Endocrinology 2 Flashcards
(719 cards)
1
Q
what are metabolic changes in pregnancy?
A
- increased erythropoietin, cortisol, noradrenaline
- high cardiac output
- plasma volume expansion
- high cholesterol and triglycerides
- pro thrombotic and inflammatory state
- insulin resistance
2
Q
what are gestational syndromes of pregnancy?
A
- pre-eclampsia
- gestational diabetes
- obstetric cholestasis
- gestational thyrotoxicosis
- transient diabetes insipidus
- lipid disorders
- postnatal depression
- postpartum thyroiditis
- postnatal autoimmune disease
- paternal disease
3
Q
what is the embryological development of the thyroid gland?
A
- 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
4
Q
what are glycoprotein hormones involved in thyroid/pregnancy?
A
- glycoprotein hormones contain two subunits, a common alpha subunit and a distinct beta subunit
- TSH, LH, FSH and hCG
5
Q
what happens with thyroid hormone levels in the first trimester of pregnancy?
A
- 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
6
Q
what are levels of thyroid hormones like in the fetus throughout pregnancy?
A
increased TBG, total T4, thyrotropin, free T4, total T3, free T3 (in order of most increased to least increased levels)
7
Q
what is responsible for higher thyroxine requirements in pregnancy?
A
- 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
8
Q
what produces thyroxine binding globulin (TBG)?
A
liver
9
Q
what is the incidence of hypothyroidism in pregnancy?
A
- 2-3%
- overt hypothyroidism 0.3-0.5% in pregnancy
- subclinical hypothyroidism 2-3%
10
Q
what are symptoms of hypothyroidism in pregnancy?
A
weight gain, cold intolerance, poor concentration, poor sleep pattern, dry skin, constipation, tiredness
11
Q
what are the ATA guidelines for TSH levels during the pregnancy?
A
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
12
Q
how does hypothyroidism affect pregnancy?
A
- inadequate treatment
- gestational hypertension
- placental abruption
- post partum haemorrhage
- low birth weight
- preterm delivery
- neonatal goitre and respiratory distress
13
Q
what is the treatment for hypothyroidism in pregnancy?
A
- 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
14
Q
when is targeted screening done for thyroid problems in pregnancy?
A
- age >30
- BMI >40
- miscarriage preterm labour
- personal or family history
- goitre
- anti TPO
- T1DM
- head and neck irradiation
- amiodarone, lithium or contrast use
15
Q
what is the prevalence of hyperthyroidism in pregnancy? what are some causes?
A
0.1-0.4% prevalence
female population 2%
85-90% due to Graves’
less common causes: MNG, gestational thyrotoxicosis, toxic adenoma, trophoblastic neoplasia, TSHoma
16
Q
how does hyperthyroidism affect pregnancy?
A
- IUGR
- low birth weight
- preeclampsia
- preterm delivery
- risk of stillbirth
- risk of miscarriage
17
Q
how does pregnancy affect hyperthyroidism?
A
- tends to worsen in first trimester
- improves latter half of pregnancy
18
Q
what is the management of hyperthyroidism in pregnancy?
A
- symptomatic treatment; beta blockers
- anti-thyroid medications
- PTU/carbimazole
- radioactive iodine is contraindicated
- surgical interventions; optimal timing is 2nd trimester
19
Q
what are effects of carbimazole and propylthiouracil on pregnancy?
A
carbimazole
- increased risk of congenital abnormalities
- aplasia cutis
- choanal atresia
- intestinal anomalies
propylthiouracil
- rare hepatotoxicity
20
Q
what is fetal thyrotoxicosis?
A
transplacental crossover of TSH-R antibodies
- 0.01% of cases
- anti-thyroid medications
21
Q
what is fetal thyrotoxicosis associated with?
A
- IUGR
- fetal goitre
- fetal tachycardia
- fetal hydrops
- preterm delivery
- fetal demise
22
Q
what are the causes of gestational thyrotoxicosis?
A
- 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
23
Q
what are the issues of gestational thyrotoxicosis?
A
- benefits of treating
- hyperemesis gravidum
- extreme; Wernicke’s encephalopathy
- thyrotoxicosis risks
24
Q
what is the prevalence of post-partum thyroiditis?
A
7%
25
what increases the risk of post-partum thyroiditis?
T1DM, Graves' in remission, chronic viral hepatitis, measure TSH 3 months post-partum
26
what is the percentage of total body water in lean body weight?
- 50-60% of lean bodyweight in men
| - 45-50% in women
27
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%)
28
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
29
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
30
where does water tend to stay?
in the soluble-containing compartment because there is less free diffusion across the membrane
31
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
32
what is the primary determinant of the distribution of water among the three major compartments?
osmotic pressure
33
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
```
34
what is contained in the ECF?
Na+ salts predominate in the interstitial fluid
| - large amounts of sodium, chloride and bicarbonate ions
35
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
36
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
37
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)
38
what does hydrostatic pressure do?
pressure of blood against the capillary wall
- tends to force fluid out of the capillaries
- due to gravity
39
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
40
what is the primary determinant of renal sodium and water excretion?
EABV
41
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
42
what causes diminished EABV?
fall in cardiac output or fall in peripheral arterial resistance (increase in the holding capacity of the arterial vascular tree)
43
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_
44
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
45
what leads to peripheral arterial vasodilation?
