Lipids module 3: clinical diagnosis of dyslipidaemia

Released17 March 2021     Expires: 17 March 2023      Programme:

Sponsorship Statement: Novartis has provided sponsorship to support the latest revision of this e-learning programme. The content has been independently written by leading UK experts. Novartis had no input into the writing of the modules and had no editorial control over the content.

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Introduction

Table 1. Different types of dyslipidaemia

Class of dyslipidaemia Lipid pattern
Hypercholesterolaemia ↑ total cholesterol
↑ low density lipoprotein cholesterol
Hypertriglyceridemia ↑ triglyceride levels
Mixed dyslipidaemia ↑ total cholesterol and
↑ triglyceride levels

Dyslipidaemias can be considered as a primary lipid disorder or secondary to an underlying disease or medication. They can be further subcategorised based on the pattern of lipoprotein disturbance observed on lipid profiling (table 1), which is important when considering the underlying cause.

For most people with a primary dyslipidaemia (see table 2), good cholesterol control is readily achieved with current therapies, of which statins are the mainstay of initial pharmacological treatment.1,2 However, clinicians must always consider the possibility of a familial cause, especially in those patients with premature atherosclerosis as well as a strong family history of vascular and coronary heart disease (CHD).3 Abnormalities in serum  lipoprotein concentrations are found in seven out of every 10 patients with premature coronary disease, with a familial disorder in more than half of these cases. Unfortunately, inherited lipid disorders may not be identified early and are commonly underdiagnosed in routine practice.

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

Disorder Abnormal lipids Prevalence
Familial combined hyperlipidaemia (FCH) ↑ LDL cholesterol, ↑ triglycerides (VLDL) or both 1:100
Heterozygous familial hypercholesterolaemia (HeFH) ↑ LDL cholesterol
(typical range 5–10 mmol/L in HeFH and 10–20 mmol/L in HoFH)
↑ Apo B
1:250
Homozygous familial hypercholesterolaemia (HoFH) 1:1,000,000
Polygenic hypercholesterolaemia 1:50
Familial hypertriglyceridaemia 1:100
Key: apoB = apolipoprotein B; LDL = low-density lipoprotein; VLDL = very-low-density lipoprotein
Derived from the European Society of Cardiology/European Atherosclerosis Society guidelines1

Accurate diagnosis is dependent upon careful assessment of personal as well as family history, physical examination, laboratory investigation and adequate exclusion of secondary causes prior to evaluating for inherited conditions (figure 1).

Lipids module 3 - Figure 1. Key methods of assessment in the accurate diagnosis of lipid disorders
Figure 1. Key methods of assessment in the accurate diagnosis of lipid disorders

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.4

Secondary dyslipidaemias

Table 3. Key tests to exclude secondary causes of dyslipidaemia

Disorder Biochemical test
Diabetes HbA1c
Chronic kidney disease Renal profile (sodium, potassium, urea, creatinine, eGFR)
Nephrotic syndrome Dipstick urinary protein
Liver failure Liver profile (ALT, AST, GGT, albumin)
Hypothyroidism Thyroid profile
Key: ALT = alanine transaminase; AST = aspartate transaminase ; eGFR = estimated glomerular filtration rate;
GGT = gamma-glutamyl transpeptidase; HbA1c = glycated haemoglobin

It is important to recognise secondary causes of dyslipidaemia for these are easily overlooked and lipid-lowering drugs may not be appropriate, and the treatment of the underlying condition should be the primary focus of management. Uncontrolled diabetes mellitus, hypothyroidism, nephrotic syndrome, cholestatic liver disease and alcohol overuse are all commonly associated with hyperlipidaemia. Renal, hepatic and endocrine disease should be excluded on initial assessment by history, examination and baseline biochemical tests (table 3). As shown in table 4, the pattern of lipoprotein disturbance also varies according to the underlying secondary cause. In some cases it may be pathognomonic, such as the appearance of lipoprotein-X (Lp-X) which is an abnormal lipoprotein found in the sera of patients with obstructive jaundice.

Table 4. Possible changes in lipoprotein levels seen in secondary causes of dyslipidaemia5,6

Disorder Lipoprotein disturbance
↑ LDL-C ↓ HDL-C ↑ Triglycerides ↑ Lipoprotein (a)
Acromegaly
Alcohol excess
Anorexia nervosa
Cholestasis
Chronic kidney disease
Cushing’s syndrome
Hyperthyroidism
Hypothyroidism
Menopause
Nephrotic syndrome
Obesity
Polycystic ovary syndrome
Type 1 and 2 diabetes
Key: LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol

In addition, a wide range of medications may commonly cause dyslipidaemia and variable patterns of lipoprotein disturbance can also be observed according to the class of drug (table 5). Hence, it is important to take into consideration the medication history when evaluating a patient with dyslipidaemia.

