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Cholesterol Screening

Editor: Shivlal Pandey Updated: 5/1/2023 6:49:22 PM

Introduction

Atherosclerotic cardiovascular disease (ASCVD) is one of the worldwide leading cause of cardiovascular morbidity and mortality. In 2013 coronary artery disease and cerebrovascular disease were the first and third causes of death, which attributed to 84.5% cardiovascular death and 28.2% of all-cause mortality, respectively.[1] Experts predict these numbers to increase in the future due to the transformation of the human lifestyle, particularly fast-food diet, and sedentary living.[2] It also contributed to substantial morbidity because coronary heart disease (CHD) is one of the most important etiology of heart failure, specifically ischemic cardiomyopathy. Due to better healthcare systems and technology, many CHD patients that experienced acute ischemic events survived but later developed heart failure.[3] The relationship between cholesterol and heart disease is well-established. Therefore, following appropriate guidelines for screening is of paramount importance.

Cholesterol is a sterol compound found in most human body tissues. From a physiologic standpoint, cholesterol and its derivatives are vitally crucial for cell membranes and myriad metabolic processes in the body. Also, cholesterol is used to make hormones, fat-soluble vitamins, and bile acids. The primary source of cholesterol is from animal-based foods, such as eggs, dairy, and cheese. Based on density, cholesterol can classify as high-density lipoproteins (HDL), low-density lipoproteins (LDL), or very-low-density lipoproteins (VLDL). Triglycerides are also part of the blood-lipid profile.[4] Of note, LDL, VLDL, and triglycerides have been correlated to increased risk of CHD, while the reverse appears to be true for HDL. Thus, higher HDL levels confer a protective effect on CHD and all-cause mortality.

Framingham Heart Study, a landmark study, is the first to demonstrate unequivocally that higher LDL concentrations were associated with a higher risk of ASCVD.[5][6][7]

Specimen Collection

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Specimen Collection

Traditionally, when patients were scheduling for cholesterol testing, they needed to fast for more than eight hours.[8] The reason behind this laboratory routine is to avoid triglyceride elevation postprandially. However, recently, routine fasting is not mandatory for every patient before cholesterol testing. Nevertheless, some circumstances require patients to fast. Thus, the decision to fast or not to fast depends on the clinical question being asked by the respective physician, as outlined below:

  • Non- fasting blood lipid profiles are acceptable in several conditions, i.e. :[9]
    1. Initial risk estimation of an untreated primary prevention patient
    2. To clarify the diagnosis of metabolic syndrome.
  • Fasting blood lipid profiles are preferred or even mandatory in several conditions, i.e. :[9]
    1. For screening and following patients with a family history of genetic hyperlipidemia or premature ASCVD (Fasting is mandatory)
    2. Establish the diagnosis of hypertriglyceridemia
    3. Residual risk estimation of treated patients
    4. Assessment of patients with or at risk for pancreatitis   

Then, patients will undergo a venous blood sampling of 0.5 to 1 mL, mostly through their antecubital vein. The container for the specimen must be a gel-barrier transport, green-top (heparin) tube, or lavender-top (EDTA) tube. Then, the serum must be separated from other blood components within 45 minutes of collection. Samples should be stored at room temperature. 

Procedures

The LDL cholesterol estimation can proceed with two distinct methods; indirect and direct. The former approach utilizes the Friedewald cholesterol estimation formula. On the other hand, the latter method utilizes homogeneous assays. In unreliable conditions, such as triglyceride >400 mg/dL, the direct methods can be used to supplement the Friedewald calculation, which has shown to able to meet the standard requirements set by National Cholesterol Education Program (NCEP) for LDL-C testing. When used for non-fasting samples, the direct method was precise and accurate (CV <4% and bias <4%).[10] 

Nonetheless, there were several limitations to direct methods. A study of comparison between direct and indirect methods with the reference method of the ultracentrifugation in HIV patients, which hypertriglyceridemia are common, found that no adequate agreement between these two tests with the ultracentrifugation. When TG is more than 400 mg/dL, the direct method tends to overestimate the actual LDL, whereas the indirect method tends to underestimate the actual LDL levels.[11]

Indications

There are many major clinical practice guidelines set by several colleges and societies with their subtle differences between them. However, the primary goals of these clinical practice guidelines are all the same, which are cholesterol testing to prevent CAD in healthy populations or primary prevention and to provide early detection and slow down the progression of diseases or secondary prevention. 

