Hyperlipidaemia

Question 1

modifyable and non modifyable risk factors

Answer 1

Age and sex = non modifiable risk factors

Smoking , BP and raised cholesterol- modifiable

Cholesterol levels- log linear relationship to CVD risk. Several studies have shown that lipid lowering drugs have benefits such as less coronary events, less CHD mortality, reduction in progression of coronary atherosclerosis, decreased mortality from all causes.

Question 2

what do Chylomicrons do

Answer 2

transport mostly triglyceride from gut to rest of body. Only appear in plasma after eating fatty foods due to their short half life.

Question 3

what does VLDL do

Answer 3

• made in liver from fat and carbohydrates. Transports triglycerides to peripheral tissues. Apo C main lipoprotein.

Question 4

what does LDL do

Answer 4

• made by metabolism of VLDL. Provides cholesterol to cells. Excess LDL taken up by liver via receptor mediated endocytosis. Main lipoprotein is Apo B.

Question 5

what does HDL do

Answer 5

Nascent HDL made by liver and intestine. Involved in transferring cholesterol to the liver or other lipoproteins. Helps protect from IHD. Main lipoprotein is Apo-A1.

Question 6

describe lipoprotein metabolism - 11 steps

Answer 6

Fats absorbed in the intestine are packaged into large, triglyceride-rich particles known as chylomicrons (step 1).

These lipoproteins undergo lipolysis (removal of triglyceride) to form chylomicron remnants (step 4), which are taken up by the liver via an apoE receptor (step 5).

The liver can also secrete triglyceride-rich lipoproteins known as VLDL (step 2). Following lipolysis, these particles can be converted to LDL (step 6) or taken up by the liver via an apoE receptor (step 7). The LDL formed is catabolized maily by the liver (step 8) or other tissues via an LDL receptor that recognizes both apoB-100 and apoE, but not apoB-48. If LDL is modified or oxidized, it can also be taken up by a scavenger receptor on macrophages, or scavenger cells (step 10).

HDL is synthesized by both the liver and the intestine (step 3). HDL picks up lipid and protein constituents from chylomicrons and VLDL as these particles undergo lipolysis (steps 4 and 6). HDL picks up free cholesterol from peripheral tissues (step 9) and macrophages (step 11), and is catabolized mainly in the liver

Question 7

why are raised triglycerides associated with increased blood coagulability

Answer 7

Raised TG’s are associated with small LDL particles and increased coaguability of blood due to increased plasma fibrinogen levels and factor VII activity

Question 8

which lipoproteins are atherogenic

Answer 8

Atherogenecity of LDL: Small LDL and oxidized LDL is more atherogenic

Smaller VLDL is atherogenic. In Type III hyperlipidaemia, chylomicron remnants and IDL can also can be taken up by macrophages

Question 9

cause of primary hyperlipidaemia

Answer 9

Most cases due to combination of increased
susceptibility(polygenic) and factors like
dietary fat and obesity. Metabolic effect is
overproduction of VLDL by the liver. This is
converted to LDL leading to overloading of LDL
receptors, decreasing its clearance from the blood.

Some people with have monogenic disorders like
familial hypercholesterolemia.

Question 10

Cause of Familial hypercholesterolemia (FH)

Answer 10

• Commonest monogenic hyperlipidemia
• Dominantly inherited.
• Heterozygous form affects 1:500 in Britain
• Caused by absent or defective cell surface receptors which mediate LDL uptake. Results in high levels of LDL particles in the circulation leading to premature atherosclerosis.

Question 11

sequelae of Familial Hypercholesterolemia

Answer 11

Homozygotes for the defect may get atherosclerosis in childhood.

Characterised by cutaneous xanthomata in childhood.

Cholesterol levels are usually >15mmol/L

Untreated patients will die before 30 yrs

Heterozygotes may present with CHD in their
30’s-40’s. Clinical signs include corneal arcus,
Xantholasmata and tendon xanthomata.