Table 5. Medications that can cause dyslipidaemia and their pattern of disturbance

Class of medication Lipoprotein disturbance
Atypical antipsychotics
Corticosteroids
Ciclosporin
↑ Cholesterol and triglyceride levels
Beta blockers
HIV / antiretroviral drugs
Oestrogens
Retinoids
↑ Triglyceride levels
Anabolic steroid ↓ High-density lipoprotein (HDL) cholesterol levels

Take a look at case scenario 1 in the box below which illustrates the importance of considering secondary causes of dyslipidaemia.

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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 μg/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. Carol’s 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

Prevalence

In the absence of secondary causes, a strong family history of premature CHD is suggestive of an atherogenic familial lipid disorder. Of all the inherited high cholesterol conditions, familial hypercholesterolaemia (FH) is the best recognised, with an estimated prevalence in Caucasians of one in 250 (0.4%).7 This is twice as high as previously thought and means that in the UK, between 130,000 to 260,000 people have FH.4 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, with a prevalence of one in one million.8

FH is characterised by elevated serum low-density lipoprotein (LDL) cholesterol levels and associated with accelerated atherosclerosis and premature cardiovascular disease. LDL cholesterol levels in individuals with HeFH are typically double normal levels from birth, reaching in adulthood the range of 5–10 mmol/L.3 In HoFH, the presence of two pathogenic alleles can increase serum LDL cholesterol to four times the mean for age and gender.9 Hence, the much rarer HoFH and compound heterozygous forms should be suspected in those with a pre-treatment LDL cholesterol greater than 13 mmol/L in adults and 11 mmol/L in children.1,2,9

HeFH increases the risk of premature CHD dramatically, by over 50% in men and at least 30% in women.10 If affected individuals are not diagnosed and treated, 50% of men and 15% of women will have developed symptomatic coronary artery disease by the age of 50.2 If HeFH individuals are diagnosed and treated, they can look forward to a normal life expectancy.4 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.11

Causes of FH

FH is primarily inherited in an autosomal codominant manner and is due to a genetic mutation affecting the LDL-receptor pathway.12 FH may be caused by a loss-of-function mutation in genes encoding the LDL-receptor (LDLR) or apolipoprotein (apo) B100 (the LDL-receptor ligand), leading to reduced hepatic uptake and degradation of LDL cholesterol.12 Further discovery was made of a gain-of-function mutation in a protease known as proprotein convertase subtilisin/kexin type 9 (PCSK-9), which is involved in the regulation of LDL-receptor recycling. An estimated >90% of FH causative mutations are thought to be attributable to LDLR, 5% due to ApoB and 1% to PCKS9.8,13 Further advances have revealed autosomal recessive mutations leading to loss of function in LDL receptor adaptor protein 1 (LDLRAP1) and very rare heterozygous mutations in APOE.14 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.

Clinical diagnosis

Due to the phenotypic variability of FH, accurate diagnosis relies on the evaluation of a combination of factors in addition to LDL cholesterol, as highlighted in figure 1. Two sets of diagnostic criteria have been designed which take into account an accumulation of these clinical and biochemical features to determine the likelihood of FH; the Simon Broome Criteria15 (table 6) and the Dutch Lipid Network Criteria (DLNC)16 (table 7).

Table 6. Simon Broome diagnostic criteria for familial hypercholesterolaemia (FH) in adults15

Simon Broome diagnostic criteria for familial hypercholesterolaemia
Adult: total cholesterol >7.5mmol/L or LDL cholesterol >4.9mmol/L
Child: total cholesterol >6.7mmol/L or LDL cholesterol >4.0mmol/L
Definite FH
Plus at least one of the two:

  1. Tendon xanthomas in patient or in first degree relative or second degree relative
  2. OR

  3. DNA-based evidence of a familial defective apo B-100, LDL receptor or PCSK9 mutation
Possible FH
Plus at least one of the two:

  1. Family history of myocardial infarction (<60 years in first degree relative or <50 years in second degree relative)
  2. OR

  3. Family history of elevated total cholesterol (>7.5mmol/L in adult first degree or second degree relative or >6.7mmol/L in child or sibling <16 years)

