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Contents:
Interpreting lipid results
Non-HDL cholesterol
Case studies
Key points
Lipid and
lipoprotein testing
A JOINT INITIATIVE OF
David Sullivan
MBBS FRACP FRCPA, Department
of Clinical Biochemistry, Royal Prince
Alfred Hospital, Missenden Rd,
Camperdown, NSW 2050.
This issue of Common Sense Pathology is a joint initiative of Common Sense Pathology editor:
Australian Doctor and the Royal College of Pathologists of Dr Steve Flecknoe-Brown
Australasia. Email: sflecknoebrown@gmail.com
For an electronic version of this and previous articles, you can visit www.australiandoctor.com.au or download an ebook version
from www.australiandoctor.com.au/ebooks You can also visit the Royal College of Pathologists of Australasias
web site at www.rcpa.edu.au Click on Library and Publications, then Common Sense Pathology.
This publication is supported by financial assistance from the Australian Federal Department of Health.
2
Some clinical
situations
such as long-
standing
diabetes or
chronic renal
impairment
... warrant
an aggressive
approach to
risk factor
intervention
irrespective of
calculated risk.
3
Figure 1: Non-HDL cholesterol = total cholesterol minus HDL cholesterol
In the case of Mrs PS, LDL cholesterol is 4.8 mmol/L and non-HDL cholesterol (estimated as total minus HDL
cholesterol) is 5.3 mmol/L. Severe elevations of these fractions are a risk for future CVD, even in the presence
of elevated HDL.4 On the other hand, this usually applies to higher levels than those seen in this patient, whose
levels remain below the thresholds suggested by NVDPA guidelines (LDL cholesterol >5mmol/L, non-HDL
cholesterol >5.5 mmol/L). So on this basis, diet could be further intensified by addition of plant sterol foods,
which might reduce total cholesterol by approximately 10%. This could result in a total cholesterol close to the
7.5 mmol/L threshold, but LDL cholesterol and non-HDL cholesterol would have declined also, to approximately
4.4 mmol/L and 4.8 mmol/L respectively. The question of whether or not to resort to pharmacological therapy
could rest on the choice between the confounded total cholesterol result or the more specific LDL or nonHDL
cholesterol levels. The latter are more appropriate.
A
4
The family
history
raises the
possibility of
inherited risk
of premature
cardiovascular
disease.
As was the case for his wife, Mr TSs total cholesterol of the possibility of underlying FH. The guidelines will
exceeds 7.5 mmol/L, so a case can be made for regarding recommend the use of the Dutch Lipid Clinic Score,
him as having a high absolute risk for cardiovascular which incorporates details concerning personal and
disease. Unlike his wife, he does not have high levels of family history of hypercholesterolaemia and premature
HDL cholesterol, so his LDL and nonHDL cholesterol cardiovascular disease (Table 1).4 The likelihood of FH
levels are considerably higher (his nonHDL cholesterol is categorised as definite, probable, possible or
is 7.6 mmol/L). unlikely. Mr TSs Dutch Lipid Clinic Score is 6, which
The family history raises the possibility of inherited suggests probable FH.
