Screening for High Blood Cholesterol
Periodic measurement of total serum cholesterol is most
important for middle-aged men, and it may also be
clinically prudent in young men, women, and the elderly
(see Clinical Intervention). All patients should receive
periodic counseling regarding dietary intake of fat
(especially saturated fat) and cholesterol (see Chapter
Burden of Suffering
High blood cholesterol, cigarette smoking, and hypertension
are the principal modifiable risk factors for coronary
artery disease (CAD), the leading cause of death in the
United States.1 About 1.5 million myocardial infarctions
(MIs) and over 520,000 deaths from ischemic heart disease
occur each year in the United States.1,2 These cardiac
events often occur without warning in persons with no
previous history of angina pectoris or other clinical
symptoms. The 30-day case-fatality rate for persons in whom
MI is the initial manifestation of CAD is about 30%.3 CAD
is also associated with significant morbidity; the
discomfort and exertional restrictions of angina pectoris
and MI can limit productivity, functional independence, and
quality of life. Cardiovascular diseases cost the United
States about $80 billion each year.2
Efficacy of Screening Test
The principal screening test for high blood cholesterol is
the measurement of total serum cholesterol in specimens
obtained by either venipuncture or finger-stick. Due to
biological variation and measurement error, such
measurements may not always reflect the patient's true
cholesterol level. Serum cholesterol levels normally
undergo substantial physiologic fluctuations related to
gender, stress, and season,4 and therefore a single blood
test may not always be representative. Repeated
measurements on the same individual have a standard
deviation of about 18 mg/dL (0.45 mmol/L), so that the 95%
confidence interval for a typical adult whose blood
cholesterol is 220 mg/dL (5.70 mmol/L) would be ;pm36 mg/dL
(0.95 mmol/L), or 184-256 mg/dL (4.75-6.65 mmol/L).5,6 Due
to this variation, a single cholesterol measurement should
not be relied on and the average of multiple tests should
be used for therapeutic decisions.
In addition to biological variation, different laboratory
instruments for measuring serum cholesterol are subject to
systematic bias and random sources of error.7 A number of
instruments in routine use consistently overestimate
(positive bias) or underestimate (negative bias) the true
cholesterol value by about 2-7%.4,7-11 More extreme errors
have also been reported. One study found that a serum
cholesterol concentration of 250 mg/dL (6.45 mmol/L) was
reported by one instrument as 285 mg/dL (7.35 mmol/L) (14%
positive bias) and by another as 301 mg/dL (7.80 mmol/L)
(20% positive bias).4 Nearly half of all laboratory
cholesterol results vary by 5% or more from the correct
value.12 Another potential source of error is poor
precision (e.g., producing different results on the same
specimen), although it is generally less of a problem than
bias.12 This accounts for about 3-4% of variation in the
results of conventional clinical laboratory equipment5,10
and desk-top office analyzers.7,13-16 There is also
significant variation between clinical laboratories (about
6%) and within individual laboratories (about 3.5%).12
Capillary sample measurements are often less accurate than
analyses of venipuncture specimens. Inadequate training and
the use of improper techniques in operating the equipment
can introduce additional sources of error.16 This is
especially important in relation to desk-top chemical
analyzers.12 Further research is needed to fully evaluate
these devices, and programs should be developed to assure
acceptable performance standards before desk-top
instruments are recommended for widespread screening.12
Since clinical decisions regarding treatment are affected
by the report of a cholesterol level above a desirable''
level, there are potentially important clinical
consequences resulting from laboratory underestimation or
overestimation of the actual cholesterol level. Persons
with high blood cholesterol requiring intervention may be
advised incorrectly that their serum lipid levels are in
the desirable range and thus not be retested for some time.
Conversely, persons who receive falsely elevated test
results may undergo the inconvenience and cost of follow-up
testing. In some cases, erroneous cholesterol test results
may generate unnecessary office visits to health care
providers. Some patients may experience anxiety and the
effects of labeling that have been observed in hypertension
screening, such as absenteeism and psychological
symptoms.17 Finally, patients receiving inadequate
follow-up testing may be exposed unnecessarily to treatment
with cholesterol-lowering drugs.
