensed for SIADH
- expensive
what is conivaptan?
- V1a/V2 receptor IV antagonist
- not licensed yet
- may be better for heart failure
what patients would benefit from vaptans?
- chronic SIADH - in community - treatment initiated and monitored by hospital-based physician
- acute SIADH for whom fluid restriction a challenge/resistant
- in acute setting there is easier understanding for ward staff
what are disadvantages of vaptans?
- ?correct diagnosis
- may cause too rapid rise in serum sodium
- more expensive; fluid restriction is free
what are advantages of vaptans?
- allow more normal drinking; likely improved quality of life
- titrate dose against effect on Na+
- less expensive if shorter hospital stay
what are clinical features of hyponatraemia with hypovolaemia?
- volume depletion
- history of gut losses, diabetes mellitus or diuretic abuse
- examination often more helpful than biochemical investigations
what is treatment for hyponatraemia with hypovolaemia for healthy patients?
directed at the primary cause whenever possible
- give oral electrolyte-glucose mixtures
- increase salt intake with slow sodium 60-80mmol/day
what is treatment for hyponatraemia with hypovolaemia for patients with vomiting or severe volume deletion?
- give IV fluid with potassium supplements, i.e. 1.5-2L 5% glucose (with 20mmol K+) and 1L 0.9% saline over 24hrs plus measureable losses
- correction of acid-base abnormalities is usually not required
what is hyponatraemia with euvolaemia?
results from an intake of water in excess of the kidney’s ability to excrete it (dilutational hyponatraemia) with no change in body sodium content but plasma osmolality is low
what are types of people/situations affected by hyponatraemia with euvolaemia?
- with normal kidney function, dilution hyponatraemia is uncommon even if a patient drinks about 1L per hour
- most common iatrogenic cause is overgenerous infusion of 5% glucose in postop patients; exacerbated by increased ADH due to stress
- postop hyponatraemia common with symptomatic hyponatraemia in 20%
- marathon runners drinking excess water and sports drinks
- premenopausal females at most risk for developing hyponatraemic encephalopathy postoperatively
how can hyponatraemia be prevented?
- avoid using hypotonic fluids postop
- administer 0.9% saline unless contraindicated
- serum sodium should be measured daily
what are clinical features of dilutational hyponatraemia?
- symptoms common when hyponatraemia develops acutely (<48hrs, often postop)
- symptoms rarely occur until serum sodium is less than 120mmol/L, associated with <110mmol/L, esp. when chronic
- symptoms are principally neurological and are due to movement of water into brain cells in response to fall in extracellular osmolality
what causes neurological symptoms in dilutational hyponatraemia?
movement of water into brain cells in response to fall in extracellular osmolality
what are sings and symptoms of hyponatraemic encephalopathy? how can it be detected?
headache, confusion and restlessness leading to drowsiness, myoclonic jerks, generalised convulsions and eventually coma
- MRI scan of the brain reveals cerebral oedema
- in context of electrolyte abnormalities and neurological symptoms, can help make a confirmatory diagnosis
what is the brain’s adaptation to hyponatraemia?
- extrusion of blood and CSF, and sodium, potassium and organic osmolality, to decrease brain osmolality
- factors interfere with successful adaptation
- these factors rather than the absolute change in serum sodium predict whether a patient will suffer hyponatraemic encephalopathy
how are children affected by hyponatraemic encephalopathy?
children under 16 years are at increased risk due to their relatively larger brain-to-intracranial volume ratio compared with adults
how are premenopausal women affected by hyponatraemic encephalopathy?
more likely to develop encephalopathy than postmenopausal females and males because of inhibitory effects of sex hormones and effects of vasopressin on cerebral circulation resulting in vasoconstriction and hypoperfusion of brain
how does hypoxaemia affect hyponatraemic encephalopathy?
- major risk factor
- patients with hyponatraemia who develop hypoxia due to non-cardiac pulmonary oedema or hypercapnic respiratory failure, have a high risk of mortality
- hypoxia is strongest predictor of mortality in patients with symptomatic hyponatraemia
what are investigations of hyponatraemia with euvolaemia?
- plasma and urine electrolytes and osmolalities
- plasma concentrations of sodium, chloride and urea are low, giving a low osmolality
- urine sodium concentration is usually higher than plasma osmolality
- maximal dilution (<50mosmol/kg is not always present)
- potassium and magnesium depletion potentiate ADH release and are causes of diuretic-associated hyponatraemia
what diseases are excluded with further investigations for hyponatraemia with euvolaemia?
exclude Addison’s disease, hypothyroidism, SIADH and drug induced water retention e.g. chlorpropamide
what is the general treatment of hyponatraemia with euvolaemia?
- underlying cause should be corrected where possible
- restriction of water intake (to 1000 or 500mL/day)
- review of diuretic therapy
- magnesium and potassium deficiency must be corrected
- in mild sodium deficiency, 0.9% saline given slowly (1L over 12 hrs is sufficient)
how should plasma sodium be corrected in general?
- should not be corrected to >125-130mmol/L
- 1mL/kg of 3% sodium chloride will raise plasma sodium by 1mmol/L, assuming that total body water comprises 50% of total bodyweight
what is the treatment of acute onset of hyponatraemia with euvolaemia with symptoms?
- acute medical emergencies, should be treated aggressively and immediately
- severe neurological signs e.g. fits or coma or cerebral oedema: hypertonic saline (3%, 513mmol/L) given slowly (no more than 70mmol/hr)
- increase sodium by 4-6mmol/L in first 4 hrs
- absolute change should not exceed 15-20mmol/L over 48hrs
what are causes of acute onset hyponatraemia with euvolaemia with symptoms?
- most common cause in adults is postoperative iatrogenic hyponatraemia
- excessive water intake associated with psychosis
- marathon running
- use of ecstasy
what is treatment of symptomatic hyponatraemia in patients with intracranial pathology?
- managed aggressively and immediately with 3% hypertonic saline (3%, 513mmol/L) given slowly (no more than 70mmol/hr)
- increase sodium by 4-6mmol/L in first 4 hrs
- absolute change should not exceed 15-20mmol/L over 48hrs
what is treatment of chronic/asymptomatic hyponatraemia?
- develops slowly in majority of patients
- brain will have adapted by decreasing intracellular osmolality
- hyponatraemia can be corrected slowly (without use of hypertonic saline)
- difficult to know how long it’s been present and salin may still be required
what is ODS?
osmotic demyelination syndrome
- central pontine demyelination
- devastating neurological complication of hyponatraemia
what causes osmotic demyelination syndrome (ODS)?
- rapid rise in extracellular osmolality, particularly if there is an overshoot to high serum sodium and osmolality
- plasma sodium concentration in patients with hyponatraemia should not rise by more than 8mmol/L per day
- rate of rising should be lower in patients at risk of ODS
what are risk factors for ODS?
- alcohol excess
- cirrhosis
- malnutrition
- hypokalaemia
- pre-existing hypoxaemia
- CNS radiation
how is ODS diagnosed?
- appearance of characteristic hypointense lesions on T1-weighted images and hyperintense lesions on T2-weighted lesions on MRI
- take up to 2 weeks or longer to appear
what is the pathophysiology of ODS?
- brain loses organic osmolytes very quickly to adapt to hyponatraemia so that osmolarity is similar between the intracellular and extracellular compartments
- neurones regain organic osmolytes slowly in phase of rapid correction of hyponatraemia
- results in hypoosmolar intracellular compartments and shrinkage of cerebral vascular endothelial cells
- BBB is functionally impaired, allowing lymphocytes, complement and cytokines to enter the brain, damage oligodendrocytes, activate microglial cells and cause demyelination
what is the mechanism of rapid correction of hyponatraemia?
- should be prevented
- rapid rise in plasma sodium is usually due to water diuresis, which happens when ADH action stops suddenly
- water diuresis due to increased distal delivery of filtraate is main cause of rapid rise
when may vasopressin (ADH) action stop suddenly?
- volume repletion in patients with intravascular volume depletion
- cortisol replacement in Addisons disease
- resolution of non-osmotic stimuli for vasopressin release e.g. nausea or pain
what is the assumption made about water excretion in absence of vasopressin?
- total urine volume is equal to volume of filtrate delivered to the distal nephron
- volume of filtrate delivered to distal nephron = GFR - volume reabsorbed in PCT
- 80% of of GFR is reabsorbed in the PCT
how is the volume of filtrate delivered to distal nephron calculated?
GFR - volume reabsorbed in PCT
why is water excretion less than volume of distal delivery of filtrate in real life?
- even in absence of vasopressin
- significant degree of water is reabsorbed in the inner medullary collecting duct through its residual water permeability, prompted by very high osmotic force in the interstitium
what is the treatment to avoid ODS?
- hypokalaemia increases the risk
- if plasma sodium rises too quickly due to water diuresis, administration of desmopressin to stop water diuresis is used
- if it rises regardless tehn lowering plasma sodium to maximum limit of correction <8mmol/L per day with 5% glucose solution
how can reversible hyponatraemia culminate in hypernatraemia?
- cause of water retention is often reversible; on correction, vasopressin levels fall and plasma sodium rises by up to 2mmol/L per hour due to excretion of dilute urine
- excessive water diuresis should be anticipated and prevented by desmopressin
- patients who are chronically hyponatraemic with concomitant hypokalaemia are susceptible to overcorrection
what is plasma sodium a function of?
function of the ratio of exchangeable body sodium plus potassium to total body water, so potassium administration increases sodium concentration
what is an example of reversible hyponatraemia culminating in hypernatraemia?
mildly symptomatic hyponatraemic patient with a plasma sodium of <120mmol/L and potassium of <2mmol/L could develop ODS due to overcorrection of hyponatraemia; simple due to replacing the large potassium deficit
what is the mechanism of action of vasopressin (ADH) antagonists?
- V2 receptor antagonists, which produce a free water diuresis, and are being used for hyponatraemic encephalopathy
- lixivaptan, tolvaptan and satavaptan are selective for the V2 receptor
- conivaptan blocks both V1a and V2 receptors
what is the mechanism of action of lixivaptan, tolvaptan and satavaptan?
- vasopressin (ADH) antagonists
- selective for V2 receptor
what is the mechanism of action of conivaptan?
- vasopressin (ADH) antagonists
- blocks both V1a and V2 receptors
what is the effect of vasopressin (ADH) antagonists?
- produce a selective water diuresis without affecting sodium and potassium excretion
- raise plasma sodium concentration in patients with hyponatraemia caused by SIADH, heart failure and cirrhosis
what is the use and effectiveness of tolvaptan?
- effective in ambulatory patients with hyponatraemia caused by SIADH, heart failure or cirrhosis
- used in euvolaemic hyponatraemia and SIADH
what is the administration and use of conivaptan?
- IV conivaptan is used for euvolaemic hyponatraemia in some countries
- 20mg bolus followed by continuous infusion of 20mg over 1-4 days
- continuous infusion increases risk of phlebitis, which requires use of large veins and changing the infusion site every 24hrs
what are features of hyponatraemia with hypervolaemia?
- reduced GFR with reabsorption of sodium and chloride in proximal tubule
- leads to reduced delivery of chloride to ascending limb of Henle’s loop and a reduced ability to generate free water
- consequent inability to excrete dilute urine
- compounded by the administration of diuretics that block chloride reabsorption and interfere with dilution of filtrate in Henles loop or distally
what are types of pituitary mass lesion?
- non-functioning pituitary adenomas
- endocrine active pituitary adenomas
- malignant pituitary tumours: functional and non-functional pituitary carcinoma
- metastases in the pituitary (breast, lung, stomach, kidney)
- pituitary cysts: Rathke’s cleft cyst, mucocoeles, others
what are developmental abnormalities that cause pituitary mass lesions?
craniopharyngioma (occasionally intrasellar location), germinoma, others
what are primary pituitary tumours of the CNS?
perisellar meningioma, optic glioma
what are vascular tumours causing pituitary mass lesions?
hemangioblastoma, others
what are malignant systemic diseases that cause pituitary mass lesions?
Hodgkin’s disease, non-Hodgkin lymphoma, leukaemic infiltration, histiocytosis X
what are granulomatous diseases that cause pituitary mass lesions?
neurosarcoidosis, Wegner’s granulomatosis, TB, syphilis
what is Rathke’s cyst? what are symptoms/presentations?
- derived from remnants of Rathke’s pouch
- single layer of epithelial cells with mucoid, cellular or serous components in cyst fluid
- mostly intrasellar component, may extend into parasellar area
- mostly asymptomatic and small
- present with headache and amenorrhoea, hypopituitarism and hydrocephalus
what are features of meningioma?
- commonest tumour of region after pituitary adenoma
- complication of radiotherapy
- associated with visual disturbance and endocrine dysfunction
- present with loss of visual acuity, endocrine dysfunction and visual field defects
what is lymphocytic hypophysitis?
inflammation of the pituitary gland due to an autoimmune reaction
- lymphocytic adenohypophysitis
- lymphocytic infundibuloneurohypophysitis
- lymphocytic panhypophysitis
what is the epidemiology of lymphocytic hypophysitis?
- 1 per 9 million based on pituitary surgery
- LAH commoner in women; 6:1
- age of presentation in women is 35, 45 in men
what is the appearance of lymphocytic hypophysitis?
- hypointense on T1 imaging
- hyperintense on T2 imaging
- stalk enlargement
- pituitary enlargement
what is the epidemiology of non-functioning pituitary adenoma?
- pituitary adenomas are <10-15% of primary intracranial tumours
- NFPAs are 14-28% of clinically relevant pituitary adenomas and 50% of pituitary macroadenomas
- most NFPAs express gonadotrophins or subunits
- 30% are classified as null cell adenomas
- diagnosed between 20 and 60 years
- 50% are incidentalomas
what are signs of aggressiveness of non functioning pituitary adenomas?