  1. Patient with a family history of premature death due to myocardial infarction in first degree relatives (<55 years [male] and <65 years [female])
  2. History of familial hypercholesterolemia or patient with stigmata of familial hypercholesterolemia (xanthoma/ xanthomata or eyelid xanthelasma)
  3. Patients with comorbidities that are likely to be benefitted from statins use, i.e., patients with diabetes, chronic kidney disease, HIV, and others.
  4. Risk stratification for patients without the disease, which might benefit from cholesterol-lowering treatment.

Potential Diagnosis

Cholesterol screening is an integral part of primary and secondary prevention of ASCVD. It can detect a vulnerable population that may be asymptomatic but with a high risk of ASCVD due to genetic predispositions. Additionally, it can detect cholesterol elevations secondary to other diseases, such as diabetes, chronic kidney disease, and HIV infection, or due to drug usage, such as oral contraceptive drugs and others.[12][13] Furthermore, abnormally high levels of cholesterol components might indicate familial hypercholesterolemia.[14][15]

Occasionally, when screening for cardiovascular disease by cholesterol test, the result might reveal low or even untraceable levels of LDL-C. When the LDL is < 80 mg/dL, hypobetalipoproteinemia might be suspected, whereas an undetected level of LDL signifies abetalipoproteinemia.[16][17]

Normal and Critical Findings

Non-fasting samples*[18]

  1. Triglycerides:
    • ≥2 mmol/L (175 mg/dL)
  2. Total cholesterol:
    • ≥5 mmol/L (190 mg/dL)
  3. LDL cholesterol:
    • ≥3 mmol/L (115 mg/dL)
  4. Remnant cholesterol (IDL + VLDL): 
    • ≥0.9 mmol/L (35 mg/dL)
  5. Non-HDL cholesterol: 
    • ≥3.9 mmol/L (150 mg/dL)
  6. Lipoprotein (a)
    • ≥0.50 g/L (50 mg/dL)
  7. Apolipoprotein B: 
    • ≥1.0 g/L (100 mg/dL)
  8. HDL cholesterol: 
    • ≤1 mmol/L (40 mg/dL)
  9. Apolipoprotein A1: 
    • ≤1.25 g/L (125 mg/dL)

*When non-fasting triglycerides concentration exceeds 5mmol/L (440 mg/dL), obtaining a fasting plasma sample may be considered.

Fasting samples

  1. Triglycerides:
    • ≥1.7 mmol/L (150 mg/dL)
  2. Total cholesterol:
    • ≥5 mmol/L (190 mg/dL)
  3. LDL cholesterol:
    • ≥3 mmol/L (115 mg/dL)
  4. Remnant cholesterol (IDL + VLDL): 
    • ≥0.8 mmol/L (30 mg/dL)
  5. Non-HDL cholesterol: 
    • ≥3.8 mmol/L (145 mg/dL)
  6. Lipoprotein (a)
    • ≥0.50 g/L (50 mg/dL)
  7. Apolipoprotein B: 
    • ≥1.0 g/L (100 mg/dL)
  8. HDL cholesterol: 
    • ≤1 mmol/L (40 mg/dL)
  9. Apolipoprotein A1: 
    • ≤1.25 g/L (125 mg/dL)

The NCEP has also set the LDL-C concentrations and their respective labels in adult >18 years old, with <100, 100 - 129, 130 - 159, 160 - 189, and >= 190 mg/dL identified as desirable, above desirable, borderline high, high, and very high, respectively.[19] For children and adolescents, cholesterol concentrations of <110mg/dL, 110 - 129 mg/dL, and >= 130 mg/dL were deemed acceptable, borderline high, and high, respectively.[20]

Interfering Factors

The original Friedewald equation is total cholesterol (TC) = HDL + LDL + Triglycerides( TG)/5, and it is comparable to the ultracentrifuge method of lipoprotein quantification. However, three conditions preclude the use of this equation, explain as follows:[21]

  • The first one is when there is chylomicron in the plasma. Chylomicrons contain triglycerides; thus, it can interfere with the formula for VLDL calculation, which is plasma TG divided by five. Fortunately, normal subjects do not have chylomicrons in their plasma. Furthermore, chylomicrons can be present in the plasma of patients that suffer type I (familial hyperchylomicronemia), type III (familial dysbetalipoproteinemia), and type V (combined hypertriglyceridemia).
  • The second one is in type III familial hypercholesterolemia (FH). In this disorder, VLDL exists in two forms, which are the normal VLDL with the ratio of TG to cholesterol around five,  and the unique VLDL which the cholesterol's content is abnormally higher with beta mobility on electrophoresis. Therefore, in type III FH, the method of choice is either by centrifugal isolation of the VLDL, checking cholesterol electrophoresis' mobility, or by finding the TG/cholesterol ratio.
  • Finally, when the plasma triglycerides concentration is higher than 400 mg/dL. Friedewald et al. noticed that when they incorporate type IV FH patient cholesterol values, they notice outlier values and the decreased correlation coefficient between ultracentrifuge and estimated cholesterol measurement. Subsequently, they found that some type IV FH patients had TG levels above 400 mg/dL. Consequently, after they excluded these patients' values, the correlation coefficient rose.

