Hyperlipidemia and atherasclerosis Flashcards
what is hyperlipidemia
Elevated levels of lipids (TAG & cholesterol) in the blood
Forms initial phase for the progression of atherosclerosis
Asymptomatic and therefore gets unnoticed until late
TAG & cholesterol play essential roles in the body but their defects lead to pathological conditions
what is primary hyperlipidemia
mainly due to genetic deficiency
what is secondary hyperlipidemia
– due to lifestyle and other metabolic diseases
what is lipoproteins
what is its role
how many categories do they have?
Lipids + proteins (noncovalently associated)
Transport vehicles for triacylglycerols and cholesterol
Classified into 5 broad categories
what are the 5 broad categories of lipoproteins
HDL
Transport endogenous cholesterol from tissues to liver
VLDL, IDL & LDL
Transport endogenous TAG & cholesterol from liver to tissues (liver produces TAG from excess CHO)
Chylomicrons
Transport exogenous TAG & cholesterol from intestines to tissues
what is the structure of lipoproteins like?
Nonpolar core: triacylglycerols and cholesteryl esters
Amphiphilic surface: Apoproteins, phospholipid & cholesterol
ApoB48: Intestine; Apo B-100: Liver
Lipoprotein from intestine is secreted into lymph
Lipoprotein from liver is secreted into plasma
Apoproteins E, CII & CIII may also come from HDL
what are the causes of hyperlipidemia?
Mostly multifactorial including nutrition, genetics, medications & metabolic diseases (e.g. diabetics & obesity)
Genetic causes include; increased sensitivity to dietary cholesterol, lack of LDL receptors, mutations in LDL and ABCA1 receptors and apoproteins and over synthesis of apoproteins
Primary hypercholesterolaemia: genetic cause; deficiency or defect in LDL receptors (e.g. familial hypercholesterolaemia)
Secondary hypercholesterolaemia: associated with metabolic diseases (e.g. type II DM) & lifestyle (e.g. high calorie diet & inactivity)
Diets rich in TAG & saturated FAs increase cholesterol synthesis & suppress LDL receptor activity
Other metabolic conditions that increase cholesterol levels; BP, hypothyroidism, nephrotic syndrome & obstructive liver diseases
Medications; β-blockers, estrogens and protease inhibitors (HIV)
Hypertriglyceridaemia: can lead to pancreatitis & eruptive xanthoma
Primary - familial hypertriglyceridaemia (deficiency LPL& apoCII)
Secondary – similar to above
what are the diagnosis of hyperlipidemia?
No obvious symptoms in most cases
Blood test is recommended in fasting conditions
Should be tested regularly for >40 years old; with family history of CVDs; obesity & diabetes or other metabolic diseases; hypertension
Total serum cholesterol Normal range 3.5-6.5 mmol/L UK average is 5.6 mmol/L Target <5 mmol/L <4 mmol/L if at high risk or have CVD
HDL cholesterol (male)
0.8-1.8 mmol/L
>1.0 mmol/L if at high risk or have CVD
HDL cholesterol (female)
1.0-2.3 mmol/L
>1.0 mmol/L if at high risk or have CVD
LDL cholesterol (fasting)
<4 mmol/L
<3 mmol/L
<2 mmol/L if at high risk or have CVD
Triglycerides (fasting)(male)
0.7-2.1 mmol/L
<1.7 mmol/L
Triglycerides (fasting)(female)
0.5-1.7 mmol/L
<1.7 mmol/L
what are the non pharmacological treatments for hyperlipidemia?
Healthy balanced diet (replace saturated fat diets with fruits/ vegetables) – avoid or reduce animal fats Regular intake of Omega-3 FAs (avocados and oily fish e.g. salmon) Regular exercise (weight loss), limiting alcohol intake & avoid smoking
what are the pharmacological treatment option for hyperlipidemia?
Medications
Statins: Inhibit cholesterol biosynthesis (HMG-CoA reductase)
Different types: atorvastatin, simvastatin and rosuvastatin
Should be prescribed only to people at high risk for CVDs
Taken for life long as it can reverse the cholesterol if stopped
Aspirin: Anti-platelet drug that inhibits platelet activation
Should be prescribed with a low dose for people at high risk
Periodic blood test is required to check the liver functions
Ezetimibe: Blocks the absorption of cholesterol from food and bile
Reduced side effects compared to statins
Can be taken on its own when statins can’t be prescribed
Taken as a combination with statins if the level is not reduced
Bile acid sequestrants: Binds to bile acid in small intestine and thus increase release of from the liver and reduce cholesterol
Bile acid sequestrants available in the UK include: colesevelam (tablets), colestyramine (resin), colestipol (resin)
May interefere with the absorption of lipid soluble nutrients
Fibrates: PPARα agonists that induce hepatic uptake and oxidation of cholesterol & TAG, and adipogenesis
bezafibrate, ciprofibrate, fenofibrate, gemfibrozil
Can be given when patients cannot take statins
Nicotinic acid or niacin or vitamin B3: Inhibits lipolysis in adipocytes and reduce lipid synthesis in the liver
Usually high concentrations are required
Associated with several side effects such as vasodilation, skin rash, hepatotoxicity and hyperglycaemia
what is atheroscleorsis?
Arteriosclerosis – hardening of arteries due to non-plaque factors
Hyperlipidaemia leads to the development of atherosclerosis
what are the different stages of progression of atherscleoris?
Different stages of progression
- Endothelial cell injury
- Migration of LDLs
- Adhesion, migration & transformation of monocytes
- Engulfing ox-LDLs
- Migration and proliferation of SMCs
- Expansion and occlusion
what does rupture of plaque cause?
Rupture of plaque leads to thrombotic events
Should be treated promptly
what is the structure of an artery wall?
Tunica intima (inner coat): endothelium, connective tissue & internal elastic membrane Tunica media (middle coat): smooth muscle cells Tunica externa (outer coat): collagen & elastic fibres
explain the development of atherosclerosis?
1) Endothelial cell injury
Elevated LDL levels, smoking, immune mechanisms and mechanical stress due to hypertension
These cause irritation or damage or dysfunction to endothelial cells
2)Migration of LDLs
Endothelial dysfunction allows the migration of excessive LDL into intima
LDLs get oxidised by ROS produced from ECs, SMCs and macrophages at later stages
3) Adhesion, migration & transformation of monocytes
Damaged endothelium expresses P-selectin & signalling molecules to attract monocytes to the damaged region
Monocytes adheres to P-selectin on EC and migrate into the intima and transform into macrophages
- Engulfing ox-LDLs
Macrophages engulf all the ox-LDLs and become foam cells
This enhances the HDL reverse cholesterol transport, however, continuous accumulation leads to further development of fat streak
Macrophages & Foam cells release growth factors - Migration and proliferation of SMCs
Growth factors enhance the migration and proliferation of SMCs
SMCs form fibrous cap with collagen, elastin, etc.
SMCs calcify the fibrous cap and harden this heavily
Dead cells release the lipid core - Expansion and occlusion
Initially the plaque grows towards the Tunica externa
Then grows towards the lumen
At a final stage, plaque can rupture and activate platelets and lead to thrombosis