- large size
- cavernous sinus invasion
- lobulated suprasellar margins
what are the main types of pituitary dysfunction?
- tumour mass effects
- hormone excess
- hormone deficiency
what are investigations of pituitary dysfunction?
hormonal tests; if hormonal tests abnormal or tumour mass effects, perform MRI pituitary
what are local mass effects of pituitary tumours?
- cranial nerve palsy and temporal lobe epilepsy
- headaches
- CSF rhinorrhoea
- visual field defects
what are some visual field defects and examples of them?
unilateral field loss e.g. left optic nerve compression
bitemporal hemianopia e.g. chiasmal compression from pituitary tumour
homonymous heminopia e.g. left cerebrovascular event
what is management of non-functioning pituitary tumours?
- no specific test, but absence of hormone secretion
- test normal pituitary function
- trans-sphenoidal surgery if threatening eyesight or progressively increasing in size
why is testing pituitary function complex?
- many hormones: GH, LH/FDH, ACTH, TSH, ADH
- may have deficiency of one or all and may be borderline
- circadian rhythms and pulsatile
what is the guiding principle of testing pituitary function?
if the peripheral target organ is working normally, the pituitary is working
how is the pituitary-thyroid axis tested?
- primary hypothyroid: raised TSH, low Ft4
- hypopituitary: low Ft4 with normal or low TSH
- Graves’ disease (toxic): suppressed TSH, high Ft4
- TSHoma: high Ft4 with normal or high TSH
- hormone resistance: high Ft4 with normal or high TSH
measure Ft4 in pituitary disease
how is the gonadal axis tested in men?
- primary hypogonadism: low testosterone, raised LH/FSH
- hypopituitary: low testosterone or low LH/FSH
- anabolic use: low testosterone and suppressed LH
measure 0900hrs fasted testosterone and LH/FSH in pituitary disease
how is the gonadal axis tested in women?
- before puberty: oestradiol very low/undetectable with low LH and FSH; FSH slightly higher than LH
- puberty: pulsatile LH increases and oestradiol increases
- post-menarche: monthly menstrual cycle with LH/FSH, mid-cycle surge in LH and FSH and levels of oestradiol increase through cycle
- primary ovarian failure: high LH and FSH with FSH greater than LH and low oestradiol
- hypopituitary: oligo or amenorrhoea with low oestradiol and normal or low LH and FSH
how is the hypothalamic-pituitary-adrenal axis tested?
- circadian rhythm
- measure 0900hrs cortisol and synacthen
- primary AI: low cortisol, high ACTH, poor response to synacthen
- hypopituitarism: low cortisol, low or normal ACTH, poor response to synacthen
what is the pattern of GH secretion?
- secreted in pulses with greatest pulse at night and low or undetectable levels between pulses
- GH levels fall with age and are low in obesity
how is the GH/IGF1 axis tested?
measure: IGF-1 and GH stimulation test
- insulin stress test
- glucagon test
- other
how are prolactin levels tested?
- under negative control of dopamine
- stress hormone
- measure prolactin or cannulated prolactin (3 samples over an hour to exclude stress of venepuncture)
why may prolactin be raised?
- stress
- drugs e.g. antipsychotics
- stalk pressure
- prolactinoma
what is dynamic testing good for?
dynamic stimulation/suppression testing may be useful in select cases to further evaluate pituitary reserve and/or pituitary hyperfunction
what dynamic testing is used in Cushing’s, acromegaly, TSHoma, gonadotropin deficiency, GH/ACTH deficiency?
- dexamethasone suppression testing; Cushing’s
- oral glucose GH suppression test; acromegaly
- CRH stimulation; Cushing’s
- TRH stimulation; TSHoma
- GnRH stimulation; gonadotropin deficiency
- insulin-induced hypoglycaemia; GH/ACTH deficiency
- glucagon test; GH deficiency
what are advantages of MRI for pituitary disorders?
- preferred imaging study for the pituitary
- better visualisation of soft tissues and vascular structures than CT
- no exposure to ionising radiation
- T1/T2 weighted images
what is the function of T1-weighted images in MRI?
- produce high-signal intensity images of fat
- structures e.g. fatty marrow and orbital fat show up as bright images
what is the function of T2-weighted images in MRI?
- produce high-intensity signals of structures with high water content
- structures e.g. CSF and cystic lesions
what are advantages of CT as radiologic evaluation of pituitary disorders?
- better at visualising bony structures and calcifications within soft tissues
- better at determining diagnosis of tumours with calcification, e.g. germinomas, craniopharyngiomas and meningiomas
- may be useful when MRI is contraindicated, e.g. in patients with pacemakers or metallic implants in the brain or eyes
what are disadvantages of CT as radiologic evaluation of pituitary disorders?
- less optimal soft tissue imaging compared to MRI
- use of IV contrast media
- exposure to radiation
what are features of GH deficiency? what is the Rx?
- short stature
- abnormal body composition
- reduced muscle mass
- poor quality of life
Rx: GH
what are features of LH/FSH deficiency? what is the Rx?
- hypogonadism
- reduced sperm count
- infertility
- menstruation problems
Rx: testosteron in males, oestradial/progesterone in females
what are features of TSH deficiency? what is the Rx?
hypothyroidism
Rx: levothyroxine
what are features of ACTH deficiency? what is the Rx?
- adrenal failure
- decreased pigment
Rx: hydrocortisone
what are features of ADH deficiency?
- diabetes insipidus
- decreased water absorption resulting in polyuria and polydipsia
Rx: DDAVP
what are microparticulates?
modified release HC
- inert core
- hydrocortisone layer
- sustained release
- enteric coat
what is done in thyroxine replacement?
- dose 1.6mg/kg/day
- aim to achieve levels to mid to upper half of reference range
- check level before levothyroxine dose
- higher doses usually required in patients on oestrogens or in pregnancy
what is done in GH replacement?
- <60 years: start 0.2-0.4mg/day
- > 60 years: start 0.1-0.2mg/day
- aiming for midrange IGF1 levels
- measure IGF1 6 weeks after dose start and change
- improves lipid profiles, body composition and bone mineral density
what is done in testosterone replacement?
- gels, injections, oral
- follow testosterone levels, FBC and prostate specific antigens
- improves bone mineral density, libido, function, energy levels and sense of well being, muscle mass and reduced fat
what is done in oestrogen replacement?
- oral oestrogen or combined oestrogen/progesterone formulations (also transdermal, topical gels, intravaginal creams)
- alleviate flushes and night sweats, improve vaginal atrophy
- reduce risk of CVD, osteoporosis and mortality
- HRT in 40 to 49 year olds is not associated with breast cancer
how is desmopressin used?
- subcutaneous, orally, intranasally, sublingually
- adjust according to symptoms
- monitor sodium levels
what are examples of complications as the presenting feature of diabetes?
- staphylococcal skin infections
- retinopathy noted during a visit to the optician
- a polyneuropathy causing tingling and numbness in the feet
- erectile dysfunction
- arterial disease -> MI or peripheral gangrene
what are other investigations (apart from IGT and HbA1c) for diabetes?
- no further tests are needed for diagnosis
- urine testing for protein, FBC, urea and electrolytes, liver biochemistry and random lipids
- random lipids is used to exclude an associated hyperlipidaemia and if elevated, should be repeated fasting after diabetes is under control
- diabetes may be secondary to other conditions, precipitated by underlying illness and be associated with autoimmune disease or hyperlipidaemia
what is the role of patient education and community care in the treatment of diabetes?
- based on self management; help and advice from those with specialised knowledge
- outcome depends on patient cooperation
- understanding risk of diabetes and benefits of glycaemic control and good lifestyle
- misinformation may occur
- organised education programmes
what do organised education programmes involve?
all healthcare workers, e.g. nurse specialists, diaticians and podiatrists; should include ongoing support and updates where possible
what is recommended in the diet for diabetics?
- low in sugar (not sugar free)
- high in starchy carbohydrate (esp. foods with low glycaemic index) i.e. slower absorption
- high in fibre
- low in fat (esp. saturated fat)
what is the recommended amount of protein in a diabetic diet?
1g/kg ideal bodyweight
what is the advice regarding total fat in a diabetic diet?
- <35% of energy intake
- limit: fat/oil in cooking, fried foods, processed meats (burgers, salami, sausages), high-fat snacks (crisps, cakes, nuts, chocolate, biscuits, pastry)
- encourage: lower-fat dairy products (skimmed milk, reduced fat cheese, low-fat yoghurt), lean milk
what is the advice regarding saturated and trans-unsaturated fat in a diabetic diet?
<10% of total energy intake
what is the advice regarding n-6 polyunsaturated fat in a diabetic diet?
<10% of total energy intake
what is the advice regarding n-3 polyunsaturated fat in a diabetic diet?
- no absolute quantity recommended
- eat fish, esp. oily fish, once or twice weekly
- fish oil supplements not recommended
what is the advice regarding cis-monounsaturated fat in a diabetic diet?
10-20% of total energy intake (olive oil, avocado)
what is the advice regarding total carbohydrate levels in a diabetic diet?
- 40-60% of total energy intake
- encourage: artificial (intense) sweeteners instead of sugar (sugar-free fizzy drinks, squashes and cordials)
- limit: fruit juices, confectionery, cake, biscuits
what is the advice regarding sucrose in a diabetic diet?
- up to 10% of total energy intake
- in context of healthy diet
what is the advice regarding fibre in a diabetic diet?
- no absolute quantity recommended
- soluble fibre has beneficial effects on glycaemic and lipid metabolism
- insoluble fibre has no effects on glycaemic metabolism, but benefits satiety and GI health
what effect does fibre have on diabetes?
- soluble fibre has beneficial effects on glycaemic and lipid metabolism
- insoluble fibre has no direct effects on glycaemic metabolism, but benefits satiety and GI health
what is the advice regarding vitamins and antioxidants in a diabetic diet?
- best taken as fruit and veg in a mixed diet
- no evidence for use of supplements
what is the advice regarding alcohol in a diabetic diet?
- not forbidden
- energy content should be taken into account
- tendency to cause delayed hypoglycaemia in those treated with insulin
what is the advice regarding salt in a diabetic diet?
<6g/day (lower in hypertension)
what is a glycaemic index? what does it mean?
number from 0 to 100 assigned to a food which represents the relative rise in the blood glucose level two hours after consumption
- low glycaemic index foods prevent rapid swings in circulating glucose; preferred in diabetes
what does glycaemic index depend on?
- quantity and type of carbohydrate it contains
- amount of entrapment of carbohydrate molecules within the food
- fat and protein content of the food
- amount of organic acids (or salts) in food
- whether it’s cooked or how it’s cooked
what is considered a low/high glycaemic index?
low GI: 55 or less
high GI: 70 or more
mid-range: 56 to 69
how is a diet prescribed?
- diet history is taken
- diet prescribed should have least possible interference with lifestyle
- advice from dieticians more impactful than doctors
- people with insulin/oral agents have been advised to eat same amount of food at same time each day
what is DAFNE? what is its basis?
dose adjustment for normal eating
- knowledgeable and motivated patients with type 1 diabetes
- feedback from regular blood glucose monitoring
- can vary amount of carbohydrate consumed, or meal times, by learning to adjust the exercise pattern and treatment
what is the action of intestinal enzyme inhibitors for diabetes?
- acarbose
- sham sugar that competitively inhibits alpha-glucosidase enzymes in the brush border of the intestine, reducing absorption of dietary carbohydrate
- undigested starch may enter the large intestine where it’s broken down by fermentation
what are side effects of intestinal enzyme inhibitors for diabetes?
- abdominal discomfort
- flatulence
- diarrhoea
what is orlistat?
- lipase inhibitor
- reduces absorption of fat from the diet
- benefits diabetes indirectly by promoting weight loss in patients under careful dietary supervision on a low fat diet
- necessary to avoid unpleasant steatorrhoea
how is gastric banding and gastric bypass surgery used for diabetes?
- used in those with marked obesity unresponsive to 6 months’ intensive attempts at dieting and graded exercise
- NICE recommends consideration of surgery in BMI >40, or those with BMI >35 and comorbidities e.g. diabetes or hypertension
what are the risks and outcomes of gastric banding and gastric bypass surgery?
- long-term specialist care and follow up are needed
- psychological support and nutritional supplements for those with bowel resection
- 1/3 of patients become non-diabetic after gastric bypass, but it may recur
what is non-insulin treatments can diabetics receive?
- BP control by ACE inhibitor or angiotensin II receptor inhibitor
- statin
- low dose aspirin
what is the practical management of type 2 diabetes?
- regular review
- most patients on tablets will eventually need insulin
- patient whose control is inadequate on oral therapy should start insulin without delay
what are types of insulin regimens?
- twice-daily mixed soluble and intermediate insulins
- three times daily soluble with intermediate or long acting insulin given before bedtime
- three times daily rapid acting analogue with long acting analogue insulin given before bedtime
what are needles like for insulin injections?
- very fine and sharp
- pen injection device/can be drawn up from a vial into special plastic insulin syringes marked in units (100U in 1ml)
- slim adults and children se a 31 gauge 6mm needle
- fatter adults a 30 gauge 8mm needle
- reusable and disposable pen devices
where is insulin injected in diabetics?
- given into fat below skin on abdomen, thighs or upper arm
- needle inserted to its full length
why should insulin injection sites be changed regularly?
to prevent areas of lipohypertrophy (fatty lumps)
what does rate of insulin absorption depend on?
- local subcutaneous blood flow
- accelerated by exercise, local massage or a warm environment
- absorption is more rapid from the abdomen than the arm, and is slowest from the thigh
- can influence shape of insulin profile
where is insulin absorbed in the body?
more rapid from the abdomen than the arm; slowest from the thigh
what is the aim of insulin therapy?
in healthy individuals, a sharp increase in insulin occurs after meals; this is superimposed on a constant background of secretions
- insulin therapy aims to reproduce this pattern
why is ideal control of insulin secretion difficult to achieve?
