ChemPath Flashcards
(141 cards)
1
Q
What are atherosclerotic plaques made up of?
A
necrotic core of cholesterol crystals
surrounded by foam cells
topped with a fibrous cap
- Foam cells = macrophages full of cholesterol ester
- Cholesterol crystals = macrophages dying, releasing enzymes which hydrolyse the cholesterol esters free cholesterol crystalise
2
Q
• Lipoproteins in order of density:
A
Chylomicron < FFA < VLDL < IDL < LDL
3
Q
main carrier of cholesterol in the fasted state
main carrier of TG in the fasted state
HDL carries cholesterol from
A
LDL
carries cholesterol from liver to periphery / bad cholesterol
VLDL
HLD - the periphery to the liver / good cholesterol
4
Q
Transporter of cholesterol
across intestinal border
back into the lumen of the intestine
A
NPC1L1
ABCG5
ABCG8
5
Q
enzyme involved in hydrolysis of cholesterol to bile acids
A
7a hydroxylase
6
Q
enzyme involved in cholesterol esterification
A
ACAT (cholesterol acetyltransferase)
7
Q
What does VLDL consist of
A
cholesterol ester
apoB
TG
transfer protein MTP is very important in this packaging process]
8
Q
function of CEPT (cholesteryl ester transfer protein)
A
- Mediates movement of cholesterol ester from HDL VLDL/LDL
- Mediates movement of TG from VLDL/LDL HDL
9
Q
Which protein mediates movement of free cholesterol from peripheral cells to HDL?
A
ABCA1
10
Q
Biggest to smallest lipoproteins
A
chylomicrons
VLDL
LDL
HDL
11
Q
Triglyceride transport + metabolism
A
• Main source of exogenous triglycerides: small intestine (diet) [from intestine to liver to plasma and then back again]
o Fatty foods get hydrolysed in the small intestine broken down to fatty acids resynthesized into TG transported via chylomicrons to the plasma
o Chylomicrons are hydrolysed by the LPL (lipoprotein lipase, present in capillaries, particularly in relation to muscles) free fatty acids
o Free fatty acids are partly taken up by the liver + also partly taken up by adipose tissue
o Liver resynthesises the free fatty acids into triglycerides + exports them as VLDL
o VLDL is acted upon by LPL and hydrolysed to free fatty acids
12
Q
What is phytosterolaemia
A
AR
high plant sterols in plasma
Due to
ABCG5
ABCG8 mutations
Normally the main function of these enzymes is to prevent the absorption of plant sterols
13
Q
What is familial hyperalpha liporoteinaemia
A
Inherited increases in HDL
Associated with longeivity
14
Q
Mode of inheritance of familial hypercholesterolaemia
A
AD
50% expression in heterozygous
100% expression in homozygous
15
Q
describe the function of the PCSK9 mutation in familial hypercholesterolaemia
A
PCSK9 – least common cause of familial hypercholesterolaemia, gain of function mutation
- Chaperone protein – Function is to bind to LDL receptor on the surface of the liver and promote its degradation
- gain of function mutations of PCSK9 increased rate of degradation of LDL receptors
- Loss of function mutations of PCSK associated with low LDL levels
16
Q
Describe the 3 types of primary hypertriglyceridemia/ hyperlipidaemia
A
• Familial type I
LPL (lipoprotein lipase) or apoC II deficiency
o ApoC II = activates LPL
o LPL = degrades chylomicrons => less breakdown of chylomicrons
o Eruptive xanthomas on the skin
o High chylomicrons
- Familial type IV: synthesis of TG, majority VLDLs
- Familial type V: apoA V deficiency (more severe form of Familial type IV), majority VLDLs + some chylomicrons
17
Q
Simple test to differentiate between type I and type IV hyperlipidaemia
A
Fridge test
after blood left overnight in fridge
type I –> chylomicrons will flow to the top and form a cream
Type IV –> cream doesnt float to the top (just the plasma) as VLDL particles dont float just by letting it stand overnight
((Type I - high chylomicrons, Type IV - high VLDLs)
18
Q
