Lipid Metabolism and Lipoproteins

Lipid Metabolism

• Lipids are classified into three main biological classes: cholesterol (hydrocarbon rings), triglycerides (esters of glycerol and fatty acids), and phospholipids (hydrophobic tail with a hydrophilic head).
• Lipids need to be absorbed from the gastrointestinal tract and transported throughout the body via lipoproteins.
• Plasma cholesterol and triglycerides are major risk factors for cardiovascular disease. Severe hypertriglyceridaemia can lead to pancreatitis.

Lipoproteins

• Lipoproteins are spherical or disc-shaped structures with a hydrophobic core and a less hydrophobic coat.
• Apolipoproteins combine with lipids to form lipoproteins and act as enzyme cofactors or cell receptor ligands.
• Variations in lipid and apolipoprotein composition result in distinct classes of lipoprotein performing specific metabolic functions.
• Lipoproteins contain: free cholesterol, phospholipids, triglycerides, and cholesteryl esters.

Dietary Determinants of Plasma Cholesterol

• Dietary intake of saturated and trans-unsaturated fatty acids reduce LDL receptor levels.
• Dietary cholesterol has little effect on fasting cholesterol.
• Plant sterols and drugs that inhibit cholesterol absorption are effective because they reduce the re-utilization of biliary cholesterol.
• Excessive carbohydrate, fat, or alcohol intake can increase plasma triglycerides through different mechanisms.

Lipids and Cardiovascular Disease

• Plasma lipoprotein levels are modifiable risk factors for cardiovascular disease.
• Increased levels of atherogenic lipoproteins(especially LDL, IDL, and chylomicron remnants) contribute to atherosclerosis.
• A subpopulation of LDL particles contains apolipoprotein (a), sharing homology with plasminogen, forming lipoprotein (a) (Lp(a)), which is atherogenic due to carrying oxidized phospholipid.
• Following oxidation, apo B-containing lipoproteins are no longer cleared by normal mechanisms.
• HDL removes cholesterol from tissues to the liver, counteracting inflammation by modulating vascular adhesion.

Investigations

• Lipid measurements are performed for screening for primary or secondary prevention of cardiovascular disease, investigating patients with lipid disorders, and monitoring response to treatment.
• Non-fasting measurements of total cholesterol (TC) and HDL-C can estimate non-HDL-C.
• A 12-hour fasting sample is required to standardize TG measurement and calculate LDL-C using the Friedewald formula: LDL-C = TC – HDL-C – (TG/2.2mmol/L) or LDL-C= Total Cholesterol – HDL Cholesterol – (Triglycerides/5).
• The formula becomes unreliable when TG levels exceed 4 mmol/L (350 mg/dL).

Secondary Hyperlipidaemia

• Various conditions can cause secondary hyperlipidaemia, including drugs (e.g., diuretics, ciclosporin, glucocorticoids, androgens), nephrotic syndrome, anorexia nervosa, and type 2 diabetes, chronic renal disease, abdominal obesity, excess alcohol, and hepatocellular disease

Classification of Hyperlipidaemia

• Predominant hypercholesterolemia, familial hypercholesterolemia, predominant hypertriglyceridemia, lipoprotein lipase deficiency, familial hypertriglyceridemia, mixed hyperlipidemia, familial combined hyperlipidemia, dysbetalipoproteinemia are different types of hyperlipidemia with differing elevated lipid and lipoprotein results, associated CHD risks and pancreatitis risks.

Hypercholesterolaemia

• Hypercholesterolaemia is a polygenic disorder.
• Homozygosity leads to extensive xanthomas and precocious cardiovascular disease, often in childhood.
• Cardiovascular risk depends on LDL-C elevation, modified by factors like low HDL-C and high Lp(a).

Familial Hypercholesterolemia in Adolescence

• Statin treatment may be needed from age 10.
• Patients should be strongly advised against smoking.
• Adhering to medication is crucial for treatment success.

Hypertriglyceridaemia

• Hypertriglyceridaemia frequently involves polygenic factors, including alcohol intake, medications (e.g., B-blockers, retinoids), type 2 diabetes, impaired glucose tolerance, central obesity, and impaired bile acid absorption.
• High TG levels (>10 mmol/L) can increase the risk of acute pancreatitis. Symptoms include abdominal pain, pancreatitis, hepatomegaly, lipaemia retinalis, and eruptive xanthomas.

Mixed Hyperlipidaemia

• Mixed hyperlipidaemia involves the presence of both hypertriglyceridemia and elevated LDL-C, or IDL.
• This condition is often linked to type 2 diabetes, impaired glucose tolerance, and/or central obesity.
• Treatment for massive hypertriglyceridemia may reduce TG faster than cholesterol.

Principles of Management

• Lipid-lowering therapies are central to prevention and treatment of cardiovascular disease.
• Assessment of absolute cardiovascular risk and lifestyle optimization (diet and exercise) guide management strategies.
• Public health organizations provide thresholds for lipid-lowering therapy initiation.

Non-Pharmacological Management

• Patients with lipid abnormalities should receive medical advice and dietary counselling to reduce saturated/trans-unsaturated fat intake (<7-10% of total energy), cholesterol consumption (<250 mg/day), and replace saturated fat and cholesterol sources with leaner options.
• Increasing physical activity and reducing energy-dense foods can help maintain/lose weight.
• Adjusting alcohol intake and prioritising nutrient-dense foods like fruits, vegetables, and lean proteins can be beneficial.

Monitoring of Therapy

• Lipid-lowering therapy effects should be assessed 6 weeks after starting (12 weeks for fibrates).
• Regular monitoring of lipids, liver function tests (LFTs), creatine kinase (CK), weight, and blood pressure is important.
• Periodic assessment of cardiovascular risk is essential.

Pharmacological Management (Statins)

• Statins inhibit HMG-CoA reductase, decreasing cholesterol synthesis, up-regulating LDL receptor activity, and reducing LDL-C by up to 60%.
• They also decrease TG by up to 40% and increase HDL-C by up to 10%.
• They reduce intermediate metabolites (e.g. isoprenes). Protection against total and coronary mortality, stroke, and cardiovascular events is noted. Statins can cause myalgia, asymptomatic CK increase, myositis, and rhabdomyolysis.

Ezetimibe

• Ezetimibe inhibits intestinal cholesterol absorption, which results in an increase in hepatic LDL receptor production, leading to LDL-C reduction, often in combination with statins.
• Ezetimibe is well tolerated with favourable side effects.

Bile Acid Sequestering Resins

• Resins stop cholesterol from re-absorbing into the body. The liver has to make more bile acid, which uses stored cholesterol.
• Colestyramine, colestipol, and colesevelam reduce LDL-C in a manner that complements statins.

PCSK9 Inhibitors

• Monoclonal antibodies (e.g., evolocumab, alirocumab) neutralize PCSK9, enhancing LDL receptor activity and lowering LDL-C significantly (up to 50-60%).
• They are administered via subcutaneous injection.

Combination Therapy

• Treatment for hypercholesterolemia frequently requires a combination of diet and statins.
• Alternative medications (ezetimibe, plant sterols, or resins) may be used in patients who do not reach LDL targets with statins alone or who are intolerant of statins.

Fibrates

• Fibrates reduce triglycerides by up to 50% and increase HDL-C by up to 20%, but LDL-C changes can be variable.
• They are usually well-tolerated but may increase the risk of cholelithiasis (gallstones).

Fish Oils

• Intake of EPA and DHA (omega-3 fatty acids) from fish oils effectively reduces VLDL and TG levels.
• Changes in HDL-C can vary, while LDL-C is not usually affected.