[17] Hyperlipidaemia Flashcards
1
Q
What is hyperlipidaemia?
A
Hyperlipidaemia is the term used to denoate raised serum levels of one or more of;
- Total cholesterol (TChol)
- Low density lipoprotein cholesterol (LDL-C)
- Triglycerides (TGs)
- Both TChol and TG (combined hyperlipidaemia)
*
2
Q
What is the clinical relevance of hyperlipidaemia?
A
Many types of hyperlipidaemia carry an increased risk of cardiovascular disease, being one of the three main modifiable risk factors
3
Q
What is dyslipidaemia?
A
A wider term that includes low levels of high-density lipoprotein cholesterol (HDL-C)
4
Q
What are lipids?
A
A structurally diverse group of compounds
5
Q
What are the types of lipids?
A
- Triacylglycerols
- Fatty acids
- Cholesterol
- Phospholipids
- Vitamins A, D, E, and K
6
Q
Are lipids hydrophilic or hydrophobic?
A
Hydrophobic
7
Q
What is the result of lipids being hydrophobic?
A
They are insoluble in water, and therefore need to be transported in the blood bound to carriers
8
Q
How are lipids transported in the blood?
A
- Bound to albumin
- In lipoprotein particles
9
Q
What % of lipids are bound to albumin?
A
2%, mainly fatty acids
10
Q
What % of lipids are carried as lipoprotein particles?
A
98%
11
Q
How is cholesterol obtained?
A
Some from the diet, most synthesised in liver
12
Q
What is the physiological role of cholesterol?
A
- Essential component of membranes that modulates fluidity
- Precursor of steroid hormones
- Precursor of bile acids
13
Q
What steroid hormones have cholesterol as their precursor?
A
- Cortisol
- Aldosterone
- Testosterone
- Oesotrogen
14
Q
In what form is cholesterol transported around the body?
A
Cholesterol esters
15
Q
What are lipoproteins?
A
A biochemical assembly, whose purpose is to transport hydrophobic lipid molecules in water, as in blood or extracellular fluid
16
Q
What is the importance of lipoproteins?
A
Many enzymes, transporters, structural proteins, antigens, adhesions, and toxins are lipoproteins
17
Q
What is the outer shell of lipoproteins made of?
A
A phospholipid monolayer with small amounts of cholesterol
18
Q
What does the outer shell of lipoproteins contain?
A
Integral apolipoproteins and peripheral apolipoproteins
19
Q
Give two examples of integral apolipoproteins
A
- apoA
- apoB
20
Q
Give two examples of peripheral lipoproteins
A
- apoC
- apoE
21
Q
What is found inside the lipoprotein?
A
- Triacylglycerols
- Cholesterol esters
- Fat soluble vitamins
22
Q
What are cholesterol esters?
A
Cholesterol linked to fatty acids
23
Q
What are the classes of lipoprotein named according to?
A
Density
24
Q
What are the classes of lipoproteins?
A
- Chylomicrons
- VLDL (very low density lipoproteins)
- IDL (intermediate density lipoproteins)
- LDL (low density lipoproteins)
- HDL (high density lipoproteins)
25
What does each class of lipoprotein contain?
A variable content of apolipoprotein, triglyceride, cholesterol, and cholesterol ester
26
What does each class of lipoprotein associated with it?
A particular complement of associated proteins, known as apolipoproteins
27
How many major classes of lipoproteins are there?
6
28
What are the important apolipoproteins?
apoB and apoAI
29
What is apoB associated with?
* VLDL
* IDL
* LDL
30
What is apoAI associated with?
HDL
31
How are apolipoproteins related to the phospholipid bilayer?
They can be integral or peripheral
32
What is the structural role of apolipoproteins?
Packing water insoluble lipid
33
What is the functional role of apolipoproteins?
* Acting as a co-factor for enzymes
* Acting as ligands for cell-surface receptors
34
Where are chylomicrons loaded?
In the small intestine
35
Where do chylomicrons enter from the small intestine?
