Lipids module 3: clinical diagnosis of dyslipidaemia

Introduction
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).

Table 1. Key tests to exclude secondary causes of dyslipidaemia

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.

Case scenario 1
Consider secondary causes of dyslipidaemia
Carol, a 49-year-old teaching assistant, was referred to the lipid clinic following admission with acute chest
pain (subsequently considered non-cardiac, cardiac troponin negative). Her total cholesterol at the time of
admission was 10.0 mmol/L. She had previously undergone thyroidectomy and radio-iodine ablation for
papillary thyroid cancer. She had a history of hypertension (blood pressure [BP] 126/80 mmHg), was
overweight (body mass index [BMI] 30.1 kg/m2), physically active, a moderate drinker (10 units per week),
ex-smoker, and dietary assessment indicated scope for improvement. Both parents had type 2 diabetes and
hypercholesterolaemia but no clinical cardiovascular disease. She was discharged on simvastatin 40 mg/day,
aspirin 75 mg/day, levothyroxine 125 g/day and lisinopril 5 mg/day. There was no evidence of stigmata
associated with hyperlipidaemia.
At the clinic one month later, her total cholesterol was 5.2 mmol/L (low-density lipoprotein [LDL] cholesterol
3.7 mmol/L, triglycerides 1.3 mmol/L, high-density lipoprotein [HDL] cholesterol 1.2 mmol/L) and thyroid
profile was within the target range for suppressive treatment (thyroid stimulating hormone [TSH] <0.05
mU/L, free thyroxine [FT4] 25.2 pmol/L). As post-ablation hypothyroidism was considered a possible cause of
her dyslipidaemia on admission, simvastatin was withdrawn to reassess her lipid profile. On repeat lipid
testing one month later, her total cholesterol was 6.3 mmol/L (LDL cholesterol 4.5 mmol/L, triglycerides 1.5
mmol/L and HDL cholesterol 1.0 mmol/L). Her Framingham 10-year cardiovascular risk was estimated at
13%. Carol was advised to continue with therapeutic lifestyle interventions and return for repeat lipid testing
in six months.
Learning point
This case scenario highlights the importance of considering secondary causes of dyslipidaemia
before instigating lipid-modifying treatment. Carols hypothyroidism due to radio-iodine ablation
was the probable cause of dyslipidaemia. Following commencement of levothyroxine her TSH
and FT4 levels normalised and her cholesterol returned to more normal levels, and these were
maintained after stopping statin therapy.

Familial hypercholesterolaemia
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

Table 2. Prevalence of common genetic dyslipidaemias in people of European origin.

Derived from the ESC/EAS guidelines(2)

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 510 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.
Clinical diagnosis

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
Table 3. Diagnostic criteria for familial hypercholesterolaemia in adults (Simon
Broome Register Criteria)(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
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.
 HEART UK Familial hypercholesterolaemia: an educational booklet for people with
FH
British Heart Foundation Life with familial hypercholesterolaemia

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

Combined hyperlipidaemia
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.

Table 4. Lipid profile associated with familial combined hyperlipidaemia(2)

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 6.59.0
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

Figure 2. showing: panel a) corneal arcus (cholesterol ring in the eye); panel b) under
the eye. Xanthelasma represent areas of lipid-laden macrophages and the presence of
these is predictive of an increased risk of coronary heart disease, atherosclerosis and
mortality

Case scenario 2 in the box below describes how to differentiate familial causes of combined
hyperlipidaemia.
Case scenario 2
Differentiating familial causes of combined hyperlipidaemia
Derek, a 40-year-old former RAF engineer, was referred to the lipid clinic after recent admission to the Rapid
Access Chest Pain Clinic with burning central chest pain (exercise electrocardiogram [ECG] was negative).
Simvastatin was initiated by the clinician but Derek later stopped this due to severe headache and fatigue.
Derek was a non-smoker, physically active, a light drinker (46 units per week), was overweight (BMI 29.5
kg/m2) and had well-controlled blood pressure (136/84 mmHg), and normal renal, hepatic and thyroid
function. Fasting glucose was 4.7 mmol/L. There was no family history of cardiovascular disease. However,
there was evidence of xanthelasma together with elevated fasting total cholesterol (8.1 mmol/L), although
triglycerides were near normal range (1.8 mmol/L). On a repeat fasting test one month later, both were
higher (8.4 mmol/L total cholesterol and 3.4 mmol/L triglycerides). HDL cholesterol was within normal limits
(1.4 mmol/L).
Learning point
This case scenario highlights the variable phenotype of the lipid abnormality in combined
dyslipidaemia and the limitations of family history. The first profile is suggestive of possible
familial hypercholesterolaemia, the second suggests that a diagnosis of combined dyslipidaemia
typically associated with metabolic syndrome may be more likely. At least two lipid profiles are
required to make a diagnosis.
Severe hypertriglyceridaemia
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.
 Figure 3. Eruptive xanthomata are characteristic of extreme hypertriglyceridaemia

Lipid profiles
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).
Lipoprotein (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).

Figure 4. LDL-apheresis
 Summary
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.
Key messages
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

References
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;32:1769818.
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;85:202533.
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].
5. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous
familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004;160:40720.
http://dx.doi.org/10.1093/aje/kwh236
6. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor:
current status. Eur Heart J 2010;31:284453. http://dx.doi.org/10.1093/eurheartj/ehq386
7. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial
hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007;4:21425.
http://dx.doi.org/10.1038/ncpcardio0836
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;25:19605. 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, ONeill FH, Marais AD. Screening for dysbetalipoproteinemia by plasma cholesterol
and apolipoprotein B concentrations. Clin Chem [Internet] 2005;51:9047.
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;302:19932000. 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
Recommended reading:
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.