- insulin injected subcutaneously passes into systemic circulation before passage to the liver; insulin-treated patients have lower portal levels of insulin and higher systemic levels
- subcutaenous soluble insulin takes 60-90min to achieve peak plasma levels, so onset and offset are too slow
- absorption of subcutaneous insulin into circulation is variable
- injected insulin peaks and declines in diabetics
what is normal secretion of insulin?
directly into the portal circulation and reaches the liver in high concentration; 50% of insulin produced by pancreas is cleared in the liver
where does subcutaneously injected insulin pass to?
passes into systemic circulation before passage to the liver
- insulin-treated patients have lower levels of portal insulin and higher systemic levels
how long does subcutaneous soluble insulin take to achieve peak plasma levels?
60-90 minutes
- onset and offset of action too slow
what insulin regimen is appropriate for younger patients?
multiple injection regimen with short-acting insulin and a longer-acting insulin at night
what are advantages of multiple insulin injection regimens?
- insulin and food go in at roughly the same time, so meal times and sizes can vary, without disturbing metabolic control
- flexibility is good
- some recovery of endogenous insulin secretion may occur over first few months
what are target blood glucose values before and after meals?
4-7mmol/L
4-10mmol/L
what is the limiting factor for many patients on multiple injection regimens?
hypoglycaemia between meals and at night
when should insulin analogues be used?
- useful substitute for soluble insulin in some patients
- reduce frequency of nocturnal hypoglycaemia due to reduced carry-over effect from the day time
- used for convenience
- bedtime intermediate acting insulin falls and absorption is variable
what are infusion devices used in diabetes?
CSII (continuous subcutaneous insulin infusion)
what is CSII?
continuous subcutaneous insulin infusion
- delivered by a small pump strapped around the waist that infuses a constant trickle of insulin via a needle in the subcutaneous tissues
- meal-time doses are delivered by the user telling the pump to deliver a bolus at the start of a meal
what are advantages and disadvantages of infusion devices for diabetics?
- useful in overnight period, as the basal overnight infusion rate can be programmed to individual needs
- attachment to a gadget, skin infections, the risk of ketoacidosis if the flow of insulin is broken, cost
- should only be used by specialised centres
what are complications of insulin therapy at the injection site?
- shallow injections lead to intradermal insulin delivery, painful and reddened lesions or scarring
- abscesses
- local allergic responses
- generalised allergic responses are very rare
- fatty lumps (lipohypertrophy) may occur due to overuse of a single injection site
how can transplantation be used to treat diabetes?
whole pancreas and pancreatic islet transplantation
how can whole pancreas transplantation be used to treat diabetes?
- performed for 30 years
- usually done in diabetic patients who require immunosuppression for a kidney transplant
- surgical advancement has improved its outcome
- patient survival better in those receiving simultaneous pancreas and kidney grafts
- some evidence of protection against or reversal of complication of diabetes, but there is long-term immunosuppression
how is islet transplantation done?
by harvesting pancreatic islets from cadavers (two/three pancreata usually needed); they’re injected into the portal vein and seed themselves into the liver
what are indications, advantages and disadvantages of islet transplantation?
- limited success for many years; improved protocols have improved results
- main indication is disabling hypoglycaemia
- need for powerful immunosuppressive therapy, with its associated costs and complications
how are urine dipstick tests used in diabetes?
- less informative than blood tests
- some feedback on metabolic control
- patients with consistently negative tests and no symptoms of hypoglycaemia are well controlled
- correlation between urine tests and simultaneous blood glucose is poor
why is the correlation between urine tests and simultaneous blood glucose poor?
- changes in urine glucose lag behind changes in blood glucose
- mean renal threshold is around 10mmol/L but range is wide (7-13mmol/L); threshold rises with age
- urine tests can give no guidance concerning blood glucose levels below the renal threshold
how is home blood glucose testing done?
- blood taken from side of fingertip (not from tip, which is densely innervated) using special lancet usually fitted to a spring-loaded device
- those on insulin treatment need more monitoring
what is glycosylation of haemoglobin?
- occurs as a 2 step reaction
- results in formation of a covalent bond between the glucose molecule and the terminal valine of the beta chain of the haemoglobin molecule
- rate at which this reaction occurs is related to prevailing glucose conc.
how is glycosylated haemoglobin expressed? what is the standardised range?
as a percentage of the normal haemoglobin (standardised range 4-6.1%; 20-44mmol/mol)
what does glycosylated haemoglobin tell us?
an index of the average blood glucose concentration over the life of the haemoglobin molecule (approximately 6 weeks)
when is glycosylated haemoglobin misleading?
if the life-span of the red cell is reduced or if an abnormal haemoglobin or thalassaemia is present
what is the lifespan of haemoglobin molecule?
6 weeks
what is an alternative measure to glycosylated haemoglobin?
glycosylated plasma proteins (fructosamine)
how are glycosylated plasma proteins measured in diabetes?
- measured as an index of blood glucose control
- glycosylated albumin is major component
- fructosamine measurement relates to glycaemic control over the preceding 2-3 weeks
when is glycosylated plasma proteins useful?
- anaemia
- haemoglobinopathy
- pregnancy (when haemoglobin turnover is changeable)
- where changes of treatment need a swift means of assessing progress
how can hypotension be a problem of management of diabetic ketoacidosis?
- may lead to renal shutdown
- plasma expanders (or whole blood) are given if the systolic BP is below 80mmHg
- central venous pressure useful
- bladder catheter inserted if no urine produed within 2hrs
how can coma be a problem of management of diabetic ketoacidosis?
- pass a nasogastric tube to prevent aspiration
- gastric stasis is common and has risk of aspiration pneumonia if drowsy patient vomits
how can cerebral oedema be a problem of management of diabetic ketoacidosis?
- rare, serious complication
- mostly reported in children or young adults
- excessive rehydration and hypertonic fluids e.g. 8.4% bicarbonate may be responsible
- high mortality
how can hypothermia be a problem of management of diabetic ketoacidosis?
- severe hypothermia with core temp below 33 may occur
- may be overlooked unless a rectal temp is taken with a low-reading thermometer
what are examples of late complications of management of diabetic ketoacidosis?
- pneumonia and DVT
- occur especially in comatose or elderly patient
what are examples of complications of therapy of diabetic ketoacidosis?
- hypoglycaemia and hypokalaemia; due to loss of K+ in urine from osmotic diuresis
- overenthusiastic fluid replacement may precipitate pulmonary oedema in the very young or very old
- hyperchloraemic acidosis may develop due to losing negatively charged electrolytes, which are replaced with chloride; corrected by kidneys spontaneously within a few days
what is the subsequent management of diabetic ketoacidosis?
- IV glucose and insulin are continued until patient feels able to eat and keep food down
- drip is taken down and similar amount of insulin is given as 4 injections of soluble insulin subcutaneously at meal times and dose of intermediate acting insulin at night
what is the mortality of diabetic ketoacidosis?
5%; increased in older patients
how is osmolality calculated?
2(Na+ + K+) + glucose + urea
what is the normal range of osmolality?
285-300mOsm/kg
what is the normal anion gap?
<17
how is anion gap capculated?
(Na+ + K+) - (Cl- + HCO3-)
what can explain the biochemical differences between hyperosmolar hyperglycaemic state and ketoacidosis?
age
- extreme dehydration characteristic of hyperosmolar hyperglycaemic state may be related to age
- old people experience thirst less acutely
- old people readily become dehydrated
- mild renal impairment associated with age results in increased urinary losses of fluid and electrolytes
degree of insulin deficiency
- less severe in hyperosmolar hyperglycaemic state
- endogenous insulin levels are sufficient to inhibit hepatic ketogenesis, but insufficient to inhibit hepatic glucose production
why is the degree of insulin deficiency less severe in the hyperosmolar hyperglycaemic state?
endogenous insulin levels are sufficient to inhibit hepatic ketogenesis, but insufficient to inhibit hepatic glucose production
what are clinical features of the hyperosmolar hyperglycaemic state? what diseases can it predispose to?
- dehydration and stupor or coma
- impairment of consciousness directly related to degree of hyperosmolality
- evidence of underlying illness e.g. pneumonia or pyelonephritis may be present
- hyperosmolar state may predispose to stroke, MI or arterial insufficiency in lower limbs
what is the prognosis of the hyperosmolar hyperglycaemic state?
- mortality 20-30%
- high mortality due to more advanced age of patients and frequency of intercurrent illness
- not an absolute indication for subsequent insulin therapy
- survivors may do well on diet and oral agents
what may increase risk of lactic acidosis in diabetics?
- biguanide therapy
- risk in patients taking metformin is low provided that the therapeutic dose is not exceeded and drug withheld in patients with advanced hepatic or renal dysfunction
what is the presentation of lactic acidosis in diabetes?
- severe metabolic acidosis
- large anion gap (<17mmol/L)
- usually without significant hyperglycaemia or ketosis
what is treatment and mortality of lactic acidosis in diabetes?
- rehydration and infusion of isotonic 1.26% bicarbonate
- mortality in excess of 50%
what are the major causes of death in diabetes?
- cardiovascular problems (60-70%)
- renal failure (10%)
- infections (6%)
what is the pathophysiology of diabetes complications due to hyperglycaemia?
- non enzymatic glycosylation of proteins
- polyol pathway
- abnormal microvascular blood flow
- other factors
- haemodynamic changes
how can non-enzymatic glycosylation cause diabetes complications?
- non-enzymatic glycosylation of proteins e.g. haemoglobin, collagen, LDL and tubulin in peripheral nerves
- leads to an accumulation of advanced glycosylated end-products causing injury and inflammation via stimulation of pro-inflammatory factors, e.g. complement, cytokines
how can the polyol pathway cause diabetes complications?
- metabolism of glucose by increased intracellular aldose reductase leads to accumulation of sorbitol and fructose
- this causes changes in vascular permeability, cell proliferation and capillary structure via stimulation of protein kinase C and TGF-beta
what does accumulation of sorbitol and fructose lead to?
this causes changes in vascular permeability, cell proliferation and capillary structure via stimulation of protein kinase C and TGF-beta
how can abnormal microvascular blood flow lead to diabetes complications?
- impairs supply of nutrients and oxygen
- microvascular occlusion is due to vasoconstrictors, e.g. endothelins and thrombogenesis
- leads to endothelial damage
what can microvascular occlusion be due to?
vasoconstrictors, e.g. endothelins, and thrombogenesis
what are other factors that can lead to diabetes complications?
- formation of ROS and growth factors stimulation (TGF-beta and VEGF)
- growth factors are released by ischaemic tissues and cause endothelial cells to proliferate
what do all the mechanisms caused by hyperglycaemia that lead to diabetes complications stem from?
a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondiral electron chain
- offers an integrated explanation of how complications develop
what are macrovascular complications of diabetes?
- stroke is twice as likely
- MI is 3-5 times as likely, and women with diabetes lose premenopausal protection from coronary artery disease
- amputation of a foot for gangrene is 50 times as likely
what are diabetic risk factors for macrovascular complications?
- duration
- increasing age
- systolic hypertension
- hyperinsulinaemia due to insulin resistance associated with obesity and the metabolic syndrome
- hyperlipidaemia, esp. hypertriglyceridaemia.low HDA
- proteinuria (including microalbuminuria)
- other factors are the same as for the general population
what risk factors should be tackled in diabetes?
- hypertension
- smoking
- lipid abnormalities
- low dose aspirin
- ACE inhibitors/angiotensin II receptor antagonists
what areas does microvascular complication of diabetes affect?
- retina
- renal glomerulus
- nerve sheaths
when do microvascular complications manifest in diabetes?
retinopathy, nephropathy and neuropathy tend to manifest 10-20 years after diagnosis in young patients
how do genetic factors affect microvascular complications of diabetes?
diabetic siblings of patients with renal and eye diseases have three to five fold increased risk of same complication in type 1 and 2 patients
what is the racial prevalence of microvascular complications of diabetes in the USA?
Pima American Indians > Hispanic/Mexican > US black > US white patients
what are features of diabetic eye disease?
- at least 90% of young patients with type 1 diabetes will develop retinal changes, but they only progress to sight-threatening retinopathy in a minority
- 30-50% will require laser photocoagulation to prevent or limit progression to proliferative retinopathy
- good control of BP essential
what is the commonest cause of blindness in under 65 year olds?
diabetes
how does diabetes affect the eye?
- diabetic retinopathy: damage to the retina and iris caused by diabetes, which can lead to blindness
- cataract: denaturation of the protein and other components of the lens which render it opaque
- external ocular palsies
what is diabetic retinopathy?
damage to the retina and iris caused by diabetes, which can lead to blindness
what is cataracts?
denaturation of the protein and other components of the lens of the eye which render it
what are external ocular palsies?
- sixth and third nerve most commonly affected in diabetes
- third nerve palsy is not associated with pain
- usually recover spontaneously within 3-6 months
what is the natural history of cataracts?
- develops earlier in people with diabetes than in the general population
- sustained very poor diabetes control with ketosis can cause an acute cataract
what can cause an acute cataract (snowflake cataract)?
sustained very poor diabetes control with a degree of ketosis; comes on rapidly
what can cause refractive variation in cataracts?
fluctuations in blood glucose concentration can cause refractive variability, due to osmotic changes within the lens (absorption of water into the lens causes temporary hypermetropica)
- presents as fluctuation difficulty in reading
- resolves with better metabolic control of the diabetes
what is the prevalence of diabetic retinopathy?
- most commonly diagnosed diabetes-related complication
- prevalence increase with duration of diabetes
- 20% of people with type 1 will have retinal changes after 10 years, rising to >95% after 20 years
- 20-30% of people with type 2 have retinopathy at diagnosis
what is the mechanism of diabetic retinopathy?