Question 12

what is Combined hypercholesterolaemia and hypertriglyceridaemia also known as

Answer 12

Type III disease

Question 13

what is Combined hypercholesterolaemia and hypertriglyceridaemia (Type III disease)

Answer 13

Associated with accelerated atherosclerosis

Cholesterol and triglyceride are raised

Clinical signs include xanthomata, striate palmar xanthomata and tuberoeruptive xanthomata.

Commonest defect is a mutation or polymorphism of the Apo E gene.

Associated with diabetes and hypothyroidism

Question 14

what is Primary hypertriglyceridaemia

Answer 14

Due to increased hepatic VLDL production with decreased triglyceride clearance.

Can be familial or secondary to other conditions e.g diabetes, alcohol, obesity.

Rare cause is lipoprotein lipase deficiency

Lipoprotein lipase is an enzyme responsible for metabolism of chylomicrons and VLDL.

Patients may have severe hypertriglyceridemia and may present with pancreatitis and hepatosplenomegaly in childhood.

Question 15

7 causes of Secondary hyperlipidaemia

Answer 15

1 - Excess alcohol – suspect in those with high triglyceride

2 - Uncontrolled Type I DM- raised triglycerides

3 - Type II DM – commonest abnormality high triglyceride
and decreased HDL cholesterol.

4 - Hypothyroidism- may present with hypocholesterolemia

5 - Nephrotic syndrome- hypercholesterolemia

6 - CKD

7 - OCP- increase TG, increased total cholesterol
Smoking – lowers HDL cholesterol.

Question 16

who should be screened for hyperlipidaemia

Answer 16

Who should be screened?

Patients presenting with CVD

Individuals with other cardiovascular risk factors e.g. diabetes, impaired glucose tolerance, hypertension, strong family history for premature cardiovascular disease, smoking, or family history/signs of hyperlipidaemia.

Question 17

what might one screen for to diagnose hyperlipidaemia

Answer 17

Strategies for screening:

Total cholesterol

Total cholesterol and HDL-cholesterol

Whole lipid profile: Total cholesterol, HDL-cholesterol, triglycerides and calculated LDL-cholesterol (this must be fasting)

Question 18

4 Patterns of hyperlipidaemia

Answer 18

Predominantly hypercholesterolemia

Predominantly hypertriglyceridaemia

Combined hyperlipidaemia

Low HDL-cholesterol

Question 19

describe the Management of hyperlipidaemia

Answer 19

1 - Secondary causes should be identified and treated

2 - Monogenic problems, specially FH should be identified and family screening recommended

3 - Dietary therapy: Aims: cutting the intake of cholesterol and saturated fat and may be increasing intake of mono-and polyunsaturated fatty acids. Advice on weight loss and on exercise. Other factors: soluble fibre, soy products, garlic, antioxidants

4 - Drug therapy

5 - Management of other risk factors, overall objective to decrease cardiovascular risk.

Question 20

Who should be treated with lipid lowering drugs ?

Answer 20

Statin therapy recommended for those with clinical
evidence of CHD (secondary prevention).

In those without evidence of CHD (primary prevention) the
benefit of lipid lowering therapy depends on overall risk, determined by all risk factors.

CVD risk can be calculated using a computer programme
or coloured charts

NICE recommend statin therapy is those with a 20% or greater than 10 year risk of CHD.

Question 21

Targets for treatment of hyperlipidaemia

Answer 21

Cholesterol < 5mmol/l (or reduce by 25%)

LDL cholesterol 1.1mmol/l in women
>1.0 mmol/l in men

Question 22

Drugs for hyperlipidaemia

Answer 22

1. Statins:
   Inhibit cholesterol synthesis
   Also lower TG’s and raise HDL-cholesterol but less effective than fibrates
   May cause derangement of liver function tests and muscle cramps. Rarely rhabdomyolysis

2 - Fibrates:  
Used to decrease serum triglycerides
Raise HDL-cholesterol
May cause myositis
Unsuitable for patients with liver problems

3.Others:
Several other classes of lipid-lowering drugs are in use