The lymphatic system
36
What is added to chylomicrons before they enter the lymphatic system?
apoB-48
37
Where to chylomicrons travel once they have entered the lymphatic system?
To the thoracic duct
38
Where does the thoracic duct empty into?
The left subclavian vein
39
What is added to chylomicrons once it enters the blood?
apoC and apoE
40
What does apoC on chylomicrons bind to?
Lipoprotein lipase (LPL) on adipocytes and muscle
41
What happens when apoC on chylomicrons binds to LPL on adipocytes and muscles?
The chylomicron releases fatty acids, which enters cells and depletes chylomicrons of their fat content
42
What happens when the triglyceride content of chylomicrons is depleted to about 20%
apoC dissociates and the chylomicron becomes a chylomicron remnant
43
What happens to chylomicron remnants?
They return to the liver, and the LDL receptor on hepatocytes binds apoE
44
What happens when the LDL receptor on hepatocytes binds the apoE on chylomicrons?
It causes the chylomicron remnant to be taken up by receptor mediated endocytosis
45
What happens once chylomicron remnants have been taken into the hepatocytes?
Lysosomes release the remaining contents for their use in metabolism
46
Where is VLDL made?
In the liver
47
What is the purpose of VLDL?
Transporting TAG to other tissues
48
What is added to VLDL during its formation?
apoB100
49
What is added to VLDL in the blood?
apoC and apoE
50
Where does the apoC and apoE added to VLDL in the blood come from?
HDL particles
51
What does VLDL bind to?
Lipoprotein lipase on endothelial cells in muscle and adipose
52
What happens when VLDL binds to LPL on muscle and adipose tissue?
It starts to become depleted of TAG
53
What happens to fatty acids release from VLDL in muscle?
They are taken up and used for energy production
54
What happens to the fatty acids released from VLDL in adipose?
The fatty acids are used for the re-synthesis of TAG and stored as fat
55
What happens as the TAG content of VLDL drops?
VLDL particles dissociate from the LPL enzyme complex and return to the liver
56
What happens if the VLDL TAG content depletes to about 30%?
The particle becomes an IDL particle
57
Why is the IDL particle short lived?
As they can be taken up by the liver, or rebind to the LPL enzyme to further deplete TAG content
58
What happens to IDL on depletion to about 10%?
It loses apoC and apoE, and becomes a LDL particle
59
What is the primary function of LDL?
Provide cholesterol from the liver to the peripheral tissues
60
How does LDL get into the peripheral tissue?
Peripheral cells express LDL receptors, and take up LDL via the process of receptor mediated endocytosis
61
Why is LDL not cleared effectively by the liver?
Because it does not have apoC or apoE, and the liver has high affinity for apoE
62
How does the half life of LDL in the blood compare to VLDL or IDL?
It is much longer
63
What is the result of LDL having a much longer half life in the blood?
It is more susceptible to oxidative damage
64
What happens to oxidised LDL?
It is taken up by macrophages that then transform to foam cells
65
What is the clinical relevance of foam cells?
They contribute to the formation of atherosclerotic plaques
66
What do cells requiring cholesterol express?
LDL reecptors on their plasma membranes
67
What acts as a ligand for LDL receptors expressed by cells requiring cholesterol?
The apoB-100 on LDL
68
What happens when LDL binds to receptors expressed by cells requiring cholesterol?
The receptor/LDL complex is taken into the cell by endocytosis into an endosome, which then fuses with lysosomes for digestion to release cholesterol and fatty acids
69
What is LDL receptor expression controlled by?
Cholesterol concentration in the cell §
70
How is HDL producted?
* Nascent HDL is synthesised by the liver and intestine
* HDL particles can bud off from chylomicrons and VLDL as they are digested by LPL
71
How does nascent HDL develop?
It accumulates phospholipids and cholesterol from cells lining blood vessels, and the hollow core progressively fills to produce a more globular shape
72
Why is HDL clinically important?
Because it has the ability to remove cholesterol from cholesterol-laden cells and return it to the liver. This is an important process for blood vessels, as it reduces the likelihood of foam cells and atherosclerotic plaque formation
73
What happens to mature HDL?
