Hyperlipidaemia

Hyperlipidaemia is the term used to denote raised serum levels of one or more of total cholesterol, low-density lipoprotein cholesterol, triglycerides, or both total cholesterol and triglyceride (combined hyperlipidaemia). Dyslipidaemia is a wider term that also includes low levels of high-density lipoprotein cholesterol.¹ Many types of hyperlipidaemia carry an increased risk of cardiovascular disease (CVD). High-density-lipoprotein cholesterol (HDL-C) however confers protection. Generally the risk of CHD rises as the ratio of total cholesterol (TC) to HDL-cholesterol (HDL-C) rises.

• The UK population has one of the highest average serum cholesterol levels in the world.¹
• Two-thirds of people have a serum cholesterol level greater than 5.2 mmol/l.²
• Low levels of high-density lipoprotein cholesterol are often associated with raised triglyceride levels (e.g. in familial combined hyperlipidaemia, and in dyslipidaemia in Type 2 diabetes).
• Heterozygous familial hypercholesterolaemia is one of the most common familial conditions, with a prevalence of about 1 in 500. Homozygous familial hypercholesterolaemia is rare. Familial combined hyperlipidaemia occurs in about 1 in 100 people.³

Epidemiological evidence suggests a:⁴

• 1% increase in chd risk for each 1% increase in LDL cholesterol.
• 2-3% reduction in chd risk for each 1% increase in HDL cholesterol.

• Most patients with hyperlipidaemia are asymptomatic. Patients with hyperlipidaemia usually present with established vascular disease or a high cholesterol concentration discovered on screening.
• A very small proportion of patients will have signs of abnormal lipid levels:
  • Xanthelasma.
  • Tendon xanthomas (usually in familial hypercholesterolaemia).
  • Premature corneal arcus (this is far more often an incidental finding.
  • Eruptive xanthoma may occur secondary to hypertriglyceridaemia.

Secondary causes of hyperlipidaemia include:

• High cholesterol: hypothyroidism, obstructive jaundice, anorexia nervosa, nephrotic syndrome.
• High triglycerides: hepatitis, hepatobiliary disease, alcohol abuse, diabetes mellitus, drugs (e.g. isotretinoin, oestrogens), pregnancy, obesity, renal failure.
• Raised cholesterol and triglycerides: oral contraceptives, steroids, high doses of thiazides, pregnancy, multiple myeloma. Conditions that predominately cause hypertriglyceridaemia may also cause combined hyperlipidaemia, e.g. Type 2 diabetes mellitus, obesity.

• Total cholesterol: non-fasting samples can be used. A mild or moderate elevation in LDL-cholesterol with a concomitant reduction in HDL-cholesterol can result in a normal total cholesterol level, which can be misleading.
• LDL Cholesterol: a fasting sample is required for an accurate result. This is not a standardised test. The gold standard ultracentrifugal measurement of LDL is time consuming and expensive and requires specialist equipment. For this reason, LDL-cholesterol is commonly estimated from quantitative measurements of total and HDL-cholesterol and plasma triglycerides (TG) using the empirical relationship of Friedewald (all values in mmol/l):⁷

  LDL-cholesterol = (Total cholesterol) - (HDL-cholesterol) - (TG / 2.2)

  
  The Friedewald equation should not be used under the following circumstances: ⁸
  • when chylomicrons are present
  • when plasma triglyceride concentration exceeds 400 mg/dL (4.52 mmol/L)
  • in patients with dysbetalipoproteinemia (type III hyperlipoproteinemia).
• HDL Cholesterol: the measurement is not standardised and there are generally only small differences between normal and abnormal levels. However the ratio of total serum cholesterol:HDL cholesterol is used in the coronary risk prediction charts.
• Triglycerides: plasma triglycerides rise dramatically after a meal so a fasting sample is required.

Lipids are insoluble in plasma. They combine with special proteins called apoproteins (apolipoproteins) - to form lipoproteins which are soluble in plasma. There are some rare disorders of apoproteins which can also cause lipid disorders.⁹

The Friedrickson Classification (now seldom used) lists five types of hyperlipidaemia (Fredrickson I to V):

• Type I - Normal or slightly raised cholesterol with very high triglycerides, xanthoma, hepatosplenomegaly & pancreatitis. It is not usually associated with cardiovascular disease.
• Type IIa - High cholesterol with normal triglyceride levels, xanthoma, xanthelasma and corneal arcus. It is hereditary and carries a very high risk of premature cardiovascular disease.
• Type IIb - Similar to type IIa, raised cholesterol and triglycerides. It is also associated with premature development of arterial disease.
• Type III - Raised cholesterol and triglycerides, xanthomas, often associated with obesity, hyperuricaemia and an impaired GTT. There is an increased risk of coronary artery and peripheral vascular disease.
• Type IV - Raised triglycerides, atheroma, raised uric acid, xanthoma, liver and spleen enlargement and often an impaired GTT. It is induced by a high fat/carbohydrate diet and is associated with gout and nephrotic syndrome. It may be familial but more often is seen secondary to diabetes mellitus, obesity, pancreatitis, alcoholism and hypothyroidism.
• Type V - Raised triglycerides, xanthoma and often an abnormal glucose tolerance test. It is induced by a high fat/carbohydrate diet and may accompany diabetes mellitus, pancreatitis and alcoholism. It is not usually associated with premature cardiovascular disease.

