Indian Journal of Endocrinology and Metabolism

REVIEW ARTICLE
Year
: 2012  |  Volume : 16  |  Issue : 1  |  Page : 7--12

Changing definitions of metabolic syndrome


Rakesh M Parikh1, Viswanathan Mohan2,  
1 Department of Diabetology, S K Soni Hospital and D Clinic, Jaipur, India
2 Dr Mohan's Diabetes Specialities Center, Chennai, India

Correspondence Address:
Rakesh M Parikh
B 09, Unnati Tower, Vidhyadhar Nagar, Jaipur 302 023
India

Abstract

The first description of patients with clustering of various metabolic abnormalities was as early as 1923 but it was more than five decades later, in 1988, that Reaven coined the term «SQ»syndrome X«SQ» for this entity. The last two decades have brought forth a number of definitions and criteria to identify this condition. Various studies have demonstrated disparities in these definitions and a few researchers have questioned the utility of these criteria and even the existence of such a syndrome. A few important definitions are reviewed in this paper and, at the end, a simplified clinical definition is given and a simple parameter - lipid accumulation product - is been described that can be used to identify this condition.



How to cite this article:
Parikh RM, Mohan V. Changing definitions of metabolic syndrome.Indian J Endocr Metab 2012;16:7-12


How to cite this URL:
Parikh RM, Mohan V. Changing definitions of metabolic syndrome. Indian J Endocr Metab [serial online] 2012 [cited 2020 Jan 25 ];16:7-12
Available from: http://www.ijem.in/text.asp?2012/16/1/7/91175


Full Text

 Introduction



A clustering of various metabolic abnormalities, e.g., hypertension, hyperglycemia, and hyperuricemia, was observed in some patients as early as 1923. [1] More than five decades after this observation, Reaven coined the term 'syndrome X' for this conglomeration of various metabolic abnormalities, including glucose intolerence, hypertension, increased very-low-density lipoproteins (VLDL), triglycerides, and decreased high-density lipoprotein cholesterol (HDL-C), with insulin resistance being the basic underlying pathophysiologic problem. [2] Over the last two decades, various organizations have proposed different definitions, using varying terminologies. We review a few important definitions in this paper.

 WHO Definition



WHO, in 1999, suggested a working definition of metabolic syndrome (MS), which was to be improved in due course of time. [3] WHO defined MS as glucose intolerence, impaired glucose tolerance (IGT) or diabetes mellitus (DM), and/or insulin resistance, together with two or more of the components listed below:



Raised arterial pressure, i.e., ≥140/90 mm of HgRaised plasma triglyceride (≥ 150 mg/dl) and/or low HDL-C (<35 mg/dl in men and <39 mg/dl in women)Central obesity, i.e., waist/hip ratio (WHR) >0.9 in men and >0.85 in women and/or body mass index (BMI) >30 kg/m 2 Microalbuminuria, i.e., urinary albumin excretion rate ≥ 20 μgm/minute or albumin/creatine ratio ≥ 30 μgm/mg.

This definition further insisted on a need for a clear description of the essential components of the syndrome, along with data to support the relative importance of each component. These conditions seem to be highly technical and the definition is rather impracticable.

 European Group for Study of Insulin Resistance Definition



The European Group for Study of Insulin Resistance (EGIR) proposed a modification of the WHO definition, using the term insulin resistance syndrome rather than MS. [4] According to the EIGR definition the diagnostic criteria included elevated plasma insulin (>75 th percentile) plus two other factors from among the following:



Abdominal obesity: waist circumference (WC) ≥94 cm in men and ≥80 cm in womenHypertension: ≥140/90 mm of Hg or on antihypertensive treatmentElevated triglycerides (≥150 mg/dl) and/or reduced HDL-C (<39 mg/dl for both men and women) Elevated plasma glucose: impaired fasting glucose (IFG) or IGT, but no diabetes

Notably, EGIR focused more on abdominal obesity than did WHO, but in contrast to WHO, EGIR excluded patients with type 2 DM from their syndrome because insulin resistance was viewed primarily as a risk factor for diabetes.

