Hyperlipidaemia is the term used to denote raised serum levels of one or more of total cholesterol (TChol), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), or both TChol and TG (combined hyperlipidaemia).
Dyslipidaemia is a wider term that also includes low levels of high-density lipoprotein cholesterol (HDL-C). Many types of hyperlipidaemia carry an increased risk of cardiovascular disease (CVD). HDL-C confers protection. It is important as one of the three main modifiable risk factors for CVD (the others being smoking and hypertension).
- The UK population has one of the highest average serum cholesterol levels in the world.
- Two thirds of the UK population have a serum cholesterol level greater than 5.2 mmol/L.
- Low levels of HDL-C are often associated with raised TG levels (eg in familial combined hyperlipidaemia (FCH) and in dyslipidaemia in type 2 diabetes).
- Heterozygous familial hypercholesterolaemia (FH) is one of the most common familial conditions, with a prevalence of about 1 in 500. Homozygous FH is rare.
Epidemiological evidence suggests a:
- 1% increase in coronary heart disease (CHD) risk for each 1% increase in LDL-C.
- 2-3% reduction in CHD risk for each 1% increase in HDL-C.
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See separate articles Primary Prevention of Cardiovascular Disease and Secondary Prevention of Cardiovascular Disease.
- Inherited disorders:
- Familial dyslipidaemias.
- Familial hypercholesterolaemia (FH).
- Familial combined hyperlipidaemia (FCH).
- Apoprotein disorders - see separate article Apolipoproteins for further details.
- Secondary causes:
- Medical conditions, eg hypothyroidism, obstructive jaundice, Cushing's syndrome, anorexia nervosa, nephrotic syndrome, diabetes mellitus, and renal failure
- Drugs, eg thiazide diuretics, glucocorticoids, ciclosporin, antiretroviral therapy, beta-blockers, combined oral contraceptive pill, atypical antipsychotics, and retinoic acid derivatives.
- Alcohol abuse.
Fredrickson's Classification is now seldom used but listed five types of hyperlipidaemia (Fredrickson I to V).
Risk factor screening (including the lipid profile) may be considered in:
- Adult men ≥40 years of age.
- Women ≥50 years of age or postmenopausal, particularly in the presence of other risk factors. All patients with evidence of atherosclerosis in any vascular bed or with type 2 diabetes (irrespective of age), are regarded as being at high risk and their lipid profile should be assessed.
- Individuals with a family history of premature CVD also deserve early screening.
- First-degree relatives of individuals with a familial dyslipidaemia.
Patients with hyperlipidaemia of any cause but no history of CHD, angina, stroke, transient ischaemic attack (TIA), peripheral vascular disease, diabetes or a monogenic lipid disorder should have a formal cardiovascular risk assessment.
Patients with hyperlipidaemia who have such a history do not require a formal risk assessment but every effort should be made to minimise their risk.
See separate articles Primary Prevention of Cardiovascular Disease and Secondary Prevention of Cardiovascular Disease (document links under 'Aetiology', above) and the separate article How to use the Coronary Risk Prediction Charts for Primary Prevention for more information.
The condition is often diagnosed during routine screening, as part of a risk assessment associated with comorbidities or other risk factors (eg obesity, smoking), or the patient may present as a relative of an index case with premature CVD. Rarely, there may be a genetic cause. Most familial dyslipidaemias go undiagnosed but, if identified, can enable more effective prevention and treatment in individuals and their families - where suspected, refer to secondary care.
Although the diagnosis is primarily biochemical, two physical signs may be evident in patients with familial hypercholesterolaemia (FH):
- Premature arcus senilis - a white or gray opaque ring in the corneal margin.
- Tendon xanthomata - these are hard, nontender nodular enlargement of tendons. They are most commonly found on the knuckles and the Achilles tendons.
Familial hypercholesterolaemia (FH)
Suspect FH where:
- Adults have a raised total cholesterol (TChol) concentration (typically >7.5 mmol/L) and there is a personal or family history of premature CHD.