Presentation of familial combined hyperlipidaemia
A
o In a family some people with high cholesterol + some people with high triglycerides
19
Q
Presentation of Familial dysβlipoproteinaemia (type III hyperlipoproteinemia)
A
o ApoE2 polymorphism – presence of ApoE 2/2 in homozygous form
o Diagnostic sign = yellow palmar crease, eruptive xanthomas on elbow
20
Q
What is Tangier disease
A
o Enlarged orange tonsils in children, peripheral neuropathy, hepatomegaly, splenomegaly
o Low HDL
o risk of CVD
o HDL deficiency caused by ABC AI mutations (mediating the movement of cholesterol from peripheral cells onto HDL) prevention of release of cholesterol + lipids accumulation in certain organs
21
Q
Ab lipoproteinaemia mutation
A
o Low levels of cholesterol (particularly VLDL, LDL)
o Recessive: therefore parents will have normal lipid levels
o AR
22
Q
MOA of
statin
fibrates (e.g. gemfibrozil)
ezetimibe
cholestyramine
A
• Statins (e.g. atorvastatin)
o HMG-CoA reductase inhibitor
o Reduces intrinsic synthesis of cholesterol in liver
- Fibrates (e.g. gemfibrozil) raise HDL, very good at reducing triglycerides
- Ezetimibe reduces LDL levels absorption blocker blocks NPC1L1 which mediates the transport of cholesterol across the intestine
- Cholestyramine binds bile acids bile acids can’t be reabsorbed no negative feedback to the liver liver makes more bile-acids cholesterol drops (bile acids are made from cholesterol) catabolism of cholesterol in the liver stimulated reduction in LDL
23
Q
Novel forms of LDL-lowering therapy
A
• Microsomal Triglyceride Transfer protein (MTP) inhibitor
o Inhibition of MTP) blockage of release of VLDL from the liver reduced LDL levels
o Deficiency of MTP gives rise to αβ-lipoproteinemia
o Lomitapide – replicates αβ-lipoproteinemia
• Anti-PCSK9 monoclonal antibody
o Evolocumab
• Anti-sense apoB oligonucleotide
o Mipomersen
o Prevents the synthesis of apoB
o Reduces synthesis of LDL, lipoprotein a
• Apolipoprotein A-I/A-1 mimetic infusion therapy
o HDL based therapy
• CETP inhibitory
o HDL-based therapy
24
Q
Which procedures reduce the HbA1c the most?
A
Biliopancreatic division > gastric bypass > medical therapy
25
Bariatric surgery
o Gastric banding
o Roux-en-y gastric bypass – distal part of the jejunum has been anastomosed to the reduced size of the stomach – part 1 is not absorbing anything because the bile acids and pancreatic enzymes that mediate absorption are coming in lower down
o Biliopancreatic diversion – reduced size of stomach, a lot of jejunum is no longer in circuit (no food goes through that part), only terminal ileum (3) is absorbing – this is where the bile acids + pancreatic enzymes come in
26
What can you add in the medications of patients to bring their BP down to normal?
Thiazide diuretic
27
• First line management of hyperlipidaemia
• First line management of hyperlipidaemia is always conservative
o Dietary modification (although dietary intake of cholesterol correlates poorly with actual TG levels)
o Exercise
28
• Statin-intolerant patients mx
```
o Ezetimibe ( absorption – block NPC1L1)
o Evolocumab (PCSK9 monoclonal antibody) – inhibits the action of PCSK9
o Plasma exchange
```
29
How does the PCSK9 antibody work
o PCSK9 binds LDLR + promotes its degradation
o PCSK9 binds to LDLR on hepatocytes + encourages endocytosis + lysosomal degradation of the LDLR less LDL taken up in the liver
o Inhibiting PCSK9 more LDLRs on hepatocytes take up LDL lower levels of LDL in the plasma reduce risk of atherosclerosis
o Gain-function mutations reduce LDL-R on liver increased plasma LDL
o Loss-function mutations increase LDL-R on liver decreased plasma LDL
o You want to inhibit PCSK9
30
What did the DCCT study show?
DCCT - T1DM, good control improves outcome
31
What did the UKPDS study show?