To minimize the adverse effects of misclassification
resulting from biological variance or laboratory error, an
average of at least two blood test results is often
recommended to provide a more accurate measure of the true
concentration of total cholesterol; three tests are
recommended if the difference between the first two tests
is greater than 30 mg/dL [0.80 mmol/L].18 In addition,
rigorous standards for improving accuracy and precision in
clinical laboratories are being developed and implemented
by the College of American Pathologists, the Centers for
Disease Control, and the National Cholesterol Coordinating
Committee Laboratory Standardization Panel.12,19 These
groups have proposed the goal of improving standards for
accuracy and precision in clinical laboratory measurement
from the current range of ;pm5% to less than 3% by 1992.
Effectiveness of Early Detection
Early detection of high blood cholesterol in asymptomatic
persons allows identification of an important modifiable
risk factor for CAD. A large body of evidence gathered over
several decades, including epidemiologic, pathologic,
animal, genetic, and metabolic studies, supports the lipid
hypothesis,'' the causal relationship between serum
cholesterol levels and the development of coronary
The question of whether the lowering of serum cholesterol
can achieve a significant reduction in the incidence of CAD
in asymptomatic persons has been of major clinical
interest. Early efforts to answer this question involved
controlled clinical trials in which asymptomatic
middle-aged men with selected cardiac risk factors were
given low-fat or modified-fat diets.24-32 Such diets
lowered serum cholesterol levels by about 10-15%, and in
most trials, this was associated with a reduction in the
incidence of cardiac events (e.g., myocardial
infarc-24,25,28-30,32 These early studies, however,
suffered from a variety of design limitations, such as
small sample size, selection bias in the recruitment of
study groups and controls, confounding variables,
inappropriate statistical analyses, and limited
generalizability.33,34 Probably due to inadequate sample
size, most of these studies did not find a significant
difference in either CAD or overall mortality between
intervention and control groups.24-27
The ability of cholesterol-lowering drugs to reduce the
incidence of CAD in asymptomatic persons has been
demonstrated in three well-designed randomized controlled
trials involving asymptomatic middle-aged men with high
blood cholesterol. In the WHO Cooperative Trial, which
involved over 15,000 men, subjects receiving clofibrate
experienced a statistically significant 20% reduction in
the overall rate of MI and 25% reduction in nonfatal MI
when compared with controls receiving olive oil
capsules.35-37 The incidence of fatal MI was similar in
both groups. The Lipid Research Clinics (LRC) Coronary
Primary Prevention Trial, a multicenter study of
cholestyramine involving 3806 men, reported an incidence of
cardiac events of 7.0% in persons receiving cholestyramine
and 8.6% in those receiving placebo.38-42 This 19%
reduction in the incidence of CAD was also statistically
significant. Nonfatal MI and CAD mortality were 19% and 24%
lower, respectively, in the group taking cholestyramine,
and the incidence of angina, positive exercise tests, and
coronary bypass surgery was also reduced. The Helsinki
Heart Study, a trial involving 4081 asymptomatic men,
reported a statistically significant 34% reduction in the
incidence of cardiac events (nonfatal MI and cardiac death)
in men receiving gemfibrozil.43
Taken together, these studies provide compelling evidence
that the incidence of nonfatal MI and fatal cardiac disease
can be reduced by lowering serum cholesterol. The
randomized controlled trials that provide the strongest
evidence, however, used drugs rather than diet to achieve
this effect and involved a select population group,
primarily white men aged 35-59 with serum cholesterol
values above 255-265 mg/dL (6.60-6.85 mmol/L).38,43 A
current focus of interest is the extent to which this
evidence is generalizable to other population groups (i.e.,
women, young men, the elderly, persons with less marked
elevation of serum cholesterol) or to dietary measures.
Women, young men, and the elderly presumably benefit to
some extent from lowering serum cholesterol. There are
uncertainties, however, regarding the magnitude of benefit
from screening these populations since elevated blood
cholesterol is either a weaker risk factor or a less common
abnormality in these34,44-47 Persons with borderline high
cholesterol (200-240 mg/dL [5.15-6.20 mmol/L]), lacking the
high blood cholesterol levels required of participants in
the above trials, may benefit less by lowering cholesterol.