It is taken up by the liver via specific receptors
74
What is type I hyperlipoproteinaemia?
Increased chylomicrons found in fasting plasma
75
What causes type I hyperlipoproteinaemia?
Defective lipoprotein lipase
76
Is there a link between type I hyperlipoproteinaemia and coronary heart disease?
No
77
What is type IIa hyperlipoproteinaemia caused by?
A defective LDL receptor
78
Is type IIa hyperlipoproteinaemia associated with coronary heart disease?
Yes, which may be severe
79
What causes type IIb hyperlipoproteinaemia?
Defect unknown
80
Is type IIb hyperlipoproteinaemia associated with CHD?
Yes
81
What is type III hyperlipoproteinaemia?
Raised IDL and chylomicron remnants
82
What causes type III hyperlipoproteinaemias?
Defective apoE
83
Is type III hyperlipoproteinaemia associated with CHD?
Yes, *but the condition is rare*
84
What causes type IV hyperlipoproteinaemia?
Defect unknown
85
Is type IV hyperlipoproteinaemia associated with coronary heart disease?
Yes
86
What is type V hyperlipoproteinaemia?
Raised chylomicrons and VLDL in fasting plasma
87
What causes type V hyperlipoproteinaemia?
Cause unknown
88
Is type V hyperlipoproteinaemia associated with CHD?
Yes
89
How does raised serum LDL lead to atheroma?
Raised serum LDL increases the oxidized LDL, which is recognised and engulfed by macrophages. Lipid laden macrophages called foam cells accumulate in the intima of blood vessel walls to form a fatty streak, which can evolve into an atherosclerotic plaque
90
How can atherosclerotic plaques cause pathology?
They grow and enrough on the lumen of the artery causing angina.
If the plaque ruptures, it triggers acute thrombosis (clot) by activating platelets and the clotting cascade, which can lead to stroke or MI
91
What are the causes of hyperlipiaemia?
* Medical conditions
* Drugs
* Pregnancy
* Obesity
* Alcohol abuse
* Inherited disorders
92
What medical conditions can cause hyperlipidaemia?
* Hypothyroidism
* Obstructive jaundice
* Cushing's syndrome
* Anorexia nervosa
* Nephrotic syndrome
* Diabetes mellitus
* CKD
93
What drugs can cause hyperlipidaemia?
* Thiazide diuretics
* Glucocorticoids
* Ciclosporin
* Anti-retroviral therapy
* Beta-blockers
* COCP
* Atypical antipsychotics
94
What inherited disorders can cause hyperlipidaemia?
* Familal dyslipidaemias
* Familial hypercholesterolaemia
* Familial combined hyperlipidaemia
* Apoprotein disorders
95
When should familial hypercholesterolaemia be suspected?
* When adults have a raised TChol concentration (typically \>7.5mmol/L) and there is a personal or family history of premature CHD
* When secondary causes of hypercholesterolaemia have been ruled out
96
When can a definite diagnosis of familial hypercholesterolaemia be made, according to the Simon Broom diagnostic criteria?
* A TChol level of \>7.5mmol/L and a LDL-C of \>4.9mmol/L, *and*
* Tendon xanthomata, or evidence of signs of these in a first or second degree relative, *or*
* DNA evidence of an LDL receptor mutation, familial defective apo-B-100, or PCSK9 mutation
97
When can a possible diagnosis of familal hypercholesterolaemia be made, according to the Simon Broom diagnostic criteria?
* A TChol level of \>7.5mmol/L and a LDL-C of \>4.9mmol/L, *and*
* A family history of MI in a second-degree relative of 50 years or younger, or first degree relative 60 years or younger, *or*
* Family history of raised TChol greater than 7.5mmol/L
98
How might hyperlipidaemia present?
* Discovered during routine screening, or as part of risk-assessmentfor co-morbidities
* Premature arcus senilis
* Tendon xanthomata
99
What is arcus senilis?
A white or grey opaque ring in the corneal margin
100
What is a tendon xanthomata?