UKDPS - new T2DM put into good control
low mortality in both groups for 15 years but then good control improved outcome = the legacy effect
32
What did the accord study show?
o Sudden aggressive glucose control can increase mortality arrhythmia, tachycardia, sudden onset VF (?hypoglycaemia properly) death
33
MOA of SGLT2 inhibitors and give examples
* SGLT2 – makes you resorb glucose
* Block the Na+/glucose co-transporter in the kidneys pee out more glucose
* Osmotic diuresis Reduce glucose re-uptake in kidneys + lower BP
* Increased risk of DKA (while taking it or shortly after stopping it), UTIs
* Show reduction in mortality after only 4 years
* Empagliflozin
* Canagliflozin
* Dapagliflozin
34
Empagliflozin - summary of actions
o Summary: bring down HbA1c, protect kidneys/renal failure, treat HF
35
GLP-1 analogues
o Exenatide - increased hypothalamic satiety
o Liraglutide - can also reduce weight, hospitalisations for HF, CV deaths, MIs, strokes
• GLP-1 secreted from gut L-cells + signals pancreas to make insulin
o Direct effect on appetite + gastric emptying
36
DDP4 inhibitors
DDP4 break down GLP-1
DDP4 inhibitors = gliptins
37
T2DM mx Only continue GLP-1 mimetic therapy if the person has a beneficial metabolic response:
o A reduction of HbA1c by at least 11 mmol/mol [1.0%] and
| o A weight loss of at least 3% of initial body weight in 6 months
38
• Which one is better?
o Metformin + DPP4 inhibitor
o Metformin + SGLT2 inhibitor
o Metformin + GLP-1-R agonist
o Metformin + SGLT2 inhibitor
o Metformin + GLP-1-R agonist
associated with better outcomes
39
Acarbose MOA
Acarbose MOA
• Inhibits α-glucosidase at the bowel wall prevention of glucose absorption
• Undigested sugar flatulence
40
Sulphonylureas MOA
• Inhibit ATP sensitive K+ channels on beta cells depolarisation of cell Ca2+ entry insulin release
• Risk of hypoglycaemia
• E.g. gliclazide, glibenclamide
o Gliclazide can lead to weight gain
41
With pioglitazone, there is increased risk of
HF, bladder cancer bone fracture
```
• Do not offer pioglitazone if pt have any of the following
o HF or hx of HF
o Hepatic impairment
o DKA
o Current or hx of bladder cancer
o Uninvestigated macroscopic haematuria
```
42
How does ADH work?
o Synthesised in hypothalamus
o Secreted by posterior pituitary
o Acts on V2 receptors in collecting duct (distal tubules) in the kidney
o Water retention through insertion of AQA2 (aquaporin 2)
43
Causes of
high
normal
low
serum osmolarity in hyponatraemia
o High serum osmolality – glucose/mannitol infusion
Osmotically active solutes draw water from cells into the plasma dilution of sodium
This is a true hyponatraemia
o Normal serum osmolality – spurious, drip arm sample, pseudohyponatremia (hyperlipidaemia/paraproteinemia e.g. MM)
o Low serum osmolality – true hyponatraemia
44
Stimuli for ADH secretion
o Raised serum osmolality – hypothalamic osmoreceptors ADH release + thirst
o Low BP/volume – baroreceptors in carotids, atria, aorta ADH release
45
ADH vs Aldosterone
ADH only resorbs water not sodium Hyponatraemia
Aldosterone reabsorbs both salt/Na and water
46
Most reliable indicator of hypovolaemia
o Low urine Na+ (<20) [most reliable indicator of hypovolaemia]
RAAS hypovolaemic low BP aldosterone release Na+/water retention low urine Na+
If you suspect hyponatremia check urine Na+ immediately before other interventions
If a patient is on diuretics you can’t determine urine sodium it will be high because of the diuretics
47
Cause of hyponatraemia in a hypovolaemic patient
Urine Na+ <20
