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CHEM PATH - Abbie > 2. Update on lipoprotein metabolism, cardiovascular disease and obesity > Flashcards

2. Update on lipoprotein metabolism, cardiovascular disease and obesity Flashcards

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1
Q

Features of atherosclerotic lesions:

A

Fibrous cap, foam cells, necrotic core

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2
Q

What are foam cells?

A

Macrophages full of cholesteryl ester. When seen histologically the organic solvent leaks out of the foam cells and leaves little holes.

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3
Q

What is a necrotic core?

A

Full of cholesterol crystals which become deposited after macrophages die and release enzymes that hydrolyse the cholesteryl ester and convert them into free cholesterol which then crystallises.

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4
Q

What are the different lipoproteins that transport cholesterol in fasting plasma?

A

Chylomicrons (largest) -> <5% (high in TGs)
VLDL -> 13% (high in TGs)
LDL -> 70% (main carrier of cholesterol)
HDL (smallest, vary in size 1 to 3) -> 17%

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5
Q

Are chylomicrons low or high in the fasted state?

A

low

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6
Q

What are sources of cholesterol?

A

Diet and bile

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7
Q

Once absorbed, cholesterol is then …

A

solubulised in mixed micelles and transported across the intestinal brush border by NPC1L1 proteins (jejunum)

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8
Q

What is the main determinant of cholesterol entering the lymphatics and the liver?

A

Cholesterol solubilised in mixed micelles transported across the intestinal brush order by NPC1L1 proteins (jejunum)

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9
Q

How is cholesterol transported back into intestinal lumen?

A

ABC G5 and G8

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10
Q

How are bile acids absorbed?

A

in the ileum via BAT (brown adipose tissue?)

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11
Q

What does cholesterol downregulate in the liver?

A

HMG CoA reductase

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12
Q

The amount of cholesterol synthesised is dependent on …

A

the amount being absorbed by the liver

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13
Q

What is cholesterol synthesised from?

A

Acetate and mevalonic acid

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14
Q

What are the 2 fates of cholesterol absorbed from the gut or synthesised in the liver?

A

Hydrolysis by 7a-OHxylase or esterified by ACAT

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15
Q

What happens when cholesterol is hydrolysed?

A

Cholesterol is hydrolysed by 7a-OHxylas to form bile acids which enter the bile duct

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16
Q

What happens when cholesterol is esterified?

A

Cholesterol is esterified by ACAT which together wuth TG and apoB is incorporated into VLDL via MTP which is important in the packaging process.

VLDL is the main precursor of LDL. LDL after circulating in the plasma for 3-4 days is taken up into the liver by LDL receptor.

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17
Q

HDL collects cholesterol from the periphery via …

A

ABC A1 which mediates movement from peripheral cells to HDL

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18
Q

Where does LDL transport cholesterol to?

A

To the periphery in places that have the LDL receptor other than the liver

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19
Q

What mediates the movement of cholesterol ester (CE) from HDL to VLDL and movement of TG from VLDL to HDL?

A

CETP

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20
Q

What is taken up by the liver via SR-B1 receptor?

A

HDL

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21
Q

What are the 3 major components of cholesterol metabolism?

A

Intestines, liver, plasma

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22
Q

What are triglycerides in fasting plasma transported by?

A

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

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23
Q

What is the major source of exogenous TG?

A

Diet e.g. fatty foods.

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24
Q

How is triglyceride transported and metabolised?

A

They are hydrolysed into fatty acids and re-synthesised into TGs and transported via chylomicrons into plasma. Chylomicrons are hydrolysed by capillary enzyme lipoprotein lipase into free fatty acids. FFAs are taken up by the liver and adipose tissue. The liver resynthesises into endogenous TGs and re-exports as VLDL which is then hydrolysed by lipoprotein lipase.

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25
Q

What are different types of dyslipidaemia?

A

Primary hypercholesterolaemia, polygenic hypercholesterolaemia, familial hyper-a-lipoproteinaemia, phytosterolaemia.

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26
Q

What are different types of hypertriglyceridaemia?

A

Primary hypertrigylceridaemia

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27
Q

What are different types of mixed hyperlipidaemia?

A

Primary mixed hyperlipidaemia, secondary hyperlipidaemia, renal dysfunction, obstructive liver disease, toxins, iatrogenic, miscellaneous causes.

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28
Q

What are different types of hypolipidaemia?

A

Aβ lipoproteinaemia, hypo-β-lipoproteinaemia, Tangier disease, hypo-α-lipoproteinaemia

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29
Q

What mutations are linked to primary hypercholesterolaemia?

A

LDL receptor, apoB, PCSK9 genes

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30
Q

In familial hypercholesterolaemia (FH - type II), a type of primary hypercholesterolaemia, what is the cause?

A

Dominant mutation of LDL receptor

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31
Q

How does LDL work and how can it give rise to familial hypercholesterolaemia?