A cohort study involving over 350,000 men48,49 and 30-year
longitudinal data from the Framingham Study50 provide
evidence that CAD risk increases in a continuous and graded
fashion beginning with serum cholesterol levels as low as
180 mg/dL (4.65 mmol/L).51 The risk rises sharply above
220-240 mg/dL (5.70-6.20 mmol/L), reaching a fourfold
increase for levels above 260 mg/dL (6.70 mmol/L), which is
the 90th percentile of middle-aged men. It follows that
reductions in persons with borderline high cholesterol
would be of less substantial benefit than for persons with
severe elevations; a 50 mg/dL (1.30 mmol/L) reduction
lowers absolute risk by about 50% in persons with a serum
cholesterol of 300 mg/dL (7.75 mmol/L) but only by 25% at a
level of 250 mg/dL (6.45 mmol/L) and only 7.5% at 200 mg/dL
Cardiac risk factors other than high blood cholesterol are
also important determinants of the benefits that can be
expected from lowering blood cholesterol. Persons at
increased risk for CAD because of a history of MI or
angina, or asymptomatic persons with other cardiac risk
factors, are thought to experience a greater reduction in
risk for any given reduction in blood cholesterol than
persons without these risk factors.18,52 These risk factors
include male sex, family history of premature CAD,
cigarette smoking, hypertension, low high-density
lipoprotein (HDL) cholesterol (less than 35 mg/dL [0.90
mmol/L]), diabetes mellitus, cerebrovascular or peripheral
vascular disease, and severe obesity.
Another question concerns the magnitude of benefit
associated with dietary measures. Animal studies,
epidemiological data, and metabolic research support a
beneficial effect from diets low in fat, primarily
saturated fat. Clinical trials in which diet was the sole
intervention have provided encouraging but not conclusive
evidence of a significant reduction in the incidence of
CAD.21,22,44,53,54 The lack of conclusive evidence is due
at least in part to design limitations (see above). It is
reasonable to extrapolate from the drug trial findings that
dietary restrictions, if successful in achieving
significant reductions in serum cholesterol, can also lower
the risk of CAD. Meta-analyses and other reviews of data
pooled from dietary trials suggest that the dose-response
relationship between dietary reduction of serum cholesterol
and the risk of CAD is similar to that observed in data
analyzed from drug trials.55
The ability of patients to achieve and maintain reductions
in dietary fat is still under study. Low-fat diets that
have been shown in experimental research to achieve
significant reductions in serum cholesterol may not be
adopted as readily by all members of the general
population.34,56 Thus, the more modest reductions in serum
cholesterol level that result from ordinary fat-controlled
diets may produce only modest reductions in CAD.
Nonetheless, when compared with pharmacologic regimens to
lower serum cholesterol, dietary measures are safer, less
expensive, and may obviate the need for prescribing
In summary, the magnitude of benefit of detecting high
blood cholesterol may be reduced in women, young men, and
the elderly; persons with borderline high cholesterol; and
persons who use dietary measures that do not lower serum
cholesterol significantly. Lowering serum cholesterol in
low-risk populations may result in only minor changes in
population-wide life expectancy.47 On the other hand,
low-risk individuals account for a large proportion of the
population. It has been argued from a public health
perspective that even modest benefits multiplied across
large numbers of individuals can have significant public
health implications.57 Even a modest 5% reduction in the
incidence of CAD would prevent about 75,000 MIs each year
in the United States.2
It is also important to consider the potential health risks
associated with lowering serum cholesterol. Long-term use
of cholesterol-lowering drugs, such as nicotinic acid,
clofibrate, and cholestyramine, is associated with a number
of unpleasant and potentially serious side effects.22,58,59
New classes of lipid-lowering drugs, such as lovastatin,
also have adverse effects60 and have not been in use for
sufficient time to establish their long-term safety. The
three major clinical trials involving lipid-lowering drugs
each reported an increase in non-CAD deaths in intervention
groups. An increase in violent deaths (accidents, suicide,
homicide) reported in two of the three trials was not
statistically significant and was attributed to chance by
the investigators,38,43 but the findings have raised
concern among others.61 The third trial reported a