Hard, non-tender nodular enlargement of tendons, most commonly found on knuckles and Achilles tendon
101
What investigations are done in hyperlipidaemia?
* Lipid profile
* Fasting blood glucose
* Renal function
* LFTs
* TSH
* DNA testing
102
What should be included in a lipid profile?
* TChol
* LDL-C
* HDL-C
* TGs
103
Why is a fasting sample required for a lipid profile?
TGs rise dramatically after a meal
104
Why is a fasting blood glucose required in the management of hyperlipideaemia?
To exclude hyperlipidaemia secondary to diabetes mellitus
105
Why is renal function testing required in hyperlipidaemia?
To exclude CKD
106
What are LFTs required in the investigation of hyperlipidaemia?
To rule out liver disease, if statins have to be initiated
107
When is a TSH done in the investigation of hyperlipidaemia?
If dyslipidaemia is present
108
Why is TSH done in investigation of dyslipidaemia?
To exclude myxoedema
109
What is the aim of treatment of hyperlipidaemia?
Prevent or reduce the risk of complications of CVD
110
What does risk-reduction involve in the management of hyperlipidaemia?
* Non-drug measures, such as addressing lifestyle factors
* Drug treatment using lipid-lowering therapy
111
What drug is offered in primary prevention of hyperlipidaemia?
Atorvastatin
112
What does of atorvastatin should be offered in the primary prevention of hyperlipidaemia?
20mg
113
Who should be offered atorvastatin in the primary prevention of hyperlipidaemia?
* People who have a 10% or greater 10 year risk of developing cardiovascular disease
* 85 years or older
* Have type 1 diabetes, and;
* Are older than 40 years
* Have had diabetes for more than 10 years
* Have established neuropathy
* Have other cardiovascular risk factors
* Have chronic kidney disease
114
What are statins?
HMG-CoA reductase inhibitors
115
What do statins do?
Lower elevated LDL-C, resulting in a substantial reduction in coronary events and death from CHD
116
Who are statins considered first-line in?
Patients with elevated risk of atherosclerotic cardiovascular disease
117
What are the therapeutic benefits of statins?
* Plaque stabilisation
* Improvement of coronary endothelial function
* Inhibition of platelet thrombus formation
* Anti-inflammatory activity
118
What is the mechanism of action of statins?
Statins are competitive inhibitors of HMG-CoA, which is the rate limiting step in cholesterol synthesis.
119
What is the result of the inhibition of de novo cholesterol synthesis by statins?
It means the intracellular supply of cholesterol is depleted
120
What is the result of the depletion of intracellular cholesterol supplies by statins?
It causes the cell to increase the number of cell surface LDL receptors, which bind and internalise circulating LDLs. This reduces plasma cholesterol.
121
By what mechanisms do statins decrease plasma cholesterol?
* Decreasing cholesterol synthesis
* Increasing LDL catabolism
122
Other than decreasing plasma cholesterol, what can statins do?
* Decrease triglyceride levels
* Increase HDL cholesterol in some patients
123
What are the therapeutic uses of statins?
Statins are effective in lowering plasma cholesterol levels in all types of hyperlipidaemias
124
What cause of hyperlipidaemia are statins much less effective in treating?
Familal hypercholesterolaemia
125
Why are statins much less effective in treating patients with familial hypercholesterolaemia?
Patients who are homozygous for familial hypercholesterolaemia lack LDL receptors, and therefore benefit from statins is much less
126
What are the adverse effects of statins?
* Elevated liver enzymes
* Myopathy and rhabdomyolysis
* Drug interactions
127
What should be done due to the potential for statins to elevate liver enzymes?
LFTs should be evaluated prior to starting therapy, or if the patient develops symptoms of liver dysfunction
128
Why is it important to check liver function with statin therapy?
As hepatic insufficiency can cause drug accumulation
129
How common are myopathy and rhabdomyolysis as side effects of statins?
Rare, but have been reported
130
What was true of the patients in most reported cases of myopathy and rhabdomyolysis with statin treatment?
