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table 1 lipoprotein classification Lipoprotein Apolipoprotein Lipid low density lipoprotein (ldl-C) apob-100 Cholesterol High density lipoprotein (Hdl-C) apoa-i; apoa-ii Cholesterol Chylomicron apob-46 triglyceride Very low density lipoprotein (Vldl) triglyceride monogenic disorders, such as lipoprotein lipase deficiency, result in marked TG elevation (fasting TG>5 mmol/L) and/or chylomicronemia, and they may be associated with pancreatitis in childhood. Familial Obesity The classic dyslipidemia associated with obesity includes elevated fasting TG levels and suppressed HDL-C levels. Therapy includes diet, lifestyle changes, and implementation of a heart-healthy lifestyle to assist the individual and the family. This type of dyslipidemia is often clustered with other CVD risk factors such as hypertension and dysglycemia. This cluster of factors, also called the metabolic syndrome, is associated with a 14-fold increased risk of clinical CVD by 50 years of age, highlighting the importance of early recognition and treatment of this disorder (9). Secondary Causes of Dyslipidemia In addition to obesity and the primary disorders resulting in dyslipidemia, numerous other clinical conditions are recognized causes of dyslipidemia in children. Important secondary causes include diabetes, hypothyroidism, chronic renal insufficiency or renal failure, and liver disease. Medications that adversely influence the lipid profile include retinoids used for the treatment of acne in youth, glucocorticoids, estrogen, progestins, and ß-blockers. Lipid Measurements Laboratory measurements of lipids should follow good quality control procedures. The National Cholesterol Education Program (NCEP) has developed criteria for the analytical performance of cholesterol assays. In addition, the CDC’s Cholesterol Reference Method Laboratory Network (CRMLN) certifies clinical diagnostic products that measure TC, HDL-C, and LDL-C. The FDA has recognized the value of the CRMLN’s certification program and encourages manufacturers to certify their products through the CRMLN. Today, TC measurements on most analyzers meet the NCEP’s 1992 criteria of 3% bias versus the reference method and imprecision. CDC’s Division of Laboratory Sciences also maintains lists of the clinical diagnostic products that have been certified by the CRMLN that can be found at www.cdc.gov/labstandards/ crmln.htm. Various methods are available to determine HDL-C, but the direct method is the most widely used. This method typically involves the selective measurement of HDL-C after shielding cholesterol in the non-HDL fractions. While direct homogeneous methods for assessing LDL-C are available on many automated analyzers, most laboratories continue to calculate LDL-C by the Friedewald equation, which is based on routinely measured TC, HDL-C, and TG. The NCEP recommends that LDL-C be calculated using one of the following equations: LDL-C (mg/dL) = TC – HDL-C – TG/5 or LDL-C (mmol/L) = TC – HDL-C – TG/2.2 Labs can use these equations to calculate LDL-C levels except when the TGs are very high or when the sample is obtained under non-fasting conditions. At very high concentrations (400 mg/dL or 4.52 mmol/L), TG/5 or TG/2.2, which is an estimate of VLDL, will not be valid due to the presence of chylomicrons. The Friedewald equation is also not valid for patients with Type III hyperlipoproteinemia. The enzymatic measurement of TG is standardized to the methylene chloride-salicylic acid chromotropic reference method of the CDC. Screening for Dyslipidemia in Youth Population-wide screening for dyslipidemia in children is not currently recommended. However, the AHA recommends screening children who are most likely to have dyslipidemia or who are at increased risk of CVD (8). The two primary target groups are children with genetic dyslipidemias, often identified by a family history of hyperlipidemia and/or premature coronary artery disease (CVD onset at < 55 years of age in male relatives, < 65 years of age in female relatives), and children who are obese. table 3 classification of cvd risk in children Total Cholesterol LDL-Cholesterol mg/dL mmol/L mg/dL mmol/L acceptable < 170 4.40 < 110 2.85 borderline 170–199 4.4–5.15 110–129 2.85–3.34 High > 200 5.15 > 130 3.34 Source: References 10 and 11. table 2 recommended interventions for children with heterozygous familial hypercholesterolemia Intervention Type Parameter Target Dietary < 30% calories from fat < 7% calories from saturated fat no trans fat Physical Activity Active play > 1 h/d Screen time < 2 h/d Other CV Risk Factors Assess and counsel: blood pressure cigarette smoking glycemic status Pharmacotherapy Consider statin