- sepsis
- cirrhosis
- arteriovenous fistula
- pregnancy
- arterial vasodilators
46
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
47
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
48
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
49
what does increased proximal tubular sodium and water reabsorption lead to?
decreased tubular sodium and water delivery
50
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
51
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
52
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
53
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
54
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
55
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
56
what are mechanisms of sodium transport in the distal tubule?
reabsorbed: 5%
luminal Na+ entry: Na+/Cl- cotransport
transport: flow dependent
57
what are mechanisms of sodium transport in the collecting ducts?
reabsorbed: 4%
luminal Na+ entry: Na+ channels
transport: aldosterone and ANP
58
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
59
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
60
where are high-pressure arterial receptors located?
carotid, aortic arch, juxtaglomerular apparatus
61
where are low-pressure volume receptors located?
cardiac atria, right ventricle, thoracic veins, pulmonary vessels
62
what is responsible for day-to-day variations in Na+ excretion?
aldosterone and possibly ANP
63
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+
64
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
65
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
66
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
67
what are examples of oedematous conditions?
cardiac failure, hepatic cirrhosis and hypoalbuminaemia
68
what is a feature of Conn's syndrome?
increased aldosterone secretion; primary hypoaldosteronism
69
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
70
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
71
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
72
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
73
what is the role of ADH (vasopressin)?
urinary concentration, by increasing the water permeability of normally impermeable cortical and medullary collecting ducts
74
what is the type of receptor for ADH (vasopressin)?
GPCR
75
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
76
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
77
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
78
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
79
what are the types of cell in the collecting duct?
principal and intercalated cells
80
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
81
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
82
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
83
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
84
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
85
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
86
at what osmolality is there no circulating ADH?
- plasma osmolality of <275mosmol/kg
| - <135-137mmol/L
87
what are the mechanisms of osmoregulation?
1. ingestion of water load
| 2. water loss
88
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
89
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
90
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+
91
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
92
what does rise in osmolality lead to?
ADH release and thirst
93
what does hypervolaemia lead to?
enhances the secretion of ANP and suppresses aldosterone secretion
-> increased excretion of Na+ without water
94
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
95
when is ADH secreted by non-osmotic stimuli?
- stress
- reduced effective circulatory volume (e.g. cardiac failure, hepatic cirrhosis)
- psychiatric disturbance and nausea
96
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
97
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
98
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
99
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
100
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
101
what level is vasopressin secretion suppressed at?
below 280mOsm/kg
102
what is the upper limit of normal vasopressin levels?
295mOsm/kg
103
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
104
when is thirst experienced?
at 298mOsm/kg of vasopressin
105
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
106
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)
107
what tumours can cause cranial diabetes insipidus?
- craniopharyngioma
- hypothalamic tumour e.g. glioma, germinoma
- metastases, esp. breast
- lymphoma/leukaemia
- pituitary with suprasellar extension
108
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
109
what is vasopressin (ADH) increased by?
- increased osmolality
- hypovolaemia
- hypotension
- nausea
- hypothyroidism
- angiotensin II
- adrenaline
- cortisol
- nicotine
- antidepressants
110
what is vasopressin (ADH) secretion decreased by?
- decreased osmolality
- hypervolaemia
- hypertension
- ethanol
- alpha-adrenergic stimulation
111
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
112
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
113
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
114
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
115
what tests are used to detect diabetes insipidus?
- water deprivation test
| - measurement of plasma vasopressin during hypertonic saline infusion
116
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
117
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
118
what is indication for a water deprivation test?
diagnosis or exclusion of diabetes insipidus
119
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
120
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
121
what indicates normal response to a water deprivation test?
serum osmolality remains within normal range (275-295mOsm/kg). urine osmolality rises to >600mOsm/kg
122
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
123
what indicates nephrogenic DI from a water deprivation test?
desmopressin doesn't concentrate urine
124
what indicates cranial DI from a water deprivation test?
urine osmolality rises by >50% after desmopressin
125
what is cranial DI?
deficiency of vasopressin (ADH) due to hypothalamic disease
126
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
127
what are other causes of polyuria and polydipsia?
- diabetes mellitus
- hypokalaemia
- hypercalcaemia
- primary polydipsia
128
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
129
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
130
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
131
what are tumours that cause SIADH?
- small-cell carcinoma of the lung
- prostate
- thymus
- pancreas
- lymphomas
- leukaemia
- sarcoma
- mesothelioma
132
what are pulmonary lesions that cause SIADH?
- pneumonia
- TB
- lung abscess
- severe asthma
- pneumothorax
- positive-pressure ventilation
- emphysema
133
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
134
what are metabolic causes of SIADH?
- alcohol withdrawl
| - porphyria
135
what are drug causes of SIADH?
- chlorproamide
- carbamazepine
- cyclophosphamide
- vincristine
- phenothizines
- clofibrate
- thiazides
- MAO inhibitors
- cyclotoxics
- desmopressin
- vasopressin
- oxytocin
- SSRIs
- PPIs
136
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
137
what are sodium levels like in SIADH?
- mild symptoms occur with levels below 125mmol/L
| - serious manifestations occur below 115mmol/L
138
what must SIADH be distinguished from?
dilutational hyponatraemia due to excess infusion of glucose/water solutions or diuretic administrations (thiazides or amiloride)
139
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
140
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
141
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
142
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
143
what is hyponatraemia?
Na+ <135mmol/L
- hyponatraemia with hypovolaemia
- hyponatraemia with euvolaemia
- hyponatraemia with hypervolaemia
144
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
145
what is artefactual hyponatraemia caused by?
taking blood from the limb into which fluid of low sodium concentration is being infused
146
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
147
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
148
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
149
what are major psychiatric illnesses that can cause hyponatraemia with euvolaemia?
- psychogenic polydipsia
- non-osmotic ADH release
- antidepressant therapy
150
what drugs cause increased sensitivity to ADH?