They had renal insufficiency, or were taking drugs such as erythromycin, gemfibrozil, or niacin
131
What is simvastatin metabolised by\>
Cytochrome P450 enzymes
132
What effect might inhibitors of cytochrome P450 enzymes have when a patient is taking simvastatin?
May increase the risk of rhabdomyolysis
133
What should be measured in patients on statins who have muscle complaints?
Plasma creatinine kinase
134
What are the common side effects of statins?
* Nosebleeds
* Sore throat
* Non-allegic rhinitis
* Headache
* Nausea
* GI disturbance
135
What drug might statins interact with?
Warfarin - statins increase the effect of warfzrin
136
What is the result of statins interacting with warfarin?
The INR must be measured regularly
137
Where are statins contraindicated?
Pregnancy and lactation
138
Are the statins administered in their active form?
Simvastatin and lovastatin are lactones are are hydrolysed to their active form.
Other statins are administered in thier active form
139
Are the statins well absorbed after oral administration?
Variable
140
Where are the statins metabolised?
Liver
141
Do statins undergo first-pass metabolism?
Yes, significantly
142
What is the result of the significant first-pass metabolism of the statins?
Their predominant effects are in the liver
143
Do statins have active metabolites?
Some do
144
How are statins excreted?
Primarily through bile and faeces, but some urinary elimination occurs
145
What is the half life of statins?
Variable
146
How do the potencies vary between statins?
Different statins have different potencies, with atorvastatin having a higher potency than simvastatin
147
What is involved in secondary prevention in hyperlipidaemia?
Start statin treatment with atorvastatin in people with cardiovascular disease
148
What does of atorvastatin is used in secondary prevention?
80mg
149
When might a lower dose of atorvastatin be used in secondary prevention?
* Potential for drug interactions
* High risk of adverse effects
* Patient prefers it
150
What should be done if a person is not able to tolerate a high-intensity statin regime?
Aim to treat at the maximum tolerated dose
151
When is ezetimibe therapy recommended?
* Monotherapy for treatment of primary hypercholesterolaemia in adults who cannot tolerate statin therapy
* Co-administration with initial statin therapy to treat primary hypercholesterolaemia if serum or total LDL cholesterol concentration is not appropriately controlled
* If change from initial staitn therapy is being considered
*
152
What is the clinical use of benxzafibrate?
It is an adjunct to diet and other appropriate measures in mixed hyperlipidaemia if statins are contraindicated or not tolerated
## Footnote
*NICE advises against its use*
153
What is the clinical use of nicotinic acid?
It is an adjunct to statins in dyslipidaemia, or alone if statins aren't tolerated
## Footnote
*NICE advises against its use*
154
By how much can ezetimibe lower LDL cholesterol?
Approx. 17%
155
What is the result of the modest statin-lowering effects of ezetimibe?
If is often used as an adjunct to statin therapy, or in statin-intolerant patients
156
What is the mechanism of action of ezetimibe?
It selectively inhibits reabsorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores, and an increase in clearance of cholesterol from the blood
157
Are adverse effects common with the use of ezetimibe?
No, they are uncommon
158
What are the contraindications for ezetimibe?
Patients with moderate or severe hepatic insufficiency
159
How is ezetimibe metabolised?
By the small intestine and liver via glucuronide conjugation
160
How is ezetimibe excreted?
Biliary and renal excretion
161
Give two examples of fibrates
* Benzofibrate
* Fenofibrate
162
What are fibrates?
Derivates of fibric acid
163
What do fibrates do?
Lower serum triglycerides and increase HDL levels
164
What are PPARs?
Peroxisome proliferator activated receptors - they are members of the nuclear receptor family that regulates lipid metabolism
165
What do PPARs function as?
Ligand-activated transcription factors
166
What activates PPARs?
Binding to their natural ligands or anti-hyperlipidaemic drugs
167
What are the natural ligands for PPARs?
Fatty acids or eicosanoids
168
What happens when PPARs are activated?