Table 7. Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolaemia16

Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolaemia (FH) Score
I. Family history
First degree relative with known premature coronary and vascular disease
(<55 years male; <60 years female)
OR
First degree relative with known LDL cholesterol above the 95th percentile
1
First degree relative with tendon xanthomas and / or corneal arcus
OR
Children <18 years with known LDL cholesterol above the 95th percentile
2
II. Clinical history
Premature coronary artery disease (<55 years male; <60 years female) 2
Premature cerebral or peripheral vascular disease (<55 years male; <60 years female) 1
III. Physical examination
Tendon xanthomas 6
Corneal arcus (<45 years) 4
IV. LDL cholesterol level (mmol/L)
>8.5 8
6.5–8.4 5
5.0–6.4 3
4.0–4.9 1
V. DNA analysis
Functional mutation in the LDLR, ApoB or PCSK9 genes 8
FH diagnosis Total
Definite >8
Probable 6–8
Possible 3–5
Unlikely 0–2

The finding of tendon xanthomas (TX) is virtually diagnostic and confirms the clinical diagnosis of definite FH according to the Simon Broome criteria (table 6). TX are subcutaneous nodules that slowly enlarge and arise from cholesterol deposits attached to tendons, most commonly the Achilles tendon or over the knuckles (figure 2). 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.17 Moreover, 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 2).2

Figure 2. Tendon xanthomata in: panel a) the foot; panel b) the hand
Figure 2. Tendon xanthomata in: panel a) the foot; panel b) the hand

Underdiagnosis

Underdiagnosis of FH is a major problem, with estimates suggesting that only 8–15% of cases are known.10 There is a central and crucial role for primary care in aiding the diagnosis and early 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. Although it sounds low, FH is readily treatable with lipid-lowering therapy and is a preventable cause of premature cardiac death. Thus, it remains a priority to identify these patients before they experience problems as early as their thirties, forties or fifties. Moreover, as FH is inherited in an autosomal co-dominant manner, 50% of first-degree relatives and 25% of second-degree relatives will be affected. Hence, early detection of pathogenic mutations in just one patient will enable timely management and prevention of disease across family members.

HEART UK cover
HEART UK booklet on FH

The National Institute for Health and Care Excellence (NICE) have published guidelines emphasising the systematic identification of at-risk patients within primary care for onward referral and genetic testing as well as cascade screening.2 The guidelines2 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. 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 cholesterol 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.2

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’

HEART UK cover
BHF booklet on FH

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,2,5 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 by 2023.18 The NHS Long Term Plan from 2019 aims to improve the identification rate of FH cases to at least 25% in the course of five years through the NHS Genomics programme.19 NICE also published FH quality standards in 2013.20 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.21 As of April 2020, genetic testing for FH is centrally funded in England through the Genomics England programme as a means to improve detection rates. The use of cascade screening is cost-effective and enables affected individuals to be identified from childhood, which not only lowers their lifetime risk but also contributes to reducing cardiovascular disease burden at the population level.10

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 8. Lipid profile associated with familial combined hyperlipidaemia3

↑ Total cholesterol (6.5–10.0 mmol/L)
↑ LDL-C
↑ Triglycerides (2.3–6.0 mmol/L or higher)
ApoB/total cholesterol >0.15
VLDL-C/total triglycerides <0.69*
Small, dense, LDL
Diagnosis is commonly based on the combination of apoB >1.20 g/L + triglycerides >1.5 mmol/L with a family history of premature cardiovascular disease2
Key: apoB = apolipoprotein B; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; VLDL-C = very-low-density lipoprotein cholesterol
* Determined by ultracentrifugation

FCH is a common metabolic disorder and 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 and 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 (see table 8).

Elevated levels of cholesterol and triglyceride, either alone or in combination, in patients and other family members confer a ‘variable phenotype’. FCH has many overlapping features with the metabolic syndrome which can make differential diagnosis challenging in clinical practice (figure 3).22 However, 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.11 The finding of an apoB concentration that is unexpectedly low (apoB/total cholesterol ratio <0.15 g/mmol) raises suspicion of remnant hyperlipidaemia (type III or familial dysbetalipoproteinaemia).23 The presence of xanthelasma (figure 4) 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.24

Lipids module 3 - Figure 3. Overlapping phenotypic features and differences between the metabolic syndrome and familial combined hyperlipidaemia
Figure 3. Overlapping phenotypic features and differences between the metabolic syndrome and familial combined hyperlipidaemia22
Figure 4. 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
Figure 4. Panel A shows corneal arcus (cholesterol ring in the eye). Panel B shows xanthelasma 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

5240894-portrait-of-middle-aged-over-weight-man-Stock-PhotoDerek, 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 (4–6 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 in a dose-dependent manner (figure 5).