Therefore, a new estimation method is proposed by Martin et al. Their estimation is more accurate because it does not use fix ratio between TG and VLDL, but it incorporates adjustable factors for the ratios of triglyceride and VLDL. Consequently, when the LDL is very low, or the TG is very high, i.e.,>400 mg/dL, this new estimation gives more accurate results.[22] This equation has also shown to be superior compared to the Friedewald equation for non-fasting samples.[23]

Clinical Significance

LDL-C and HDL-C levels are essential for calculating the 10-year risk of ASCVD derived from the Lloyd-Jones et al. study, which is applicable for men and women, age 40 to 79, and African American/Non-Hispanic White.[24] However, for other ethnicities, Non-Hispanic White is used. Nonetheless, it can overestimate or underestimate the risk.[25]

Another risk-estimation tool identified as heart score, which is adopted by the European Society of Cardiology, also incorporates total cholesterol and HDL levels.[26] It derives from a study by Conroy et al., which involved 12 European cohort studies, 250,000 patient-data sets, with 3 million person-years of observation, and 7000 fatal cardiovascular events.[27]

References


[1]

Barquera S, Pedroza-Tobías A, Medina C, Hernández-Barrera L, Bibbins-Domingo K, Lozano R, Moran AE. Global Overview of the Epidemiology of Atherosclerotic Cardiovascular Disease. Archives of medical research. 2015 Jul:46(5):328-38. doi: 10.1016/j.arcmed.2015.06.006. Epub 2015 Jun 29     [PubMed PMID: 26135634]

Level 3 (low-level) evidence

[2]

Ignarro LJ, Balestrieri ML, Napoli C. Nutrition, physical activity, and cardiovascular disease: an update. Cardiovascular research. 2007 Jan 15:73(2):326-40     [PubMed PMID: 16945357]


[3]

Lip GY, Gibbs CR, Beevers DG. ABC of heart failure: aetiology. BMJ (Clinical research ed.). 2000 Jan 8:320(7227):104-7     [PubMed PMID: 10625270]


[4]

Blesso CN, Fernandez ML. Dietary Cholesterol, Serum Lipids, and Heart Disease: Are Eggs Working for or Against You? Nutrients. 2018 Mar 29:10(4):. doi: 10.3390/nu10040426. Epub 2018 Mar 29     [PubMed PMID: 29596318]


[5]

DAWBER TR, KANNEL WB, LYELL LP. An approach to longitudinal studies in a community: the Framingham Study. Annals of the New York Academy of Sciences. 1963 May 22:107():539-56     [PubMed PMID: 14025561]


[6]

Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet (London, England). 2014 Mar 15:383(9921):999-1008. doi: 10.1016/S0140-6736(13)61752-3. Epub 2013 Sep 29     [PubMed PMID: 24084292]

Level 3 (low-level) evidence

[7]

Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998 May 12:97(18):1837-47     [PubMed PMID: 9603539]

Level 2 (mid-level) evidence

[8]

Anderson TJ, Grégoire J, Pearson GJ, Barry AR, Couture P, Dawes M, Francis GA, Genest J Jr, Grover S, Gupta M, Hegele RA, Lau DC, Leiter LA, Lonn E, Mancini GB, McPherson R, Ngui D, Poirier P, Sievenpiper JL, Stone JA, Thanassoulis G, Ward R. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. The Canadian journal of cardiology. 2016 Nov:32(11):1263-1282. doi: 10.1016/j.cjca.2016.07.510. Epub 2016 Jul 25     [PubMed PMID: 27712954]


[9]

Driver SL, Martin SS, Gluckman TJ, Clary JM, Blumenthal RS, Stone NJ. Fasting or Nonfasting Lipid Measurements: It Depends on the Question. Journal of the American College of Cardiology. 2016 Mar 15:67(10):1227-1234. doi: 10.1016/j.jacc.2015.12.047. Epub     [PubMed PMID: 26965545]


[10]

