5.2 Lipid Disease

What physiological factors affect serum levels?

Age (lipids rise through life, mainly LDL), gender (females have higher HDL, lower TG; oestrogen lowers LDL-C), body weight (TG and slightly cholesterol increase; HDL decreases), and physical activity (reduces TG, total cholesterol and LDL-C; increases HDL-C).

How does smoking affect lipid levels and cardiovascular risk?

Smoking lowers HDL cholesterol and also oxidises LDL, increasing its uptake by macrophages and promoting plaque formation.

What dietary factors raise or lower cardiovascular risk?

Saturated fats raise cholesterol and CHD risk; polyunsaturated fats (especially n-3 PUFAs) are protective. High carbohydrate intake raises TG and VLDL. Alcohol in moderation raises HDL and lowers LDL, but excess raises VLDL and TG.

Name the main cardiovascular risk factors and a remedy for each.

Male sex, age, smoking (→ cessation), high plasma LDL (→ diet + drugs), low HDL (→ exercise, cessation), hypertension (→ diet + drugs), obesity (→ attain ideal weight), sedentary lifestyle (→ exercise), diabetes (→ insulin + lipid-lowering if dyslipidaemia present).

What tissue complications arise from prolonged hyperlipidaemia?

Lipids accumulate in arterial intima causing atheromatous plaque formation and potential ischaemia; cholesterol can also deposit in subcutaneous tissues forming xanthomas (tendons, knees, hands) or corneal arcus around the eye.

What are the main types of hyperlipoproteinaemia and their underlying defects?

Type I: ↓ LPL or ApoC-II deficiency → chylomicrons ↑. Type IIa: ↓ LDL receptor → LDL ↑ (familial hypercholesterolaemia). Type IIb: VLDL overproduction → VLDL + LDL ↑. Type III: abnormal ApoE → IDL/remnants ↑. Type IV: ↑ VLDL production/↓ elimination → VLDL ↑. Type V: unknown → chylomicrons + VLDL ↑.

How does hyperlipidaemia appear visually in a serum sample?

A creamy white layer forms on top of the serum after it stands, representing excess chylomicrons or VLDL. This turbidity (lipaemia) is visible in a Tiger-top SST collection tube.

How do diabetes mellitus and alcoholism cause secondary dyslipidaemia?

Type 1 diabetes: no insulin → no TG uptake, increased TG mobilisation. Type 2: insulin resistance → reduced TG uptake, increased VLDL synthesis. Alcoholism: excess calories converted to fat, liver enzyme deficiencies → increased TG and VLDL.

Why does restricting dietary cholesterol not always lower plasma cholesterol?

When dietary cholesterol falls, endogenous cholesterol synthesis in the liver increases to compensate. More than two-thirds of cholesterol comes from synthesis, not diet.

What is the role of omega-3 vs omega-6 PUFAs in LDL quality?

Omega-6 PUFAs (n-6) are precursors of pro-inflammatory eicosanoids and are easily incorporated into LDL, increasing its susceptibility to oxidation. Omega-3 PUFAs (n-3) inhibit n-6 effects. A high n-6/n-3 ratio raises small dense oxidised LDL, worsening cardiovascular risk.

How do statins lower plasma cholesterol?

Statins are HMG-CoA reductase inhibitors. They reduce endogenous cholesterol synthesis and also upregulate LDL receptors in the liver, increasing LDL clearance from plasma. Examples: pravastatin, simvastatin.

What is the mechanism of bile acid sequestrants in cholesterol management?

Bile acid sequestrants (e.g. cholestyramine, colestipol) bind bile acids in the gut, promoting their excretion. The liver compensates by converting more cholesterol to bile acids and by upregulating hepatic LDL receptors, reducing plasma LDL-C.

How does nicotinic acid lower lipid levels?

Nicotinic acid decreases hepatic VLDL synthesis, which also reduces downstream LDL production.

What is the mechanism of PCSK-9 inhibitors (e.g. evolocumab)?

PCSK-9 normally binds to hepatic LDL receptors and marks them for lysosomal degradation. Evolocumab (a monoclonal antibody) blocks PCSK-9, preventing LDLR degradation. More receptors are recycled back to the hepatocyte surface, increasing LDL uptake and reducing plasma LDL by 50–60%.