This definition was followed by a simpler definition released by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). [5]

 NCEP ATP III Definition



According to this definition, a subject has the MS if he or she has three or more of the following criteria:



Abdominal obesity: WC ≥102 cm in men and ≥88 cm in womenHypertriglyceridemia: ≥150 mg/dl (1.695 mmol/l) Low HDL-C: <40 mg/dl in men and <50 mg/dl in womenHigh blood pressure (BP): >130/85 mmHgHigh fasting glucose: >110 mg/dl

This definition differs from the WHO definition on several fronts. The NCEP ATP III did not believe that insulin resistance is mandatory for the development of MS and hence suggested the term MS instead of the previously used term 'insulin resistance syndrome.' This definition recognizes central obesity as the culprit and hence body mass index (BMI,) which is a parameter for generalized obesity, has not been included in this definition. Central obesity has been quantified using WC instead of the WHR used by WHO. This definition considers low HDL and high triglycerides as separate components (both of them being individually atherogenic) rather than viewing dyslipidemia as a single component. The cutoff points used for BP and HDL are stringent as compared to those suggested in the WHO definition, but by avoiding the need for clamp techniques and measurement of microalbuminuria, the NCEP ATP III definition is much more practically applicable. The NCEP ATP III considers the proinflamatory state and prothrombotic state as components of MS though these have not been included among the criteria necessary to define MS.

 American Association of Clinical Endocrinologists Definition



The American Association of Clinical Endocrinologists (AACE) too preferred using the term insulin resistance syndrome over MS. [6] The major criteria they considered were IGT, elevated triglycerides, reduced HDL-C, elevated BP, and obesity. They did not specify any particular number of criteria for diagnosis, rather they left it to clinical judgment. They suggested that factors like family history of atherosclerotic cardiovascular disease or type 2 DM, polycystic ovary syndrome, and hyperuricemia be considered while exercising clinical judgement. Patients with type 2 DM were excluded from the definition of insulin resistance syndrome. The various components suggested by the AACE are as follows:

Some degree of glucose intoleranceIFG/IGTAbnormal uric acid metabolismPlasma uric acid concentrationRenal uric acid clearanceDyslipidemiaTriglyceridesHDL-CLDL particle diameter (small, dense LDL-particles)Postprandial accumulation of TG-rich lipoproteinsHemodynamic changesSympathetic nervous system activityRenal sodium retentionBlood pressure (~50% of patients with hypertension are insulin resistant)Prothrombotic factorsPlasminogen activator inhibitor-1FibrinogenMarkers of inflammationC-reactive protein, white blood cell count, etc.Endothelial dysfunctionMononuclear cell adhesionPlasma concentration of cellular adhesion moleculesPlasma concentration of asymmetric dimethylarginineEndothelial-dependent vasodilatation

ADA lowered the fasting plasma glucose threshold used to identify individuals with IFG from 110 mg/dl to 100 mg/dl. Subsequently, the NCEP ATP III has also suggested that the fasting plasma glucose concentration for diagnosing MS be lowered to 100 mg/dl. [7]

Researchers worldwide preferred using the NCEP ATP III definition because it was relatively simple and clinically applicable. Various researchers noted that the WC cutoffs suggested by this definition were not applicable in other countries. [8],[9],[10],[11] Though the WC cutoffs suggested by various groups differ, the generally accepted cutoffs for Asians are 90 cm for men and 80 cm for women. [8],[12]

 International Diabetes Federation Global Consensus Definition



Against the backdrop of all these controversies related to diagnostic criteria and the lack of consensus regarding WC cutoffs, the International Diabetes Federation (IDF) released a global consensus definition for MS, along with race- and gender-specific WC cutoffs. [13] This definition identified central obesity as an essential component of MS and defined MS as central obesity (based on race- and gender-specific WC cutoffs) plus any two of the following four parameters:



Raised triglycerides: ≥150 mg/dl (1.7 mmol/l) or history of specific treatment for this lipid abnormalityReduced HDL cholesterol: < 40 mg/dl (1.03 mmol/l) in males and < 50 mg/dl (1.29 mmol/l) in females or history of specific treatment for this lipid abnormalityRaised blood pressure: systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg or on treatment for previously diagnosed hypertensionRaised FPG: ≥ 100 mg/dl or previously diagnosed type 2 DM

The race- and gender-specific WC cutoffs suggested are as follows:

[INLINE:1]

This global consensus definition was immediately followed by a joint statement from the American Diabetes Association and the European Association for the Study of Diabetes questioning the use of the term 'metabolic syndrome.' The statement concluded that too much critically important information is missing to warrant its designation as a 'syndrome.' [14] It was also argued that having a label of MS does not add any risk in addition to the risk contributed by the individual components.