- metabolic consequences of poorly-controlled diabetes causes intramural pericyte death and thickening of the BM in small blood vessels of the retina
- initially leads to incompetence and increased permeability of the vascular walls and later to occlusion of the vessels
- different consequences in peripheral retina and in the macular area
what are microaneurysms?
- Charcot-Bouchard aneurysm
- aneurysms of the brain vasculature occurring in the small blood vessels
- small red dots
what happens when vessel walls are breached? what is the process of hard exudate formation?
- superficial (blot) haemorrhages occur in the ganglion cell an douter plexiform layers
- damaged blood vessels leak fluid into the retina
- fluid is cleared into the retinal veins, leaving behind protein and lipid deposits causing hard exudates
- hard exudates are cleared by macrophages
how is hard exudate formed?
- damage blood vessels leak fluid into the retina
- fluid is cleared into the retinal veins, leaving behind protein and lipid deposits, causing hard exudates
- hard exudates are eventually cleared by macrophages
what causes cotton wool spots?
- microinfarcts within the retina due to occluded vessels cause cotton wool spots
- spot itself is due to accumulation of axoplasmic debris (removed by macrophages)
what are cytoid bodies?
white dots at site of previous cotton wool spots that have been removed by macrophages
what does damage to the walls of veins cause?
causes their calibre to vary (venous beading) and elongation to occur, causing venous loops
what is venous beading?
damage to the walls of veins causing their calibre to vary
how are venous loops created?
damage to the walls of veins causing elongation to occur, forming venous loops
what does ischaemia in areas of capillary non-perfusion in diabetes lead to?
release of vascular growth factors e.g. VEGF -> new blood vessels to grow in retina (neovascularisation)
what is neovascularisation?
growth of new blood vessels in the retina due to release of vascular growth factors e.g. VEGF, due to ischaemia in areas of capillary non-perfusion
what is IRMAs (diabetes)?
intraretinal microvascular abnormalities
- caused by new blood vessels growing in the retina (neovascularisation)
- some new blood vessels are inside the retina and are helpful
- new intraretinal vessels, and other vessels whose walls are damaged and dilated, give appearance of IRMAs
what happens to new vessels formed in the retina in diabetes?
- intraretinal
- other new vessels emerge through the retina and lie on its surface, usually at the margin of an area of capillary closure
- normal shearing stresses within the eye can cause the poorly supported new vessels to bleed
- small haemorrhages give rise to pre-retinal haemorrhages (boat shaped)
what kind of haemorrhage occurs in diabetic retinopathy?
- normal shearing stresses within the eye can cause the poorly supported new vessels to bleed
- small haemorrhages give rise to pre-retinal haemorrhages (boat shaped)
- further bleeding leads to vitreous haemorrhage occurs with consequent sudden loss of vision
what causes fibrotic bands in diabetic retinopathy?
later collagen tissue grows along the margins of the new vessels formed in the retina
what is the action of fibrotic bands in diabetic retinopathy?
bands may contract and pull on the retina causing further haemorrhage and retinal detachment
what is rubeosis?
vessels that have been induced to grow on the pupil margin and in the angle of the anterior chamber of the eye
- gives rise to rapid increase in intraocular pressure (rubeotic glaucoma)
what can diabetic retinopathy be like in the macular area?
- fluid from leaking vessels is cleared poorly in the macular area due to its anatomy differing from the rest of the retina
- above a certain rate of formation, clearance fails and macular oedema occurs
- oedema distorts and thickens the retina at the macula
- if sustained, the distortion causes loss of central vision
- capillary occlusion in macular area will also cause loss of central vision
why are surrogate markers used for the presence of macular oedema in diabetic retinopathy?
macular oedema is not visible with the opthalmoscope or with retinal photography
what is bedside examination of the eye?
- visual acuity should be checked using a pinhole and the patient’s distance spectacles
- ocular movements are assessed to detect any ocular motor palsies
- iris is examined for rubeosis and the pupils dilated with 1% tropicamade; 30 minutes later, the eye is examined for the presence of cataract by looking at the lens with a +10.00 lens in opthalmoscope and viewing the lens against the red reflex
- retina examined systematically looking at the disc, then all four quadrants, and finally the macula
what is eye screening for diabetic eye disease?
- screening for sight-threatening eye disease with universal access offers the best hope of displacing diabetes as the commonest cause of blindness
- National Screening Committee in the UK has established digital photography-based screening across the country, based on a national set of standards
- all people with diabetes aged 12+ are offered annual measurement of their acuity, and photographs of retina
what is the management of cataracts (diabetic eye disease)?
- extraction and intraocular lens implantation is indicated if the cataract is causing visual disability to the patient or is giving rise to inability to view the retina adequately
- cataract extraction is straightforward if no retinopathy is present
- pre-existing retinopathy may worsen after cataract extraction
what are diabetic retinopathy grades?
peripheral retina and central retina
what are types of peripheral retina diabetic retinopathy?
- background (R1)
- pre-proliferative (R2)
- proliferative (R3)
- advanced retinopathy
what are types of central retina diabetic retinopathy?
maculopathy (MI)
what is the retinal abnormality and action needed of background (R1) peripheral retina diabetic retinopathy?
- dot haemorrhages (capillary microaneurysms, usually appear first)
- blot haemorrhages (leakage of blood into deeper retinal layers)
- hard exudates (exudation of plasma rich in lipids and protein)
- cotton wool spots/cytoid bodies
action needed: annual screening only
what is the retinal abnormality and action needed of pre-proliferative (R2) peripheral retina diabetic retinopathy?
- venous beading/loops
- intraretinal microvascular abnormalities (IRMAs)
- multiple deep round haemeorrhages
action needed: non-urgent referral to an opthalmologist
what is the retinal abnormality and action needed of proliferative (R3) peripheral retina diabetic retinopathy?
- new blood vessel formation/neovascularisation
- preretinal or subhyaloid haemorrhage
- vitreous haemorrhage
action needed: urgent referral to an ophthalmologist
what is the retinal abnormality and action needed of advanced peripheral retina diabetic retinopathy?
- retinal fibrosis
- traction retinal detachment
action needed: urgent referral to an ophthalmologist; but much vision already lost
what is the retinal abnormality and action needed of maculopathy of the central retina in diabetes?
- hard exudates within one disc-width of macula
- lines or circles of hard exudates within 2 disc-widths of macula
- microaneurysms or retinal haemorrhages within 1 disc-width of macula if associated with an unexplained visual acuity 6/12 or worse
action needed: referral to an opthalmologist soon
what is management of retinopathy?
- risk reduced by tight metabolic control of diabetes and BP
- development or progression of retinopathy may be accelerated by rapd improvement in glycaemic control, pregnancy and in nephropathy
what is used to define the extent of potentially sight-threatening diabetic retinopathy?
Fluorescein angiography (fluorescent dye is injected into an arm vein and photographed in transit through the retinal vessels)
what is the use of OCT in diabetic retinopathy?
ocular coherence tomography
- used to image content of the layers of the retina at the macula
- measure retinal thickness
- detects macular oedema and other macular abnormalities
what is the treatment of proliferative retinopathy?
- new vessels are an indication for laser photocoagulation therapy
- new vessels on the disc carry worst prognosis and warrant urgent laser therapy
- laser should be directed at new vessels and to the associated areas of capillary non-perfusion
- PRP used if progressed to new vessels developing on the optic disc
- rubeosis is treated with PRP
- vitreoretinal surgery is used if bleeding is recurrent and preventing laser therapy
how is laser photocoagulation therapy used in treatment of proliferative retinopathy?
- new vessels are an indication for this
- new vessels on the disc carry worst prognosis and warrant urgent laser therapy
- laser should be directed at new vessels and areas of capillary non-perfusion
what is the use of PRP in proliferative retinopathy?
panretinal photocoagulation
- used if proliferative retinopathy has progressed to new vessels developing on the optic disc
- involves multiple laser burns to the peripheral retina, esp. in areas of capillary non-perfusion
- rubeosis treated with this
when is surgery used in proliferative retinopathy?
- vitreoretinal surgery used if bleeding is recurrent and preventing laser therapy
- used to salvage some vision after vitreous haemorrhage and to treat fibrotic traction/retinal detachment in advanced retinopathy
what is the treatment of maculopathy?
- extrafoveal exudates can be watched; if encroaching the fovea then the centre of rings of exudates, should be treated by laser photcoagulation
- grid photocoagulation used if oedema has spread to centre of macula, where laser burns are scattered
- ischaemic maculopathy not treatable, leads to central visual loss
how can the kidney be damaged by diabetes?
- glomerular damage
- ischaemia resulting from hypertrophy of afferent and efferent arterioles
- ascending infection
what is the epidemiology of diabetic nephropathy?
- clinical nephropathy secondary to glomerular disease manifests 15-25 years after diagnosis
- affects 25-35% of patients diagnosed under 30
- leading cause of premature death in young diabetics
- older patients also develop nephropathy
- incidence of end-stage kidney disease has fallen
what is the pathophysiology of diabetic nephropathy?
- earliest functional abnormality is renal hypertrophy associated with raised GFR; related to poor glycaemic control
- as kidney becomes damaged by diabetes, the afferent arteriole becomes vasodilated more than the efferent arteriole
- increases intraglomerular filtration pressure, further damaging capillaries
- increased pressure leads to increased local shearing forces which contribute to mesangial cell hypertrophy and increased secretion of extracellular mesangial matrix material; eventually leads to glomerular sclerosis
- initial structural lesion in glomerulus is thickening of BM
- disruption of protein cross-linkages which make it a filter; progressive leak of large molecules into urine
what is microalbuminuria?
amounts of urinary albumin so small that it;s undetectable by standard dipsticks
what can test for microalbuminuria?
radioimmunoassay or by special dipsticks
what is microalbuminuria a predictive marker for?
marker of progression to nephropathy in type 1 diabetes, and of increased CV risk in type 2
how does microalbuminuria progress?
- may progress after some years to intermittent albuminuria, followed by persistent proteinuria
- light-microscopic changes of glomerulosclerosis become manifest; both diffuse and nodular glomerulosclerosis can occur
- Kimmelstiel-Wilson lesion
- at later stage of glomerulosclerosis, glomerulus is replaced by hyaline material
- proteinuria may become so heavy to induce a transient nephrotic syndrome, with peripheral oedema and hypoalbuminaemia
what are clinical features of nephropathy?
- normochromic normocytic anaemia and a raised erythrocyte sedimentation rate (ESR)
- hypertension
- rise in plasma creatinine is a late feature that progresses to renal failure
what is the natural history of nephropathy?
- typical onset is 15 years after diagnosis
- plasma creatinine rises
- GFR falls
- mean BP slowly rises
- intermittent proteinuria leads to persistent proteinuria; large increase to peak, then decrease
what are features of ischaemic lesions in diabetes?
- arteriolar lesions, with hypertrophy and hyalinisation of the vessels
- appearances similar to those of hypertensive disease
- lead to ischaemic damage to the kidneys
what are features of infective lesions in the kidney in diabetics?
- UTIs more common in women, but not in men
- ascending infection may occur due to bladder stasis from autonomic nephropathy, and infections become established in damaged renal tissue
- interstitial changes suggestive of infection; ischaemia may produce similar changes
- true frequency of pyelonephritis in diabetes is uncertain
what can untreated infections in diabetics lead to?
renal papillary necrosis; renal papillae are shed in urine - very rare
what is the diagnosis of diabetic kidney disease?
- urine checked at least annually for protein
- microalbuminuria screening
- albumin creatinine ration (ACR) tested
- once proteinuria is present, other possible causes should be considered, and once excluded, presumtive diagnosis of diabetic nephropathy
- aggressive antihypertensive therapy can delay progression to end-stage kidney disease
- renal biopsy
- 24-hour urine collection
- plasma creatinine level measurement with eGFR
what is ACR? what are normal levels?
albumin creatinine ratio
- tested mid-stream first morning urine sample
- <2.5 in healthy men, <3.5mg/mmol in women
what does diabetic nephropathy lead to? what can delay its progression?
- implies inevitable progression to end-stage kidney disease
- time course slowed by aggressive antihypertensive therapy
what can delay the onset of frank proteinuria?
- meticulous glycaemic control
- early antihypertensive treatment, esp. with ACE inhibitors and ang. II blokers
what provokes clinical suspicion of a non-diabetic cause of nephropathy?
- atypical history
- absence of diabetic retinopathy (usually but not invariably present with diabetic nephropathy)
- presence of red cell casts in urine
- renal biopsy shoudl be considered
what is the management of diabetic nephropathy?
- aggressive treatment of BP with target below 130/80mmHg; ACE inhibitors or ang. II antagonist
- above drugs used in normotensive patients with persistent microalbuminuria; reduction in albuminuria with this treatment
- oral hypoglycaemic agents partially excreted via kidney should be avoided
- insulin sensitivity increases and drastic reductions in insulin dosage may be needed
- associated diabetic retinopathy progresses rapidly, and supervision is neded
what is the management of end-stage kidney disease in diabetes?
- complicated by blindness, autonomic neuropathy or peripheral vascular disease
- vascular shunts tend to calcify rapidly and thus chronic ambulatory peritoneal dialysis may be better than haemodialysis
- failure of renal transplants higher in diabetics
- segmental pancreatic or islet graft may be performed
why may chronic ambulatory peritoneal dialysis be preferred to haemodialysis in diabetics?
vascular shunts tend to calcify rapidly
what causes diabetic neuropathy?
- vascular hypothesis: occlusion of vasa nervorum; likely in isolated mononeuropathies, but diffuse symmetrical nature of common forms of neuropathy implies metabolic cause
- hyperglycaemia leads to increased formation of sorbitol and fructose in Schwann cells; accumulation may disrupt function and structure
what are the earliest changes in diabetic neuropathy?