Nauck M, Warnick GR, Rifai N. Methods for measurement of LDL-cholesterol: a critical assessment of direct measurement by homogeneous assays versus calculation. Clinical chemistry. 2002 Feb:48(2):236-54     [PubMed PMID: 11805004]


[11]

Evans SR, Fichtenbaum CJ, Aberg JA, A5087 Study Team. Comparison of direct and indirect measurement of LDL-C in HIV-infected individuals: ACTG 5087. HIV clinical trials. 2007 Jan-Feb:8(1):45-52     [PubMed PMID: 17434848]


[12]

Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, Herink M, Ito MK. Medication Induced Changes in Lipid and Lipoproteins. Endotext. 2000:():     [PubMed PMID: 26561699]


[13]

Stone NJ. Secondary causes of hyperlipidemia. The Medical clinics of North America. 1994 Jan:78(1):117-41     [PubMed PMID: 8283927]


[14]

Brett T, Qureshi N, Gidding S, Watts GF. Screening for familial hypercholesterolaemia in primary care: Time for general practice to play its part. Atherosclerosis. 2018 Oct:277():399-406. doi: 10.1016/j.atherosclerosis.2018.08.019. Epub     [PubMed PMID: 30270077]


[15]

Weng SF, Kai J, Andrew Neil H, Humphries SE, Qureshi N. Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT). Atherosclerosis. 2015 Feb:238(2):336-43. doi: 10.1016/j.atherosclerosis.2014.12.034. Epub 2014 Dec 20     [PubMed PMID: 25555265]

Level 3 (low-level) evidence

[16]

Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Current opinion in lipidology. 2014 Jun:25(3):161-8. doi: 10.1097/MOL.0000000000000072. Epub     [PubMed PMID: 24751931]

Level 3 (low-level) evidence

[17]

Linton MF, Farese RV Jr, Young SG. Familial hypobetalipoproteinemia. Journal of lipid research. 1993 Apr:34(4):521-41     [PubMed PMID: 8496659]


[18]

Nordestgaard BG, Langsted A, Mora S, Kolovou G, Baum H, Bruckert E, Watts GF, Sypniewska G, Wiklund O, Borén J, Chapman MJ, Cobbaert C, Descamps OS, von Eckardstein A, Kamstrup PR, Pulkki K, Kronenberg F, Remaley AT, Rifai N, Ros E, Langlois M, European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) joint consensus initiative. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points-a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. European heart journal. 2016 Jul 1:37(25):1944-58. doi: 10.1093/eurheartj/ehw152. Epub 2016 Apr 26     [PubMed PMID: 27122601]

Level 3 (low-level) evidence

[19]

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16:285(19):2486-97     [PubMed PMID: 11368702]

Level 1 (high-level) evidence

[20]

Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011 Dec:128 Suppl 5(Suppl 5):S213-56. doi: 10.1542/peds.2009-2107C. Epub 2011 Nov 14     [PubMed PMID: 22084329]


[21]

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical chemistry. 1972 Jun:18(6):499-502     [PubMed PMID: 4337382]


[22]

Martin SS, Blaha MJ, Elshazly MB, Toth PP, Kwiterovich PO, Blumenthal RS, Jones SR. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA. 2013 Nov 20:310(19):2061-8. doi: 10.1001/jama.2013.280532. Epub     [PubMed PMID: 24240933]


[23]

Sathiyakumar V, Park J, Golozar A, Lazo M, Quispe R, Guallar E, Blumenthal RS, Jones SR, Martin SS. Fasting Versus Nonfasting and Low-Density Lipoprotein Cholesterol Accuracy. Circulation. 2018 Jan 2:137(1):10-19. doi: 10.1161/CIRCULATIONAHA.117.030677. Epub 2017 Oct 16     [PubMed PMID: 29038168]


[24]

Lloyd-Jones DM, Leip EP, Larson MG, D'Agostino RB, Beiser A, Wilson PW, Wolf PA, Levy D. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006 Feb 14:113(6):791-8     [PubMed PMID: 16461820]


[25]

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2019 Jun 25:73(24):3168-3209. doi: 10.1016/j.jacc.2018.11.002. Epub 2018 Nov 10     [PubMed PMID: 30423391]

Level 1 (high-level) evidence

[26]

Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O, ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. European heart journal. 2020 Jan 1:41(1):111-188. doi: 10.1093/eurheartj/ehz455. Epub     [PubMed PMID: 31504418]


[27]

Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D, Ducimetière P, Jousilahti P, Keil U, Njølstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM, SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. European heart journal. 2003 Jun:24(11):987-1003     [PubMed PMID: 12788299]

Level 2 (mid-level) evidence