Urine Na+ >20
Urine Na+ <20 – non-renal
• D+V, excess sweating, third space loss (Ascites, burns)
Urine Na+ >20 – cause is renal
• Diuretics/Addison’s disease(low aldosterone)/salt losing nephropathies (kidney failing to reabsorb sodium so water is lost as well)
48
Euvolaemic hyponatraemia
plasma osmolarity
urine osmolarity
urine sodium
causes
low plasma osmolarity
high urine osmolarity
high urine sodium (>100)
Hypothyroidism - TFTs
Adrenal insufficiency - short synACTHen test
SIADH - low plasma osmolarity, high urine osmolarity
49
Hypervolaemic hyponatraemia
Urine Na+ <20
Urine Na+ >20
Urine Na+ <20 – non-renal cause
• CF, cirrhosis, inappropriate IVF, TURP
Urine Na+ >20 – renal cause
• Renal failure, nephrotic syndrome, AKI, CKD
50
Causes of hyponatraemia in a hypervolaemic patient
HF
Cirrhosis
Renal failure
51
Volume status
Plasma osmolality
urine osmolarity in SIADH
Euvolemic
low plasma osmolality
high urine osmolarity
52
SIADH mx
• Fluid restriction + treat the cause
• Demeclocycline induces nephrogenic diabetes insipidus
o Decreased responsiveness of collecting tubule cells to ADH
o Monitor U+Es risk of nephrotoxicity
• Tolvaptan – V2 receptor antagonist
53
Risk of increasing Na + too quickly
central pontine myelinolysis
o Serum sodium must not increase >8-10mmol/L in the first 24h
o If the sodium has done up too quickly you need to bring it down again dextrose and desmopressin
o Quadriplegia, dysarthria, seizures, coma, death
o Pseudobulbar palsy, paraparesis, locked in syndrome
54
Causes of high sodium
* Medical high intake – hypertonic saline, sodium bicarbonate
* Dietary high intake – salty infant formula, high dietary salt
* Conn’s syndrome – high aldosterone : renin ratio
* Bilateral adrenal hyperplasia – high aldosterone : renin ratio
* Renal artery stenosis – low GFR from RAS low BP at JGA renin high aldosterone
* Cushing’s syndrome – overactivation of mineralocorticoid receptor by cortisol aldosterone-like effects
55
What kind of hypernatraemia does diabetes insipidus cause?
Hypovolaemic hypernatraemia
Patient is clinically euvolemic
56
What investigations would you order in a patient with suspected diabetes insipidus?
What investigations would you order in a patient with suspected diabetes insipidus?
```
Serum glucose (exclude diabetes mellitus)
Serum potassium (exclude hypokalaemia)
Serum calcium (exclude hypercalcaemia)
```
can cause resistance to ADH, effectively causing a “nephrogenic” diabetes insipidus which can easily be treated by correcting these biochemical abnormalities
Plasma & urine osmolality
- High plasma osmolality
- Low urine osmolality
(vs psychogenic polydipsia where plasma osmolality would be low)
Water deprivation test
o 8h deprivation test
o Normal urine concentration increases >600 mOsmol/kg
o Primary polydipsia urine concentrates >400-600 mOsmol/kg
o Cranial DI urine concentrates only after administration of desmopressin
o Nephrogenic DI urine does not concentrate even after administration of desmopressin
57
Mx of nephrogenic diabetes insipidus
Thiazide diuretics
58
Complication of rapid correction of hypernatraeia
cerebral oedema
59
Mx of
hypernatremia
hypovolemia
hypernatremia- 5% dextrose
hypovolemia - 0.9% saline
serum Na + measurements every 4-6h
60
What are the effects of diabetes mellitus on serum sodium?
Variable
Hyperglycaemia draws water out of the cells leading to hyponatraemia
Osmotic diuresis in uncontrolled diabetes leads to loss of water and hypernatraemia
61
How do we calculate corrected serum calcium and why is it useful?