statistically significant 44% increase in all-cause
mortality in men taking clofibrate.35-37 Because clofibrate
also causes gallstones,35 its use for lowering cholesterol
to prevent CAD is no longer recommended. Studies have
reported associations between decreased levels of serum
cholesterol and cancer24,62-65 and gastrointestinal
disease.24,35,43 Evidence from a large longitudinal study,
however, indicates that the association with cancer may
represent an effect of preclinical cancer on blood
cholesterol rather than an effect of low cholesterol on the
development of the disease.66 An increased incidence of
cancer was also not apparent in the three drug trials
Cholesterol screening during childhood has received
increased attention in recent years. The detection of high
blood cholesterol during childhood is of potential value in
identifying those children who are at increased risk for
developing CAD as adults and who might benefit from more
intensive dietary interventions and follow-up than would be
offered in the course of routine well-child care. Studies
have shown that children with increased intake of dietary
fat and cholesterol are at increased risk of having high
blood cholesterol,67 and children with high blood
cholesterol are more likely than other children to have
elevated cholesterol levels as adults.68 Dietary habits
learned in childhood may persist into adult life, and
parents of children with high cholesterol levels are more
likely to experience CAD.69 High blood cholesterol may
produce early atherosclerotic changes before adulthood;
postmortem studies have demonstrated fatty streaks lining
the aortas of children and adolescents with high blood
cholesterol levels.70 Autopsy studies have also noted
evidence of CAD in adolescent and young adult war
casualties.71 It is unclear how strongly these pathologic
changes are associated with subsequent CAD, however. A
relationship between lowering cholesterol during childhood
and decreased incidence of CAD during later life has yet to
be demonstrated in controlled studies, in part due to the
difficulty of performing such studies. This lack of
evidence is of concern because it is currently unclear
whether a policy of routine cholesterol screening of the
50-60 million children72 in the United States would achieve
sufficient clinical benefit in later years to justify the
costs and potential adverse effects of widespread testing.
Due to the low prevalence of high blood cholesterol in
children, routine screening is likely to generate a large
proportion of false positives. There is little information
on the potential psychological effects on children of being
labeled'' as having high blood cholesterol. Also, some
pediatricians have expressed concern that dietary
restrictions during childhood may affect the child's source
of calories, calcium, and iron.73 The issue is still under
Recommendations of Others
The National Heart, Lung, and Blood Institute has issued
recommendations on cholesterol screening in the clinical
setting in the report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in
Adults.18 These recommendations were endorsed by the
National Cholesterol Coordinating Committee, which includes
representatives from the leading national medical
organizations. The report recommends routine measurement of
nonfasting serum cholesterol in all adults aged 20 and
above at least once every five years and provides a
detailed protocol to guide follow-up of test results. The
protocol sets a lower treatment threshold for persons with
CAD or who are at high risk for CAD and recommends
averaging two to three separate measurements of total
cholesterol and low-density lipoprotein (LDL) cholesterol
to help guide drug treatment decisions. Specific
recommendations to improve the effectiveness of public
screening for high blood cholesterol have been issued
through a workshop sponsored by the National Heart, Lung,
and Blood Institute.74 The American Academy of Pediatrics
recommends regular elective testing for high blood
cholesterol only for children over age 2 who have a family
history of hyperlipidemia or early MI.75 Others have
recently recommended universal cholesterol screening for
all children.76 Recommendations on public screening outside
the medical setting are currently being prepared by the
National Cholesterol Coordinating Committee.
Serum cholesterol testing of adults in the United States
has the potential of achieving a significant reduction in
the nationwide incidence of CAD. Care is, however, required
for any program targeting more than 150 million people72
for testing and follow-up to guard against unnecessary
health care expenditures and adverse personal consequences.