- clorpropamide
| - tolbutamide
151
what are unmeasured osmotically active substances that stimulate osmotic ADH release?
- glucose
- chronic alcohol abuse
- mannitol
- sick-cell syndrome (leakage of intracellular ions)
152
what are causes of hyponatraemia with hypervolaemia?
- heart failure
- liver failure
- oliguric kidney injury
- hypoalbuminaemia
- CCF
- cirrhosis of liver
153
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
154
what makes up the ECF?
```
intravascular fluid (1/4, 3.5L)
interstitial fluid (3/4, 10.5L)
```
155
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
156
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
157
what controls release of vasopressin (ADH)?
osmoreceptors in hypothalamus - day to day
baroreceptors in brainstem and great vessels - emergency
158
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
159
where does variable water excretion occur?
kidneys
- 180L filtrate/day
- total urine output 1-1.5 L/day
160
what affects osmolality?
- sodium, potassium, chloride, bicarbonate, urea and glucose
| - alcohol, methanol, polyethylene glycol or manitol (exogenous)
161
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
162
what are normal osmolality levels?
282-295mOsmol/kg
163
how is plasma osmolality in hyponatraemia calculated?
Na+: 125 x 2
glucose: 4.5
urea: 6
total = 260.5mmol/L
164
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
165
what are primary causes of cranial DI (lack of vasopressin)?
genetic
- DIDMOAD (Wolfram syndrome)
- autosomal dominant
- rarely autosomal recessive
developmental
- septo-optic dysplasia
166
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)
167
what are familial causes of nephrogenic DI (resistance to vasopressin action)?
- X linked (V2 receptor defect)
| - autosomal recessive (aquaporin 2 defect)
168
what is management of nephrogenic DI?
- try and avoid precipitating drugs
| - congenital DI: free access to water, high dose desmopressin, hydrochlorothiazide or indomethacin
169
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
170
what are signs and symptoms of hyponatraemia at 130-135mmol/l?
asymptomatic/headache
171
what are signs and symptoms of hyponatraemia at 125-130mmol/l?
- lethargy
- anorexia and abdominal pain
- weakness
- confusion/hallucinations
172
what are signs and symptoms of hyponatraemia at <125mmol/l?
- agitation
| - decreased conscious level
173
what are signs and symptoms of hyponatraemia at <115mmol/l?
- fitting
| - coma
174
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
175
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
176
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
177
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
178
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
179
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
180
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
181
what are examples of vaptans?
tolvaptan and conivaptan
182
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
183
what is conivaptan?
- V1a/V2 receptor IV antagonist
- not licensed yet
- may be better for heart failure
184
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
185
what are disadvantages of vaptans?
- ?correct diagnosis
- may cause too rapid rise in serum sodium
- more expensive; fluid restriction is free
186
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
187
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
188
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
189
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
190
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
191
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
192
how can hyponatraemia be prevented?
- avoid using hypotonic fluids postop
- administer 0.9% saline unless contraindicated
- serum sodium should be measured daily
193
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
194
what causes neurological symptoms in dilutational hyponatraemia?
movement of water into brain cells in response to fall in extracellular osmolality
195
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
196
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
197
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
198
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
199
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
200
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
201
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
202
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)
203
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
204
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
205
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
206
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
207
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
208
what is ODS?
osmotic demyelination syndrome
- central pontine demyelination
- devastating neurological complication of hyponatraemia
209
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
210
what are risk factors for ODS?
- alcohol excess
- cirrhosis
- malnutrition
- hypokalaemia
- pre-existing hypoxaemia
- CNS radiation
211
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
212
what is the pathophysiology of ODS?
1. brain loses organic osmolytes very quickly to adapt to hyponatraemia so that osmolarity is similar between the intracellular and extracellular compartments
2. neurones regain organic osmolytes slowly in phase of rapid correction of hyponatraemia
3. results in hypoosmolar intracellular compartments and shrinkage of cerebral vascular endothelial cells
4. BBB is functionally impaired, allowing lymphocytes, complement and cytokines to enter the brain, damage oligodendrocytes, activate microglial cells and cause demyelination
213
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
214
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
215
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
216
how is the volume of filtrate delivered to distal nephron calculated?
GFR - volume reabsorbed in PCT
217
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
218
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
219
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
220
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
221
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
222
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
223
what is the mechanism of action of lixivaptan, tolvaptan and satavaptan?
- vasopressin (ADH) antagonists
| - selective for V2 receptor
224
what is the mechanism of action of conivaptan?
- vasopressin (ADH) antagonists
| - blocks both V1a and V2 receptors
225
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
226
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
227
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
228
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
229
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
230
what are developmental abnormalities that cause pituitary mass lesions?
craniopharyngioma (occasionally intrasellar location), germinoma, others
231
what are primary pituitary tumours of the CNS?
perisellar meningioma, optic glioma
232
what are vascular tumours causing pituitary mass lesions?
hemangioblastoma, others
233
what are malignant systemic diseases that cause pituitary mass lesions?
Hodgkin's disease, non-Hodgkin lymphoma, leukaemic infiltration, histiocytosis X
234
what are granulomatous diseases that cause pituitary mass lesions?
neurosarcoidosis, Wegner's granulomatosis, TB, syphilis
235
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
236
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
237
what is lymphocytic hypophysitis?
inflammation of the pituitary gland due to an autoimmune reaction
- lymphocytic adenohypophysitis
- lymphocytic infundibuloneurohypophysitis
- lymphocytic panhypophysitis
238
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
239
what is the appearance of lymphocytic hypophysitis?