corrected ca = Serum Ca + 0.02 x (40- serum albumin (g/l))
example:
○ Albumin = 30, total Ca = 2.2 mM
○ corrected ca = 2.2 + 0.2 x 10 = 2.4 mM
○ Corrected ca shows if the problem is albumin
○ If albumin is 40 (normal value), then the total serum calcium = corrected calcium
○ Therefore if corrected calcium is different than total serum calcium, the problem is the albumin and that the ionised calcium will also be normal
62
PTH absorbs Ca from 3 sources
○ Bone
○ Gut - absorption (indirect – PTH activates 1α hydroxylate in the kidney 🡪 production of calcitriol (1,25 OH vitamin D) 🡪 calcitriol promotes Ca absorption through the gut)
○ Kidney - reabsorption + activation of 1α hydroxylase
63
PTH effect on kidney
○ Increased Ca2+ resorption
○ Increased phosphate excretion
○ Stimulation of synthesis of 1α hydroxylase
64
1,25 hydroxycholecacliferol effect on
small intestine
kidneys
bone
● Small intestine
○ Ca absorption
○ Phosphate absorption
● Kidneys
○ Increases Ca absorption
● Bone - minor effect, stimulates osteoblasts (critical for bone formation)
65
Vitamin D3
inactive, stored, measured form
physiologically active form
inactive, stored, measured form
● 25 (OH) D3
physiologically active form
● 1,25 (OH)2 D3
66
Precursor of cholecalciferol
UBV: 7-dehydrocholesterol → cholecalciferol (vitamin D3)
therefore vitamin D3 is synthesised in the skin
67
Rate limiting step of vit D3 activation
1a hydroxylase
activated by PTH
68
seasonal hypercalcaemia
feature of sarcoid - sarcoid tissue can sometimes express 1a hydroxylase
● in sunlight → more vitamin D activation → Calcium goes up
69
PTH in pregnancy
Low
● Placenta + Breast milk make PTHrP → baby steals calcium from mother to build his skeleton
70
What is FHH/FBH
● Familial hypocalciuric/benign hypercalcaemia (FHH/FBH)
○ CaSR mutation - sensors do not recognize the high calcium
○ High calcium
○ High set point for PTH release suppression → mild hypercalcaemia
○ Reduced urine Ca2+
○ DDx: Primary HPT
71
Commonest cause of hypercalcaemia
Primary hyperparathyroidism
parathyroid adenoma> parathyroid hyperplasia > parathyroid carcinoma
high Ca
High urinary Ca
High/N PTH
Low PO43-
72
Ca and phosphate in secondary hyperparathyroidism
Low/N ca
| High PO43-
73
DEXA scan values
○ Measures bone density
○ Hip (NOF etc) + Lumbar spine
○ T-score - SD from mean of young healthy population (useful to determine # risk)
○ Z-score - SD from mean of aged-matched control (useful to identify accelerated bone loss in younger patients)
○ Osteoporosis = T-score T > -2.5 (between -1 and -2.5)
osteopenia is the stage before osteoporosis)
74
Osteoporosis mx
```
Tx
Lifestyle
● weight-bearing exericse
● stop smoking
● reduce EtOH
```
Drugs
● Vitamin D/Ca
● Alendronate (bisphosphonate)
○ Decrease bone resorption
○ osteonecrosis of the jaw
● Teriparatide
○ PTH derivative
○ Anabolic
● Strontium
○ anti-resorptive
○ Anabolic
● Oestrogens
○ HRT
● Raloxifene
○ SERMs
○ (oestrogen like drugs)
● Denosumab
○ Biologic anti-RANK-L antibody
75
Osteomalacia in adults findings
Low [Ca]
Low [PO43-]
High [ALP]
```
Mature skeleton
Looser’s zones
Codfish vertebrae
Bending deformities
Osteopenia
```
76
Osteomalacia in adults findings
```
Low [25-OH cholecalciferol]
Low [Ca]
Low [PO43-]
High [ALP]
High [PTH]
High urine phosphate
```
Bowed legs (rickets)
Costochondral swelling (rickety rosary)
Widened epiphyses at the wrists
Myopathy
77
Pagets disease findings
Normal [Ca]
Normal [PO43-]
High [ALP]
```
Focal pain
Warmth - increased vascularisation
Bone Deformity
great thickening of the bones of the skull with demineralisation
Fracture (spontaneous)
Arthritis
Cardiac failure
Spinal cord compression (blindness, deafness)
```
78
Pagets disease ix and management
Nuclear med scan scan
Bisphosphonates for pain
79
```
Which has the lowest calcium?
