For most people with a primary dyslipidaemia, good cholesterol control is readily achieved with current therapies, of which statins are the mainstay.1 However, clinicians must always consider the possibility of a familial cause, especially in those patients with a strong family history of coronary heart disease (CHD).2 Abnormalities in plasma lipoprotein concentrations are found in seven of out every 10 patients with premature coronary disease, with a familial disorder in more than half of these cases. Unfortunately, inherited lipid disorders are commonly underdiagnosed in practice. With accurate diagnosis, therapeutic lifestyle changes and instigation of appropriate lipid-lowering therapy, major cardiovascular complications can be prevented, highlighting the importance of early identification and treatment of affected family members.3
Accurate diagnosis depends on careful assessment of:
- personal and family history
- clinical signs and laboratory tests (features which together define the phenotype)
- exclusion of secondary causes by appropriate investigation before inherited conditions are sought.
It is important to recognise secondary causes of dyslipidaemia as these are easily overlooked and lipid lowering drug treatment may not be appropriate. Uncontrolled diabetes mellitus, hypothyroidism, nephrotic syndrome, cholestastatic liver disease and alcohol overuse are all associated with hyperlipidaemia and must be excluded by history, examination and baseline biochemical tests (table 1). The pattern of lipoprotein disturbance varies and in some cases may be pathognomonic, such as the appearance of lipoprotein-X (Lp-X). Lipoprotein-X is an abnormal lipoprotein found in the sera of patients with obstructive jaundice (table 1).
In addition, a wide range of medications may commonly cause dyslipidaemia, including:
• atypical antipsychotics, corticosteroids and ciclosporin, which increase cholesterol and triglycerides
• beta blockers, HIV/antiretroviral drugs, oestrogens and retinoids, which increase triglycerides
• anabolic steroids, which lower high-density lipoprotein (HDL) cholesterol.
Take a look at case scenario 1 in the box below which illiustrates the importance of considering secondary causes of dyslipidaemia.
In the absence of secondary causes, a strong family history of premature CHD is suggestive of an atherogenic familial lipid disorder (table 2). Of all the inherited high cholesterol conditions, familial hypercholesterolaemia (FH) is the best recognised, with an estimated prevalence in Caucasians of one in 500 (0.2%). This means that in the UK, about 120,000 people have FH.4 However only around 20,000 or so cases have been identified. FH is present from birth and almost all affected people are heterozygotes (HeFH). Homozygous FH (HoFH) is extremely rare (~one in one million).5
Recent data suggest that the prevalence of FH may be considerably higher than one in 500, perhaps as high as one in 200. 6
Low-density lipoprotein (LDL) cholesterol levels in individuals with HeFH are typically double normal levels from birth, reaching in adulthood, the range of 5–10 mmol/L.2 The much rarer HoFH and compound heterozygous forms should be suspected in those with an LDL-C greater than 13 mmol/L.
HeFH increases the risk of premature CHD dramatically, with a cumulative risk of 50% in men by age 50 and 30% in women by age 60.4 If affected individuals are not diagnosed and treated, 50% of men and 15% of women will have developed symptomatic coronary artery disease by age 50. 4 If HeFH individuals are diagnosed and treated, they can look forward to a normal life expectancy.3 In HOFH, however, severe aorto-coronary disease may be found in childhood and as response to lipid-lowering therapy is poor, LDL-apheresis is required. 6
Causes of FH
FH is due to a genetic mutation affecting the LDL-receptor pathway.7 FH may be caused by mutations in genes coding for the LDL-receptor (LDLR), apolipoprotein (apo) B100 (the LDL-receptor ligand), and a protease known as proprotein convertase subtilisin/kexin type 9 (PCSK-9), which is involved in the regulation of LDL-receptor recycling.As FH is inherited as an autosomal co-dominant condition, 50% of first-degree relatives and 25% of second-degree relatives will be affected.
The finding of tendon xanthomas (TX) confirms the clinical diagnosis of definite FH according to the Simon Broome criteria (table 3). In addition to its diagnostic significance, the presence of this clinical sign is also associated with a significant increase in cardiovascular disease risk across all age groups.8 Although TX are found in fewer than 30% of cases, most of those with TX have monogenic FH with a disease defining mutation in LDLR, apoB or PCSK9 genes (figure 1).4
Although other as yet undiscovered genes may account for some cases of monogenic FH, the absence of a mutation suggests the likelihood of polygenic hypercholesterolaemia, which does not usually show a clear dominant pattern of inheritance. The National Institute for Health and Care Excellence (NICE) guidelines4 recommend DNA analysis for confirmation of the diagnosis in the index case and family cascade testing where the mutation has been identified, to ensure unequivocal diagnosis in affected family members (table 3). If no mutation is identified or genetic testing is not available, affected relatives can be identified on the basis of age- and sex-specific LDL-C thresholds (as recommended by NICE) but in up to one third of cases it may not be possible to make a firm diagnosis, making this approach much less efficient. 4
Underdiagnosis of FH is a major problem, with estimates suggesting that less than 25% of people are diagnosed.4 As FH is readily treatable with statins,3 there is clearly a role for primary care in the diagnosis and identification of affected family members with FH. From a GP perspective, the average group practice of 10,000 patients, will have around 20 cases of FH. This sounds low but because FH is such an important cause of premature cardiac death, and the likelihood that some individuals will develop heart problems or die from cardiovascular causes prematurely in their thirties, forties or fifties, makes identifying these patients a priority.