- hypointense on T1 imaging
- hyperintense on T2 imaging
- stalk enlargement
- pituitary enlargement
240
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
241
what are signs of aggressiveness of non functioning pituitary adenomas?
- large size
- cavernous sinus invasion
- lobulated suprasellar margins
242
what are the main types of pituitary dysfunction?
- tumour mass effects
- hormone excess
- hormone deficiency
243
what are investigations of pituitary dysfunction?
hormonal tests; if hormonal tests abnormal or tumour mass effects, perform MRI pituitary
244
what are local mass effects of pituitary tumours?
- cranial nerve palsy and temporal lobe epilepsy
- headaches
- CSF rhinorrhoea
- visual field defects
245
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
246
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
247
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
248
what is the guiding principle of testing pituitary function?
if the peripheral target organ is working normally, the pituitary is working
249
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
250
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
251
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
252
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
253
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
254
how is the GH/IGF1 axis tested?
measure: IGF-1 and GH stimulation test
- insulin stress test
- glucagon test
- other
255
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)
256
why may prolactin be raised?
- stress
- drugs e.g. antipsychotics
- stalk pressure
- prolactinoma
257
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
258
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
259
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
260
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
261
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
262
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
263
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
264
what are features of GH deficiency? what is the Rx?
- short stature
- abnormal body composition
- reduced muscle mass
- poor quality of life
Rx: GH
265
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
266
what are features of TSH deficiency? what is the Rx?
hypothyroidism
Rx: levothyroxine
267
what are features of ACTH deficiency? what is the Rx?
- adrenal failure
- decreased pigment
Rx: hydrocortisone
268
what are features of ADH deficiency?
- diabetes insipidus
- decreased water absorption resulting in polyuria and polydipsia
Rx: DDAVP
269
what are microparticulates?
modified release HC
- inert core
- hydrocortisone layer
- sustained release
- enteric coat
270
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
271
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
272
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
273
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
274
how is desmopressin used?
- subcutaneous, orally, intranasally, sublingually
- adjust according to symptoms
- monitor sodium levels
275
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
276
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
277
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
278
what do organised education programmes involve?
all healthcare workers, e.g. nurse specialists, diaticians and podiatrists; should include ongoing support and updates where possible
279
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)
280
what is the recommended amount of protein in a diabetic diet?
1g/kg ideal bodyweight
281
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
282
what is the advice regarding saturated and trans-unsaturated fat in a diabetic diet?
<10% of total energy intake
283
what is the advice regarding n-6 polyunsaturated fat in a diabetic diet?
<10% of total energy intake
284
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
285
what is the advice regarding cis-monounsaturated fat in a diabetic diet?
10-20% of total energy intake (olive oil, avocado)
286
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
287
what is the advice regarding sucrose in a diabetic diet?
- up to 10% of total energy intake
| - in context of healthy diet
288
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
289
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
290
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
291
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
292
what is the advice regarding salt in a diabetic diet?
<6g/day (lower in hypertension)
293
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
294
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
295
what is considered a low/high glycaemic index?
low GI: 55 or less
high GI: 70 or more
mid-range: 56 to 69
296
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
297
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
298
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
299
what are side effects of intestinal enzyme inhibitors for diabetes?
- abdominal discomfort
- flatulence
- diarrhoea
300
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
301
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
302
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
303
what is non-insulin treatments can diabetics receive?
- BP control by ACE inhibitor or angiotensin II receptor inhibitor
- statin
- low dose aspirin
304
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
305
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
306
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
307
where is insulin injected in diabetics?
- given into fat below skin on abdomen, thighs or upper arm
| - needle inserted to its full length
308
why should insulin injection sites be changed regularly?
to prevent areas of lipohypertrophy (fatty lumps)
309
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
310
where is insulin absorbed in the body?
more rapid from the abdomen than the arm; slowest from the thigh
311
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
312
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
313
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
314
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
315
how long does subcutaneous soluble insulin take to achieve peak plasma levels?
60-90 minutes
| - onset and offset of action too slow
316
what insulin regimen is appropriate for younger patients?
multiple injection regimen with short-acting insulin and a longer-acting insulin at night
317
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
318
what are target blood glucose values before and after meals?
4-7mmol/L
| 4-10mmol/L
319
what is the limiting factor for many patients on multiple injection regimens?
hypoglycaemia between meals and at night
320
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
321
what are infusion devices used in diabetes?
CSII (continuous subcutaneous insulin infusion)
322
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
323
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
324
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
325
how can transplantation be used to treat diabetes?
whole pancreas and pancreatic islet transplantation
326
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
327
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
328
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
329
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
330
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
331
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
332
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.
333
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)
334
what does glycosylated haemoglobin tell us?
an index of the average blood glucose concentration over the life of the haemoglobin molecule (approximately 6 weeks)
335
when is glycosylated haemoglobin misleading?
if the life-span of the red cell is reduced or if an abnormal haemoglobin or thalassaemia is present
336
what is the lifespan of haemoglobin molecule?
6 weeks
337
what is an alternative measure to glycosylated haemoglobin?
glycosylated plasma proteins (fructosamine)
338
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
339
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
340
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
341
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
342
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
343
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
344
what are examples of late complications of management of diabetic ketoacidosis?
- pneumonia and DVT
| - occur especially in comatose or elderly patient
345
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
346
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
347
what is the mortality of diabetic ketoacidosis?
5%; increased in older patients
348
how is osmolality calculated?
2(Na+ + K+) + glucose + urea
349
what is the normal range of osmolality?
285-300mOsm/kg
350
what is the normal anion gap?
<17
351
how is anion gap capculated?