risk of premature cardiovascular disease. One prevalent The use of total cholesterol level to flag the possible
cause of inherited risk of premature cardiovascular presence of FH poses the same problem that arose in
disease is familial hypercholesterolaemia (FH). This case 1 concerning the calculation of absolute risk. The
dominantly inherited disturbance of the function of LDL underlying question is the degree to which the pro-
receptors leads to an approximate doubling of total and atherosclerotic fractions (reflected by LDL cholesterol, or
LDL cholesterol levels, resulting in an acceleration of
cardiovascular disease by 20 to 40 years. The prevalence
Table 1: Dutch Lipid Clinic criteria for Familial
of FH is approximately 1:500 to 1:200, which implies
Hypercholesterolaemia
that it affects nearly 40,000 Australians. Models of
Care recommend family cascade screening of first- 8 points DNA Mutation, or LDL-C >8.5
degree relatives to detect undiagnosed cases and to offer 6 points Tendon xanthomas
preventive therapy (see Online resources). Unfortunately, 5 points LDL-C 6.58.4
the detection and treatment of FH in Australia lags 4 points Arcus senilis <45 yrs
behind best practice. 3 points LDL 5.06.4
The soon-to-be-released clinical decision support tools
2 points Xanthomas or premature arcus in 1st
and recommendations concerning the reporting of lipid
degree relative, childhood LDL >95th
results developed by the Royal College of Pathologists percentile, or premature CHD
of Australasia will aim to increase the diagnosis of this
1 point 1st degree relative with premature CVD
important condition. Severe hypercholesterolaemia is one
or LDL >95th percentile, personal his-
of the leading indicators of the presence of FH. Physical tory of LDL 4.04.9 or premature CVD
signs such as corneal arcus and tendon xanthomas take
Definite: Probable: Possible Unlikely FH:
time to develop and are relatively insensitive. Total
>8 points 68 points FH: 3-5 <3
cholesterol levels >7.5 mmol/L warrant consideration
A
5
non-HDL cholesterol) are increased. In the case of Mr TS, hypertriglyceridaemia is present. This is an important
LDL cholesterol is 6.9mmol/L and non-HDL cholesterol issue because FH usually results in hypercholesterolaemia
is 7.6mmol/L. Using this more sophistocated analysis, Mr alone. If Mr LS has a combination of
TS is considered a case of probable FH: his wife is not. hypertriglyceridaemia as well as hypercholesterolaemia, it
The thresholds suggested by NVDPA guidelines (LDL makes it more likely that the family is affected by familial
cholesterol >5 mmol/L, non-HDL cholesterol >5.5 combined hyperlipidaemia rather than FH. Familial
mmol/L) may also provide a more specific filter for the combined hyperlipidaemia is a less clearly defined
suspicion of FH than total cholesterol. diagnosis in which affected family members may exhibit
hypercholesterolaemia, or hypertriglyceridaemia, or a
CASE 3 combination of the two.
Case 3 is Mr LS, the 36-year-old son of Mr TS in case 2. The mere fact that Mr LSs non-fasting triglyceride
He undertook this lipid test in response to the Family level is elevated should be taken as an indication of
Cascade Screening conducted in response to his fathers increased risk of cardiovascular disease. In this regard,
probable familial hypercholesterolaemia result. He food intake may be regarded as a stress test for
informs you that he was in a rush on the day he attended lipoprotein metabolism, increasing the sensitivity of
the blood collection, so he forgot to fast. The results triglyceride as a risk factor. Of course the variability of
include: food intake interferes with the standardisation of the
Total cholesterol = 6.9 mmol/L measurements, so the results should only be interpreted
Triglycerides = 3.4 mmol/L semi-quantitatively. The evidence suggests that samples
HDL cholesterol = 1.1 mmol/L collected approximately four hours after food intake are
Can any useful information be derived from this particularly informative.5
non-fasting set of results regarding a) diagnosis of Mr LSs non-fasting lipid results can contribute
hyperlipidaemia or b) assessment of CVD risk? to assessment of cardiovascular risk in other ways.
The total cholesterol is elevated, but not to the same Although it is true that food intake marginally reduces
extent as either parent. Failure to fast does not drastically HDL cholesterol, the total and HDL cholesterol
affect total cholesterol level, so fasting levels are likely to can provide the necessary lipid and lipoprotein
remain elevated if tests are repeated. components to estimate absolute risk using the NVDPA
The triglyceride level is also elevated, but th is may cardiovascular risk calculator. On the other hand, the
reflect recent food intake. A 12-hour fasting specimen absence of a fasting triglyceride result precludes the use
is required to standardise the measurement of plasma of the Friedewald equation used by most laboratories to
triglyceride, and hence determine whether or not estimate LDL cholesterol.
A
6
NonHDL
cholesterol can
be calculated
using the
results from
non-fasting
samples.