Primary hyperparathyroidism
Secondary hyperparathyroidism
Osteoporosis
Pagets disease of the bone
Breast cancer
```
Secondary hyperparathyroidism
80
renal osteodystrophy findings
Low [Ca2+]
High [PO43-]
High [ALP]
Consequence of CKD
Due to secondary hyperparathyroidism + aluminium retention from dialysis fluid
```
Increased bone resorption (osteitis fibrosa cystica)
Osteomalacia
Osteoporosis
Osteosclerosis
Growth retardation
```
Subperiosteal bone erosions
Brown tumours
Sclerosis – axial skeleton/vertebral end plates giving a rugger jersey spine
Soft tissue calcification (arteries/cartilage)
81
Hypercalcaemia of malignancy biochemistry
High [Ca]
High [PO43-]
High [ALP]
Low [PTH] - appropriate
82
What causes osteitis fibrosa cystica?
Secondary hyperparathyroidism
83
What kind of hyperparathyroidism is
parathyroid bone disease
renal bone disease
Parathyroid bone disease – primary PTH
| Renal bone disease – secondary PTH
84
What is a risk of CKD causing secondary hyperparathyroidism?
can progress to tertiary hyperparathyroidism where there is autonomous PTH secretion despite normal Ca levels
Initial chronic low plasma [Ca], parathyroid gland stimulated for a long time PTH becomes autonomous, stops responding to –ve feedback (similar primary hyperparathyroidism)
85
Calcium in osteoporosis will be
Normal
86
Which is the most abundant intracellular ion
K+
87
Angiotensinogen (in the liver) --> angiotensin I
```
by renin (from JGA)
in the liver
```
88
Angiotensin I --> Angiotensin II
```
by ACE (from lungs)
in the lungs
```
stimulates release of aldosterone from adrenal glands
89
Triggers for renin release
Low BP
| Low Na+ in the macula densa by JGA
90
Triggers for aldosterone release
Angiotensin II
| High K+
91
Where does aldosterone act?
on the cortical collecting tubule cells
92
How does aldosterone work
Increases number of Na channels on luminal membrane
Increases sodium resorption
This makes the lumen electronegative + creates an electrical gradient
K+ is secreted into the lumen
93
Na + K channel names
ENaC (Epithelial sodium channels) - Na resorption
ROMK (renal outer medullary potassium) - K excretion
94
How does aldosterone increase the number of Na channels on luminal membrane
Though Nedd4*
Binds on the MR receptor
upregulated sgk-1
Nedd 4 phosphorylation + inhibition --> decreased degradation of sodium channels
*Nedd4 usually degrades Na channels
95
How does acidosis affect K+ levels?
Causes hyperkalaemia
96
Medications that cause hyperkalaemia
ACEi
ARBs
Spironolactone
NSAIDs (block renin)
97
In general, what causes hyperkalaemia
Anything that opposes the action of aldosterone
Reduced GFR
Reduced renin (T4TA (diabetic nephropathy), NSAIDs)
ACEi
ARB
Addison's disease
Aldosterone antagonists e.g. K+ sparring diuretics
K+ release from cells - rhabdomyolysis, acidosis, insulin shortage in DKA
98
Hyperkalaemia mx
10ml 10% calcium gluconate
50ml 50% dextrose + 10 IU insulin
Nebulised salbutamol
Treat underlying cause
99
How do diuretics affect potassium?
Cause hypokalaemia
o Triple or co-transporter is blocked less Na+ absorbed in the ascending LoH more goes to the distal nephron/DCT
Loop diuretics (furosemide) block triple transporter Na+/K+/Cl- in the AL of the LoH
• Bartter syndrome is a mutation in this channel
Thiazide diuretics (Bendroflumethiazide) block co-transporter Na+/Cl- in the DCT
• Gitelman syndrome is a mutation in this channel
o More Na+ reaches + is absorbed in the DCT more electronegative nephron
o loss of K+ down the electrochemical gradient through ROMK channels in the cortical collecting tubule cells
100
2 diuretics that cause hypokalaemia
```
Thiazide diuretics (block Na/Cl co transporter)
Loop diuretics (block Na/K/Cl transporter)
```
101
Which electrolyte abnormality can cause hypokalaemia
Hypomagnesaemia
102
Hypokalaemia + acid-base balance
• Hypokalaemia causes metabolic alkalosis
o Hypokalaemia shift of H+ into cells in exchange for K+ (H+/K+ anti-transporter) metabolic alkalosis
• Metabolic alkalosis causes hypokalaemia
o Alkalosis shift of K+ into cells in exchange for H+ (H+/K+ anti-transporter) hypokalaemia
103
What can cause nephrogenic DI?