(Na+ + K+) - (Cl- + HCO3-)
352
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
353
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
354
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
355
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
356
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
357
what is the presentation of lactic acidosis in diabetes?
- severe metabolic acidosis
- large anion gap (<17mmol/L)
- usually without significant hyperglycaemia or ketosis
358
what is treatment and mortality of lactic acidosis in diabetes?
- rehydration and infusion of isotonic 1.26% bicarbonate
| - mortality in excess of 50%
359
what are the major causes of death in diabetes?
- cardiovascular problems (60-70%)
- renal failure (10%)
- infections (6%)
360
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
361
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
362
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
363
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
364
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
365
what can microvascular occlusion be due to?
vasoconstrictors, e.g. endothelins, and thrombogenesis
366
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
367
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
368
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
369
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
370
what risk factors should be tackled in diabetes?
- hypertension
- smoking
- lipid abnormalities
- low dose aspirin
- ACE inhibitors/angiotensin II receptor antagonists
371
what areas does microvascular complication of diabetes affect?
- retina
- renal glomerulus
- nerve sheaths
372
when do microvascular complications manifest in diabetes?
retinopathy, nephropathy and neuropathy tend to manifest 10-20 years after diagnosis in young patients
373
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
374
what is the racial prevalence of microvascular complications of diabetes in the USA?
Pima American Indians > Hispanic/Mexican > US black > US white patients
375
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
376
what is the commonest cause of blindness in under 65 year olds?
diabetes
377
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
378
what is diabetic retinopathy?
damage to the retina and iris caused by diabetes, which can lead to blindness
379
what is cataracts?
denaturation of the protein and other components of the lens of the eye which render it
380
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
381
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
382
what can cause an acute cataract (snowflake cataract)?
sustained very poor diabetes control with a degree of ketosis; comes on rapidly
383
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
384
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
385
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
386
what are microaneurysms?
- Charcot-Bouchard aneurysm
- aneurysms of the brain vasculature occurring in the small blood vessels
- small red dots
387
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
388
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
389
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)
390
what are cytoid bodies?
white dots at site of previous cotton wool spots that have been removed by macrophages
391
what does damage to the walls of veins cause?
causes their calibre to vary (venous beading) and elongation to occur, causing venous loops
392
what is venous beading?
damage to the walls of veins causing their calibre to vary
393
how are venous loops created?
damage to the walls of veins causing elongation to occur, forming venous loops
394
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)
395
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
396
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
397
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)
398
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
399
what causes fibrotic bands in diabetic retinopathy?
later collagen tissue grows along the margins of the new vessels formed in the retina
400
what is the action of fibrotic bands in diabetic retinopathy?
bands may contract and pull on the retina causing further haemorrhage and retinal detachment
401
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)
402
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
403
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
404
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
405
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
406
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
407
what are diabetic retinopathy grades?
peripheral retina and central retina
408
what are types of peripheral retina diabetic retinopathy?
- background (R1)
- pre-proliferative (R2)
- proliferative (R3)
- advanced retinopathy
409
what are types of central retina diabetic retinopathy?
maculopathy (MI)
410
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
411
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
412
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
413
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
414
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
415
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
416
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)
417
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
418
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
419
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
420
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
421
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
422
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
423
how can the kidney be damaged by diabetes?
- glomerular damage
- ischaemia resulting from hypertrophy of afferent and efferent arterioles
- ascending infection
424
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
425
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
426
what is microalbuminuria?
amounts of urinary albumin so small that it;s undetectable by standard dipsticks
427
what can test for microalbuminuria?
radioimmunoassay or by special dipsticks
428
what is microalbuminuria a predictive marker for?
marker of progression to nephropathy in type 1 diabetes, and of increased CV risk in type 2
429
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
430
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
431
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
432
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
433
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
434
what can untreated infections in diabetics lead to?
renal papillary necrosis; renal papillae are shed in urine - very rare
435
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
436
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
437
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
438
what can delay the onset of frank proteinuria?
- meticulous glycaemic control
| - early antihypertensive treatment, esp. with ACE inhibitors and ang. II blokers
439
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
440
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
441
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
442
why may chronic ambulatory peritoneal dialysis be preferred to haemodialysis in diabetics?
vascular shunts tend to calcify rapidly
443
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
444
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
445
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
446
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
447
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
448
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
449
why is neurological assessment of a patient with acute painful neuropathy difficult?
hyperaesthesia
450
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
451
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
452
what is a characteristics feature of diabetic 3rd nerve lesions?
pupillary reflexes are retained, due to sparing of pupillomotor fibres
453
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
454
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
455
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
456
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
457
what are normal and abnormal responses to supine to erect BP: systolic BP fall (mmHg)?
normal: 10
abnormal: 30+
458
what are normal and abnormal HR responses to deep breathing (6 breaths/min) max to min HR?
normal: 15+
| abnormal <10
459
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
460
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
461
what is R-R interval?
time between R and next R on ECG
462
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
463
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
464
what are manifestations of male erectile dysfunction in diabetes?
- incomplete erection which may progress to total failure
| - retrograde ejaculation in autonomic neuropathy
465
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
466
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
467
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
468
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
469
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
470
what are features of the diabetic foot?
ischaemia, infection and neuropathy combine to produce tissue necrosis
471
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
472
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
473
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
474
what are the four main threats to the skin and subcutaneous tissues in the diabetic foot?
- infection
- ischaemia
- abnormal pressure
- wound environment
475
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
476
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
477
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
478
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
479
what skin infections are poorly-controlled diabetics susceptible to?