- earliest functional change in diabetic nerves is delayed nerve conduction velocity
- earliest histological change is segmental demyelination, caused by damage to Schwann cells
- in early stages axons are preserved, implying prospects of recovery, but at later stage, irreversible axonal degeneration develops
what are the varieties of neuropathy that occur in diabetes?
- symmetrical mainly sensory polyneuropathy (distal)
- acute painful neuropathy
- mononeuropathy and mononeuritis multiplex; cranial nerve lesions or isolated peripheral nerve lesions
- diabetic amyotrophy (asymmetric motor diabetic neuropathy)
- autonomic neuropathy
what are signs and complications of symmetrical mainly sensory polyneuropathy (diabetes)?
- often unrecognised by patient in its early stages
- early signs: loss of vibration sense, pain sensation (deep before superficial) and temp sensation in feet
- later signs: feeling of walking on cotton wool, losing balance due to impaired proprioception
- involvement of hangs is much less common
- complications: unrecognised trauma, beginning as blistering due to an ill-fitting shoe or hot-water bottle, leading to ulceration
what is the sequelae of symmetrical mainly sensory polyneuropathy (diabetes)?
- involvement of motor nerves to small muscles of feet leads to interosseous wasting
- unbalanced traction by long flexor muscles -> characteristic shape of foot (high arch and clawing of toes) -> abnormal distribution of pressure on walking -> callus formation under first metatarsal head or on tips of toes and perforating neuropathic ulceration
- neuropathic arthropathy (Charcot’s joints) in ankle
- hands have small muscle wasting and sensory changes
what are features of acute painful neuropathy?
- less common
- burning or crawling pains in feet, shins and anterior thighs
- symptoms are worse at night and pressure from bedclothes may be intolerable
- may present at diagnosis or develop after sudden improvement in glycaemic control
- remits spontaneously after 3-12 months if good control is maintained
- chronic form may be resistant to therapy
- muscle wasting not a feature, objective signs may be minimal
why is neurological assessment of a patient with acute painful neuropathy difficult?
hyperaesthesia
what is management of acute painful neuropathy?
- explore non-diabetic causes
- explanation and reassurance about high likelihood of remission within months
- duloxetine (NICE recommended as first line), tricyclics, gabapentin or pregabalin, mexiletine, valproate and carbamazepine all reduce perception of neuritic pain
- TENS
- topical capsaicin-containing creams
- acupuncture
what are features of mononeuritis and mononeuritis multiplex (multiple mononeuropathy) (diabetes)?
- any nerve can be involved
- onset is abrupt and sometimes painful
- radiculopathy (involvement of a spinal root) may occur
- isolated palsies of nerves to external eye muscles, esp. third and sixth nerves, are more common in diabetes
- characteristic feature of diabetic 3rd nerve lesions is pupillary reflexes are retained owing to sparing of pupillomotor fibres
- full spontaneous recovery for most episodes of mononeuritis over 3-6 months
- lesions at common sites for external pressure palsies or nerve entrapment
what is a characteristics feature of diabetic 3rd nerve lesions?
pupillary reflexes are retained, due to sparing of pupillomotor fibres
what are features of diabetic amyotrophy?
- usually seen in older men with diabetes
- presentation is with painful wasting usually asymmetrical, of quadrceps/shoulders
- wasting may be marked and knee reflexes are diminished or absent
- affected area is tender
- extensor plantar responses may develop and CSF protein content is elevated
- associated with periods of poor glycaemic control, may be present at diagnosis
- often resolves in time with careful metabolic control of diabetes
how does autonomic neuropathy affect the cardiovascular system (diabetes)?
- vagal neuropathy -> tachycardia at rest and loss of sinus arrhythmia
- heart may become denervated at later stage
- reflexes e.g. Valsalva manoevre are impaired
- postural hypotension due to loss of sympathetic tone to peripheral arterioles
- warm foot with bounding pulse in polyneuropathy due to peripheral vasodilation
what is involved in bedside testing of autonomic function (diabetes)?
- supine to erect BP: systolic BP fall (mmHg)
- HR response to deep breathing (6 breaths over 1min) max to min HR
- HR response to valsalva manoeuvre (15s): ratio of longest to shorted R-R interval (on ECG)
- HR response to lying to standing ratio of R-R interval of 30th to 15th beats
what is the Valsalva maneouvre?
- performed by moderately forceful attempted exhalation against a closed airway
- done by closing mouth, pinching nose while expelling air out
- ear is examined with an otoscope
what are normal and abnormal responses to supine to erect BP: systolic BP fall (mmHg)?
normal: 10
abnormal: 30+
what are normal and abnormal HR responses to deep breathing (6 breaths/min) max to min HR?
normal: 15+
abnormal <10
what are normal and abnormal HR responses to the Valsalva manoeuvre (15s): ratio of longest to shorted R-R interval?
normal: 1.21+
abnormal: <1.2
what are normal and abnormal HR responses to lying to standing ratio of R-R interval of 30th to 15th beats?
normal: 1.01+
abnormal: <1
what is R-R interval?
time between R and next R on ECG
what is the effect of autonomic neuropathy on the GI tract (diabetes)?
- vagal damage -> gastroparesis, may lead to intractable vomiting
- autonomic diarrhoea occurs at night with urgency and incontinence
- diarrhoea and steatorrhoea may occur due to small bowel bacterial overgrowth; treated with antibiotics e.g. tetracycline
what is the effect of autonomic neuropathy on the bladder?
- loss of tone
- incomplete emptying
- stasis (predisposing to infection)
- > atonic, painless, distended bladder
- treatment with intermittent self-catheterisation, permanent catheterisation and prophylactic antibiotic therapy
what are manifestations of male erectile dysfunction in diabetes?
- incomplete erection which may progress to total failure
- retrograde ejaculation in autonomic neuropathy
what are the causes of erectile dysfunction in diabetes?
- anxiety/depression
- alcohol excess
- drugs (e.g. thiazides and beta-blockers)
- primary or secondary gonadal failure
- hypothyroidism
- inadequate vascular supply due to atheroma in pudendal arteries
what is the history and examination of erectile dysfunction in diabetes?
- focus on possible causes
- blood taken for LH, FSH, testosterone, prolactin and thyroid function
what is treatment for erectile dysfunction in diabetes?
- sympathetic counselling of both partners
- phosphodiesterase type-5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) which enhance the effects of nitric oxide on smooth muscle and increase penile blood flow
what are the effects of phosphodiesterase type-5 inhibitors? what are some examples?
- sildenafil, tadalafil, vardenafil, avanafil
- enhance effects of NO on smooth muscle and increase penile blood flow
- used for erectile dysfunction, in those who don’t take nitrates for angina
- 60% benefit
- headache and green tinge to vision the next day
what are alternatives to phosphodiesterase inhibitors for erectile dysfunction?
- apomorphine 2 or 3mg sublingually 20min before sexual activity
- alprostadil (prostaglandin E1 preparation) given as small pellet inserted with device into urethra (125ug initially, maximum 500ug)
- intracavernosal injection or insertion of a pellet of alprostadil into urethra (2.5ug initially, maximum 40ug)
- vacuum devises
what are features of the diabetic foot?
ischaemia, infection and neuropathy combine to produce tissue necrosis
what are symptoms, inspection, palpation and ulceration patterns of ischaemia in the diabetic foot?
symptoms: claudication and rest pain
inspection: dependent rubor and trophic changes
palpation: cold and pulseleses
ulceration: painful and heels/toes
what are symptoms, inspection, palpation and ulceration patterns of neuropathy in the diabetic foot?
symptoms: usually painless, sometimes painful
inspection: high arch, clawing of toes, no trophic changes
palpation: warm, bounding pulses
ulceration: painless, plantar
what are principles of diabetic foot care?
- inspect feet daily
- moisturise dry skin
- seek early advice for any damage
- check shoes inside and out for sharp bodies/areas before wearing
- use lace-up shoes with room for toes
- keep feet away from sources of heat
- check bath temp before stepping in
- regular podiatrist care
what are the four main threats to the skin and subcutaneous tissues in the diabetic foot?
- infection
- ischaemia
- abnormal pressure
- wound environment
how does infection assessed/treated in the diabetic foot?
- early antibiotic treatment essential
- antibiotic therapy adjusted in light of culture results
- organisms grown from skin surface may not be organism causing deeper infection
- collections of pus are drained and excision of infected bone is needed if osteomyelitis develops and doesn’t respond to antibiotic therapy
- regular xrays needed
how is ischaemia assessed/treated in the diabetic foot?
- blood flow to feet assessed clinically and with Doppler ultrasound
- femoral angiography used to localise areas of occlusion amenable to bypass surgery or angioplasty
how is abnormal pressure assessed/treated in the diabetic foot?
- ulcerated site kept non-weight-bearing
- resting affected leg
- special deep shoes and insoles
- removable/non-removable casts of leg
- sharp surgical debridement by chiropodist to prevent callus distorting local wound architecture and causing damage to normal skin
how is wound environment assessed/treated in the diabetic foot?
- dressings used to absorb or remove exudate, maintain moisture, and protect wound from contaminating agents, and should be easily removable
- expensive new dressing containing growth factors and active agents may be used
what skin infections are poorly-controlled diabetics susceptible to?
- staphylococcal infections (boils, abscesses, carbuncles)
- mucocutaneous candidiasis
what GI tract infections are poorly-controlled diabetics susceptible to?
- periodontal disease
- rectal and ischiorectal abscess formation
what urinary tract infections are poorly-controlled diabetics susceptible to?
- UTIs
- pyelonephritis
- perinephric abscess
what lung infections are poorly-controlled diabetics susceptible to?
- staphylococcal and pneumococcal pneumonia
- Gram-negative bacterial pneumonia
- TB
what bone infection are poorly-controlled diabetics susceptible to?
spontaneous staphylococcal spinal osteomyelitis
why does poorly controlled diabetes lead to infection?
chemotaxis and phagocytosis by polymorphonuclear leucocytes are impaired because at high blood glucose concentrations, neutrophil superoxide generation is impaired
how does diabetes affect cancer risk?
- double the risk of carcinoma of the uterus an pancreas
- 20-50% increase in risk of colorectal and breast cancer
- associations may be mediated by obesity
- metformin-treated patients have lower cancer risk than those on other therapies
how does diabetes affect the skin and joints?
- joint contractures in hands due to childhood diabetes
- metacarpophalangeal and interphalangeal joints cannot be opposed
- thickened, waxy skin on backs of fingers
- may be due to glycosylaiton of collagen; not progressive
- diabetic cheiroarthropathy
- osteopenia in extremities in type 1
what are some obstetric problems associated with diabetes?
- affect cardiac and skeletal development, e.g. caudal regression syndrome
- poorly-controlled diabetes associated with stillbirth, mechanical problems in birth canal due to fetal macrosomia, hydramnios and pre-eclampsia
- ketoacidosis in pregnancy has 50% fetal mortality
what are neonatal problems in diabetes?
- maternal diabetes associated with fetal macrosomia
- more susceptible to hyaline membrane disease
- neonatal hypoglycaemia
what is the mechanism of neonatal hypoglycaemia?
- maternal glucose crosses the placenta, but insulin doesn’t
- fetal islets hypersecrete insulin to combat maternal hyperglycaemia
- rebound to hypoglycaemic levels occur when umbilical cord is severed
due to hyperglycaemia in third trimester
what is gestational diabetes?
glucose intolerance that develops or is first recognised in pregnancy; typically asymptomatic and usually remits following delivery
who is at risk for gestational diabetes?
- previous history of gestational diabetes
- older or overweight
- history of large babies
- certain ethnic groups
what is unstable diabetes?
patients with recurrent ketoacidosis and/or recurrent hypoglycaemic coma
- largest group made up of those with recurrent severe hypoglycaemia
what is the epidemiology of recurrent severe hypoglycaemia?
- affects 1-3% of insulin-dependent patients
- most are adults who have had diabetes for >10 years
- by this stage, endogenous insulin secretion is negligible in majority of patients
what are features of recurrent severe hypoglycaemia?
- pancreatic alpha cells are still present in undiminished numbers, but glucagon response to hypoglycaemia is virtually absent
- long-term patinets are subject to hyperinsulinaemia owing to erratic absorption o insulin from injection sites, and lack a major component of hormonal defence against hypoglycaemia
- adrenaline secretion becomes vital, but may become impaired
what factors may predispose to recurrent severe hypoglycaemia?
- overtreatment of insulin (lowers glucose level at which symptoms develop)
- unrecognised low renal threshold for glucose (attempts to render urine sugar free will produce hypoglycaemia)
- excessive insulin doses (when more frequent injections may be needed)
- endocrine causes (pituitary insufficiency, adrenal insufficiency and premenstrual insulin sensitivity)
- alimentary causes (exocrine pancreatic failure and diabetic gastroparesis)
- chronic kidney disease (clearance of insulin diminished)
- patient causes (unintelligent, uncooperative or may manipulate therapy)
what are primary causes of recurrent ketoacidosis in diabetes?
- usually occurs in adolescents or young adults, esp. girls
- metabolic decompensation may develop rapidly
- combination of chaotic food intake and insulin omission, is primary cause
- often with psychosocial problems, esp. eating disorders
- 30% of women with diabetes have had an ED
what are other causes of recurrent ketoacidosis?
- iatrogenic: inappropriate insulin combinations causing swinging glycaemic control
- intercurrent illness: unsuspected infections, e.g. UTI and TB, and thyrotoxicosis
why does hypoglycaemia develop in the non-diabetic?
when hepatic glucose output falls below the rate of glucose uptake by peripheral tissues
what can reduce hepatic glucose output?