As an alternative, direct measurement of LDL situations. Mr LSs nonHDL cholesterol level is 5.8
cholesterol could be performed on a non-fasting sample, mmol/L. This is undesirably high, but clinical decisions
but this may not be necessary for several reasons. Most should be based on his calculated absolute risk.
importantly, there is increasing enthusiasm for the use In the future, it is likely that LDL cholesterol will
of nonHDL cholesterol (calculated as total minus be superseded by non-HDL cholesterol. This process
HDL cholesterol) as an alternative. Firstly, nonHDL may be accelerated by the introduction of new drugs
cholesterol can be calculated using the results from non- such as CETP inhibitors which alter the composition of
fasting samples. The small change in HDL cholesterol LDL and other lipoproteins, rendering LDL cholesterol
that follows food intake will have little effect on the final calculated by the Friedewald equation inaccurate. The
nonHDL cholesterol result. nonHDL cholesterol threshold and target levels are
Secondly, there is increasing evidence to suggest that likely to be approximately 0.50.8 mmol/L higher than
nonHDL cholesterol provides more accurate estimation their LDL cholesterol counterparts.
of cardiovascular risk than LDL cholesterol.This is The three cases described here demonstrate significant
true for both risk prediction of cardiovascular risk and changes in the way in which lipid and lipoprotein levels
assessment of response to treatment.6,7 are interpreted.
This can be explained by the fact that elevated Firstly, levels need to be considered in the broader
triglyceride levels promote changes in the composition of context of other risk factors and overall clinical status.
cholesterol-rich lipoproteins such as LDL and HDL. The This can be achieved by use of the NVDPA Australian
action of Cholesteryl Ester Transfer Protein (CETP) leads calculator to estimate absolute risk of cardiovascular
to cholesterol depletion of LDL and HDL and temporary disease in the following five years. Secondly, total
triglyceride enrichment. The subsequent hydrolysis of cholesterol is a combination of pro- and anti-
triglyceride results in smaller, denser LDL particles and atherosclerotic components. This confounds interpretation
unstable HDL particles. Thus hypertriglyceridaemia of total cholesterol, so it is more appropriate to be guided
is often associated with low HDL cholesterol and the by LDL, or preferably nonHDL cholesterol. In those
presence of so-called small, dense LDL. The latter cases in which unequivocal elevation of atherogenic
is significant because the LDL cholesterol level may lipoproteins has been demonstrated, the diagnosis of
not reflect the greater number and atherogenicity of familial hypercholesterolaemia should be considered.
the particles present. There are several measurements, The Dutch Lipid Clinic Score is a useful tool to assess the
including apolipoprotein B and LDL particle number, likelihood of this diagnosis, which, if confirmed, warrants
which compensate for this problem, but the performance family cascade screening of first-degree relatives to detect
of nonHDL cholesterol is likely to be sufficient for most those at risk.
A
7
Evidence now
suggests that
non-HDL
cholesterol
is superior
to LDL
cholesterol.
1. Lipid
and lipoprotein levels need to be considered in the context of other risk factors.
Key 2. T he NVDPA Australian calculator should be used to estimate the patients absolute risk of
points cardiovascular disease in the following five years.
3. Interpretation of total cholesterol, which is a combination of pro- and anti-atherosclerotic
components, is confounded.
4. It is better to use LDL, or preferably nonHDL cholesterol, rather than total cholesterol.
5. Familial hypercholesterolaemia should be considered, according to the Dutch Lipid Clinic Score, when levels
of atherogenic lipoproteins are severely elevated.
6. Confirmed familial hypercholesterolaemia warrants family cascade screening of first-degree relatives to
detect affected family members.
7. Useful lipid information can be derived from non-fasting blood samples because elevated non-fasting
triglyceride levels are indicative of increased cardiovascular risk.
8. Non-fasting total and HDL cholesterol can be used to calculate absolute risk and nonHDL cholesterol,
which is a useful alternative to LDL cholesterol
9. LDL cholesterol thresholds and targets are likely to be supplemented, and eventually replaced by their non
HDL cholesterol equivalents.
10. The levels of non-HDL cholesterol are usually 0.5 to 0.8 mmol/L higher than corresponding LDL cholesterol levels.
A
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