- Rule out secondary causes of hypercholesterolaemia.
- Do not rule out FH simply because physical signs such as tendon xanthomata are not present.
- Make a diagnosis using the Simon Broome criteria (see below).
- Check two fasting LDL-C measurements to confirm the diagnosis.
The Simon Broom diagnostic criteria:
- Definite FH is diagnosed if an individual has:
- A TChol level in an adult of >7.5 mmol/L (>6.7 mmol/L in a child) and an LDL-C of >4.9 mmol/L (>4.0 mmol/L in a child); PLUS
- Tendon xanthomata or evidence of these signs in a first-degree or second-degree relative; OR
- DNA evidence of an LDL receptor mutation, familial defective apo-B-100 or a PCSK9 mutation.
- Possible FH should be diagnosed if the cholesterol concentrations fit these criteria and the individual has at least one of the following:
- A family history of myocardial infarction in a second-degree relative aged 50 years or younger, or in a first-degree relative aged 60 years or younger.
- A family history of raised TChol greater than 7.5 mmol/L in adult first-degree or second-degree relatives or greater than 6.7 mmol/L in a child, brother or sister aged younger than 16 years.
Familial combined hyperlipidaemia (FCH)
This is the most common genetic dyslipidaemia, occurring in about 1 in 100 people but is usually polygenic in origin.
Lipid phenotypes in FCH vary considerably but suspect where:
- There is family history of hyperlipidaemia or premature CHD not due to FH.
- Moderate-to-severe mixed hyperlipidaemia (typically TChol 6.5-8.0 mmol/L and TG 2.3-5.0 mmol/L).
Before considering pharmacological treatment of dyslipidaemias, always try to identify and correct/optimise any secondary or contributory causes.
If possible, blood sampling should be made after 12-hour fasting, but this is requested only for the evaluation of TG, needed for the calculation of LDL-C with the Friedewald formula. A lipid profile includes:
- TChol: fasting samples are not strictly necessary. A mild or moderate elevation in LDL-C with a concomitant reduction in HDL-C can result in a normal TChol level, which can be misleading. A fasting sample should, however, be taken in patients who have non-fasting cholesterol levels that would require treatment, or who are being investigated for dyslipidaemia.
- LDL-C: a fasting sample is required for an accurate result. This is not a standardised test. The gold standard ultracentrifugal measurement of LDL-C is time-consuming and expensive and requires specialist equipment. For this reason, LDL-C is commonly estimated from quantitative measurements of TChol and HDL-C and plasma triglycerides (TGs) using the empirical relationship of Friedewald (all values in mmol/L):
LDL-C = (TChol) - (HDL-C) - (TG/2.2)
The Friedewald equation should not be used under the following circumstances:
- When chylomicrons are present.
- When plasma TG concentration exceeds 4.52 mmol/L.
- in patients with dysbetalipoproteinemia (type III hyperlipoproteinemia).
- HDL-C: 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-C is used in the coronary risk prediction charts.
- TGs: plasma TGs rise dramatically after a meal so a fasting sample is required.
- Fasting blood glucose: this should be done to exclude hyperlipidaemia secondary to diabetes mellitus.
- Renal function: this should be done to exclude chronic kidney disease.
- LFTs (transaminases): to rule out liver disease in the event of a statin having to be initiated (raised transaminases should not preclude the use of a statin if levels are less than three times the upper limit of normal).
- TSH: this should be done if dyslipidaemia is present, to exclude myxoedema.
The aim of treating hyperlipidaemia is to prevent or reduce the risk and complications of CVD. Such risk reduction includes nondrug measures (such as addressing lifestyle factors) and drug treatment using lipid-lowering therapy.
It should be noted that cardiovascular risks exceeding the 5-10% level may be found in elderly gentlemen based on age (and gender) only, even when other CV risk factor levels are relatively low. This could lead to excessive usage of drugs in the elderly and should be evaluated carefully by the clinician.