- inhibition of hepatic glycogenolysis and gluconeogenesis by insulin
- depletion of hepatic glycogen reserves by malnutrition, fasting, exercise or advanced liver disease
- impaired gluconeogenesis (e.g. following alcohol ingestion)
what are biochemical features of causes of reduced hepatic glucose output?
inhibition of hepatic glycogenolysis and gluconeogenesis by insulin
- raised insulin levels
- liver contains adequate glycogen stores
- hypoglycaemia can be reversed by glucagon
depletion of hepatic glycogen reserves/impaired gluconeogenesis
- insulin levels low
- glucagon ineffective
what affects peripheral glucose uptake?
increased by high insulin levels and by exercise; these conditions are normally balanced by increased hepatic glucose output
what are the most common symptoms and signs of hypoglycaemia?
neurological
- brain consumes about 50% of total glucose produced by liver
- needed to generate ATP used to maintain potential difference across axonal membranes
how much hepatic glucose does the brain use? what for?
- brain consumes about 50% of total glucose produced by liver
- needed to generate ATP used to maintain potential difference across axonal membranes
what are presenting features of insulinoma?
- diplopia
- sweating, palpitations, weakness
- confusion or abnormal behaviour
- loss of consciousness
- Grand mal seizures
what are insulinomas?
pancreatic islet cell tumours that secrete insulin
what are features of insulinomas?
- most are sporadic
- some have multiple tumours arising from neural crest tissue
- 95% of tumours are benign
- fasting hypoglycaemia; early symptoms may develop in late morning or afternoon
- recurrent hypoglycaemia often present for months or years before diagnosis is made; symptoms atyptical or bizarre
what are common misdiagnoses of insulinomas?
psychiatric disorders, esp. pseudodementia in elderly, epilepsy and cerebrovascular disease
what is Whipple’s triad? when is it satisfied?
basis of clinical diagnosis of an insulinoma
- symptoms are associated with fasting or exercise
- hypoglycaemia is confirmed during these episodes
- glucose relieves symptoms
- demonstration of inappropriately high insulin levels during hypoglycaeia
how is diagnosis of insulinoma confirmed?
demonstration of hypoglycaemia in association with inappropriate and excessive insulin secreiton
how is hypoglycaemia demonstrated?
- measurement of overnight fasting (16hrs) glucose and insulin levels on three occasions. 90% if patients w/ insulinomas have low glucose and normal/elevated insulin levels
- prolonged 72 hour supervised fast if overnight testing is inconclusive and symptoms persist
how is autonomous insulin secretion demonstrated?
lack of the normal feedback suppression during hypoglycaemia
- may be shown by measuring insulin, C-peptide or proinsulin during spontaneous episode of hypoglycaemia
what is treatment of insulinoma?
surgical excision of tumour; often very small and difficult to localise
how can insulinomas be localised?
- sensitivity and specificity of techniques vary between centres and operators
- highly sensitive angiography, contrast-enhanced high-resolution CT scanning, scanning with radiolabelled somatostatin and endoscopic and intraoperative ultrasound scanning
- venous sampling for detection of hot spots of high insulin conc. in intra-abdominal veins still used
- diazoxide for malignancy, unlocatable tumour, elderly
- somatostatin analogue
what tumours other than insulinomas can hypoglycaemia occur in?
- advanced neoplasia and cachexia
- certain massive tumours, esp. sarcomas, may produce hypoglycaemia due to IGF-1 secretion
- true ectopic insulin secretion is extremely rare
when may true postprandial hypoglycaemia occur?
- alcohol; primes cells to produce an exaggerated insulin response to carbohydrate
- after gastric surgery due to rapid gastric emptying and mismatching of nutrient absorption and insulin secretion (dumping)
what are hepatic and renal causes of hypoglycaemia?
- liver can maintain normal glucose output despite extensive damage
- kidney has subsidary role in glucose production (via gluconeogenesis in renal cortex) and hypoglycaemia is problem in terminal renal failure
- hereditary fructose intolerance occurs in 1/20000 live births, can cause hypoglycaemia
what are endocrine causes of hypoglycaemia?
- deficiencies of hormones antagonistic to insulin are rare
- e.g. hypopituitarism, isolated ACTH deficiency, Addison’s disease
what are predisposing factors to drug-induced hypoglycaemia?
- sulfonylureas may be used in diabetes or in non-diabetics in suicide attempts
- quinine may produce severe hypoglycaemia in treatment for falciparum malaria
- salicylates may cause hypoglycaemia; usually accidental ingestion by children
- propanolol can induce hypoglycaemia in strenuous exercise or starvation
- pentamidine used in treatment of resistant pneumocystis pneumonia
how can alcohol induce hypoglycaemia?
- alcohol inhibits gluconeogenesis
- occurs in poorly-nourished chronic alcoholics, binge drinkers and in children as they have diminished hepatic glycogen reserve
- present with coma and hypothermia (due to suppression of central thermoregulation)
what is factitious hypoglycaemia?
- common variant of self-induced disease
- more common than insulinoma
- hypoglycaemia caused by surreptitious self-administration of insulin or sulfonylureas
- extensively tested for insulinoma
- measurement of C-peptide levels during hypo can identify those injecting insulin
- sulfonylurea abuse detected by chromatography of plasma or urine
what is the general embryology of the reproductive system?
- up to 8 weeks gestation, there is a primitive genital tract including the Wolffian and Muellerian ducts. primitive perineum and primitive gonads
what is the embryology of the male reproductive system?
- Y chromosome -> potential testis develops while ovary regresses
- production of Muellerian inhibitory factor from testis -> atrophy of Muellerian duct
- testosterone and dihydrotestosterone -> Wolffian duct differentiates into epididymis, vas deferens, seminal vesicles and prostates
- androgens -> transformation of perineum to include penis, penile urethra, scrotum containing testes
what is testicular volume at birth?
0.5-1mL
what is the embryology of the female reproductive system?
absence of Y chromosome -> potential ovary develops and related ducts form a uterus and upper vagina
what is erectile dysfunction?
inability of the male to achieve or sustain an erection adequate for satisfactory intercourse
what is azoospermia?
absence of sperm in the ejaculate
what is oligospermia?
reduced numbers of sperm in the ejaculate
what is libido?
sexual interest or desire; often difficult to assess and greatly affected by stress, tiredness and psychological factors
what is menarche?
age at first period
what is primary amenorrhoea?
failure to begin spontaneous menstruation by age 16
what is secondary amenorrhoea?
absence of menstruation for 3 months in a woman who has previously had cycles
what is oligomenorrhoea?
irregular long cycles; often used for any length of cycle above 32 days
what is dyspareunia?
pain or discomfort in the female during intercourse
what is menstruation?
onset of spontaneous (usually regular) uterine bleeding in the female
what is virilisation?
occurrence of male secondary sexual characteristics in the female
what the HPG axis in the male?
- pulses of GnRH are released from the hypothalamus and stimulate LH and FSH release from the pituitary
- LH stimulates testosterone production from Leydig cells of the testis
- testosterone acts via nuclear androgen receptors which interact with coregulatory proteins to produce appropriate tissue responses: male secondary sexual characteristics, anabolism and libido. aids spermatogenesis. negative feedback to inhibit GnRH secretion
- FSH stimulates Sertoli cells in seminiferous tubules to produce mature sperm and inhibins A and B
- inhibin feeds back to pituitary to decrease FSH secretion. activin counteracts inhibin
what is the structure of LH and FSH?
composed of 2 glycoprotein chains (alpha and beta subunits); alpha subunits are identical and shared with TSH, and beta subunit confers specific biological activity
what is the action of LH in the male?
stimulates testosterone production from Leydig cells of the testis
what produces testosterone?
Leydig cells of the testis (stimulated by LH)
what are the actions of testosterone?
- acts via nuclear androgen receptors which interact with coregulatory proteins to produce appropriate tissue responses: male secondary sexual characteristics, anabolism and maintenance of libido
- acts locally to aid spermatogenesis
- circulates largely bound to sex hormone binding globulin
- feeds back on the hypothalamus/pituitary to inhibit GnRH secretion
what is testosterone bound to in circulation?
sex hormone binding hormone
what is the action of FSH in males?
stimulates Sertoli cells in seminiferous tubules to produce mature sperm and inhibins A and B
what is the action of inhibin in males? what counteracts it?
feeds back to the pituitary to decrease FSH secretion; activin counteracts inhibin
what are the secondary sexual characteristics of the male?
- growth of pubic, axillary and facial hair
- enlargement of external genitalia
- deepening of voice
- sebum secretion
- muscle growth
- frontal balding
testosterone is necessary
what is the HPG axis/physiology in the female?
- higher brain centres impose menstrual cycle of 28 days upon activity of hypothalamic GnRH
- pulses of GnRH, at about 2hr intervals, stimulate release of pituitary LH and FSH
- LH stimulates ovarian androgen production by ovarian theca cells
- FSH stimulates follicular development and aromatase activity in ovarian granulosa cells, and release of inhibin from ovarian stromal cells, which inhibits FSH release
- by day 8-10 a leading follicle is selected for development into a mature Graafian follicle
- oestrogens have double feedback action on the pituitary
- follicle differentiates into corpus luteum, secreting progesterone and oestradiol in second half of cycle (luteal phase)
- oestrogen and progesterone cause uterine endometrial proliferation for potential implantation
what stimulates release of LH and FSH in females?
pulses of GnRH, at about 2hr intervals
what is the action of LH in females?
stimulates ovarian androgen production by the ovarian theca cells
what is the action of FSH in females?
- stimulates follicular development and aromatase activity (an enzyme required to convert ovarian androgens to oestrogens) in the ovarian granulosa cells
- stimulates release of inhibin from ovarian stromal cells, which inhibits FSH release
what is the selection of follicle?
- many follicles are recruited for development in early folliculogenesis
- by day 8-10 a leading follicle is selected for development into a mature Graafian follicle
what effect do oestrogens have on the pituitary?
double feedback action
how do oestrogens have a double feedback action on the pituitary?
- initially they inhibit gonadotrophin secretion (negative feedback)
- high-level exposure later -> increased GnRH secretion and increased LH sensitivity to GnRH (positive feedback)
- leads to mid-cycle LH surge inducing ovulation from the leading follicle
what causes the LH surge? what does it lead to?
- positive feedback effect of oestrogens on the pituitary leading to increased GnRH secretion and increased LH sensitivity to GnRH
- mid cycle
- induces ovulation in the leading follicle
what happens in the luteal phase?
leading follicle differentiates into a corpus luteum, which secretes progesterone and oestradiol during the second half of the cycle
what does oestrogen and progesterone secreted by the corpus luteum in the luteal phase lead to?
oestrogen initially and then progesterone cause uterine endometrial proliferation in preparation for possible implantation
what happens if implantation does not occur?
corpus luteum regresses and progesterone secretion and inhibin levels fall so the endometrium is shed (menstruation) allowing increased GnRH and FSH secretion
what happens if impantation and pregnancy does occur?
human chorionic gonadotrophin (hCG) production from the trophoblast maintains corpus luteum function until 10-12 weeks of gestation, by which time the placenta will be making suficient oestrogen and progesterone to support itself
what are secondary sexual characteristics of the female?
- development of breast and nipples
- vaginal and vulval growth
- pubic hair development
- growth and maturation of uterus and fallopian tubes
what causes the mechanisms initiating puberty?
withdrawal of central inhibition of GnRH release
what is involved in timing of puberty?
- environmental and physical factors involved in timing of puberty (including body fat changes, physical exercise)
- genetic factors (e.g. G protein coupled receptor gene, GPR54) required for pubertal maturation
- kisspeptin is the endogenous ligand for kisspeptin receptor KISSIR (formerly GPR54); plays crucial role in regulation of GnRH production and timing of puberty
what is GPR54 also known as?
kisspeptin receptor
what is the action of kisspeptin?
- endogenous ligand for kisspeptin receptor (KISSIR)/GPR54
- regulates GnRH production and timing of puberty
what are levels of LH and FSH before/during puberty?
- low in prepubertal child
- in early puberty, FSH begins to rise first, initially in nocturnal pulses
- followed by a rise in LH and subsequent increase in testosterone/oestrogen levels
what are features of normal puberty in boys?
- changes begin 10-14 years
- complete between 15-17 years
- genitalia develop, testes enlarge and area of pubic hair increases
- peak height velocity is reached between ages 12 and 17 during stage 4 of testicular development
- full spermatogenesis occurs comparatively late
when is peak height velocity reached in boys?
between ages 12 and 17 during stage 4 of testicular development
what are features of normal puberty in girls?
- breast bud enlargement begins 9-13yrs, continues 12-18yrs
- pubic hair growth commences 9-14yrs and completed at 12-16yrs
- menarche occurs relatively late 11-15yrs
- peak height velocity reached at 10-13yrs
- growth completed much earlier than in boys
what are the types of testicular volume in boys during puberty?
2mL, 4mL, 12mL, 20mL
what is premature puberty?
development of secondary sexual characteristics before 8yrs in girls or 9yrs in boys or menarche in girls before 9yrs
- all require assessment by paediatric endocrinologist
what is idiopathic (true) precocity?
- most common in girls, very rare in boys
- diagnosis of exclusion
- with no apparent cause for premature breast or pubic hair development and an early growth spurt, it may run in families
- 1 in 5000-10000
- 90% of patients female
- idiopathic CPP
what is the treatment of idiopathic (true) precocity?
- long-acting GnRH analogues (given by nasal spray, subcutaneous injection or implant)
- cause suppression of gonadotropin release via downregulation of the receptor; reduced sex hormone production
- cyproterone acetate, an antiandrogen with progestational activity, is also used
what are other forms of precocity?
- cerebral precocity
- McCune-Albright syndrome
- premature thelarche
- premature adrenarche
what is cerebral precocity?
- form of precocious puberty
- many causes of hypothalamic disease, esp. tumours, present this way
- in boys it must be rigorously excluded
- MRI scan is always indicated to exclude this
what is McCune-Albright syndrome?
- form of precocious puberty
- usually occurs in girls
- precocity, polyostotic fibrous dysplasia and skin pigmentation
what is premature thelarche?
- form of precocious puberty
- early breast development alone, usually transient, at age 2-4yrs
- may regress or persist until puberty
- no evidence of follicular development
what is premature adrenarche?