Great strides are being made by HEART UK – The Cholesterol Charity and the British Heart Foundation (BHF) to increase awareness of FH. Both charities produce useful and practical booklets on the condition.
A nationwide, proactive, systematic approach to cascade testing (identifying people at risk for a genetic condition by tracing it through their family) is recommended in guidelines,2,4 but commissioning support for implementation is lacking in most parts of the UK.
National FH services have been established in Northern Ireland, Scotland and Wales. In England there is a renewed interest in implementation of an FH service. The Cardiovascular Disease Outcomes Strategy aims for approximately 50% of English people with FH to be diagnosed and treated appropriately with potent statins.9 NICE also published FH quality standards in 2013.10 Yet, despite this, there were no population-based cascade testing programmes in England at the beginning of 2013 since Clinical Commissioning Groups (CCGs) consider new FH services to be unaffordable given existing spending commitments and the need to make savings.11
If you would like to learn more about FH, watch our podcast.
A mixed lipid profile showing raised total cholesterol, triglycerides or both can be suggestive of a number of dyslipidaemias. These include:
- familial combined hyperlipidaemia (FCH)
- remnant hyperlipidaemia (Type III or familial dysbetalipoproteinaemia)
- dyslipidaemia associated with the metabolic syndrome,
- milder presentations of familial hypertriglyceridaemia.
All appear to show a common genetic basis, with an increased burden of common triglyceride raising gene variants conferring susceptibility to adverse lifestyle and secondary causes such as obesity.
FCH affects about one in 100 people. 1 The underlying mechanism involves overproduction of very-low-density lipoprotein (VLDL) and apoB. The genetic basis is complex influenced by environmental factors. As there is considerable variability in presentation, diagnosis can often be missed in practice. FCH should be suspected if total cholesterol levels are in the range 6.5–9.0 mmol/L and/or triglycerides between 2.3 and 5.0 mmol/L (table 4).
Elevated levels of cholesterol and triglyceride, either alone or in combination, in patients and other family members confer a ‘variable phenotype’. ApoB is invariably elevated and is, therefore, a useful diagnostic tool, with levels >1.20 g/L, together with elevated triglycerides and family history of cardiovascular disease, strongly suggestive of the diagnosis.6 The finding of an apoB concentration that is unexpectedly low (apoB/total cholesterol ratio <0.15 g/mmol) raises suspicion of remnant hyperlipidaemia.12 The presence of xanthelasma (figure 2) is not of specific diagnostic significance but is more frequently seen in FCH and represents an area of lipid-laden macrophages, which is independently predictive of an increased risk of CHD, atherosclerosis and mortality.13
Case scenario 2 in the box below describes how to differentiate familial causes of combined hyperlipidaemia.
Patients with severely elevated triglycerides (>10 mmol/L) have significant accumulation of chylomicrons in the fasting state and are at greatly increased risk of pancreatitis (figure 3). Like those with mild to moderate hypertriglyceridaemia, most of these patients have underlying polygenic defects of triglyceride clearance with but with additional secondary precipitating factors (table 1). However those presenting with severe disease at a young age or recurrent pancreatitis in childhood are more likely to have an underlying monogenic cause. Once secondary causes have been addressed dietary fat restriction is the cornerstone of management. Treatment with statins may be ineffective and most patients with predominant hypertriglyceridaemia respond better to fibrate drugs.
Clearly the full lipid profile is key to diagnosis of dyslipidaemia. The baseline lipid evaluation should comprise total cholesterol, triglycerides and HDL cholesterol.14 Because total cholesterol involves measurement of both atherogenic (LDL-, intermediate-density lipoprotein [IDL]- and VLDL cholesterol) and anti-atherogenic (HDL cholesterol) lipid fractions, it is inadequate for monitoring treatment. Instead, LDL- and non-HDL cholesterol are preferred.
Of the two, there is a strong case for preferential use of non-HDL cholesterol, given that:
- it is a simple calculation (non-HDL cholesterol = total cholesterol – HDL cholesterol)
- it can be readily measured in non-fasting samples.15
In contrast, LDL cholesterol must be measured in fasting samples. Its calculation assumes a constant cholesterol/triglyceride ratio in VLDL of 0.45. This assumption does not hold in non-fasting conditions or when the fasting triglyceride concentration exceeds 4.5 mmol/L.2 Furthermore, the ratio is altered by statin treatment. Therefore, the main role for calculated LDL cholesterol is in assessment of suspected FH before treatment.