A

LDL travels in the plasma. There are LDL receptors in the periphery and surface of the liver within coated pits. LDL binds to receptors in the pit and is subsequently endocytosed into the liver and taken to lysosomes for further processing. here are >1000 mutations in the LDL receptor gene each one of which can give rise to FH. The severity of the disorder depends on the part of the receptor mutated and the size of the mutatuons

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32
Q

How common is homozygous FH?

A

Very uncommon, 1 x 10^6, can see corneal arcus in young children

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33
Q

How common is heterozygous FH? What are the signs?

A

More common, 1 in 500, can see corneal arcus and xanthalasma around eyes, tendon xanthoma are all tell-tale signs. NOTE in a CV exam feel back of Achilles tendon.

34
Q

What happens in mutations of PCSK9 and how does that cause primary hypercholesterolaemia?

A

Function is to bind to LDL receptor and promote its degradation. Rarely, FH is caused by dominantly inheriting gain of function mutations in PCSK9 which would increase the rate of degradation of LDLr -> therefore high circulating LDL. Loss of function mutations of PCSK9 are associayed wit low LDL levels

35
Q

True or false - primary hypercholesterolaemia is rarely autosomal recessive inheritance (LDLRAP1)

A

True

36
Q

What is polygenic hypercholesteraemia?

A

Multiple locci including NPC1L1, HMGCR, CYP7A1 polymorphisms each with a small effect giving a large combined effect

37
Q

What is familial hyper-α-lipoproteinaemia?

A

There is an increase in HDL - relatively benign presentation in terms of CV disease. Sometimes associated with CETP deficiency.

38
Q

What is phytosterolaemia?

A

It is caused by mutations of ABC G5 and g8 (gate keepers). Plant sterols can enter the plasma and there is a premature risk of atherosclerosis. Plant sterols are as if not more atherogenic as cholesterol itself.

39
Q

What is hypertriglyceridaemia?

A

Familial type I - caused by ddeficiency in lipoprotein lipase that degrades chylomicrons of apoC II. In standing blood, chylomicrons float to the top. Patients may have eruptive xanthomas on skin (pustules/papules)

Familial type IV caused by increased synthesis of TG. No chylomicrons floating to the top, just VLDL separates.

Familial type V sometimes caused by apoA V deficiency. VLDL and chylomicrons above on standin blood.

40
Q

What are the familial types I-V

A

Familial type I - caused by ddeficiency in lipoprotein lipase that degrades chylomicrons of apoC II. In standing blood, chylomicrons float to the top. Patients may have eruptive xanthomas on skin (pustules/papules)

Familial type II - Dominant mutation of LDL receptor

Familial type III - uncommon, caused by aberrant ApoE 2/2. Signs include yellow palmar crease (palmar striae is pathognomonic) and eruptive xanthomas on elbow.

Familial type IV caused by increased synthesis of TG. No chylomicrons floating to the top, just VLDL separates.

Familial type V sometimes caused by apoA V deficiency. VLDL and chylomicrons above on standin blood.

41
Q

What are the different types of primary mixed hyperlipidaemia?

A
  1. Familial combined hyperlipidaemia – cause unknown
  2. Familial hepatic lipase deficiency
  3. Familial dys-β-lipoproetinaemia (type III) –
42
Q

What is familial dys-β-lipoproetinaemia (type III) caused by?

A

Caused by aberrant ApoE 2/2.

43
Q

What are signs of familial dys-β-lipoproetinaemia (type III)?

A

Yellow palmar crease (palmar striae is pathognomonic) and eruptive xanthomas on elbow

44
Q

What is the ApoE in patients who are normal, have familial dys-β-lipoproetinaemia (type III), and have Alzheimer’s disease?

A

Normal = ApoE 3/3
Familial dys-β-lipoproetinaemia (type III) = ApoE 2/2
Alzhemiers disease = ApoE 4/4

45
Q

What can cause secondary hyperlipidaemia?

A
  1. Hormonal factors (pregnancy, exogenous sex hormones, hypothyroidism)
  2. Metabolic disorders (diabetes, gout, progressive partial lipodystrophy, storage disorders)
  3. Renal dysfunction (nephrotic syndrome, chronic renal failure on dialysis or post-transplant)
  4. Obstructive liver disease,
  5. Toxins (alcohol, dioxin and chlorinated hydrocarbons)
  6. Iatrogenic (antihypertensives, immunosuppressents e.g. cyclosporine, other drugs)
  7. Miscellaneous causes
46
Q

What causes Aβ lipoproteinaemia?

A

MTP deficiency

47
Q

How common is Aβ lipoproteinaemia ?

A

Extremely rare, recessive

48
Q

What does Aβ lipoproteinaemia do?

A

Gives rise to extremely low levels of cholesterol

49
Q

What causes hypoβ-lipoproteinaemia?

A

Truncated ApoB

50
Q

What does hypoβ-lipoproteinaemia result in?