- staphylococcal infections (boils, abscesses, carbuncles)
| - mucocutaneous candidiasis
480
what GI tract infections are poorly-controlled diabetics susceptible to?
- periodontal disease
| - rectal and ischiorectal abscess formation
481
what urinary tract infections are poorly-controlled diabetics susceptible to?
- UTIs
- pyelonephritis
- perinephric abscess
482
what lung infections are poorly-controlled diabetics susceptible to?
- staphylococcal and pneumococcal pneumonia
- Gram-negative bacterial pneumonia
- TB
483
what bone infection are poorly-controlled diabetics susceptible to?
spontaneous staphylococcal spinal osteomyelitis
484
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
485
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
486
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
487
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
488
what are neonatal problems in diabetes?
- maternal diabetes associated with fetal macrosomia
- more susceptible to hyaline membrane disease
- neonatal hypoglycaemia
489
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
490
what is gestational diabetes?
glucose intolerance that develops or is first recognised in pregnancy; typically asymptomatic and usually remits following delivery
491
who is at risk for gestational diabetes?
- previous history of gestational diabetes
- older or overweight
- history of large babies
- certain ethnic groups
492
what is unstable diabetes?
patients with recurrent ketoacidosis and/or recurrent hypoglycaemic coma
- largest group made up of those with recurrent severe hypoglycaemia
493
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
494
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
495
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)
496
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
497
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
498
why does hypoglycaemia develop in the non-diabetic?
when hepatic glucose output falls below the rate of glucose uptake by peripheral tissues
499
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)
500
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
501
what affects peripheral glucose uptake?
increased by high insulin levels and by exercise; these conditions are normally balanced by increased hepatic glucose output
502
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
503
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
504
what are presenting features of insulinoma?
- diplopia
- sweating, palpitations, weakness
- confusion or abnormal behaviour
- loss of consciousness
- Grand mal seizures
505
what are insulinomas?
pancreatic islet cell tumours that secrete insulin
506
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
507
what are common misdiagnoses of insulinomas?
psychiatric disorders, esp. pseudodementia in elderly, epilepsy and cerebrovascular disease
508
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
509
how is diagnosis of insulinoma confirmed?
demonstration of hypoglycaemia in association with inappropriate and excessive insulin secreiton
510
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
511
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
512
what is treatment of insulinoma?
surgical excision of tumour; often very small and difficult to localise
513
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
514
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
515
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)
516
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
517
what are endocrine causes of hypoglycaemia?
- deficiencies of hormones antagonistic to insulin are rare
| - e.g. hypopituitarism, isolated ACTH deficiency, Addison's disease
518
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
519
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)
520
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
521
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
522
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
523
what is testicular volume at birth?
0.5-1mL
524
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
525
what is erectile dysfunction?
inability of the male to achieve or sustain an erection adequate for satisfactory intercourse
526
what is azoospermia?
absence of sperm in the ejaculate
527
what is oligospermia?
reduced numbers of sperm in the ejaculate
528
what is libido?
sexual interest or desire; often difficult to assess and greatly affected by stress, tiredness and psychological factors
529
what is menarche?
age at first period
530
what is primary amenorrhoea?
failure to begin spontaneous menstruation by age 16
531
what is secondary amenorrhoea?
absence of menstruation for 3 months in a woman who has previously had cycles
532
what is oligomenorrhoea?
irregular long cycles; often used for any length of cycle above 32 days
533
what is dyspareunia?
pain or discomfort in the female during intercourse
534
what is menstruation?
onset of spontaneous (usually regular) uterine bleeding in the female
535
what is virilisation?
occurrence of male secondary sexual characteristics in the female
536
what the HPG axis in the male?
1. pulses of GnRH are released from the hypothalamus and stimulate LH and FSH release from the pituitary
2. LH stimulates testosterone production from Leydig cells of the testis
3. 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
4. FSH stimulates Sertoli cells in seminiferous tubules to produce mature sperm and inhibins A and B
5. inhibin feeds back to pituitary to decrease FSH secretion. activin counteracts inhibin
537
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
538
what is the action of LH in the male?
stimulates testosterone production from Leydig cells of the testis
539
what produces testosterone?
Leydig cells of the testis (stimulated by LH)
540
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
541
what is testosterone bound to in circulation?
sex hormone binding hormone
542
what is the action of FSH in males?
stimulates Sertoli cells in seminiferous tubules to produce mature sperm and inhibins A and B
543
what is the action of inhibin in males? what counteracts it?
feeds back to the pituitary to decrease FSH secretion; activin counteracts inhibin
544
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
545
what is the HPG axis/physiology in the female?
1. higher brain centres impose menstrual cycle of 28 days upon activity of hypothalamic GnRH
2. pulses of GnRH, at about 2hr intervals, stimulate release of pituitary LH and FSH
3. LH stimulates ovarian androgen production by ovarian theca cells
4. FSH stimulates follicular development and aromatase activity in ovarian granulosa cells, and release of inhibin from ovarian stromal cells, which inhibits FSH release
5. by day 8-10 a leading follicle is selected for development into a mature Graafian follicle
6. oestrogens have double feedback action on the pituitary
7. follicle differentiates into corpus luteum, secreting progesterone and oestradiol in second half of cycle (luteal phase)
8. oestrogen and progesterone cause uterine endometrial proliferation for potential implantation
546
what stimulates release of LH and FSH in females?
pulses of GnRH, at about 2hr intervals
547
what is the action of LH in females?
stimulates ovarian androgen production by the ovarian theca cells
548
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
549
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
550
what effect do oestrogens have on the pituitary?
double feedback action
551
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
552
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
553
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
554
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
555
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
556
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
557
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
558
what causes the mechanisms initiating puberty?
withdrawal of central inhibition of GnRH release
559
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
560
what is GPR54 also known as?
kisspeptin receptor
561
what is the action of kisspeptin?
