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PathY5 > Lipoprotein metabolism, cardiovascular disease and obesity > Flashcards

Lipoprotein metabolism, cardiovascular disease and obesity Flashcards

1
Q

What is in an atherosclerotic plaque?

A

> Fibrous cap
Foam cells
Necrotic core with cholesterol crystals (from macrophage death and enzyme release)

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2
Q

What transports cholesterol in fasting plasma (with%)?

A

> Chylomicrons <5% (biggest)
VLDL 13%
LDL 70%
HDL 17% (smallest)

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3
Q

How is cholesterol released from peripheral cells?

A

Cholesterol efflux (ABC A1 protein) via fatty acids

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4
Q

How is cholesterol transported to the liver in the blood?

A

SR B1 - HDL receptor on the liver- efflux of cholesterol from peripheries to liver

CETP - Cholesterol ester transport protein moves cholesterol esters and TGs between VLDL, LDL and HDL (this receptor can promote disease development by reducing HDL levels)

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5
Q

How is cholesterol metabolised in the liver?

A

Cholesterol is converted to CE using ACAT

MTP transfers lipids (incl. TG and CE) into ApoB containing lipoproteins (uncl. VLDL)

VLDLs can be broken down in the plasma to LDLs and stimulate the LDL receptor

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6
Q

How does cholesterol from diet and Bile get absorbed in the liver?

A

Jejunum: NPC1L1, - for transfer of cholesterol to liver for EHC
ABC G5/G8 transfers cholesterol back into the lumen
It is a balance between these molecules

ACAT causes esterification

Ileum: BAT transfer bile acids for EHC

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7
Q

What transports TG in fasting plasma (with%)?

A

Chylomicrons <5%
VLDL 55%
LDL 29%
HDL 11%

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8
Q

What are lipoproteins in order of denstiy?

A

Chylomicron < FFA < VLDL < LDL < IDL < HDL

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9
Q

What is PCSK9?

A

> Binds LDLR and promotes its degradation

> Loss of function mutation of PCSK9 -> low LDL
levels

> Novel form of LDL-lowering therapy is AntiPCSK9 MAb

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10
Q

Which lipoprotein is a CVD risk factor?

What is the treatment?

A

Lipoprotein(a) is a CVD RF

Tx: Nicotinic acid

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11
Q

What would you consider dyslipidaemia?

A

Hypercholesterolaemia
Hypertriglyceridaemia
Mixed hyperlipidaemia
Hypolipidaemia

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12
Q

Which diseases are considered primary hypercholesterolaemia and what are their mutations?

A
  1. Familial hypercholesteraemia
    (type II)
    > AutoDom: LDLR, apoB, PCSK9
    > AutoRec: LDLRAP1
  2. Polygenic hypercholesteraemia
    > Several polymorphisms
    > incl. NPC1L1, HMGCR, CYP7A1
  3. Familial hyperα-lipoproteinaemia (high HDL)
    > CETP deficiency
  4. Phytosterolaemia
    > ABC G5 & G8 (prevent absorption of non sterols- premature atherosclerosis)
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13
Q

What are the signs of high cholesterol?

A

> xanthelasma and tendon xanthomata
Corneal arcus
Atheromous disease

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14
Q

What are the types of primary hypertriglyceridaemia?

A

> Familial type I: lipoprotein lipase or apoC II deficiency​

> Familial type IV: Increased synthesis of TG​
? Cause​

> Familial type V: sometimes due to apoA V deficiency

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15
Q

What are the types of primary hypertriglyceridaemia and their causes?

A

> Familial type I: lipoprotein lipase or apoC II deficiency​

> Familial type IV: Increased synthesis of TG ? Cause​

> Familial type V: sometimes due to apoA V deficiency

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16
Q

What are the types of primary mixed hyperlipidaemia?

A

Familial Combined hyperlipidaemia

Familial dysβlipoproteinaemia (type III) - elbow xanthoma and shiny palmar crease

Familial hepatic lipase deficiency

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17
Q

What are the types and causes of Hypolipidaemia?

A

> Aβ-lipoproteinaemia: MTP def

> Hypoβ-lipoproteinaemia: Truncated apoB protein

> Tangier Disease: HDL def (ABC AI mutations)

> Hypoα-lipoproteinaemia: apoA-I mutations (sometimes)

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18
Q

What are the causes of secondary hyperlipidaemia?

A

Hormonal factors (e.g. pregnancy, hypothyroid)

Metabolic disorders (e.g. diabetes, obesity, gout)

Renal dysfunction (e.g. nephrotic syndrome and chronic renal failure)

Obstructive liver disease (like PBC)

Toxins

Iatrogenic

Hypothyroidism

Misc.

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19
Q

What relationship does serum cholesterol have to CHD?

A

Positively correlated

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20
Q

How are Total Chol: HDL ratios related to CHD?

A

Positively (increased HDL decreases CHD risk)

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21
Q

How are TGs related to CHD?

A

Positively

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22
Q

What is the management of hyperlipidaemia?

A

> First line is always conservative – dietary
modification and exercise [although dietary
intake of cholesterol correlates poorly with
actual triglyceride levels]

> Statin therapy
> HMG-CoA reductase inhibitor
> Reduces intrinsic synthesis of cholesterol in the liver
> Side effects – myopathy/rhabdomyolysis, fatigue

> Other agents more rarely used include Ezetimibe

23
Q

How do you manage obesity?

