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