- endogenous ligand for kisspeptin receptor (KISSIR)/GPR54
| - regulates GnRH production and timing of puberty
562
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
563
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
564
when is peak height velocity reached in boys?
between ages 12 and 17 during stage 4 of testicular development
565
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
566
what are the types of testicular volume in boys during puberty?
2mL, 4mL, 12mL, 20mL
567
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
568
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
569
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
570
what are other forms of precocity?
- cerebral precocity
- McCune-Albright syndrome
- premature thelarche
- premature adrenarche
571
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
572
what is McCune-Albright syndrome?
- form of precocious puberty
- usually occurs in girls
- precocity, polyostotic fibrous dysplasia and skin pigmentation
573
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
574
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
575
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
576
what happens in constitutional pubertal delay?
pubertal development, bone age and stature are in parallel
| - family history taken
577
what indicates the onset of puberty in boys?
a testicular volume >5mL
| - rising serum testosterone is an earlier clue
578
what indicates the onset of puberty in girls?
breast bud is first sign
| - ultrasound allows assessment of ovarian and uterine development
579
what can be given to induce puberty?
low-dose short-term sex hormone therapy
580
what factors cause insulin resistance and beta-cell dysfunction?
- diabetes genes
- adipokines
- inflammation
- hyperglycaemia
- free fatty acids
- other factors
581
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)
582
what are atherosclerotic clinical events?
acute and chronic coronary syndromes, stroke, peripheral artery disease
583
what is the mechanism of action and target tissue site of Pramlintide?
GI tract
- delay of gastric emptying
- inhibition of glucagon release
584
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
585
what is the mechanism of action and target tissue site of sulfonylureas?
pancreatic beta cell
| - acute stimulation of insulin release
586
what is the mechanism of action and target tissue site of meglitinides?
pancreatic beta cell
| - acute stimulation of insulin release
587
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
588
what is the mechanism of action and target tissue site of metformin?
liver
- inhibition of glucose production
- increase in hepatic insulin sensitivity
589
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
590
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
591
what can metformin + sulfonylurea be combined with in triple therapy?
- TZD
- DPP4 inhibitor
- SGLT2 inhibitor
- GLP-1-RA
- insulin
592
what can metformin + thiazolidinedione be combined with in triple therapy?
- SU
- DPP4 inhibitor
- SLGT2 inhibitor
- GLP1RA
- insulin
593
what can metformin + DPP4 inhibitor be combined with in triple therapy?
- SU
- TZD
- SGL2 inhibitor
- insulin
594
what can metformin + SGLT2 inhibitor be combined with in triple therapy?
- SU
- TZD
- DPP4 inhibitor
- insulin
595
what can metformin + GLP1RA be combined with in triple therapy?
- SU
- TZD
- insulin
596
what can metformin + basal insulin be combined with in triple therapy?
- TZD
- DPP4 inhibitor
- SGLT2 inhibitor
- GLP1RA
597
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
598
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
599
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
600
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
601
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
602
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
603
what are examples of TZD?
rosiglitazone, pioglitazone
604
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
605
what are advantages and disadvantages of SUs?
- newer class entrants may have reduced CV risk
- may increase risk of CV events; hypoglycaemia
- weight gain
606
what are advantages and disadvantages of TZDs?
- low risk of hypoglycaemia; positive effects on biomarkers
- increased CV risk; lipid abnormalities
- weight gain
607
what are examples of SGLT-2 inhibitors?
empaglifozin, dapaglifozin, canaglifozin
608
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
609
what is puberty?
describes the physiological, morphological and behavioural changes as the gonads switch from infantile to adult forms
610
what are definitive signs of puberty?
girls: menarche (first menstrual bleeding)
boys: first ejaculation, often nocturnal
do not signify fertility
611
what causes voice deepening in male puberty?
testicular androgens causing enlargement of larynx and laryngeal muscles
612
what is Tanner stage 1 in boys?
- prepubertal: no pubic hair
- testicular length: <2.5cm
- testicular volume: <3mL
613
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
614
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
615
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
616
what is Tanner stage 5 in boys?
- adult-type hair spread to medial surface of thighs
| - genitalia adult size and shape
617
what measures testicular volume in mL?
orchidometer
618
what are pre-pubertal testicular volumes?
1-3mL
619
what are normal adult male testicular volumes?
15-25mL
620
what is Tanner stage 1 in girls?
- prepubertal: no pubic hair
| - elevation of papilla only
621
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
622
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
623
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
624
what is Tanner stage 5 in girls?
- hair adult-type and distributed in classic inverse triangle
- adult contour breast with projection of papilla only
625
what is normal puberty in girls?
mean age at onset of
- breast development
- pubic hair
- menses (menarche)
626
what is thelarche?
breast development
627
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
628
what are effects of oestrogen on thelarche?
- ductal proliferation
- site specific adipose deposition
- enlargement of the areola and nipple
629
what are other hormones involved in thelarche?
prolactin, glucocorticoids, insulin
630
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
631
what are characteristics of the prepubertal ovaries?
- volume 0.2-1.6ml
| - non functional
632
what are characteristics of the pubertal/adult uterus?
- corpus:cervix ratio 2:1
- pear shape
- length 5-8cm
- volume 3-15ml
- endometrium increased thickness
633
what are characteristics of the pubertal/adult ovaries?