A

> Conservative measures

> Medical- No medication has been safely proven to provide sustained weight loss

> > Orlistat (A gut lipase inhibitor) is used however side effects of profound flatus and diarrhoea are often too cumbersome for patients to tolerate
Rimonabant (a cannabinoid antagonist) was trialled and
discontinued from use as there was an increased risk of adverse events in the form of suicide

> Surgical
> Bariatric surgery is indicated in patients with a BMI >40 or >35 with a comorbidity associated with obesity
> To be considered requires extensive screening and must commit to long term follow up usually.

24
Q

What are the risks and benefits of bariatric surgery?

A

Benefits:
Success = > 50% ↓ in excess weight (i.e. actual – ideal)​

Diabetes ↓ 72%​

Serum triglyceride ↓ 50-60%​
HDL cholesterol ↑13-47%​

Fatty liver ↓​

Hypertension ↓​

Risks:
Post-op mortality 0.1-2%

25
Q

What are the types of bariatric surgery?

A

Gastric Banding
Roux en Y
Biliopancreatic diversion

26
Q

What are some novel therapies to control cholesterol?

A

LDL lowering:
> MTP inhibitor (lomitapide)
> Anti PCSK 9 monoclonal antibody (REGN727)
> Anti sense apoB oligonucelotide (mipomersen)

HDL based:
> Apolipoprotein A1 mimetic infusion therapy
> CETP inhibitors

27
Q

How can we use Lp(a) in CVD?

A

> 1 x Lp(a) measurement, using isoform-insensitive assay, for intermediate or high CVD/CHD risk, incl. FH or statin resistant young CVD

> A desirable level of Lp(a) is <500 mg/L. Treatment should primarily be nicotinic acid 1–3 g/day. In refractory cases, weekly LDL-apheresis is effective in removing Lp(a).

28
Q

Does cholesterol downregulate HMG CoA reductase?

A

Yes, when it is transported into the liver it downregulates HMG CoA Reductase which reduces cholesterol synthesis

29
Q

What happens to cholesterol when it is made or deposited in the liver (2)?

A
  1. It is hydrolysed using 7 alpha hydroxylase into bile acids (into bile duct)
  2. Esterification with ACAT, then ApoB and TG to make VLDL - MTP is important in making VLDL
30
Q

What happens to VLDL?

A

VLDL -> LDL which is taken up by LDLr after 3-4 days

31
Q

What happens to HDL?

A

Picks up excess cholesterol using ABC A1 and brings to liver

32
Q

What does CETP do?

A

Cholesterol ester transfer protein mediates the movement of CE from HDL to VLDL and of TG from VLDL to HDL

33
Q

What does SRB1 do?

A

Takes up cholesterol ester

34
Q

What is the main source of TG?

A

Small intestine from diet - transported via chylomicrons into plasma which is hydrolysed by the capillary enzyme lipoprotein lipase which are partly taken up by liver and adipose - liver moves TG in VLDL

35
Q

What is the biggest problem with homozygous FH?

A

Aortic root atheroma

36
Q

What does PCSK9 do?

A

Function is to bind to LDL receptor and promote its degradation.

37
Q

What is the association of PCSK9 and FH?

A

Rarely FH is caused by dominantly-inherited gain of function mutations of PCSK9, which increase rate of degradation of LDL receptors.

Loss of function mutations of PCSK9 are associated with low LDL levels.

38
Q

What are the common bariatric procedures?

A

Gastric banding
Roux en Y
Biliopancreatic diversion

39
Q

What drugs can you add if someone with high CVD risk (previous MI) and hypertension if BP is not controlled by beta blocker alone?

A

Thiazide diuretics
Amlodipine

Don’t do nothing- keeping BP down decreases risk (if SBP>130)

40
Q

Are thiazides cheap?

A

Both cheap AND effective

41
Q

Post MI what is optimal medical therapy?

A

Lifestyle modification and education (smoking, diet, alcohol)

Aspirin
High dose statin (40-80mg OD)
BP control - thiazide

Assessment for diabetes

42
Q

What are the options for statin intolerant patients?

A

Ezetimibe
Plasma exchange
Evolocumab (PCSK9 monoclonal Ab)

43
Q

How do PCSK9 inhibitors work?

A

PCSK9 sits on LDLr and affects how LDLr is recycled

Adding an inhibitor reduces LDL in blood

44
Q

How long does it take for glucose control to make a difference?

A

15 years (UKPDS)

45
Q

Is it better to have tight control early on?

A

Tight control early on has long term benefits (legacy benefits)

46
Q

What did the Accord study show?

A

Intensive therapy dropped HbA1c more than standard therapy but death was higher in intensive therapy group

Intensive therapy increases mortality

47
Q

DCCT study

A

T1DM good control improves outcome

48
Q

UKPDS study

A

New T2DM put onto good control

Legacy Affect

49
Q

Accord study

A

Unexpected death with intense control in older people

50
Q

Is empagliflozin good?

A

Yes- HbA1c falls, BP falls, Weight falls, reduces albuminuria and loss in kidneys

Reduced death within 6 months

51
Q

Name some GLP-1 agonists

A

Exanatide
Liragutide (Saxenda)
Semaglutide

52
Q

SGLT2inh > DPP4 inh

A

SGLT2inh > DPP4 inh

53
Q

What is an odd requirement for GLP-1 agonists?

A

Those who meet a certain BMI boundary

54
Q

What did advance show?

A

Small improvement (vs Accord)

PathY5 (98 decks)

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