therapy if : male patient is at least 10 years old, female patient has undergone menarche, LDL-C persists at ≥4.9 mmol/L or ≥4.2 mmol/L with other CV risk factor(s) or family history of PCAD Source: Reference 8. In addition, the 2006 scientific statement from AHA recommends lipid screening profiles for children with a number of pediatric disorders that increase their risk of CVD in young adulthood (8). Diabetes type 1 and 2, Kawasaki disease with coronary aneurysms, and chronic and end-stage renal disease may predispose children to very early coronary events. Hyperglycemia in type 1 diabetes is a primary mediator of atherosclerosis, while in type 2 diabetes, both hyperglycemia and insulin resistances are implicated in endothelial dysfunction. In children with chronic kidney disease, morbidity and mortality is related not only to the kidney disease but also to CVD. The recommendations and goals for intervention have been tailored to risk (2). Target Values Elevated LDL-C is the most clinically significant marker of dyslipidemia in children and is used as the basis for treatment. Table 3 summarizes the NCEP (10) and < 200 mg/dL total cholesterol < 3.35 mmol/L or 130mg/dL LDL-C American Academy of Pediatrics (AAP) (11) classification categories based on TC and LDL-C levels. A major concern among pediatric care givers has been that a single cutoff value does not reflect the changes associated with sex, growth, and maturation. The Lipid Research Clinics (LRC) Prevalence study also defined target values for TC. This 1972–1976 study, sponsored by the National Heart, Lung, and Blood Institute, used fasting samples from a cross- sectional survey of various North American populations. More age-specific and sex-specific data from the LRC prevalence data are shown in Table 4. Levels above the 95th percentile are considered abnormal. More recently, researchers developed age- and sex-specific lipoprotein threshold concentrations for adolescents 12–20 years of age based on data from the National Health and Nutrition Examination Surveys (NHANES) (13). They linked the cut points to the adult health-based thresholds for table 4 lipid prevalence data by age Total cholesterol Age (years) Males Females 75 th 95 th 75 th 95 th mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L 5–9 168 4.34 189 4.89 176 4.55 197 5.09 10–14 173 4.47 202 5.22 171 4.42 205 5.30 15–19 168 4.34 191 4.94 176 4.55 207 5.35 ldl-cholesterol Age (years) Males Females 75 th 95 th 75 th 95 th mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L 5–9 103 2.66 129 3.34 115 2.97 140 3.62 10–14 109 2.82 132 3.41 110 2.84 135 3.52 15–19 109 2.82 130 3.36 111 2.87 137 3.54 Source: Reference 12. CliniCal laboratory news JuLy 2008 11
abnormal lipoproteins. Using the NHANES database for risk stratification may be problematic, however, as it does not take into account the measurement variability of lipids and lipoproteins. Until the clinical applicability of these threshold concentrations has been more thoroughly investigated, single measurements on at least two different occasions are recommended to establish an individual’s cholesterol value. Although AAP recommends measuring HDL-C in children with hypercholesterolemia, its usefulness in managing risk is also not clear. A target value of < 5th percentile (< 40mg/dL or 1.04 mmol/L) is considered low. Measurement of Apolipoproteins in Children Measurement of apolipoproteins for predicting CVD risk in children is controversial. Recent studies in adults have suggested that apolipoprotein B may be superior to LDL-C in vascular disease risk prediction and that the apo-B/apo A-1 ratio may be superior to TC/HDL-C as an overall index. Apo A-1 is the major structural protein of HDL. On the other hand, apo-B is mostly associated with LDL, but it is also a component of chylomicrons, VLDL, IDL, and lipoprotein(a). In general, apo-B levels 12 CliniCal laboratory news JuLy 2008 may be useful to guide therapy, but its use in managing dyslipidemia in adults is still discretionary. Researchers have also studied apolipoprotein levels in children 4 years of age and older in a population from NHANES III (14,15). Measuring apoB levels has the advantage of not requiring the patient to fast, and in one study researchers demonstrated that it was a better screening tool than TC for identifying elevated LDL-C in youth (15). However, medical groups have not reached a consensus on using apolipoproteins to screen for dyslipidemia in children. Further investigation will be needed before any consensus can be reached. Avoiding CVD in the Future Based on the knowledge that atherosclerosis begins in youth and that childhood elevated cholesterol levels usually persist into adulthood, identifying dyslipidemia in children is important for prevention of the vascular changes associated with increased CVD risk later in life. Currently the management of hypercholesterolemia is aimed at reducing LDL-C, and appropriate agerelated target values for intervention have been recommended. The appropriate use of HDL-C and apolipoproteins in managing risk requires further investigation. CLN REFERENCES 1. Freedman DS, Shear CL, Srinivasan SR, Webber LS, Berenson GS. Tracking of serum lipids and lipoproteins in children over an 8-year period: the Bogalusa Heart Study. Prev Med 1985;14(2):203–216. 