See separate Primary Prevention of Cardiovascular Disease article, Secondary Prevention of Cardiovascular Disease article and the separate article Lipid-regulating Drugs, which includes using fibrates in primary care.
- The INTERHEART study suggested that 45% of heart attacks in Western Europe are due to abnormal blood lipids.
- People with heterozygous familial hypercholesterolaemia (FH) have a four-fold increased risk of CHD.
- People with familial combined hyperlipidaemia (FCH) 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-C are also an independent risk factor for CHD.
- Suspected familial hypercholesterolaemia (FH):
- Offer referral to a lipid specialist if:
- Confirmation of diagnosis is needed or cascade testing (a method of identifying whether a person is at risk of a genetic condition, by a process of family contact tracing).
- A child or young person needing investigation for FH or who has been diagnosed with FH.
- An adult with FH is at very high risk of a coronary event because they have established CHD, a family history of premature CHD or two or more other cardiovascular risk factors (eg male gender, smoking, obesity, diabetes).
- Offer referral to a cardiologist if:
- A person has been diagnosed with homozygous FH (suspect adults with an LDL-C concentration greater than 13 mmol/L, children/young people with an LDL-C concentration greater than 11 mmol/L).
- A person with FH has symptoms or signs of possible CHD (refer urgently unless immediately life-threatening, in which case refer as an emergency).
- Asymptomatic children or young people with heterozygous FH do not routinely need to be referred.
- Offer referral to a lipid specialist if:
- Suspected familial combined hyperlipidaemia (FCH), ie 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 TChol greater than 10 mmol/L.
- Very severe hypertriglyceridaemia: triglycerides (TGs) greater than 10 mmol/L.
Further reading & references
- The Joint British Societies Cardiovascular Risk Assessor (V01.06), Heart Uk Website
- No authors listed; JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005 Dec;91 Suppl 5:v1-52
- European guidelines on cardiovascular disease prevention in clinical practice, European Society of Cardiology (2007)
- Jessani S, Watson T, Cappuccio FP, et al; Prevention of cardiovascular disease in clinical practice: The Joint British Societies' (JBS 2) guidelines. J Hum Hypertens. 2006 Jun 1.
- Familial hypercholesterolaemia, NICE Clinical Guideline (August 2008)
- No authors listed; Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486-97.
- Lipid modification - cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease, NICE Clinical Guideline (May 2008, amended May 2010)
- The Donald S. Fredrickson Papers, Profiles in Science, 2006
- Cardiovascular disease - statins, NICE (January 2006)
- Zech LA Jr, Hoeg JM; Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia. Lipids Health Dis. 2008 Mar 10;7:7.
- Appendix F Simon Broome Diagnostic criteria for index individuals and relatives, NICE Familial hypercholesterolaemia guidance (August 2008)
- Guidelines for the Management of Dyslipidaemias, European Society of Cardiology (2011)
- Friedewald WT, Levy RI, Fredrickson DS; Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972 Jun;18(6):499-502.
- Frost PH, Havel RJ; Rationale for use of non-high-density lipoprotein cholesterol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholesterol screening and assessment of risk and therapy. Am J Cardiol. 1998 Feb 26;81(4A):26B-31B.
- Yusuf S, Hawken S, Ounpuu S, et al; Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004 Sep 11-17;364(9438):937-52.
- Rees A; Familial hypercholesterolaemia: underdiagnosed and undertreated. Eur Heart J. 2008 Nov;29(21):2583-4. Epub 2008 Oct 7.
- Fung MA, Frohlich JJ; Common problems in the management of hypertriglyceridemia. CMAJ. 2002 Nov 26;167(11):1261-6.
- Peloso GM, Demissie S, Collins D, et al; Common genetic variation in multiple metabolic pathways influences susceptibility J Lipid Res. 2010 Sep 20.
|Original Author: Dr Huw Thomas||Current Version: Dr Hayley Willacy||Peer Reviewer: Prof Cathy Jackson|
|Last Checked: 28/09/2011||Document ID: 1397 Version: 27||© EMIS|
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