Figure 5. Eruptive xanthomata are characteristic of extreme hypertriglyceridaemia
Figure 5. Eruptive xanthomata are characteristic of extreme hypertriglyceridaemia

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 (tables 2 and 3). Elevated triglyceride levels are commonly associated with obesity, metabolic syndrome and diabetes mellitus as well as certain lifestyle factors, such as excessive alcohol intake, and is causally linked to atherosclerosis. Interventions to treat include lifestyle modification, such as abstinence from alcohol as well as exercise, weight loss, blood glucose control, administration of fibrates and omega-3 fatty acids.25

However, those presenting with severe disease at a young age or recurrent pancreatitis in childhood are more likely to have an underlying monogenic cause. A rare familial cause of severe hypertriglyceridaemia is familial chylomicronaemia syndrome, which has an autosomal recessive inheritance and can present in childhood.26 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.

Lipid profiles

Clearly the full lipid profile is key to diagnosis of dyslipidaemia, and its key components are summarised in figure 6. The baseline lipid evaluation should comprise total cholesterol, triglycerides and HDL cholesterol.27 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.

Lipids module 3 - Figure 6. The components of a lipid profile on biochemical testing
Figure 6. The components of a lipid profile on biochemical testing

Of the two, there is a strong case for preferential use of non-HDL cholesterol, given that:

  1. it is a simple calculation (non-HDL cholesterol = total cholesterol – HDL cholesterol)
  2. it can be readily measured in non-fasting samples.28

In contrast, LDL cholesterol must be measured in fasting samples and is determined via the Friedewald equation:

LDL-C = total cholesterol – (HDL cholesterol +   triglycerides ) in mmol/L
2.2

Its calculation assumes a constant cholesterol to 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. In clinical practice, LDL-C levels have a role in monitoring response to lipid-lowering treatment as well as setting recommended target levels in FH patients and those with or without pre-existing cardiovascular disease as per the 2019 European Society of Cardiology (ESC) / European Atherosclerosis Society (EAS) guidelines (see table 9).1 LDL cholesterol concentration is also used in the NICE Technology Appraisal [TA394] guidance as a threshold for offering treatment with a PCSK9 inhibitor.29

Table 9. Recommendations for treatment goals for LDL cholesterol, adapted from the 2019 ESC / EAS Guidelines for the management of dyslipidaemia1

Cardiovascular risk category* Recommended treatment goal
Secondary prevention for patients at very high risk LDL-C <1.4 mmol/L
Primary prevention for patients at very high risk, with or without FH LDL-C <1.4 mmol/L and ≥50% reduction from baseline
Patients with ASCVD who experience a second vascular event within two years on maximally-tolerated statin therapy LDL-C <1.0 mmol/L
Patients at high risk LDL-C <1.8 mmol/L and ≥50% reduction from baseline
Individuals with moderate risk LDL-C <2.6 mmol/L
Individuals with low risk LDL-C <3.0 mmol/L
Key: ASCVD = atherosclerotic cardiovascular disease; EAS = European Atherosclerosis Society; ESC = European Society of Cardiology; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol
* as classified by the 2019 ESC / EAS guidelines for the management of dyslipidaemia

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). Non-HDL cholesterol secondary treatment goals are <2.2, <2.6 and <3.4 mmol/L in moderate, high and very-high cardiovascular risk patient groups, respectively, as per the 2019 ESC / EAS guidelines.1 The NICE clinical guideline [CG181] recommend aiming for a 40% reduction in non-HDL cholesterol27 and the JBS3 criteria set a non-HDL cholesterol target of <2.5 mmol/L.30

Lipoprotein(a)

Table 10. Cardiovascular risk as determined by lipoprotein(a) serum concentration, as per the HEART UK consensus statement32

Lipoprotein(a) level (nmol/L) Cardiovascular risk
32–90 Minor
90–200 Moderate
200–400 High
>400 Very high

Table 11. Patient groups in whom the HEART UK consensus statement recommends lipoprotein(a) measurement32

Lipoprotein(a) measurement is recommended in:
a. A personal or family history of premature atherosclerotic cardiovascular disease (<60 years)
b. First degree relatives with a raised lipoprotein(a) level (>200nmol/L)
c. Genetic dyslipidaemias such as familial hypercholesterolaemia
d. Calcific aortic valve stenosis
e. Borderline increased (<15%) 10-year risk of a cardiovascular event