In particular, the use of inaccurate laboratory or desk-top
instruments for screening can lead to large numbers of both
false-negative and false-positive results. The former can
delay needed clinical intervention and the latter can lead
to considerable inconvenience, costs, and adverse
psychological and medical consequences in persons not
needing intervention. It is therefore important for
clinicians to exercise discretion in selecting accurate and
reliable methods of obtaining blood specimens in the
clinical setting, to use clinical laboratories that adhere
to accepted standards of quality control, and to properly
design treatment strategies based on results confirmed by
Discretion is especially important in the use of
cholesterol-lowering drugs. The efficacy of such drugs in
preventing CAD has been demonstrated most convincingly in
middle-aged men with serum cholesterol levels above 255-265
mg/dL (6.60-6.85 mmol/L).38,43 The effect on CAD of using
lipid-lowering drugs in young men, women, or elderly
persons, or in those with only mild to moderate elevations
in blood cholesterol, has not been studied in clinical
trials of asymptomatic persons. It is therefore reasonable
to limit the exposure of low- or moderate-risk individuals
to the unpleasant side effects of lipid-lowering drugs, the
inconvenience of daily, long-term administration, and the
potential health risks of agents for which long-term safety
has yet to be established. There are also economic
implications to prescribing lipid-lowering drugs in light
of their expense and the quantities required for long-term
therapy. Some studies examining the economic benefits of
preventing CAD have questioned the cost-effectiveness of
routine drug therapy for elevations in blood
It has been shown that a low level of HDL cholesterol is an
independent predictor of CAD. Persons whose HDL cholesterol
level is at the 20th percentile have two to four times the
risk of developing CAD as persons whose level is at the
80th percentile.81,82 Lipid-fractionation studies, which
enable the calculation of HDL and LDL levels, can therefore
provide more meaningful information on CAD risk and the
effectiveness of therapy than can total cholesterol
measurement. Concerns that total blood cholesterol
measurements may fail to detect persons at increased risk
due to low HDL cholesterol (despite a normal total
cholesterol level) have led to recent recommendations to
perform lipoprotein analysis routinely on all persons with
borderline or high total blood cholesterol.83
There are substantial economic considerations in the
performance of fractionation studies as a routine follow-up
to finding elevated total cholesterol. For example,
examining lipid profiles on all adults with high blood
cholesterol (240 mg/dL [6.20 mmol/L] or greater) would
require performing a $20-$40 test on nearly one-quarter of
the 150 million adults in the United States.72,84 Although
it is likely that the information would be useful to
clinicians, further research is necessary to determine the
exact prevalence of low HDL cholesterol, the efficacy of
measures to raise HDL cholesterol, and whether the added
information provided by routine lipoprotein analysis
results in an overall improvement in clinical outcome.
Until this evidence becomes available, lipid fractionation
studies may be best reserved for the smaller group of
persons for whom the information is most important, such as
those being considered for drug therapy and those being
monitored for response to treatment with
All patients should receive periodic counseling regarding
dietary intake of fat (especially saturated fat) and
cholesterol (see Chapter 50). Periodic measurement of total
serum cholesterol (nonfasting) is most important for
middle-aged men, and it may also be clinically prudent in
young men, women, and the elderly. The optimal frequency
for cholesterol measurement in asymptomatic persons has not
been determined on the basis of scientific evidence and is
left to clinical discretion; an interval of every five
years (and more frequently for persons with previous
evidence of elevated cholesterol) has been recommended on
the basis of expert opinion.18 Cholesterol tests should be
performed on venous blood samples analyzed by an accredited
laboratory that meets current standards of accuracy and
reliability. Abnormal results should be confirmed by a
second measurement of nonfasting total cholesterol, and the
mean of both results should be used for subsequent
All adults with high blood cholesterol (at or above 240
mg/dL [6.20 mmol/L]) and those persons with borderline high
cholesterol (200-239 mg/dL [5.15-6.15 mmol/L]) who have
known CAD or two or more cardiac risk factors should
receive information about the meaning of results, intensive
dietary counseling, and follow-up evaluation. The most
important cardiac risk factors to be considered include
male gender, premature CAD in a first-degree relative,
smoking, hypertension, serum HDL cholesterol less than 35
mg/dL (0.90 mmol/L) (when this information is available),
diabetes mellitus, previous stroke or peripheral vascular
disease, and severe obesity. The recommended two-step
dietary program to lower serum cholesterol has been
described in detail elsewhere.18 The primary objective of
the Step-One diet is to reduce all dietary fat intake to
less than 30% of total calories (with saturated fat
contributing less than 10% of total calories) and to reduce
dietary cholesterol intake to less than 300 mg/day. The
Step-Two diet, which is recommended if the goals of therapy
are not achieved after three months, differs from the first
by further restricting intake of saturated fats (to 7% of
total calories) and dietary cholesterol (200 mg/day).
Cholesterol-lowering drugs should be considered in
middle-aged men in whom blood cholesterol remains
significantly elevated after a thorough six-month trial of
dietary intervention. A suggested threshold for drug
treatment is 240 mg/dL (6.20 mmol/L) or greater in persons
with CAD or at least two cardiac risk factors and 265 mg/dL
(6.85 mmol/L) or greater in persons without risk factors.
The patient should receive information on the potential
benefits and risks of long-term therapy before beginning
treatment on cholesterol-lowering drugs. It is clinically
prudent to perform lipid fractionation studies on persons
being considered for drug treatment and those being
monitored for response to drug therapy over time.
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