- form of precocious puberty
- early development of pubic hair w/out significant other changes, usually after 5yrs, more common in girls
- more common in obese children due to reduced SHBG levels leading to higher free circulating androgens
when should delayed puberty be investigated?
- over 95% of children show signs of pubertal development by 14yrs
- in its absence, investigation should begin by age 15yrs
- causes of hypogonadism are relevant but most cases are constitutional delay
what happens in constitutional pubertal delay?
pubertal development, bone age and stature are in parallel
- family history taken
what indicates the onset of puberty in boys?
a testicular volume >5mL
- rising serum testosterone is an earlier clue
what indicates the onset of puberty in girls?
breast bud is first sign
- ultrasound allows assessment of ovarian and uterine development
what can be given to induce puberty?
low-dose short-term sex hormone therapy
what factors cause insulin resistance and beta-cell dysfunction?
- diabetes genes
- adipokines
- inflammation
- hyperglycaemia
- free fatty acids
- other factors
what factors lead to subclinical atherosclerosis? how?
- infection (lowered defence mechanisms and increased pathogen burden)
- inflammation (increased IL-6, CRP and SAA)
- hyperglycaemia (increased AGE and oxidative stress)
- insulin resistance (HTN, endothelial dysfunction)
- dyslipidaemia (increased LDL, increaesd TG, decreased HDL)
- thrombosis (increased PAI-I, increased TF, decreased tPA)
what are atherosclerotic clinical events?
acute and chronic coronary syndromes, stroke, peripheral artery disease
what is the mechanism of action and target tissue site of Pramlintide?
GI tract
- delay of gastric emptying
- inhibition of glucagon release
what is the mechanism of action and target tissue site of alpha-glucosidase inhibitors?
GI tract
- inhibition of glucose absorption
- stimulation of GLP-1 release
what is the mechanism of action and target tissue site of sulfonylureas?
pancreatic beta cell
- acute stimulation of insulin release
what is the mechanism of action and target tissue site of meglitinides?
pancreatic beta cell
- acute stimulation of insulin release
what is the mechanism of action and target tissue site of GLP1/DPP4 inhibitors?
pancreatic beta cell
- acute stimulation of insulin release
- stimulation of insulin biosynthesis
- inhibition of beta cell apoptosis
- stimulation of beta cell differentiation
what is the mechanism of action and target tissue site of metformin?
liver
- inhibition of glucose production
- increase in hepatic insulin sensitivity
what is the mechanism of action and target tissue site of thiazolidinediones?
liver
- increase in hepatic insulin sensitivity
muscle
- increase in muscle insulin sensitivity
adipose tissue
- suppression of NEFA release
- fat redistribution (visceral to subcutaneous)
- modulation of adipokine release
what are potential sequences of antihyperglycaemic therapy for type 2 diabetics?
monotherapy: metformin
dualtherapy: metformin AND
- sulfonylurea
- thiazolidine
- DPP4 inhibitor
- SGLT2 inhibitor
- GLP1 receptor agonist
- insulin (basal)
triple therapy
combinable injectable therapy: metformin + basal insulin + mealtime insulin or GLP-1-RA
what can metformin + sulfonylurea be combined with in triple therapy?
- TZD
- DPP4 inhibitor
- SGLT2 inhibitor
- GLP-1-RA
- insulin
what can metformin + thiazolidinedione be combined with in triple therapy?
- SU
- DPP4 inhibitor
- SLGT2 inhibitor
- GLP1RA
- insulin
what can metformin + DPP4 inhibitor be combined with in triple therapy?
- SU
- TZD
- SGL2 inhibitor
- insulin
what can metformin + SGLT2 inhibitor be combined with in triple therapy?
- SU
- TZD
- DPP4 inhibitor
- insulin
what can metformin + GLP1RA be combined with in triple therapy?
- SU
- TZD
- insulin
what can metformin + basal insulin be combined with in triple therapy?
- TZD
- DPP4 inhibitor
- SGLT2 inhibitor
- GLP1RA
what is the approach to preventing T2DM?
- early treatment and prevention can reduce burden
- intensive diet and exercise can delay onset or prevent it
- include use of metformin and TZDs
- difficult to maintain over long term, costly
- unwanted side effects of medications
when are sulfonylureas considered?
- not overweight
- require rapid response due to hyperglycaemic symptoms
- unable to tolerate metformin or where metformin is contraindicated
- where blood glucose control remains or becomes inadequate on metformin
what are incretins? what are their actions?
- hormones secreted by intestinal endocrine cells in response to nutrient intake
- influence glucose homeostasis via actions including glucose-dependent insulin secretion, postprandial glucagon suppression, slowing of gastric emptying
when is GLP-1 secreted? what is its effect?
secreted upon ingestion of food
- promotes satiety and reduces appetite (brain)
- alpha cells: decreases postprandial glucagon secretion
- beta cells: enhances glucose-dependent insulin secretion
- liver: decreased glucagon reduces hepatic glucose output
- stomach: helps regulate gastric emptying
- affects skeletal muscle, adipose tissue, cardiac tissue, pulmonary
what are the effects of DPP4 inhibitors?
- orally available
- small increase in endogenous GLP1
- little effect on gastric emptying
- do not cause nausea/vomiting
- no effect on weight
- effects mediated by multiple receptors
what are the effects of GLP1 analogues?
- injectable only
- large increase in GLP1 level
- induces delay in gastric emptying
- likely to induce nausea/vomiting
- induces weight loss
- effects mediated by GLP1 receptor
what are examples of TZD?
rosiglitazone, pioglitazone
what are advantages and disadvantages of metformin?
- low risk of hypoglycaemia
- BP reduction
- possible cardioprotective benefits
- weight neutral or slight weight loss
- lactic acidosis
- caution indicated in older patients with CHF
what are advantages and disadvantages of SUs?
- newer class entrants may have reduced CV risk
- may increase risk of CV events; hypoglycaemia
- weight gain
what are advantages and disadvantages of TZDs?
- low risk of hypoglycaemia; positive effects on biomarkers
- increased CV risk; lipid abnormalities
- weight gain
what are examples of SGLT-2 inhibitors?
empaglifozin, dapaglifozin, canaglifozin
what is the use of SGLT-2i with renal impairment?
- efficacy declines with increasing renal impairment
- in patients with eGFR >45ml/min/1.73m2 canaglifosin (100mg) and empaglifosin used; reduce HbA1c
- in patients with eGFR >60, dapaglifosin used
- avoid in eGFR <30
- does not worsen kidney disease
- similar to ACEi
what is puberty?
describes the physiological, morphological and behavioural changes as the gonads switch from infantile to adult forms
what are definitive signs of puberty?
girls: menarche (first menstrual bleeding)
boys: first ejaculation, often nocturnal
do not signify fertility
what causes voice deepening in male puberty?
testicular androgens causing enlargement of larynx and laryngeal muscles
what is Tanner stage 1 in boys?
- prepubertal: no pubic hair
- testicular length: <2.5cm
- testicular volume: <3mL
what is Tanner stage 2 in boys?
- sparse growth of slightly curly pubic hair, mainly base of penis
- testes >3mL (>2.5cm in longest diameter)
- scrotum thinning and reddening
what is Tanner stage 3 in boys?
- thicker, curlier hair spread to mons pubis
- growth of penis in width and length; further growth of testes
what is Tanner stage 4 in boys?
- adult-type hair, not yet spread to medial surface of thighs
- penis further enlarged; testes larger, darker scrotal skin colour
what is Tanner stage 5 in boys?
- adult-type hair spread to medial surface of thighs
- genitalia adult size and shape
what measures testicular volume in mL?
orchidometer
what are pre-pubertal testicular volumes?
1-3mL
what are normal adult male testicular volumes?
15-25mL
what is Tanner stage 1 in girls?
- prepubertal: no pubic hair
- elevation of papilla only
what is Tanner stage 2 in girls?
- sparse growth of long, straight or slightly curly, minimally pigmented hair, mainly on labia
- breast bud noted/palpable; enlargement of areola
what is Tanner stage 3 in girls?
- darker, coarser hair spreading over mons pubis
- further enlargement of breast and areola, with no separation of contours
what is Tanner stage 4 in girls?
- thick adult-type hair, not yet spread to medial surface of thighs
- projection of areola and papilla to form secondary mound above level of breast
what is Tanner stage 5 in girls?
- hair adult-type and distributed in classic inverse triangle
- adult contour breast with projection of papilla only
what is normal puberty in girls?
mean age at onset of
- breast development
- pubic hair
- menses (menarche)
what is thelarche?
breast development
what are characteristics of thelarche?
- first visible change of puberty
- induced by oestrogen
- completed in about 3yrs
- effects of oestrogen on the breast: ductal proliferation, site specific adipose deposition, enlargement of the areola and nipple
- may be unilateral for several months
- other hormones involved: prolactin, glucocorticoids, insulin
what are effects of oestrogen on thelarche?
- ductal proliferation
- site specific adipose deposition
- enlargement of the areola and nipple
what are other hormones involved in thelarche?
prolactin, glucocorticoids, insulin
what are characteristics of the prepubertal uterus?
- corpus:cervix ratio 1:2
- tubular shape
- length 2-3cm
- volume 0.4-1.6ml
- endometrium single layer of cuboidal cells
what are characteristics of the prepubertal ovaries?
- volume 0.2-1.6ml
- non functional
what are characteristics of the pubertal/adult uterus?
- corpus:cervix ratio 2:1
- pear shape
- length 5-8cm
- volume 3-15ml
- endometrium increased thickness
what are characteristics of the pubertal/adult ovaries?
- volume 2.8-15ml
- multicystic
what is looked at in pelvic ultrasound during female puberty?
are the Mullerian structures present?
morphology of uterus?
morphology of ovaries?
requires experienced examiner - careful when reporting absence of structures
what are characteristics of the prepubertal vagina?
- reddish in colour
- thin atrophic columnar epithelium
- pH neutral
- length 2.5-3.5cm
what are characteristics of the pubertal/adult vagina?
- dulling of the reddish colour
- thickening of the epithelium
- cornification of the superficial layer: stratified squamous epithelium
- pH acidic: 3.8-4.2
- secretion of clear whitish discharge in months before menarche
- length 5-8cm
what is the maturation of the external genitalia under the effect of oestrogens?
- labia majora and minora increase in size and thickness
- rugation and change in colour of the labia majora
- hymen thickens
- clitoris enlarges
- vestibular glands begin secretion
what is the maturation of the external genitalia under the effect of adrenal and ovarian androgens?
growth of pubic and axillary hair
what are the consequences of delayed puberty?
leads to reduced peak bone mass and osteoporosis
what is delayed puberty?
absence of secondary sexual characteristics by 14yrs (girls) and 16yrs (boys)
what affects the GnRH neuron?
OPR, GABAR, GPR54, GluR, IGFR, FGFR, PGFR, TGHbetaR
what are increased stimulatory factors for puberty (GnRH secretion)?
glutamate and kisspeptin
what causes decreased inhibitory tone for puberty (GnRH secretion)?
GABAergic neurons secreting gamma-aminobutyric acid (GABA) and opioidergic neurons
what causes the start of puberty?
increased stimulatory factors and decreased inhibitory tone (GnRH secretion)
what is adrenarche?
- maturational process of the adrenal gland
- developmental process where a specialised subset of cells arises forming the androgen-producing zona reticularis (ZR)
- developmentally programmed peri-pubertal activation of adrenal androgen production (premature or exaggerated adrenarche up to 2yrs earlier)
what happens in adrenarche?
- increased DHEA, DHEA-S
- mild advanced bone age, axillary hair, oily skin, mild acne, body odour
- more pronounced in obese children
what is pubarche? what is it caused by?
- most pronounced clinical result of adrenarche
- first appearance of pubic hair in a child
- result of androgen action on the pilosebacous unit transforming vellus hair into terminal hair in hair-growth prone parts of the skin
what happens from birth to adrenarche?
- functional GnRH neurons before birth
- mini-puberty of infancy (peak gonadotropin levels, then fall)
- suppression of GnRH neurons after birth and just before adrenarceh (low gonadotropin levels)
- increased BMI/leptin provides permissive signals
what happens to gonadotropin levels from adrenarche to menopause?
- GPR54 reactivates GnRH pulse generator -> gonadal development and sex steroid feedback (increased gonadotropin levels to peak, then maintenance)
- gonadal senescence (females) -> menopause (increased gonadotropin levels from previously maintained from puberty levels)
what is precocious pseudopuberty?
- hCG secreting tumours: gonads, brain, liver, retroperitoneum, mediastinum
- adrenal sex hormones -> sex hormone action
- hCG acts on gonads -> gonadal sex hormones -> action
what is differential diagnosis by GnRH (LHRH) test of true precocious puberty?
- stimulation gives pubertal range
- stimulated LH:FSH ratio >1
what is differential diagnosis by GnRH (LHRH) test of precocious pseudopuberty?
- stimulation gives pre-pubertal range or suppression
- stimulate LH:FSH ratio <1
what is the difference between true and pseudo precocious puberty?
true is GnRH dependent, pseudo GnRH independent
what are causes of true (central) precocious puberty (GnRH dependent)?
- idiopathic precocious puberty
- CNS tumours
- CNS disorders
- secondary central precocious puberty
- psychosocial, i.e. adoption from abroad
what are CNS tumours that cause true (central) precocious puberty (GnRH dependent)?
- optic glioma associated with NF1
- hypothalamic astrocytoma
what are CNS disorders that cause true (central) precocious puberty (GnRH dependent)?
- developmental abnormalities, hypothalamic hamartoma
- encephalitis, brain abscess
- hydrocephalus, myelomeningocele, arachnoid cyst
- vascular lesion
- cranial irradiation
what are causes of precocious pseudo-puberty (GnRH independent)?