Hypokalaemia
| Hypercalcaemia
104
Hypokalaemia mx
[K+] = 3.0-3.5 mmol/L
Oral KCl 2 SandK tablets, TDS, 48h
Recheck K+
o [K+] = <3.0mmol/L
IV KCl
Max rate – 10mmol/h
• If rate >20mmol/h irritate peripheral veins, risk of arrhythmia
105
renal tubular acidosis and potassium
T4 - hyperkalaemia
T1, T2 - hypokalaemia
106
Hyponatraemia mx
* Hypovolemic hyponatremia volume replacement with 0.9% saline + treat cause
* Euvolemic hyponatremia fluid restrict (500-750ml/day + Abx infusions) + treat underlying cause
* Hypervolemic hyponatremia fluid restrict (500-750ml/day + Abx infusions) + treat underlying cause, consider adding loop diuretic or spironolactone
* Severe hyponatremia (lowGCS, seizures) seek extra help + hypertonic 3% saline
107
Causes of hyperkalaemia
Renal impairment > drugs > Addison’s > release from cells
108
• Persistent HTN despite maximal HTN control ix
aldosterone: renin ratio (? Conn’s)
109
Hyponatraemia + hypokalaemia
| Hyperkalaemia + hypernatremia
Hyponatraemia + hypokalaemia – furosemide
| Hyperkalaemia + hypernatremia – DKA (insulin deficiency hyperkalaemia, loss of water hypernatremia)
110
Which hormones are released by TRH stimulation
TSH
Prolactin
Since TRH stimulates prolactin release: Primary Hypothyroidism Hyperprolactinaemia
111
Prolactin
6000
600-6000
6000 prolactinoma
600-6000 non functioning pituitary adenoma
112
What is the combined pituitary function test and what is it being used for
Insulin + TRH + GnRH/LHRH
used to ix anterior pituitary function + to see if the pituitary gland responds adequately to metabolic stress
indications
hypopituitarism
prolactinoma
Insulin
Increase in GHRH --> Increase in GH
Increase in CRT --> increase in ACTH --> increase in cortisol
TRH
Increase in TSH + T4
(hyperthyroidism - TSH remains suppressed, hypothyroidism - exaggerated response)
Increase in prolactin
GnRH
Increase in LH + FSH
113
How low should the glucose go in CPFT?