This joint statement did not discourage researchers working in the field of MS and number of papers supporting the use of MS as screening tool to identify subjects at high risk of cardiovascualr disease were published. [15],[16],[17],[18] Disparities in the data generated due to the use of various definitions still remained a major issue. [19],[20],[21],[22],[23] For example, from the subanalysis of the Chennai Urban Rural Epidemiology Study, MS was identified in 546 subjects (23.2%) by the WHO definition, in 430 subjects (18.3%) by the NCEP ATPIII definition, and in 607 subjects (25.8%) by the IDF definition. It is worthy of note that only 224 of these subjects were identified as MS by all the three criteria. [6]

A joint interim statement of the IDF Task Force on Epidemiology and Prevention; the National Heart, Lung, and Blood Institute; the American Heart Association; the World Heart Federation; the International Atherosclerosis Society; and the International Association for the Study of Obesity suggested using the IDF global consensus definition, but without having central obesity as an obligatory parameter. It was suggested that the presence of three or more of the five parameters could be considered as diagnostic of MS. [24] This joint statement suggested that the IDF-recommended race- and gender-specific cutoffs be used until WC cutoffs could be further evaluated based on data from various regions. The WC cutoffs suggested by various researchers from Japan, [25],[26] Korea, [27],[28] Iran, [29] Iraq, [30] and other regions [31] has further confused the definition of MS as there are now numerous race- and gender-specific WC cutoffs.

Looking at the various race- and gender-specific cutoffs of WC suggested by the IDF and the corresponding average heights of the different population groups, it was postulated that the need for various race- and gender-specific cutoffs can be largely attributed to differences in the average heights (32). A novel parameter, the index of central obesity (ICO), defined as the ratio of the WC to the height, was suggested as an alternative. [32] The utility of ICO for defining MS among diabetic [33] as well as nondiabetic subjects [34] has been evaluated.

The ICO has been widely studied and has been shown to have a good correlation with central adipocity [35] and tissue glucose utilization; [36] it was found to be a good predictor of type 2 DM. [37] ICO has also been shown to have a strong correlation with leptin levels and atherogenic lipid profile, [38] oxidative stress, [39] and increased cardiovascular risk. [40] Besides, it has been shown to be useful in identifying childhood central obesity [41] and insulin resistance in children. [42]

 Simplified Definition of Metabolic Syndrome



In view of all the above evidence, we have proposed that WC be replaced by ICO in all definitions of MS. [43] With the use of ICO, the need for various race- and gender-specific cutoffs for WC can be obviated. Although a number of studies have proposed ICO cutoffs ranging between 0.45 and 0.55, we propose the use of a simple cutoff of 0.5 across both genders and all races. MS is a screening tool, and we believe that it should be used to identify people at high risk of metabolic complications and cardiovascular disease so that further detailed investigations can be performed. This definition translates into a very simple message to the community 'If your waist size is more than half of your height, you should consult your doctor.' Thus, all patients with ICO >0.5 should be evaluated for high blood pressure, prediabetes, and dyslipidemia.

 Indian Diabetes Risk Score



Identification of MS can be made more clinical by including clinical parameters like age, family history, personal history, etc., as parameters to define MS. Indian diabetes risk score (IDRS) is one such parameter comprising simple clinical information like age, WC, family history of diabetes, and physical activity. [44] IDRS ≥ 60 been found to be useful In predicting MS and cardiovascular disease [Table 1]. [45] {Table 1}

 Lipid Accumulation Product



In view of the role of central obesity and dyslipidemia in atherosclerotic process, an alternative continuous index of lipid overaccumulation, the lipid accumulation product (LAP), has been proposed. LAP is computed using WC and fasting triglycerides level (in mmol/l): (WC − 65) × TG (men) and (WC − 58) × TG (women). [46] This parameter has been found to be better than BMI for predicting diabetes [47] and has also been suggested for use in the identification MS. [48] It has been shown to be a good predictor of cardiovascular disease [49] though one study has shown that it may not be better than ICO or WHR for predicting cardiovascular disease.

 Conclusion



In spite of the large number of controversies regarding the existence of MS as an entity and the nomenclature to be used, this conglomeration of various metabolic abnormalities has been widely accepted as a screening tool for identifying subjects at high risk of cardiovascular disease. While the various definitions proposed by different organizations have provided us with remarkable scientific insights into this syndrome, it has also complicated what was supposed to a simple screening tool. With the ongoing research in the area, we might soon have a very simple clinical definition to identify subjects at high risk of metabolic complications and cardiovascular disease.

References

1Kylin E. Studies of the hypertension hyperglycemia hyperuricemia syndrome. Zentralbl Innere Med 1923;44:105-27.
2Reaven GM. Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes 1988;37:1595-607.
3World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: Report of a WHO Consultation. Part 1: diagnosis and classification of diabetes mellitus. Geneva, Switzerland: World Health Organization; 1999. Available from: http://www.whqlibdoc.who.int/hq/1999/WHO_NCD_NCS_99.2.pdf. [Last accessed on 2011 Jun 03].
4Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999;16:442-3.
5National Institutes of Health: Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive Summary. Bethesda, MD, National Institutes of Health, National Heart, