Screening for Lipid Disorders

Number: 0525

Policy

Note: Cholesterol screening of asymptomatic persons is not covered for members whose plans do not provide coverage for preventive services.  Diagnostic cholesterol testing is covered when medically necessary, regardless of whether the member’s plan provides coverage for preventive services.  Please check benefit plan descriptions for details.

  1. Aetna considers total serum cholesterol and high-density lipoprotein cholesterol (HDL-C) screening medically necessary for screening and diagnosis of lipid abnormalities.

  2. Aetna considers measurement of serum triglycerides medically necessary for screening and diagnosis of lipid abnormalities.

  3. Aetna considers direct measurement of very low-density lipoprotein (VLDL) cholesterol experimental and investigational, as calculated VLDL cholesterol levels are sufficiently accurate.

  4. Aetna considers directly measured low-density lipoprotein cholesterol (LDL-C) medically necessary in persons with triglyceride levels greater than 250 mg/dL and in persons with type 2 diabetes.  Directly measured LDL-C is considered experimental and investigational in persons without type 2 diabetes or hypertriglyceridemia because calculated LDL cholesterol levels are sufficiently accurate.

  5. Aetna considers cholesterol skin testing experimental and investigational because its effectiveness in predicting coronary heart disease risk as compared to standard methods of cholesterol testing has not been established.

  6. Aetna considers breath isoprene measurements for screening members for lipid disorders or monitoring of the success of therapies in persons with lipid disorders experimental and investigational because its effectiveness has not been established.

See also CPB 0381 - Cardiovascular Disease Risk Tests.

Background

Levels of serum cholesterol have been correlated with a person's subsequent risk of heart disease.  Clinical studies have shown that serum cholesterol screening may reduce the risk of heart disease in adults, and for high-risk children and adolescents.

The U.S. Preventive Services Task Force (USPSTF) recommends periodic total serum cholesterol and high-density lipoprotein cholesterol (HDL-C) screening for all men aged 35 and older.  The USPSTF recommends screening beginning at aged 20 for both men and women with other risk factors for coronary heart disease (e.g., diabetes, family history suggestive of hyperlipidemia, a family history of cardiovascular disease before age 50 years in male relatives or age 60 years in female relatives, or patients with multiple coronary heart disease risk factors (e.g., tobacco use, hypertension)).  They concluded that an interval of 5 years has been recommended, but longer intervals may be reasonable in low-risk subjects, including those with previously desirable cholesterol levels.  For average risk individuals, the benefit of measuring triglycerides as an initial screening is unproven.

The USPSTF recommends screening with total cholesterol, HDL-C, and lipoprotein analysis for persons with major coronary heart disease risk factors (e.g., smoking, hypertension, and diabetes).  These guidelines recommend, for high-risk persons, lipoprotein analysis to help identify individuals at highest risk of coronary heart disease (CHD) in whom individual diet or drug therapy may be indicated.  The optimal frequency of screening has not been determined and is left to clinical discretion.

In a statement on screening for lipid disorders in children, the USPSTF (2007) concluded that the evidence is insufficient to recommend for or against routine screening for lipid disorders in infants, children, adolescents, or young adults (up to age 20).

The American College of Physicians (ACP) - American Society of Internal Medicine, in guidelines revised in 1996, concluded that screening serum cholesterol was appropriate but not mandatory for asymptomatic men aged 35 to 65 and women aged 45 to 65; the guidelines do not recommend screening for younger persons unless they have evidence of having a familial lipoprotein disorder or have multiple cardiac risk factors.  The ACP concluded that evidence was not sufficient to recommend for or against screening asymptomatic persons between the ages of 65 and 75, but the ACP recommends against screening after age 75.

The Canadian Task Force on the Periodic Health Examination concluded there was insufficient evidence to recommend routine cholesterol screening but endorsed case-finding in men 30 to 59 years old.

Also, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III, convened by the National Heart and Blood Institute, recommends routine measurement of a fasting lipoprotein profile (total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein (HDL) cholesterol, and triglyceride) in all adults age 20 and older at least once every 5 years.  The American Academy of Family Physicians recommends measurement of total cholesterol at least every 5 years in adults age 19 and older.

The American College of Obstetricians and Gynecologists recommends periodic screening of cholesterol in all women over age 20, and in selected high-risk adolescents.

Selective screening of children and adolescents is recommended by the NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents, the National Center for Education in Maternal and Child Health's Bright Futures guidelines, the American Medical Association Guidelines for Adolescent and Preventive Services (GAPS), and the American Academy of Family Physicians.  Screening with non-fasting cholesterol in all children and adolescents who have a parental history of hypercholesterolemia, and with fasting lipid profile in those with a family history of premature cardiovascular disease, is recommended by these organizations.  These organizations also recommend that children who have multiple risk factors for CHD (such as smoking or obesity) and whose family history can not be ascertained be screened at the discretion of the physician.  

An updated report on lipid screening in childhood by the American Academy of Pediatrics (Daniels et al, 2008) stated that a fasting lipid profile is recommended after 2 years of age for children and adolescents with a family history of dyslipidemia or premature (less than or equal to 55 years of age for men and less than or equal to 65 years of age for women) cardiovascular disease or dyslipidemia, and in children for whom family history is not known or those with other cardiovascular disease risk factors, such as over-weight (body mass index [BMI] greater than or equal to 85th percentile but less than 95th percentile), obesity (BMI greater than or equal to 95th percentile), hypertension (blood pressure greater than or equal to 95th percentile), cigarette smoking, or diabetes mellitus.  If the values are normal on initial screening, re-testing is recommended in 3 to 5 years.  The AAP does not recommend screening before 2 years of age.

The NCEP recommends screening once with total blood cholesterol for children and adolescents 2 years of age or older whose parents have a blood cholesterol level greater than 240 mg/dL.  The NCEP recommends periodic total blood cholesterol screening children and adolescent with several risk factors whose family history can not be ascertained; the optimal screening frequency for high blood cholesterol in this risk group has not been determined and is left to clinical discretion.  Risk factors for coronary vascular disease include smoking, hypertension, physical inactivity, obesity, and diabetes mellitus.  The NCEP recommends screening once with a fasting lipid profile for children and adolescents 2 years of age and older with a family history of coronary or peripheral vascular disease before the age of 55 years.  Although routine cholesterol screening is recommended only for high-risk children, pediatricians should suggest that all children 2 years of age and older follow the American Heart Association's Step One Diet, which is essentially a low-cholesterol diet.

The NCEP recommends measurement of triglyceride levels. According to the NCEP, calculated very low density lipoprotein (VLDL) levels are sufficiently accurate; VLDL is calculated as total triglycerides divided by 5.  The NCEP recommends direct measurement of LDL cholesterol in persons with triglyceride levels greater than 400 mg/dL, as calculated LDL cholesterol measurements may be inaccurate at that level of hypertriglyceridemia.  Directly measured LDL cholesterol is not recommended for persons without hypertriglyceridemia because calculated LDL cholesterol levels are sufficiently accurate.

If the triglyceride level is between 250 and 400 mg/dL, the calculation of LDL-C is less accurate, but could still be used to calculate the LDL-C, Because of the high rate of hypertriglyceridemia in type 2 diabetes, direct LDL measures should be considered as the preferred LDL assay. In addition, LDL-C does not have to be performed on a fasting sample.

Cholesterol skin testing is a non-invasive test that entails placement of a few drops of fluid in the fleshy area of the palm near the base of the thumb and measurement of the resulting color change with a special device.  The test, known as "Cholesterol 1,2,3" (IMI International Medical Innovations Inc., Toronto, Canada), does not involve fasting or waiting hours or days for results, which will be available in 3 minutes.  Well-designed clinical trials are needed to ascertain the effectiveness of cholesterol skin testing in predicting CHD as compared to standard methods of cholesterol testing (e.g., blood cholesterol tests).

Reiter and colleagues (2007) evaluated the role of skin tissue cholesterol (SkinTc) in predicting the presence of atherosclerosis.  SkinTc concentrations were determined in 318 consecutive patients by using the non-invasive PREVU POC Skin Sterol Test.  Additionally, a complete lipid status and cardiovascular risk profile according to the PROCAM and Framingham scores as well as an evaluation by carotid duplex sonography and ankle-brachial blood pressure index testing was obtained from all patients.  SkinTc concentrations did not differ significantly among patients suffering from cerebrovascular disease and peripheral arterial disease compared to the corresponding control groups and among patients with a calculated cardiovascular risk greater than 10 % in 10 years compared to patients with a risk less than 10 % (all p > 0.05).  Additionally, SkinTc concentrations were not significantly higher in the 245 patients with at least one documented atherosclerotic disease compared with the remaining 73 patients without evidence of atherosclerosis.  The authros concluded that SkinTc concentrations determined by the PREVU POC Skin SterolTest are not related to the presence of cerebrovascular disease and peripheral arterial disease or to an elevated cardiovascular risk, indicating that this parameter can not be used as a reliable indicator of atherosclerosis.

Isoprene is a volatile compound that is formed endogenously in humans.  While the biochemical pathways of biosynthesis and exact origins of isoprene found in human breath are still unclear, its measurement in exhaled breath has been suggested as a non-invasive indicator with diagnostic potential.  It has been suggested that isoprene is related to cholesterol biosynthesis.  As a result, breath isoprene measurements could potentially be used for mass screening for lipid disorders and may serve as an additional parameter to complement invasive tests for monitoring the effectiveness of lipid-lowering therapy (pharmacological agents and/or dietary or lifestyle modifications).  However, this test has not yet reached the level of routine clinical methods and is still under development (Salerno-Kennedy and Cashman, 2005).  In a review on the diagnostic potential of breath analysis of volatile organic compounds, Miekisch and colleagues (2004) noted that due to technical problems of sampling and analysis and a lack of normalization and standardization, huge variations exist between results of different studies.  The authors stated that these are among the main reasons why breath analysis could not yet been introduced into clinical practice.

O'Hara et al (2008) stated that analysis of volatile organic compounds (VOCs) on human breath has great potential as a non-invasive diagnostic technique.  It is, thus, surprising that no single, standard procedure has evolved for breath sampling.  These researchers presented a novel repeated-cycle isothermal re-breathing method, where 1 cycle comprises 5 rebreaths, which could be adopted for breath analysis of VOCs.  For demonstration purposes, the authors presented measurements of 3 common breath VOCs
  1. isoprene,
  2. acetone and
  3.  methanol. 
Their concentrations measured in breath are shown to increase with number of re-breaths until a plateau value is reached by at least 20 re-breaths.  The average ratio of plateau concentration to single mixed expired breath concentration was found to be 1.92 +/- 0.57 for isoprene, 1.25 +/- 0.13 for acetone and 1.12 +/- 0.12 for methanol.  Measurements from on-line single exhalations were presented, which demonstrated a positive slope in the time-dependent expirograms of isoprene and acetone.  The slope of the isoprene expirogram was persistently linear and the end-expired concentration of isoprene was highly variable in the same subject depending on the duration of exhalation.  End-expired values of acetone are not as sensitive to the length of exhalation, and were the same to within measurement uncertainty for any duration of exhalation for any subject.  The authors concluded that uncontrolled single on-line exhalations are unsuitable for the reliable measurement of isoprene in the breath and that re-breathing can be the basis of an easily tolerated protocol for the reliable collection of breath samples.

Tashakkor and Mancini (2013) provided a systematic review of clinical data to assist physicians counselling patients that have undergone skin cholesterol testing and provided a framework for future research.  Multiple electronic databases were systematically searched for studies published from 1970 through February 2013.  Selection criteria included English language, peer-reviewed studies that quantitatively examined the relationship between non-invasively measured skin cholesterol levels and indices of vascular disease or cardiovascular risk factors in human subjects.  These researchers identified 9 cohorts reported in 11 studies.  The studies suggested that skin cholesterol does not correlate with traditional markers of cardiovascular disease such as serum lipid values and inflammatory markers, and integrated risk scores (Framingham and Prospective Cardiovascular Munster [PROCAM]).  Single studies reported a significant relationship between skin cholesterol levels and evidence of underlying atherosclerosis as implied by positive exercise testing, invasive coronary angiography, increased calcium scores in Caucasian patients, and presence of carotid plaque detected using B-mode ultrasound.  Two studies identified a significant relationship using B-mode measurements of carotid intima medial thickening.  The authors concluded that skin cholesterol might be a marker of underlying vascular atherosclerosis.  Moreover, they stated that further prospective investigations are needed to establish utility of this point-of-care test for identifying subjects warranting formal cardiovascular risk assessment.

Kelishadi and colleagues (2015) stated that different viewpoints exist about lipid screening in all children or only in children with positive family history of premature CVDs or hypercholesterolemia. This systematic review and meta-analysis evaluated the effectiveness of lipid screening in children and adolescents according to the existence of positive family history of CVD risk factors.  PubMed, Scopus, and Google scholar were searched to identify relevant papers that were published from November 1980 until November 30, 2013.  Irrelevant studies were set aside after studying their title, abstract, and full text.  Then, the relevant studies were assessed by using a quality appraisal check-list.  These researchers used random effect model for meta-analysis and calculating the total estimation of sensitivity, specificity, and the positive predictive value (PPV) of family history in predicting dyslipidemia among children and adolescents.  A total of  17,214 studies were identified in the primary search, out of which 19 primary studies were qualified for study entry.  The sensitivity of positive family history of premature CVD or dyslipidemia for predicting dyslipidemia among children varied between 15 and 93.  Moreover, the effectiveness of screening children for dyslipidemia according to premature CVD or dyslipidemia in their relatives was low in 86.9 % of the primary studies.  The total estimation of sensitivity, specificity, and predictive value was 42.6, 59, and 20.7, respectively, according to the meta-analysis results.  The authors concluded that the present meta-analysis indicated that selecting target population for screening children and adolescents for dyslipidemia according to their family history has low sensitivity.

Low-Density Lipoprotein Particle (LDL-P) Testing

Ip and colleagues (2009) stated that measures of LDL subfractions have been proposed as an independent risk factor for cardiovascular disease.  These investigators reviewed published studies that reported relationships between LDL subfractions and cardiovascular outcomes.  Data sources used for searching included MEDLINE (1950 to 5 January 2009), CAB Abstracts (1973 to 30 June 2008), and Cochrane Central Register of Controlled Trials (second quarter of 2008), limited to English-language studies.  Three reviewers selected longitudinal studies with 10 or more participants that reported an association between LDL subfractions and incidence or severity of cardiovascular disease and in which plasma samples were collected before outcome determination.  Data were extracted from 24 studies.  The 10 studies that used analytical methods available for clinical use (all of which used nuclear magnetic resonance) had full data extraction, including quality assessment (good, fair, or poor).  All studies were extracted by 1 researcher and verified by another.  All 24 studies, and the subset of 10 nuclear magnetic resonance studies, were heterogeneous in terms of the specific tests analyzed, analytical methods used, participants investigated, and outcomes measured.  Higher LDL particle number was consistently associated with increased risk for cardiovascular disease, independent of other lipid measurements.  Other LDL subfractions were generally not associated with cardiovascular disease after adjustment for cholesterol concentrations.  No study evaluated the incremental value of LDL subfractions beyond traditional cardiovascular risk factors or their test performance.  The authors concluded that higher LDL particle number has been associated with cardiovascular disease incidence, but studies have not determined whether any measures of LDL subfractions add incremental benefit to traditional risk factor assessment.  They stated that routine use of clinically available LDL subfraction tests to estimate cardiovascular disease risk is premature.

Krauss (2010) noted that subfractions of LDL and HDL defined by differences in particle size and density have been associated to varying degrees with risk of cardiovascular disease.  Assessment of these relationships has been clouded by lack of standardization among the various analytic methodologies as well as the strong correlations of the subfractions with each other and with standard lipid and lipoprotein risk markers.  These researchers summarized the properties of the major LDL and HDL particle subclasses, and recent evidence linking their measurement with risk of atherosclerosis and cardiovascular disease.  Several recent studies have shown independent relationships of levels of LDL- and HDL-size subclasses to risk of both coronary artery and cerebrovascular disease.  However, the 2 largest studies, employing nuclear magnetic resonance and ion mobility, respectively, did not find evidence that these measurements improved risk assessment compared with standard lipoprotein assays.  In the latter study, principal component analysis was used to group multiple subfraction measurements into 3 distinct and statistically independent clusters that were related both to cardiovascular outcomes and to genotypes that may reflect underlying metabolic determinants.  The authors concluded that although there is as yet inconclusive evidence as to the extent to which LDL and HDL subfraction measurements improve clinical assessment of cardiovascular disease risk beyond standard lipid risk markers, recent studies suggested that more refined analyses of lipoprotein subspecies may lead to further improvements in cardio-vascular diseases (CVDs) risk evaluation and particularly in identification of appropriate targets for therapeutic intervention in individual patients. 

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) practice guideline on "Assessment of cardiovascular risk in asymptomatic adults" (Greenland et al, 2010) stated that "Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond a standard fasting lipid profile is not recommended for cardiovascular risk assessment in asymptomatic adults".  (Level of Evidence: C).

Steffen et al (2015) noted that the ACC and AHA have issued guidelines indicating that the contribution of apolipoprotein B-100 (ApoB) to cardiovascular risk assessment remains uncertain.  The present analysis examined if lipoprotein particle measures convey risk of CHD in 4,679 Multi-Ethnic Study of Atherosclerosis (MESA) participants.  Cox regression analysis was performed to determine associations between lipids or lipoproteins and primary CHD events.  After adjustment for non-lipid variables, lipoprotein particle levels in 4th quartiles were found to convey significantly greater risk of incident CHD when compared to 1st quartile levels (hazard ratio [HR]; 95 % confidence interval [CI]): ApoB (HR, 1.84; 95 % CI: 1.25 to 2.69), ApoB/ApoA-I (HR, 1.91; 95 % CI: 1.32 to 2.76), total low-density lipoprotein-particles (LDL-P; HR, 1.77; 95 % CI: 1.21 to 2.58), and the LDL-P/HDL-P (high-density lipoprotein-P) ratio (HR, 2.28; 95 % CI: 1.54 to 3.37).  Associations between lipoprotein particle measures and CHD were attenuated after adjustment for standard lipid panel variables.  Using the AHA/ACC risk calculator as a baseline model for CHD risk assessment, significant net re-classification improvement scores were found for ApoB/ApoA-I (0.18; p = 0.007) and LDL-P/high-density lipoprotein-P (0.15; p < 0.001).  C-statistics revealed no significant increase in CHD event discrimination for any lipoprotein measure.  The authors concluded that lipoprotein particle measures ApoB/ApoA-I and LDL-P/high-density lipoprotein-P marginally improved net re-classification improvement scores, but null findings for corresponding c-statistic are not supportive of lipoprotein testing.  The attenuated associations of lipoprotein particle measures with CHD after the adjustment for lipids indicate that their measurement does not detect risk that is unaccounted for by the standard lipid panel.  However, the possibility that lipoprotein measures may identify CHD risk in a subpopulation of individuals with normal cholesterol, but elevated lipoprotein particle numbers cannot be ruled out.

Furthermore, an UpToDate review on "Screening for lipid disorders" (Vijan, 2015 and 2016) states that "While LDL subfractions may perform better than LDL-C alone, they have not been adequately assessed relative to existing risk scores".  The review also states that "In patients whose prior lipid measurement places them clearly below an appropriate threshold for treatment, we suggest repeating measurements every 5 years. In patients near a threshold for treatment based on total CV risk and in patients above a threshold for treatment, we suggest repeating measurements every 3 years".

Logano and associates (2016a) systematically reviewed the evidence on benefits and harms of screening adolescents and children for multi-factorial dyslipidemia for USPSTF.  Medline, Cochrane Central Register of Controlled Trials, and PubMed were searched for studies published between January 1, 2005, and June 2, 2015; studies included in a previous USPSTF evidence report and reference lists of relevant studies and ongoing trials were also searched.  Surveillance was conducted through April 9, 2016.  Fair- and good-quality studies in English with participants 0 to 20 years of age were selected for analysis.  Two investigators independently reviewed abstracts and full-text articles and extracted data into evidence tables; results were qualitatively summarized.  Main outcome measures included dyslipidemia (total cholesterol [TC] greater than or equal to 200 mg/dL or LDL-C greater than or equal to 130 mg/dL) and atherosclerosis in childhood; myocardial infarction and ischemic stroke in adulthood; diagnostic yield (number of confirmed cases per children screened); and harms of screening or treatment.  Simulated diagnostic yield was calculated as initial screening yield × positive predictive value from a study with confirmatory testing.  Screening of children for multi-factorial dyslipidemia has not been evaluated in randomized clinical trials.  Based on 1 observational study (n = 6,500) and nationally representative prevalence estimates, the simulated diagnostic yield of screening for elevated TC varies between 4.8 % and 12.3 % (higher in obese children [12.3 %] and at the ages when TC naturally peaks – 7.2 % at age 9 to 11 years and 7.2 % at age 16 to 19 years); 1 good-quality randomized clinical trial (n = 663) found a modest effect of intensive dietary counseling for a low-fat, low-cholesterol diet on lipid levels at 1 year in children aged 8 to 10 years with mild-to-moderate dyslipidemia; mean between-group difference in TC change from baseline was -6.1 mg/dL (95 % CI: -9.1 to -3.2 mg/dL; p < 0.001).  Between-group differences dissipated by year 5.  The intervention did not adversely affect nutritional status, growth, or development over the 18-year study period; 1 observational study (n = 9,245) found that TC concentration at age 12 to 39 years was not associated with death before age 55 years.  The authors concluded that the diagnostic yield of lipid screening varied by age and BMI.  No direct evidence was identified for benefits or harms of childhood screening or treatment on outcomes in adulthood.  Intensive dietary interventions may be safe, with modest short-term benefit of uncertain clinical significance.

Logano and colleagues (2016b) systematically reviewed the evidence on benefits and harms of screening adolescents and children for heterozygous familial hypercholesterolemia (FH) for the USPSTF.  Medline, the Cochrane Central Register of Controlled Trials, and PubMed were searched for studies published between January 1, 2005, and June 2, 2015; studies included in a previous USPSTF report were also searched.  Surveillance was conducted through April 8, 2016.  Fair- and good-quality studies in English with participants 0 to 20 years of age were selected for analysis.  Two investigators independently reviewed abstracts and full-text articles and extracted data into evidence tables; results were qualitatively summarized.  Main outcome measures included myocardial infarction and ischemic stroke in adulthood; lipid concentrations and atherosclerosis in childhood; diagnostic yield of screening; any harm of screening or treatment.  Based on 2 studies (n = 83,241), the diagnostic yield of universal screening for FH in childhood is 1.3 to 4.8 cases per 1,000 screened.  There was no eligible evidence on the benefits or harms of FH screening in childhood; 8 placebo trials of statin drugs (n = 1,071, 6 to 104 weeks) found LDL-C decreases of 20 % to 40 %; 1 trial (n = 214) showed a 2.01 % decrease in carotid intima-media thickness with statins, compared with 1.02 % with placebo (p = 0.02); 3 placebo trials of bile acid-sequestering agents (n = 332, 8 to 52 weeks) showed LDL-C reductions of 10 % to 20 %.  In 1 trial (n = 248), ezetimibe with simvastatin resulted in greater LDL-C reductions compared with simvastatin alone at 33 weeks (mean, -54.0 % [SD, 1.4 %] versus -38.1 % [SD, 1.4 %]); 1 trial of ezetimibe monotherapy (n = 138) showed mean LDL-C decreases of 28 % (95 % CI: -31 % to -25 %) from baseline and negligible change with placebo at 12 weeks; 18  studies found statins generally well-tolerated; 1 observational study found lower, but still normal, dehydroepiandrosterone sulfate concentrations in statin-treated males with FH at 10-year follow-up.  Bile acid-sequestering agents were commonly associated with adverse gastro-intestinal symptoms and poor palatability.  There was no eligible evidence on the effect of FH treatment on myocardial infarction or stroke in adulthood.  The authors concluded that screening can detect FH in children, and lipid-lowering treatment in childhood can reduce lipid concentrations in the short-term, with little evidence of harm.  There is no evidence for the effect of screening for FH in childhood on lipid concentrations or cardiovascular outcomes in adulthood, or on the long-term benefits or harms of beginning lipid-lowering treatment in childhood.