They bind to peroxisome proliferator response elements, which ultimately leads to decrased TAG concentration through increased expression of lipoprotein lipase, and decreasing apolipoportein CII concentration
169
How do fibrates increase cholesterol?
By increasing the expression of apo AI and apoAII
170
What are the therapeutic uses of fibrates?
They are used in the treatment of hypertriglyceridaemias
171
What kind of hypertriglyceridaemias are fibrates particularly useful in?
Type III hyperlipidaemia
172
What happens in type III hyperlipidaemias?
Intermediate-density lipoprotein particles accumulate
173
What are the adverse effects of fibrates?
* Mild GI disturbance
* Gallstones
* Myositis
* Drug interactions
174
What happens to the adverse effect of GI disturbance with fibrate as therapy progresses?
It lessens
175
Why do fibrates cause a predisposition to gallstone formation?
Because they increase biliary cholesterol excretion
176
What should be done as a result of myositis being a potential adverse effect of fibrates?
Muscle weakness or tenderness should be evaulated
177
Who might be at increased risk of myositis caused by fibrates?
Patients with renal insufficiency
178
What drug might interact with fibrates?
It increases the effects of warfarin
179
What should be done due to fibrates potentially increasing the effects of warfarin?
Monitor INR regularly AGAIN OBVIOUSLY I HATE THIS JUST GIVE THEM BLOODY RIVAROXIBAN
180
What are the contraindications to fibrates?
They should not be used in patients with severe hepatic or renal dysfunction, or pre-existing gallbladder disease
181
Are fibrates well absorbed after oral administration?
Yes, completely
182
Describe the distribution of fibrates
They distribute widely, bound to albumin
183
What happens to fenofibrate in the body?
Fenofibrate is a prodrug which is convereted to the active moiety fenofibric acid
184
Do fibrates undergo biotransformation?
Yes, extensively
sorry this is a bit of a leading question lol why would it ask if the answer was no
185
whos my best boy
eddie
186
i wonder if you'll ever actually get 186 cards deep in hyperlipidaemia
if you do let me know hheheh
187
How are fibrates excreted?
In the urine as glucuronide conjugates
188
What is nicotinic acid also known as?
Niacin
189
How effective is nicotinic acid?
It can reduce LDL-C by 10-20%, is the most effective agent for increasing HDL-C, and lowers triglycerides by 20-35% at typical doses of 1.5-3g/day
190
What can nicotinic acid be used in combination with?
Statins
191
What combination of nicotinic acid and statins is available?
A fixed-dose combination of lovostatin and long-acting nicotinic acid
192
What is the mechanism of action of nicotinic acid?
At therapeutic doses, it strongly inhibits lipolysis in adipose tissue, thereby reducing production of free fatty acids. The liver normally uses circulating free fatty acids as a major precursor for tryglyceride synthesis, and so reduced liver triglyercide levels decrease hepatic VLDL production, which in turn reduces LDL-C plasma concentrations
193
What are the therapeutic uses of nicotinic acid?
It is useful in the treatment of familial hyperlipidaemias
It is also used to treat other severe hypercholesterolaemiaes, often in combination with other agents
194
What are the adverse effects of nicotinic acid?
* Intense cutaneous flush accompanied by uncomfortable feeling of warmth
* Pruritis
* Nausea and abdominal pain
* Hyperuricaemia and gout
* Impaired glucose tolerance
* Hepatotoxicity
195
What mediates the flush caused by nicotic acid?
Prostaglandins
196
How can the adverse effect of flush with nicotinic acid be decreased?
Administration of aspirin prior to nicotinic acid
197
How can some of the bothersome initial adverse effects of nicotinic be reduced?
Slow titration of the dosage, or usage of sustained release formulations
198
Why does niacin predispose to hyperuricaemia and gout?
Because it inhibits tubular secretion of uric acid
199
When should the use of nicotinic acid be avoided?
In hepatic disease
200
How is nicotinic acid administered?
Orally
201
What happens to nicotinic acid in the body\>
It is convereted to nicotinamide, which is incorporated into the cofactor NAD+
202
How are nicotinic acid and its derivates excreted?
Into the urine
