Cardiology - Dyslipidaemia Flashcards Preview

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Flashcards in Cardiology - Dyslipidaemia Deck (19):

What is hyperlipidaemia?

Hyperlipidaemia is defined as elevated levels of cholesterol and/ or triglycerides. Hypercholesterolaemia is common: >60% of UK population have a total cholesterol >5.2mmol/L


What are lipoproteins?

Cholesterol and triglycerides (important form of dietary energy) are transported in the bloodstream complexed with phospholipid and proteins (apoproteins) called lipoproteins.

Apoproteins act as signalling molecules or enzymes and play a key role in controlling lipid transport.


What are the main blood lipoproteins?

The main classes of blood lipoproteins include:
- chylomicrons
- very low density lipoproteins (VLDL)
- intermediate density lipoprotein (IDL)
- low density lipoprotein (LDL)
- high density lipoprotein (HDL)


What is the function of chylomicrons?

Chylomicrons are produced in intestinal cells from dietary lipid and transport them from the gut to the liver in the post prandial state.

They have a large amount of triglyceride (85%) and have very little protein.


What are VLDLs and where are they produced?

Very low density lipoprotein (VLDL) are rich in triglycerides and are synthesized from the liver mostly from carbohydrate sources.

The triglycerides of chylomicrons and VLDL are hydrolyzed in the bloodstrem by lipoprotein lipase to fatty acids and glycerol. In adipose cells, these fatty acids are converted to triglycerides and stored.


What is IDL?

Intermediate density lipoproteins consist of the remnants of VLDL after digestion of some of the triglycerides. IDLs can either be endocytosed by liver cells and digested by lysosomal enzymes or converted to LDL by further digestion of triglycerides.


What is the function of HDLs?

HDLs transfer proteins to chylomicrons and VLDL. HDL also picks up cholesterol from peripheral tissues and from other blood lipoproteins (reverse cholesterol transport). This cholesterol ultimately returns to the liver where it is converted into bile salts.


What happens during the fasting state to blood lipids?

During the fasting state, fatty acids (derived from adipose triglyceride stores) are oxidised by various tissues to produce energy. In the liver, fatty acids are converted to ketone bodies which are oxidised by tissues such as the muscle and kidney.


What diseases produce secondary hyperlipidaemias?

Chronic renal failure or nephrotic syndrome
Chronic liver disease, especially alcoholic
Chronic biliary obstruction
Drugs: steroids, oestrogens


What are the genetic hyperlipidaemias?

Single gene defects in lipid metabolism causing extreme hyperlipidaemias are rare. However, common genetic variability or heterozygote status is a very important determinant of cholesterol levels in the general population.

Abnormalities include:
- familial hypercholesterolaemia
- polygenetic hypercholesterolaemia and familial combined hyperlipidaemia
- apoprotein E genotype
- lipoprotein lipase deficiency and ApoCII deficiency


What is familial hypercholesterolaemia?

This is a group of single gene disorders affecting low density lipoprotein receptor and causing deficient uptake of LDL particles which accumulate in the bloodstream. Homozygotes have extremely high cholesterol levels and coronary artery disease in their teens or twenties. Heterozygotes have moderately high cholesterol and are at risk of premature CAD. Patients may have corneal arcus, xanthelasma and tendon xanthoma.


What is polygenetic hypercholesterolaemia and familial combined hyperlipidaemia?

This is an inherited condition characterised by moderately elevated cholesterol (7-12mmol/L) with or without high triglycerides. It is not caused by a single gene disorder although in some inheritance is apparently autosomal dominant.

It is a very important cause of increased atherosclerosis risk in the population. Very high triglycerides may cause pancreatitis.


Apoprotein E genotype

Genetic variation in the apoprotein E gene results in different isoforms of the ApoE protein. The ApoE2 isoform binds less avidly to hepatic receptors, resulting in hyperlipidaemia. ApoE2 homozygotes are uncommon, but ApoE2 heterozygotes (15% of the population) appear to have a significantly increased risk of CAD.


How is cholesterol levels related to development of CAD?

A total cholesterol of >6.5mmol/L doubles the risk of lethal CAD; >7.8mmol/L increases the risk 4 fold.

Reducing total cholesterol by 20% reduces coronary risk by 10%.

The strongest association is with LDL cholesterol, whereas HDL cholesterol is protective. The LDL:HDL cholesterol ratio is a useful indicator , a ratio of >4 indicating a higher risk.


Why does cholesterol increase the risk of developing CAD?

Elevated cholesterol (especially levels of LDL) damages the endothelium early in atherosclerosis and is taken up into the lipid core of established plaques by macrophages (foam cells). Lowering LDL cholesterol reduces cholesterol deposition into atherosclerotic plaques and may reverse this process. Crucially, cholesterol lowering stabilises plaques and reduces the likelihood of acute plaque rupture and MI.


Is diet sufficient to reduce cholesterol and risk of CAD?

No. Diet alone lowers cholesterol by 1mmol/L and reduces body weight. But diet alone is insufficient in patients with elevated cholesterol and CAD.


Give an example of a bile acid sequestrant and how it lowers serum cholesterol?

Bile acid sequestrants ("resins") e.g. cholestyramine lower cholesterol by binding cholesterol in the GIT, interupting enterohepatic circulation, so increasing cholesterol excretion. They are distasteful and may have intolerable GI side effects. But they can be effective and remain useful in treating familial hypercholesterolaemia.


How do statins work and in what groups of patients should they be started?

Statins are HMG CoA reductase inhibitors (e.g. simvastatin, pravastatin) are potent agents that inhibit this enzyme that is the rate limiting enzyme in cholesterol biosynthesis. This increases hepatic cholesterol uptake because reduced intracellular cholesterol biosynthesis increased expression of cell surface LDL receptors. For this reason, they are less effective in patients with familial hypercholesterolaemia. Statins typically lower cholesterol by 30% or more and may modestly increase HDL cholesterol. They have little effect on plasma triglycerides.

They should be started on any patient who has a cardiovascular (Q) risk score of greater than 20%.


What are fibrates?

Fibric acid derivatives (e.g. bezafibrate, fenofibrate) reduce cholesterol moderately but also reduce triglycerides and increase HDL cholesterol. The mechanism of action is complex but involves stimulation of lipoprotein lipase activity (increases chylomicrons and VLDL catabolism) and increased cholesterol excretion via bile acids. They are more useful in patients with mixed hyperlipidaemia and/or low HDL.

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