The USPSTF (2016) updated their 2007 recommendation on screening for lipid disorders in children, adolescents, and young adults.  The USPSTF reviewed the evidence on screening for lipid disorders in children and adolescents 20 years or younger – 1 review focused on screening for heterozygous familial hypercholesterolemia, and 1 review focused on screening for multi-factorial dyslipidemia.  Evidence on the quantitative difference in diagnostic yield between universal and selective screening approaches, the effectiveness and harms of long-term treatment and the harms of screening, and the association between changes in intermediate outcomes and improvements in adult cardiovascular health outcomes are limited.  The USPSTF concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for lipid disorders in children and adolescents 20 years or younger.

Cascade Testing in Relatives for Familial Hypercholesterolemia

Leonardi-Bee et al (2021) noted that cascade testing in relatives of index cases is the most cost-effective approach to identifying individuals with FH; however, it is currently unclear which strategy to contact relatives would be the most effective.  In a systematic review, these investigators examined the effectiveness of different strategies in cascade testing of FH.  They carried out comprehensive searches of 3 electronic databases and grey literature sources (from inception to May 2020).  Screening, data extraction and assessments of methodological quality were made independently by 2 reviewers.  Meta-analyses of proportions were performed using random effects models.  Effect measures were reported as percentages with 95 % CIs.  A total of 24 non-comparative studies were included, of which 11 used a direct, 8 used an indirect, and 5 used a combination of both direct and indirect cascade strategies.  The median number of new relatives with FH per known index case was approximately 1.  The combination strategy resulted in the largest yields of relatives tested for FH out of those contacted (40 %, 9 5% CI: 37 % to 42 %, 1 study) and relatives responding to testing out of those contacted (54 %, 1 study); however, the direct strategy had the largest yield of index cases participating in cascade testing out of those with FH confirmed (94 %, 8 studies) compared to other strategies (p ≤ 0.01 for all comparisons).  The authors concluded that evidence is limited; however, a combination strategy, which allowed the index case to decide on method of contacting relatives, appeared to lead to better yields compared to using the direct or indirect strategy.  Moreover, these researchers stated that further evidence to support the combination approach requires experimental studies to compare the cascade approaches or interrogation of routine datasets and FH registers held on the cascade testing and the modality of contact with relatives.

The authors stated that all of the studies included in this review reported on a single cascade strategy; thus, future studies should be carried out to compare different cascade strategies, employing either quasi-experimental (such as controlled before-after studies) or preferably randomized controlled designed studies.  Furthermore, to enable the findings from future studies to be compared to determine whether combination approach to cascade testing has a greater yield compared to direct or indirect approaches, it is important that a core set of outcome measures for such studies is agreed on and reported.  Aligned with current guidelines, index cases should have FH genetically confirmed or with definitive clinical diagnosis.  These researchers recommended that as a minimum, studies report on the numbers of relatives eligible and contacted for, who responded to a request for, cascade testing, and the number of relatives tested and confirmed to have a diagnosis of FH.  Another hypothesis worth examining is whether the efficiency of cascade testing is related to family size and the extent of index’ patients contact with other family members.

Strategies for Screening for Familial Hypercholesterolemia

Qureshi et al (2021) stated that FH is a common inherited condition that is associated with premature cardiovascular disease.  The increased cardiovascular morbidity and mortality, resulting from high levels of cholesterol since birth, can be prevented by starting lipid-lowering therapy; however, the majority of patients in the United Kingdom and worldwide remain undiagnosed.  Established diagnostic criteria in current clinical practice are the Simon-Broome and Dutch Lipid Clinical network criteria and patients are classified as having probable, possible or definite FH.  In a Cochrane review, these investigators examined the effectiveness of healthcare interventions strategies to systematically improve identification of FH in primary care and other community settings compared to usual care (incidental approaches to identify FH in primary care and other community settings).  The authors concluded that currently, there are no RCTs or controlled non-randomized studies of interventions (NRSI) evidence to determine the most appropriate healthcare strategy to systematically identify possible or definite clinical FH in primary care or other community settings.  Uncontrolled before-and-after studies were identified; but were not eligible for inclusion.  These researchers stated that further studies examining healthcare strategies of systematic identification of FH need to be performed with diagnosis confirmed by genetic testing or validated through clinical phenotype (or both).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:
80061 Lipid panel
82465 Cholesterol, serum or whole blood, total
83718 Lipoprotein, direct measurement; high density cholesterol (HDL cholesterol)
84478 Triglycerides