Lp(a) is an atherogenic and prothrombotic LDL-like particle, that promotes atherosclerosis. Lp(a) levels are primarily genetically-determined with an autosomal codominant inheritance and can thus be measured once in a lifetime, unless a secondary cause (table 4) is suspected and Lp(a) concentration may reduce post-treatment.31 An elevated Lp(a) has become well-established as an independent and causal risk factor for atherosclerotic cardiovascular disease and myocardial infarction, as determined by serum concentration (table 10).32 It is associated with an 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.11 The association between elevated Lp(a) and increased cardiovascular disease risk appears continuous and independent of LDL cholesterol levels. As such, the HEART UK consensus statement on Lp(a) recommends its measurement in five main categories which identifies at-risk patients for cardiovascular events (table 11).32 Currently, LDL apheresis is the only treatment to substantially reduce Lp(a) (figure 7). Other agents showing promise are discussed in module 4. In clinical practice, aspirin is sometimes used to mitigate the prothrombotic risk associated with an elevated Lp(a) and hyperlipidaemic control is recommended with a non-HDL cholesterol target of <2.5mmol/L.32

Figure 7. LDL-apheresis
Figure 7. LDL-apheresis

Although there has been much debate concerning the role of other novel risk factors such as the systemic inflammatory biomarker C-reactive protein (CRP), 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 cardiovascular disease risk in UK guidelines (NICE CG18127 and JBS330).

It is also important to always remember modifiable risk factors in cardiovascular disease prevention such as diet, smoking and lifestyle as well as optimising blood pressure and diabetic control.

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 cholesterol levels and places patients at greatly increased 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 lipoprotein 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

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References

1. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41: 111–88.

2. National Institue for Health and Care Excellence. Familial hypercholesterolaemia: identification and management. Clinical Guideline [CG71]. London: NICE, published date: 27 August 2008; last updated: 4 October 2019. www.nice.org.uk/guidance/CG71

3. 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.

4. 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.

5. Cegla J, Scott J. Lipid disorders. In: Oxford Textbook of Medicine, 6th Edition. Oxford: Oxford University Press, 2020. https://oxfordmedicine.com/mobile/view/10.1093/med/9780198746690.001.0001/med-9780198746690-chapter-232

6. Newman CB, Blaha MJ, Boord JB, et al. Lipid management in patients with endocrine disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2020;105:1–70.

7. Akioyamen LE, Genest J, Shan SD, et al. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open 2017;7:e016461. http://dx.doi.org/10.1093/aje/kwh236

8. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004;160:407–20. http://dx.doi.org/10.1093/aje/kwh236

9. France M, Rees A, Datta D, et al. HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom. Atherosclerosis 2016;255:128–39.

10. Public Health England (PHE). Familial hypercholesterolaemia: implementing a systems approach to detection and management. London: PHE, 2018. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/731873/familial_hypercholesterolaemia_implementation_guide.pdf

11. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844–53. http://dx.doi.org/10.1093/eurheartj/ehq386

12. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007;4:214–25. http://dx.doi.org/10.1038/ncpcardio0836

13. 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

14. Iacocca MA, Hegele RA. Recent advances in genetic testing for familial hypercholesterolemia. Expert Rev Mol Diagn 2017;17:641–51.

15. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ 1991;303:893–6.

16. WHO Human Genetics Programme. Familial hypercholesterolaemia (FH) : report of a second WHO consultation, Geneva, 4 September 1998. Geneva: World Health Organisation, 1999. https://apps.who.int/iris/handle/10665/66346

17. 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

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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.

If you would like to learn more about familial hypercholesterolaemia, watch our podcast.

These podcasts have been made possible by a grant from Sanofi, who have had no control over their content. Job codes: SAGB.CMR.15.04.0462, SAGB.CMR.15.04.0462a, SAGB.CMR.15.04.0462b. Date of preparation: May 2015

BJC FH podcast

This podcast is intended to provide an overview of FH, advising on what to look out for to improve diagnosis and to review current best treatments as well as some novel options for the future. The podcast is comprised of two parts. First we take you to Cape Town, South Africa, to the office of lipid expert, Dr Dirk Blom. South Africa has among the worlds highest rates of FH among its population groups, such as the white Afrikaaner community. Dr Blom explains the reasons why and outlines how the local healthcare systems cope with identifying and treating large numbers of patients.

The second part of the podcast features Dr Dermot Neely, another lipid specialist, from Newcastle upon Tyne, and the author of this module. He explains how we are starting to tackle the problem here in the UK, promoting the use of cascade screening of first- and second-degree relatives. These initiatives are supported by HEART UK – The Cholesterol Charity and the British Heart Foundation. They are helping to provide an infrastructure for cascade screening, and genetic testing. Clinical Commissioning Groups are embracing their targets to identify the one in 500 patients who have FH. He also discusses new treatments and whether they will need to be taken life-long, and indeed whether the NHS will be able to afford them.

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