- increased androgen secretion
- gonadotropin secreting tumours
- McCune-Albright syndrome
- ovarian cyst
- oestrogen secreting neoplasm
- hypothyroidism
- iatrogenic or exogenous sex hormones
what are causes of increased androgen secretion?
- congenital adrenal hyperplasia (21OHD, 11OHD)
- virilising neoplasm
- Leydig cell adenoma
- familial male precocious puberty - testotoxicosis
what are gonadotropin secreting tumours?
chorioepitheliomas, germinoma, teratoma, hepatoma, choriocarcinoma
what are types/causes of delayed puberty?
- idiopathic (constitutional) delay in growth and puberty (delayed activation of the hypothalamic pulse generator)
- hypogonadotrophic hypogonadism (sexual infantilism related to gonadotrophin deficiency)
- hypergonadotrophic hypogonadism (primary gonadal problems)
what does delay in puberty lead to?
- delay in acquisition of secondary sex characteristics
- psychological problems
- defects in reproduction
- reduced peak bone mass
what are indications for investigation in puberty for girls?
- lack of breast development by 13yrs
- more than five years between breast development and menarche
- lack of pubic hair by age 14yrs
- absent menarche by age 15-16yrs
what are indications for investigation in puberty for boys?
- lack of testicular enlargement by age 14yrs
- lack of pubic hair by age 15yrs
- more than 5yrs to complete genital enlargement
what is CDGP?
constitutional delay of growth and puberty
- commonest cause in both sexes; more common in boys
- extreme of normal physiologic variation
- diagnosis of exclusion
- more likely to be short for age with history of normal growth rate
- delay in bone maturation, delay in adrenarche
- frequent family history of late menarche in mother/sister or delayed growth spurt in father
- onset of puberty corresponds better with bone age than chronological age
what is done in history taking for CDGP?
- totally absent or started then arrested
- family history (constitutional delay, infertility, delayed puberty)
- review of symptoms
- perinatal history
- prior medical illness
- medication
- psychosocial deprivation
- nutrition, exercise intensity
- neurological symptoms
- hypoglycaemia
- cancer history
- testicular injury
what laboratory investigations are done for CDGP?
- complete red blood count (FBC)
- U+E, renal, LFT, coeliac ab
- LH, FSH
- testosterone/oestradiol
- thyroid function, prolactin
- DHEA-S, ACTH, cortisol
- karyotyping (in all girls with short stature)
- GnRH stimulation test
what is bone age like in puberty?
- done at first visit to assess skeletal maturation
- skeletal age more closely correlated with pubertal development than chronological age
- bone age above 13yrs for girls and 14yrs for boys makes constitutional delay less likely
what are functional causes of CDGP?
- chronic renal disease
- chronic GI disease/malnutrition
- sickle cell disease/ion overload
- chronic lung disease/CF
- anorexia nervosa
- bulimia
- psychosocial stress
- extreme disease
- drugs
- AIDS
- poorly controlled T1DM
- hypothyroidism
- Cushing’s
- hyperprolactinaemia
what causes primary hypogonadism?
gonads fail (hypogonadism) -> lack of feedback due to lack of hormone -> increased activity of hypothalamus and pituitary -> increased GnRH and LH/FSH
what causes secondary/teritiary hypogonadism?
hypogonadotrophic (decreased activity of hypothalamus and pituitary) leading to hypogonadism (gonads)
- LH and FSH low
- no response to feedback
- sex hormone decreases
what can go wrong in female puberty? how can it cause primary/secondary hypogonadism?
ovary fails: primary hypogonadism
- oestrogen decreases
- lack of feedback
- LH and FSH
hypothalamus/pituitary fail: secondary hypogonadism
- LH and FSH low
- no response to feedback
- oestrogen decreases
what can go wrong in male puberty? how can this lead to primary/secondary hypogonadism?
testes fail: primary hypogonadism
- testosterone goes down
- lack of feedback
- LH and FSH increase
hypothalamus/pituitary fail: secondary hypogonadism
- LH and FSH low
- no response to feedback
- testosterone decreases
what are causes of hypogonadotrophic hypogonadism?
- CNS disorders (tumours and other causes)
- isolated gonadotropin deficiency
- idiopathic and genetic forms of multiple pituitary hormone deficiencies
what are CNS tumours tumours that cause hypogonadotrophic hypogonadism?
- craniopharyngiomas
- germinomas
- other germ cell tumours
- hypothalamic and optic gliomas
- astrocytomas
- pituitary tumours (MEN-1, prolactinoma)
what are other CNS causes of hypogonadotrophic hypogonadism?
- Langerhans’ histiocytosis
- postinfectious lesions of the CNS
- vascular abnormalities of the CNS
- radiation therapy
- congenital malformations esp. associated with craniofacial anomalies
- head trauma
- lymphocytic hypophysitis
what are causes of isolated gonadotrophin deficiency?
- Kallmann’s syndrome (with hyposmia or anosmia)
- LHRH receptor mutation
- congenital adrenal hypoplasia (DAX1 mutation)
- isolated LH/FSH deficiency
- prohormone convertase 1 deficiency (PCI)
what is Kallman syndrome? what is it caused by?
- causes hypogonadotrophic hypogonadism
- 1 in 10000, M:F 4:1
- anosmia in 75%
- failure of migration of GnRH neurons
- multiple generic causes )X-linked, AR or AD; mutations in Kal-1, FGF-receptor 1, prokineticin; GnRH-receptor, GPR54)
what are genetic defects that cause hypogonadotrophic hypogonadism?
GnRH neuron migration
GnRH synthesis and release
GnRH action
gonadotrophin synthesis
what are genetic aspects of GnRH neuron migration?
KAL1, FGFR1, NELF, PROK2, PROKR2
what are genetic aspects of GnRH synthesis and release?
GPR54, LEP, LEPR, SF1, DAX1
what are genetic aspects of GnRH action?
GnRHr
what are genetic aspects of gonadotropin synthesis?
LHB, FSHB, SF1, DAX1
what are causes of hypergonadotrophic hypogonadism in males?
- Klinefelter’s syndrome (47XXY)
- other forms of primary testicular failure
- chemotherapy
- radiation therapy
- testicular steroid biosynthetic defects
- sertoli-only syndrome
- LH receptor mutation
- anorchia and cryptorchidism
- trauma/surgery
what are causes of hypergonadotrophic hypogonadism in females?
- Turner’s syndrome and its variation
- XX and XY gonadal dysgenesis
- familial and sporadic XX/XY gonadal dysgenesis and its variants
- aromatase deficiency
- other forms of primary ovarian failure
- premature menopause
- radiation therapy
- chemotherapy
- autoimmune oophoritis
- galactosaemia
- glycoprotein syndrome type 1
- resistant ovary
- FSH receptor mutation
- LH/hCG resistance
- PCOS
- noonan’s or pseudo Turners syndrome
- ovarian steroid biosynthetic defects
what are features of Klinefelter’s syndrome?
- 1 in 1000 males
- 47 XXY
- primary hypogonadism
- azoospermia, gynaecomastia
- reduced secondary sexual hair
- osteoporosis
- tall stature
- reduced IQ in 40%
- 20 fold increased risk of breast cancer
what are features of Turner’s syndrome in girls?
- 1 in 2000 girls
- at birth, oedema of dorsa of hands, feet and loose skinfolds at nape of neck
- webbing of neck, low posterior hairline, small mandible, prominent ears, epicanthal folds, high arched palate, broad chest, cubitus valgus, hyperconvex fingernails
- hypergonadotrophic hypogonadism, streak gonads
- CV malformations
- renal malformations
- recurrent otitis media
- short stature
what hormone replacement is given in females (puberty)?
- ethinyl estradiol (tablet) or oestrogen (tablets, transdermal)
- start with low doses and gradual increasing doses to provide time for pubertal growth and gradual breast development
- several incremental steps of 2 years until full adult replacement dose achieved
- once full replacement dose achieved, progesterone should be added
what hormone replacement is given in males (puberty)?
- testosterone enanthate, IM injection
- increasing use of transdermal testosterone
- several incremental steps of 2-4yrs until full adult replacement dose achieved
what is fertility treatment for patients with hypogonadotrophic hypogonadism?
fertility induced by pump administered GnRH-TX (requires intact pituitary) or parenteral combination of gonadotrophin TX (LH/hCG and FSH)
what are the types of pattern of hormonal secretion?
continuous and pulsatile
what is continuous secretion?
shown by thyroid hormones, with half life of 7-10 days for T4 and 6-10 hours for T3, with little variation in levels over the day, month and year
what are examples of pulsatile hormone secretion?
- normal pattern for gonadotrophins, LH and FSH, with major pulses released ever 1-2 hours depending on menstrual cycle
- GH secreted in pulsatile fashion, with undetectable levels in between pulses
- single measurement not helpful to diagnose GH deficiency or excess
what is circadian?
changes over the 24 hours of the day-night cycle and is best shown for the pituitary adrenal axis
what are plasma cortisol levels like?
levels are highest in early morning and lowest overnight; cortisol release is pulsatile, following pulsation of pituitary ACTH; normal cortisol levels vary during the day and great variations are seen in samples taken only 30mins apart
what are regulatory factors affecting patterns of hormonal secretion?
- stress (rapid increase in ACTH and cortisol, GH, prolactin, adrenaline/noradrenaline)
- sleep (secretion of GH and prolactin increased during sleep esp. REM phase)
- feeding and fasting (secretion of insulin increased and GH decreased after ingestion of food)
what are normal ranges for plasma cortisol levels at 0900 and 2400hrs?
0900: 180-70nmol/L
2400: <100nmol/L
what is the central clock in circadian rhythms?
suprachiasmatic nuclei (affected by light)
what are the peripheral clocks that the central clock controls?
muscle, lung, hormones, liver, kidney, stomach, heart, brain
- glucocorticoids are secondary messenger
what is primary adrenal insufficiency?
Addison’s disease (93-140/M)
- autoimmune adrenalitis >60% of cases
- APS type 1 10-15% of cases
- CAH 1:15000 live births
- adrenoleukodystrophy
- mets, haemorrhage, infection
what is secondary adrenal insufficiency?
hypopituitarism (150-280/M)
- pituitary macroadenoma
- apoplexy
- hypophysitis
- mets, infiltration, infection
- radiotherapy
- congenital
what is tertiary adrenal insufficiency?
suppression of HPA
- steroids, oral, inhaler, creams
what history should be taken in diagnosis of adrenal insufficiency?
- symptoms: fatigue, weight loss, poor recovery from illness, adrenal crisis, headache
- past history: TB, post partum bleed, cancer
- family history: autimmunity, congenital disease
- treatment: any steroids, etomidate, ketoconazole
what are signs of adrenal insufficiency?
pigmentation and pallor, hypotension
what is the biochemistry of adrenal insufficiency?
- low Na, high K
- eosinophilia
- borderline elevated TSH
what tests are used to investigate adrenal insufficiency and what are their results?
0900 cortisol and ACTH
- cortisol >500nmol/L AI unlikely
- cortisol <100nmol/L AI likely
- ACTH >22ng/L primary
- ACTH <5ng/L secondary
renin/aldo
- elevated renin in primary
synacthen test
- 250ug IV measure 0’ and 30’ unlikely
- > 450nmol/L AI unlikely
what are causes of primary adrenal insufficiency?
- adrenal antibodies
- very long chain fatty acids
- 17-OHP
- imaging
- genetic
what are causes of secondary adrenal insufficiency?
- any steroids
- imaging
- genetic
what is the goal of treatment of adrenal insufficiency?
mirror the normal physiological state
what is the treatment of adrenal insufficiency?
- hydrocortisone (pharmaceutical name for cortisol) twice or three times daily at a dose to replace cortisol levels 15-25mg
- in primary AI also replace aldosterone with fludrocortisone
what is common presentation of adrenal insufficiency?
- hypotension and cardiovascular collapse
- fatigue
- fever
- hypoglycaemia
- hyponatraemia and hyperkalaemia
what is the management o adrenal crisis?
- take bloods if possible for cortisol and ACTH
- immediate hydrocortisone 100mg IV, IM, SC
- fluid resuscitation (1L N/saline 1 hour)
- hydrocortisone 50-100mg IV/IM 6 hourly
- in primary start fludrocortisone 100-200ug (when HC <50mg)
- when patient stable wean to normal replacement over 24-72hrs: 50mg orally TDS; 20mg orally TDS; 10mg orally TDS
what are sick day rules?
- always carry 10 x 10mg tablets hydrocortisone
- if unwell with fever or flu-like illness, double dose of steroids
- if in doubt, double dose of steroids
- if vomiting or increasingly unwell take emergency injection of hydrocortisone 100mg IM (SC)
- if unable to have injection take hydrocortisone 20mg and repeat if vomit
- go to ER/ring ambulance
- you cannot harm yourself in the short term taking extra steroid
what are the consequences of adrenal insufficiency?
- standardised mortality ratio: 2.7
- impaired quality of life
- increased cardiovascular risk
- osteoporosis; low BMD
what is the challenge of adrenal insufficiency treatment?
gut length and transit time
what are microparticles?
microcrystalline bead -> hydrocortisone layer -> delayed release coat
treats adrenal insufficiency
what is a circadian rhythm?
- natural, internal process that regulates the sleep-wake cycle and repeats roughly every 24hrs
- any biological process that displays an endogenous, entrainable oscillation of about 24hrs
- driven by a circadian clock
what is a circadian clock?
biochemical oscillator that that stables with a stable phase and is synchronised with solar time
what are the main features of circadian rhythms?
- has an endogenous free running period that lasts approximately 24hrs
- persists in constant conditions (free running period)
- rhythms are entrainable; can be reset by exposure to external stimuli
- exhibit temperature compensature; maintain circadian periodicity over a range of physiological temperatures
what is entrainment?
biological rhythm can be reset by exposure to external stimuli (e.g. light and heat)