CPT codes not covered for indications listed in the CPB:
83719 Lipoprotein, direct measurement; VLDL cholesterol

ICD-10 codes covered if selection criteria are met:
E78.1 Pure hyperglyceridemia
E78.2 Mixed hyperlipidemia
Z13.220 Encounter for screening for lipoid disorders

Hypertriglyceridemia:

CPT codes covered if selection criteria are met:
83721 Lipoprotein, direct measurement; LDL cholesterol

ICD-10 codes covered if selection criteria are met:
E08.00 - E13.9 Diabetes mellitus
E78.1 Pure hyperglyceridemia
E78.2 Mixed hyperlipidemia

The above policy is based on the following references:

  1. Alberta Heritage Foundation for Medical Research (AHFMR). Lifestream Technologies cholesterol monitor. Techscan. Edmonton, AB: AHFMR; 2000.
  2. American Academy of Family Physicians (AAFP). Summary of policy recommendations for periodic health examinations. Leawood, KS: AAFP; August 2003.
  3. American Academy of Pediatrics, Committee on Nutrition. Statement on cholesterol. Pediatrics. 1992;90(3):469-473.
  4. American Academy of Pediatrics. National Cholesterol Education Program. Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992;89(3 Pt 2):525-584.
  5. American College of Obstetricians and Gynecologists (ACOG), Committee on Primary Care. Primary and Preventive Care: Periodic Assessments. Committee Opinion No. 229. Washington, DC: ACOG; December 1999.
  6. American College of Physicians - American Society of Internal Medicine. Guidelines for using serum cholesterol, high-density lipoprotein cholesterol, and triglyceride levels as screening tests for preventing coronary heart disease in adults. Ann Intern Med. 1996;124(5):515-517.
  7. American Medical Association (AMA). Guidelines for Adolescent Services (GAPS): Recommendations and Rationale. Chicago, IL: AMA; 1994.
  8. Brigham and Women's Hospital. Cardiovascular disease in women: A guide to risk factor screening, prevention and management. Boston, MA: Brigham and Women's Hospital; 2002.
  9. Canadian Task Force on the Periodic Health Examination. Lowering the blood total cholesterol level to prevent coronary heart disease. In: Canadian Guide to Clinical Preventive Health Care. Ottawa, ON: Canada Communication Group; 1994:650-659.
  10. Daniels SR, Greer FR and the Committee on Nutrition; American Academy of Pediatrics. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122(1):198-208.
  11. Eddy DM, ed. Common Screening Tests. Philadelphia, PA: American College of Physicians; 1991.
  12. Evelegh MJ, Norton B, Pearce GL. Three-minute skin test measures cholesterol levels. Meeting Report. Dallas, TX: American Heart Association; November 14, 2000. Available at: http://216.185.112.5/presenter.jhtml?identifier=3193. Accessed January 14, 2002.
  13. Garber AM, Browner WS, Hulley SB. Cholesterol screening in asymptomatic adults, revisited. Ann Intern Med. 1996;124(5):518-531.
  14. Girardet JP, Luc G, Rieu D, et al. Recommendations for children with hypercholesterolemia. Arch Pediatr. 2011;18(2):217-229.
  15. Green M, ed. Bright Futures Guidelines for Health Supervision of Infants, Children and Adolescents. Arlington, VA: National Center for Maternal and Child Health; 1994.
  16. Greenland P, Alpert JS, Beller GA, et al; American College of Cardiology Foundation, American Heart Association. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010;56(25):e50-e103.
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