- volume 2.8-15ml
| - multicystic
634
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
635
what are characteristics of the prepubertal vagina?
- reddish in colour
- thin atrophic columnar epithelium
- pH neutral
- length 2.5-3.5cm
636
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
637
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
638
what is the maturation of the external genitalia under the effect of adrenal and ovarian androgens?
growth of pubic and axillary hair
639
what are the consequences of delayed puberty?
leads to reduced peak bone mass and osteoporosis
640
what is delayed puberty?
absence of secondary sexual characteristics by 14yrs (girls) and 16yrs (boys)
641
what affects the GnRH neuron?
OPR, GABAR, GPR54, GluR, IGFR, FGFR, PGFR, TGHbetaR
642
what are increased stimulatory factors for puberty (GnRH secretion)?
glutamate and kisspeptin
643
what causes decreased inhibitory tone for puberty (GnRH secretion)?
GABAergic neurons secreting gamma-aminobutyric acid (GABA) and opioidergic neurons
644
what causes the start of puberty?
increased stimulatory factors and decreased inhibitory tone (GnRH secretion)
645
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)
646
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
647
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
648
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
649
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)
650
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
651
what is differential diagnosis by GnRH (LHRH) test of true precocious puberty?
- stimulation gives pubertal range
| - stimulated LH:FSH ratio >1
652
what is differential diagnosis by GnRH (LHRH) test of precocious pseudopuberty?
- stimulation gives pre-pubertal range or suppression
| - stimulate LH:FSH ratio <1
653
what is the difference between true and pseudo precocious puberty?
true is GnRH dependent, pseudo GnRH independent
654
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
655
what are CNS tumours that cause true (central) precocious puberty (GnRH dependent)?
- optic glioma associated with NF1
| - hypothalamic astrocytoma
656
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
657
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
658
what are causes of increased androgen secretion?
- congenital adrenal hyperplasia (21OHD, 11OHD)
- virilising neoplasm
- Leydig cell adenoma
- familial male precocious puberty - testotoxicosis
659
what are gonadotropin secreting tumours?
chorioepitheliomas, germinoma, teratoma, hepatoma, choriocarcinoma
660
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)
661
what does delay in puberty lead to?
- delay in acquisition of secondary sex characteristics
- psychological problems
- defects in reproduction
- reduced peak bone mass
662
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
663
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
664
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
665
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
666
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
667
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
668
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
669
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
670
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
671
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
672
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
673
what are causes of hypogonadotrophic hypogonadism?
- CNS disorders (tumours and other causes)
- isolated gonadotropin deficiency
- idiopathic and genetic forms of multiple pituitary hormone deficiencies
674
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)
675
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
676
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)
677
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)
678
what are genetic defects that cause hypogonadotrophic hypogonadism?
GnRH neuron migration
GnRH synthesis and release
GnRH action
gonadotrophin synthesis
679
what are genetic aspects of GnRH neuron migration?
KAL1, FGFR1, NELF, PROK2, PROKR2
680
what are genetic aspects of GnRH synthesis and release?
GPR54, LEP, LEPR, SF1, DAX1
681
what are genetic aspects of GnRH action?
GnRHr
682
what are genetic aspects of gonadotropin synthesis?
LHB, FSHB, SF1, DAX1
683
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
684
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
685
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
686
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
687
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
688
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
689
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)
690
what are the types of pattern of hormonal secretion?
continuous and pulsatile
691
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
692
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
693
what is circadian?
changes over the 24 hours of the day-night cycle and is best shown for the pituitary adrenal axis
694
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
695
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)
696
what are normal ranges for plasma cortisol levels at 0900 and 2400hrs?
0900: 180-70nmol/L
2400: <100nmol/L
697
what is the central clock in circadian rhythms?
suprachiasmatic nuclei (affected by light)
698
what are the peripheral clocks that the central clock controls?
muscle, lung, hormones, liver, kidney, stomach, heart, brain
| - glucocorticoids are secondary messenger
699
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
700
what is secondary adrenal insufficiency?
hypopituitarism (150-280/M)
- pituitary macroadenoma
- apoplexy
- hypophysitis
- mets, infiltration, infection
- radiotherapy
- congenital
701
what is tertiary adrenal insufficiency?
suppression of HPA
| - steroids, oral, inhaler, creams
702
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
703
what are signs of adrenal insufficiency?
pigmentation and pallor, hypotension
704
what is the biochemistry of adrenal insufficiency?
- low Na, high K
- eosinophilia
- borderline elevated TSH
705
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
706
what are causes of primary adrenal insufficiency?
- adrenal antibodies
- very long chain fatty acids
- 17-OHP
- imaging
- genetic
707
what are causes of secondary adrenal insufficiency?
- any steroids
- imaging
- genetic
708
what is the goal of treatment of adrenal insufficiency?
mirror the normal physiological state
709
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
710
what is common presentation of adrenal insufficiency?
- hypotension and cardiovascular collapse
- fatigue
- fever
- hypoglycaemia
- hyponatraemia and hyperkalaemia
711
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
712
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
713
what are the consequences of adrenal insufficiency?
- standardised mortality ratio: 2.7
- impaired quality of life
- increased cardiovascular risk
- osteoporosis; low BMD
714
what is the challenge of adrenal insufficiency treatment?
gut length and transit time
715
what are microparticles?
microcrystalline bead -> hydrocortisone layer -> delayed release coat
treats adrenal insufficiency
716
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
717
what is a circadian clock?
biochemical oscillator that that stables with a stable phase and is synchronised with solar time
718
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
719
what is entrainment?
biological rhythm can be reset by exposure to external stimuli (e.g. light and heat)
