ChemPath Flashcards
What are atherosclerotic plaques made up of?
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
• Lipoproteins in order of density:
Chylomicron < FFA < VLDL < IDL < LDL
main carrier of cholesterol in the fasted state
main carrier of TG in the fasted state
HDL carries cholesterol from
LDL
carries cholesterol from liver to periphery / bad cholesterol
VLDL
HLD - the periphery to the liver / good cholesterol
Transporter of cholesterol
across intestinal border
back into the lumen of the intestine
NPC1L1
ABCG5
ABCG8
enzyme involved in hydrolysis of cholesterol to bile acids
7a hydroxylase
enzyme involved in cholesterol esterification
ACAT (cholesterol acetyltransferase)
What does VLDL consist of
cholesterol ester
apoB
TG
transfer protein MTP is very important in this packaging process]
function of CEPT (cholesteryl ester transfer protein)
- Mediates movement of cholesterol ester from HDL VLDL/LDL
- Mediates movement of TG from VLDL/LDL HDL
Which protein mediates movement of free cholesterol from peripheral cells to HDL?
ABCA1
Biggest to smallest lipoproteins
chylomicrons
VLDL
LDL
HDL
Triglyceride transport + metabolism
• 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
What is phytosterolaemia
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
What is familial hyperalpha liporoteinaemia
Inherited increases in HDL
Associated with longeivity
Mode of inheritance of familial hypercholesterolaemia
AD
50% expression in heterozygous
100% expression in homozygous
describe the function of the PCSK9 mutation in familial hypercholesterolaemia
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
Describe the 3 types of primary hypertriglyceridemia/ hyperlipidaemia
• 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
Simple test to differentiate between type I and type IV hyperlipidaemia
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)
Presentation of familial combined hyperlipidaemia
o In a family some people with high cholesterol + some people with high triglycerides
Presentation of Familial dysβlipoproteinaemia (type III hyperlipoproteinemia)
o ApoE2 polymorphism – presence of ApoE 2/2 in homozygous form
o Diagnostic sign = yellow palmar crease, eruptive xanthomas on elbow
What is Tangier disease
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
Ab lipoproteinaemia mutation
o Low levels of cholesterol (particularly VLDL, LDL)
o Recessive: therefore parents will have normal lipid levels
o AR
MOA of
statin
fibrates (e.g. gemfibrozil)
ezetimibe
cholestyramine
• 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
Novel forms of LDL-lowering therapy
• 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
Which procedures reduce the HbA1c the most?
Biliopancreatic division > gastric bypass > medical therapy
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
What can you add in the medications of patients to bring their BP down to normal?
Thiazide diuretic
• 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
• Statin-intolerant patients mx
o Ezetimibe ( absorption – block NPC1L1) o Evolocumab (PCSK9 monoclonal antibody) – inhibits the action of PCSK9 o Plasma exchange
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
What did the DCCT study show?
DCCT - T1DM, good control improves outcome
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
What did the accord study show?
o Sudden aggressive glucose control can increase mortality arrhythmia, tachycardia, sudden onset VF (?hypoglycaemia properly) death
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
Empagliflozin - summary of actions
o Summary: bring down HbA1c, protect kidneys/renal failure, treat HF
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
DDP4 inhibitors
DDP4 break down GLP-1
DDP4 inhibitors = gliptins
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
• 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
Acarbose MOA
Acarbose MOA
• Inhibits α-glucosidase at the bowel wall prevention of glucose absorption
• Undigested sugar flatulence
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
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
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)
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
Stimuli for ADH secretion
o Raised serum osmolality – hypothalamic osmoreceptors ADH release + thirst
o Low BP/volume – baroreceptors in carotids, atria, aorta ADH release
ADH vs Aldosterone
ADH only resorbs water not sodium Hyponatraemia
Aldosterone reabsorbs both salt/Na and water
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
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)
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
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
Causes of hyponatraemia in a hypervolaemic patient
HF
Cirrhosis
Renal failure
Volume status
Plasma osmolality
urine osmolarity in SIADH
Euvolemic
low plasma osmolality
high urine osmolarity
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
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
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
What kind of hypernatraemia does diabetes insipidus cause?
Hypovolaemic hypernatraemia
Patient is clinically euvolemic
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