2. Lauer RM, Clarke WR. Use of cholesterol measurements in childhood for the prediction of adult hypercholesterolemia. The Muscatine Study. JAMA 1990;264(23):3034–3038. 3. Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study. Circulation 2001;104(23):2815–2819. 4. Li S, Chen W, Srinivasan SR, Bond MG, Tang R, Urbina EM et al. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA 2003;290(17):2271–2276. 5. Sprecher DL, Schaefer EJ, Kent KM, Gregg RE, Zech LA, Hoeg JM et al. Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients. Am J Cardiol 1984;54(1):20–30. 6. Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD et al. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet 2004;363(9406):369–370. 7. Wiegman A, Hutten BA, de Groot E, Rodenburg J, Bakker HD, Buller HR et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004;292(3):331–337. 8. Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel. Circulation 2006; 114(24):2710– 2738. 9. Morrison JA, Friedman LA, Gray- McGuire C. Metabolic syndrome in childhood predicts adult cardiovascular disease 25 years later: the Princeton Lipid Research Clinics Follow-up Study. Pediatrics 2007;120(2):340–345 10. National Cholesterol Education Program (NCEP): Highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 1992;89: 495–501. 11. American Academy of Pediatrics, Committee on Nutrition. Cholesterol in Childhood. Pediatrics 1998;101:141–147. 12. National Heart LaBI. The Lipid Research Clinics population studies data book, Volume I: The prevalence study. In: US Department of Health and Human Services, Public Health Service N, editors. NIH Publication 80-1527 ed. Bethesda, MD: 1980 13. Jolliffe CJ, Janssen I. Distribution of lipoproteins by age and gender in adolescents. Circulation 2006;114:1056–1062. 14. Gillum RF. Indices of adipose tissue distribution, apolipoproteins B and AI, lipoprotein (a), and triglyceride concentration in children age 4–11 years: the Third National Health and Nutrition Examination Survey. J Clin Epidemiol 2001;54(4):367– 375. 15. Dennison BA, Kikuchi DA, Srinivasan SR, Webber LS, Berenson GS. Measurement of apolipoprotein B as a screening test for identifying children with elevated levels of low-density lipoprotein cholesterol. J Pediatr 1990;117(3):358–363. Katherine M. Morrison, MD, FRCPC, is associate professor in the Department of Pediatrics at McMaster University, Hamilton, Ontario, and a physician in the Pediatric Lipid Clinic at the McMaster Children’s Hospital. Vijaylaxmi Grey, PhD, FCACB, is a laboratory scientist responsible for pediatric clinical biochemistry in the Hamilton Regional Laboratory Medicine Program at McMaster University and is an associate professor in the Department of Pathology and Molecular Medicine, as well as an associate member of the Department of Pediatrics. ask the authors need clarification or more information on the subject in the article? go to the article on www.aacc. org, then click “ask the authors” to send your question. CLN will post all questions and answers on aaCC’s web site so that the information is shared in the clinical laboratory community. silent auction & reception fundraiser Wednesday, july 30th, 5:30 p.m.–7:30 p.m. The arts club of Washington silent auction offerings will include travel and dining certificates, a 2009 aaCC annual Meeting registration and suite package, framed photographs and artwork, a hand-made king size quilt, a Michel delacroix print, one-of-a-kind jewelry, gift cards, original art by the editor of Clinical Chemistry, plus much more! if you would like to donate a prize or cash contribution, please contact grace won at gwon@aacc.org or (202) 835-8712. tickets are $75 each. order yours by calling grace won, or see page 73 of your 2008 aaCC annual Meeting registration brochure, or buy them online, item #4819 on your annual Meeting registration form. All monies from your ticket purchase and the silent auction will go directly to deserving students and scientists from emerging areas worldwide, thanks to the generous support of AutoGenomics and Perkin Elmer.
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