A

Low LDL

51
Q

Is hypoβ-lipoproteinaemia autosomal recessive or dominant?

A

It is autosomal dominant

52
Q

What is Tangier disease?

A

HDL deficiency caused by ABC A1 mutations which mediated the movement of cholesterol from peripheral cells into HDL

53
Q

What is hypo-α-lipoproteinaemia?

A

Hypolipidaemia someties due to ApoA-I mutations

54
Q

How is cornary vascular disease related to LDL and HDL?

A

Related to increases in LDL and inversely related to increases in HDL

55
Q

What should the total HDL: cholesterol ratio be?

A

Less than 3

56
Q

How does atherosclerosis form?

A

Mostly due to LDL which becomes oxidised once it penetrates the vacular wall. The oxidised LDL is taken up by macrophages and the cholesterol in LDL becomes esterified = foam cells. Lipid rich coronary plaques can rupture and form thrombi

57
Q

What happens when lipid rich coronary plaques rupture?

A

Can rupture due to running or unusual stress and lead to thrombus. The thrombus can heal - plaque becomes larger.

58
Q

What are the different types of thrombi that can form?

A

Mural intraluminal thrombus and intraintimal thrombus can form. Occlusive intraluminal thrombus can also form.

59
Q

What are some lipid regulating drugs?

A

Statins, fibrates, ezetimibe, colestyramine, and nicotinic acid (no longer available)

60
Q

What is the main way of reducing LDL cholesterol?

A

Statins. Also a slight increase in HDL and modest reduction in TG.

61
Q

Which lipid regulating drug is not very good at reducing LDL or but good at raising HDL and very good at lowering TG ?

A

Fibrates e.g. gemfibrozil

62
Q

How does ezetimibe work as a lipid regulating drug?

A

Ezetimibe is a cholesterol absorption blocker at NPC1L1 transporter in the intestine and reduced LDL levels

63
Q

How does colestyramine work as a lipid regulating drug?

A

Colestyramine is an ion exchange resin that binds bile acids so they cannot be absorbed, this is sensed by the liver which makes more bile acids – bile acids are made from cholesterol hence reducing circulating levels of LDL

64
Q

What are the results of the meta-analysis of the statin trials?

A

Total mortality (12%), coronary mortality (19%) reduced. Major vascular events including stroke reduced (25%) for each 1mmol/L reduction in LDL cholesterol. 50% reduction in CHD between 1969-2005 due to introductionof statins.

65
Q

What are some novel LDL-lowering therapies?

A

MTP inhibitor e.g. lomitapide, anti-PCSK9 monoclonal antibody e.g. REGN727, anti-sense ApoB oligonucleotide e.g. mipomersen

66
Q

What is an example of an MTP inhibitor (novel LDL-lowering therapy)?

A

Lomitapide

67
Q

What is an example of an anti-PCSK9 monoclonal (novel LDL-lowering therapy)?

A

REGN727

68
Q

What is an example of an anti-sense ApoB oligonucleotide (novel LDL-lowering therapy)?

A

mipomersen

69
Q

How does MTP inhibitor work?

A

Replicates symptoms of Aβ lipoproteinaemia such as impaired fat absorption and fatty liver

70
Q

How does anti-PCSK9 monoclonal work?

A

Fortnightly injection

71
Q

How does anti-sense ApoB oligonucleotide work?

A

Preventing synthesis of ApoB and production of LDL. Unwanted side effects and so not licensed by EMA.

72
Q

What are novel HDL-based therapies?

A
  1. Apolipoprotein A1 or A1 mimetic infusion therapy. 2. CETP inhibitors.
73
Q

What does treatment for obesity include?

A

Hypocaloric diet and exercise, iatrogenic malabsorption, bariatric surgey.

74
Q

Example of treatment for iatrogenic malabsorption

A

Orlistat - a pancreatic lipase inhibitor but causes steatorrhea

75
Q

When is bariatric surgery recommended and what is its success rate?

A

BMI > 40kg/m^2.

Success rate is >50% reduction in weight.

76
Q

How does bariatic surgery improve: diabetes, serum TG, HDL, fatty liver and hypertension

A

Reduces diabetes by 72%

Reduces serum TG by 60%

Increases HDL by 47%

Reduces fatty liver and hypertension

77
Q

True or false, bariatric surgery improves HbA1c in obese diabetics more than medical therapy?

A

True

78
Q

Types of bariatric surgery

A

Gastric banding, Roux-en-Y gastric bypass, biliopancreatic diversion

79
Q

What is gastric banding?

A

Size of stomach is reduced using a band so that you feel full even after a small meal

80
Q

What is Roux-en-Y gastric bypass?

A

Distal part of the jejunum has been anastomosed to the stomach

81
Q

What is biliopancreatic diversion?

A

The stomach is reduced in size, so a lot of used jejunum. A connection is made straight from the stomach to the terminal ileum.

CHEM PATH - Abbie (14 decks)

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