Ensure adequate hypoglycaemia (<2.2 mM)
if severe hypoglycaemia (<1.5mm) patient will get aggressive --> 50ml 20% glucose
114
What do you measure during CPFT
Glucose
Cortisol
GH
TSH
T4
Prolactin
LH
FSH
every 30 mins
Response
everything >10
cortisol >550
115
Hormone replacement order of urgency
Hydrocortisone
Thyroxine
Oestrogen
GH
+ give cabergoline or bromocriptine --> reduce prolactin
116
Acromegaly tests
IGF-1
Produced in the liver in response to GH
OGTT
GH should fall with glucose administration
GH not used as pulsatile
117
Acromegaly mx
1. Transphenoidal surgery
2. Radiotherapy
3. Cabergoline
4. Somatostatin analogue (octreotide)
cabergoline bc GH often co-secreted with prolactin
118
What can cause nephrogenic DI
Lithium
Hypercalcaemia
Renal failure
119
Osmolality equation
2(Na+K) + U + glucose
mosm/kg
Normal osmolality = 275-295 mosm/kg
120
Anion gap equation
Na+ K - Cl - HCO3
Normal anion gap = 16-20
121
* Marker of glucose control over last 3 weeks –
| * Marker of glucose over the last 3 months
* Marker of glucose control over last 3 weeks – fructosamine (esp. useful in pregnant women)
* Marker of glucose over the last 3 months – HbA1c
122
Osmolar gap
Measured osmolarity - calculated osmolarity
123
DKA vs HHS (hyperglycaemia hyperosmolar state)
pH
osmolarity
DKA ph <7.3
HHS ph >7.3
osmolarity
HHS > DKA
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What can metformin overdose lead to
Lactic acidosis
Metabolic acidosis
* The metabolic pathway by which lactate is produced by anaerobic glycolysis in the muscles
* Lactate moves to the liver to be converted to glucose
* Glucose returns to the muscle to be metabolised to lactate
• Metformin
o Inhibits lactate conversion to glucose in the liver
o Can cause lactic acidosis because it inhibits hepatic gluconeogenesis
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Causes of high anion gap
Methanol
Ethanol
Lactate
Ketones
Metformin excess/ OD
Normal anion gap = 16-20
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Diabetes drugs that cause hypoglycaemia
Sulfonylureas - gliclazide, glibenclamide
| Insulin
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Diabetes drugs that cause weight gain
Sulfonylureas - gliclazide, glibenclamide
Thiazolidinedione/Glitazones (pioglitazone)
Insulin
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Diabetes drugs that cause weight loss
SGLT2 inhibitor - empagliflozin
GLP-1 agonist - exenatide, liraglutide
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Diabetes drugs that dont change the weight
DDP4 inhibitor - gliptins (sitaglipin, vildagliptin)
| Metformin (biguanide)
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Blood drainage from the adrenal gland
o Left drains to left renal vein
| o Right drains to IVC
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What is Schmidt's syndrome?
Polyglandular autoimmune syndrome type II
Addison's disease + Hypothyroidism
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Commonest cause of Addison's disease
in the UK
Worldwide
UK - Autoimmune
Worldwide - TB
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What kind of tumour is phaeochromocytoma?
Adrenal medullary tumour
Secretes adrenaline
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Where are the tumours in Conn's syndrome and Cushing's syndrome found?
Conn's - tumour in granulosa secreting aldosterone
Cushing's - tumour in fasciculata secreting cortisol
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Why does cortisol act like aldosterone at high concentrations?
* At high concentrations, cortisol activates the mineralocorticoid receptors
* 11b-hydroxysteroid dehydrogenase usually degrades cortisol to stop this happening but at a high concentration the enzyme is overwhelmed HTN
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Two commonest causes of Cushing's syndrome
Iatrogenic (1)
Pituitary tumour (2) = Cushing's disease
then adrenal adenoma (zona fasciculata) (3)
then ectopic ACTH (4)
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Next steps after a positive low dose dexamethasone test
IPSS (inferior petrosal sinus sampling) with CRH stimulation
IPSS has made he HDDST redundant and it is therefore no longer performed
IPSS
Distinguishing from ectopic ACTH
Catheterise the pituitary veins
Measure prolactin to prove you’re in the pituitary
Measure ACTH every week
ACTH levels are sampled every week from the veins that drain the pituitary gland
These levels are then compared with the ACTH levels in the peripheral blood to determine whether a pituitary tumour as opposed to an ectopic source of ACTH is responsible for ACTH-dependent Cushing syndrome
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If the high dose dexamethasone suppression test was still being carried out what would it show
If cortisol was suppressed with a higher dose of dexamethasone, then the cause of Cushing’s syndrome was pituitary dependent Cushing’s disease
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OGTT – used to investigate 2 conditions
DM (2 samples), acromegaly (5 samples, GH is suppressed by glucose)
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Ectopic ACTH managment
Ketoconazole --> inhibits 17a hydroxylase activity => reduces cortisol production
Metyrapone --> inhibits 11b hydroxylase
Mifepristone --> glucocorticoid receptor antagonist
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What is Nelson's syndrome?
Hypopituitarism + pigmentation after an adrenalectomy
Removal of adrenal leads to pituitary enlargement (stalk becomes compressed --> hypopituitarism) + increased ACTH release (pigmentation)