Why did torcetrapib (CETP inhibitor) fail in clinical trials?

Although torcetrapib raised HDL-C and reduced LDL-C, clinical trials showed a 60% increase in deaths. It raised blood pressure and aldosterone levels and caused electrolytic disturbances. Additionally, the HDL produced was dysfunctional and did not improve reverse cholesterol transport.

Describe the initial steps of atherosclerosis.

Atherosclerosis begins with injury to the arterial intima (e.g. from hypertension or blood flow damage). LDL accumulates and becomes oxidised, stimulating an inflammatory response. Macrophages migrate into the intima, engulf oxidised LDL via scavenger receptors, and become lipid-filled foam cells.

What is a fatty streak and how does it progress to an atherosclerotic plaque?

Accumulating foam cells form a fatty streak in the artery wall. Foam cells secrete pro-inflammatory cytokines, which stimulate smooth muscle cell migration, proliferation, and secretion of collagen (fibrosis) and metalloproteinases, forming a fibrotic cap over the fatty core.

How does plaque rupture lead to a clinical event (e.g. MI)?

Metalloproteinases secreted by macrophages weaken the fibrotic cap. Cap rupture exposes tissue factor (coagulation factor III) to circulating coagulants, triggering thrombus (clot) formation. The clot can block blood flow, causing tissue ischaemia, damage, and death (e.g. myocardial infarction).

What are the two major driving factors in atherogenesis?

Elevated lipids (particularly LDL-C) and raised blood pressure are the two major factors. The characteristic lesion is a fibrous plaque with a lipid-rich necrotic core, reducing the vessel lumen to less than 25% of its original diameter.

What are xanthomas and arcus senilis, and what do they indicate?

Xanthomas are yellowish subdermal deposits of cholesterol-rich lipid that can form on tendons, palms, or elbows (e.g. palmar xanthoma, tuberoeruptive xanthoma). Arcus senilis is a yellow/white ring around the cornea. Both are clinical manifestations of prolonged hyperlipidaemia.

What are the desirable vs high-risk reference ranges for plasma lipids?

Total cholesterol: desirable < 5.2 mmol/L; CHD risk increases above 6.5 mmol/L; inherited disorders often > 7.8 mmol/L. Triglycerides: desirable < 2.3 mmol/L; pancreatitis risk at > 10 mmol/L. HDL-C: protective ≥ 1.4 mmol/L; increased CHD risk < 0.9 mmol/L.

How does oxidised LDL promote coronary artery disease?

Oxidised LDL (ox-LDL) has an increased negative charge, making it taken up by macrophage scavenger receptors (not normal LDL receptors). This leads to foam cell formation and insoluble cholesterol deposits in the plaque. Smoking oxidises LDL; antioxidants (vitamin E, carotenoids, flavonoids) can reduce LDL oxidation.

What is the relationship between HDL-C and arterial disease?

There is a negative correlation between HDL-C levels and arterial disease risk. HDL transports excess cholesterol from peripheral tissues back to the liver for excretion as bile salts (reverse cholesterol transport). Strenuous exercise and weight loss increase HDL-C.

What is familial hypercholesterolaemia (FH) and what causes it?

FH is caused by a defect in the gene for the LDL receptor (ApoB-100 receptor). Heterozygous FH affects ~1 in 500 (cholesterol ~2× normal); homozygous FH affects ~1 in 1,000,000 (cholesterol ~4× normal). It leads to very early-onset atherosclerosis, xanthomata, and corneal arcus.

What is familial combined hyperlipidaemia (FCH) and how is it managed?

FCH (0.5% prevalence) involves elevated cholesterol and triglycerides due to high rates of apoB100 and VLDL synthesis. Diagnosis requires family studies. Diet alone is insufficient; gemfibrozil (lipoprotein lipase stimulator) is used to reduce TG. FCH accounts for 1–20% of coronary artery disease cases.

What is remnant removal disease (Type III hyperlipoproteinaemia) and what is its genetic basis?

Also known as dysbetalipoproteinaemia, it is caused by a decreased affinity of the hepatic B/E receptor, leading to accumulation of VLDL and chylomicron remnants and raised cholesterol and TG. ApoE2/E2 isoform is the genetic basis (1% prevalence, but only 0.01% develop disease). ApoE4 is linked to Alzheimer's disease.