Non-Drug

• Diet can decrease both cholesterol and triglycerides levels. It should be regarded as an adjunct therapy. A Mediterranean diet contains many of the dietary elements that are thought to be protective in CHD and includes replacing butter with olive oil and mono-unsaturated margarine, eating less red meat and more poultry, more fish, more bread (especially whole-grain bread), more root vegetables and green vegetables and more fruit.
• Other appropriate measures include weight reduction, regular physical exercise and, when appropriate, additional measures to reduce cardiovascular risk such as smoking cessation and blood pressure and blood glucose control.

Drugs

• Statins: (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin):
  • Are more effective than other classes of drugs in lowering LDL-cholesterol but less effective than the fibrates in reducing triglycerides.
  • Reduce coronary events, all cardiovascular events, and total mortality. They should be considered for all patients, including the elderly, at risk of cardiovascular disease such as those with coronary heart disease, peripheral vascular disease, non-haemorrhagic stroke or transient ischaemic attacks, or diabetes mellitus.
  • Statins produce benefits irrespective of the initial cholesterol concentration but patients with a total serum-cholesterol concentration of 5 mmol/litre or greater are likely to benefit most.¹¹
• Fibrates: bezafibrate, ciprofibrate, fenofibrate and gemfibrozil.
  • Mainly decrease serum triglycerides, with variable effects on LDL-cholesterol.
  • They may reduce the risk of coronary heart disease events in those with low HDL-cholesterol or with raised triglycerides.
  • All can cause a myositis-like syndrome, especially in patients with impaired renal function. There is an increased risk of rhabdomyolysis when used in combination with a statin.¹¹
  • Results from trials relating to use of fibrates in diabetic patients have been disappointing.
• Ezetimibe:
  • Inhibits the intestinal absorption of cholesterol.
  • It is licensed as adjunctive therapy to dietary manipulation in patients with hypercholesterolaemia in combination with a statin or alone (if a statin is inappropriate), in patients with homozygous familial hypercholesterolaemia in combination with a statin and in patients with homozygous familial sitosterolaemia (phytosterolaemia).¹¹
• Anion-exchange resins:¹¹
  • Cholestyramine and colestipol act by binding bile acids, preventing their reabsorption. The resultant increased LDL-receptor activity of liver cells increases the clearance of LDL-cholesterol.
  • Both drugs effectively reduce LDL-cholesterol but can aggravate hypertriglyceridaemia.
• Nicotinic acid:
  • Role in treatment is limited by its side-effects, especially vasodilatation.
  • Is licensed for use with a statin if the statin alone cannot adequately control dyslipidaemia (raised LDL-cholesterol, triglyceridaemia, and low HDL-cholesterol).
  • It can be used alone if the patient is intolerant of statins.
  • Acipimox has fewer side-effects than nicotinic acid but may be less effective in its lipid-modulating capabilities.¹¹
• Omega-3 fatty acid compounds: ¹¹ (fish oils). These can be used with a statin, as an alternative to a fibrate¹¹:
  • Maxepa: is rich in omega-3-marine triglycerides and is useful in the treatment of severe hypertriglyceridaemia. It may aggravate hypercholesterolaemia and should be used with caution in diabetes.
  • Omacor contains omega-3-acid ethyl esters and is licensed for hypertriglyceridaemia and secondary prevention after myocardial infarction.
• Plant sterols and stanols:³
  • These may be beneficial for patients with hyperlipidaemia (typically available as additions in margarine, yoghurts and milk drinks)
  • Recommend up to 2.5 g of plant sterols or stanols in the daily diet.
  • This can reduce plasma LDL cholesterol by about 10% .
  • Avoid if pregnant, breast feeding and in children.^3,11

Other Notes

• Severe hyperlipidaemia often requires a combination of lipid-regulating drugs such as a statin with ezetimibe or with a fibrate. Such treatment should generally be under specialist supervision.
• Combinations of a statin with nicotinic acid or a fibrate carry an increased risk of side-effects (including rhabdomyolysis) and should be used with caution. Gemfibrozil and statins should not be used together.¹
• Correction of hypothyroidism itself may resolve the lipid abnormality. Untreated hypothyroidism increases the risk of myositis with lipid-regulating drugs.

• About 46% of deaths due to coronary heart disease (CHD) may be attributable to raised serum cholesterol.³
• People with heterozygous familial hypercholesterolaemia have a four-fold increased risk of CHD.
• People with familial combined hyperlipidaemia also have an increased risk of CHD, but CHD usually only presents after the age of 60 years.
• Very severe hypertriglyceridaemia (more than 10 mmol/l) is a risk factor for pancreatitis.
• Decreased levels of serum HDL cholesterol (HDL-C) are also an independent risk factor for CHD.

These include:

• Suspected familial hypercholesterolaemia: TC greater than 7.5 mmol/l (or LDL-C greater than 4.9 mmol/l) and at least one of the following:
  • Tendon xanthomata in patient or in a first- or second-degree relative
  • Family history of premature coronary heart disease
  • Family history of TC greater than 7.5 mmol/l
• Suspected familial combined hyperlipidaemia, i.e. mixed hyperlipidaemia and a family history of hyperlipidaemia or premature CHD
• Failure of therapy: failure to meet target lipid reduction despite maximally tolerated therapy
• Severe hypercholesterolaemia: initial TC greater than 10 mmol/l
• Very severe hypertriglyceridaemia: triglycerides greater than 10 mmol/l

EMIS is grateful to Dr Colin Tidy, Dr Huw Thomas and Dr Jim McMorran for updating this article. The final copy has passed peer review of the independent Mentor GP authoring team. Record last amended and reviewed July 2006.