Non-HDL cholesterol represents the total sum of cholesterol in apoB-containing lipoproteins. This includes lipoprotein(a) (Lp[a]), which comprises a cholesterol-rich LDL particle with one molecule of apo B100 and an additional plasminogen-like protein, apolipoprotein(a).
Elevated Lp(a) is associated with increased risk of cardiovascular disease, particularly if levels exceed 50 mg/dL (500 mg/L or 125 nmol/L) where the risk of myocardial infarction is increased two- to three-fold.6 The association between elevated Lp(a) and increased cardiovascular disease risk appears continuous and independent of LDL cholesterol levels. On this basis, a position statement from the European Atherosclerosis Society16 has recommended measurement of Lp(a) in people with a personal or family history of premature cardiovascular disease and in those with recurrent events despite statin treatment. There is no specific treatment available to lower Lp(a) currently apart from LDL-apheresis (figure 4).
Although there has been much debate concerning the role of other novel risk factors such as the systemic inflammatory biomarker C-Reactive Protein, measured by a high sensitivity assay (hsCRP), the currently available evidence suggests that these add little and are not recommended for use in routine assessment of CVD risk in UK guidelines (NICE CG181 and JBS3).
Abnormalities in the lipid profile can arise from secondary causes or can be caused by genetic and environmental factors. Known secondary causes of dyslipidaemia are easily identified on routine clinical chemistry and it is important to treat the underlying cause in such cases. Familial forms of dyslipidaemia are common and are underdiagnosed and undertreated. In particular FH features elevated total and LDL serum cholesterol levels and places patients at greatly elevated risk of premature coronary artery disease. More rare and severe causes of dyslipidaemia such as HoFH can cause advanced aorto coronary atherosclerosis earlier in life and often require removal of lipid particles by advanced therapies such as serum apheresis. Combined hyperlipidaemia arises where elevations of triglyceride are seen in tandem with elevations in total and LDL cholesterol. Hypertriglyceridaemias have mixed monogenic or polygenic aetiology and place patients at risk of developing pancreatitis when severe.
- Diagnosis of dyslipidaemia should involve a thorough clinical assessment. Secondary causes of dyslipidaemia should be excluded
- LDL cholesterol is important in the diagnosis of familial hypercholesterolaemia; apoB is diagnostic in mixed dyslipidaemia
- Measurement of lipoprotein(a) should be considered in patients with premature coronary heart disease
- Systemic inflammatory risk markers add little to risk assessment
1. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769–818. http://dx.doi.org/10.1093/eurheartj/ehr158
2. Genest JJ Jr, Martin-Munley SS, McNamara JR et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992;85:2025–33.
3. Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DCG, Liem AH, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008;337:a2423.
4. National Collaborating Centre for Primary Care. CG71 Familial hypercholesterolaemia: full guideline. Identification and management of familial hypercholesterolaemia (FH). August 2008. Available from: http://guidance.nice.org.uk/CG71/Guidance/pdf/English [accessed 13 December 2011].
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8. Civeira F, Castillo S, Alonso R et al.; Spanish Familial Hypercholesterolemia Group. Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene mutation. Arterioscler Thromb Vasc Biol 2005;25:1960–5. http://dx.doi.org/10.1161/01.ATV.0000177811.14176.2b
9. Department of Health. Cardiovascular disease outcomes strategy. London: Department of Health, 2013. http://www.dh.gov.uk/publications
10. National Institute for Health and Care Excellence. Familial hypercholesterolaemia. NICE quality standard 41. London: NICE, 2013. www.nice.org.uk/guidance/qs41
11. Pears R, Griffin M, Watson M. The reduced cost of providing a nationally recognised service for familial hypercholesterolaemia. Open Heart 2014;1:e000015. http://dx.doi.org/10.1136/openhrt-2013-000015
12. Blom DJ, O’Neill FH, Marais AD. Screening for dysbetalipoproteinemia by plasma cholesterol and apolipoprotein B concentrations. Clin Chem [Internet] 2005;51:904–7.
13. Christoffersen M, Frikke-Schmidt R, Schnohr P et al. Xanthelasmata, arcus corneae, and ischaemic vascular disease and death in general population: prospective cohort study. BMJ 2011;343:d5497. http://dx.doi.org/10.1136/bmj.d5497
14. National Institute for Health and Care Excellence. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. London: NICE, 2014. www.nice.org.uk/guidance/cg181
15. The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000. http://dx.doi.org/10.1001/jama.2009.1619
16. Nordestgaard BG, Chapman MJ, Humphries SE et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90a. http://dx.doi.org/10.1093/eurheartj/ehj273
Watts GF, Gidding S, Wierzbicki AS et al. Integrated guidance on the care of familial hypercholesterolaemia from The international FH Foundation. Int J Cardiol 2014;171:300-325. http://dx.doi.org/10.1016/j.ijcard.2013.11.025 Epub 2013 Nov 20.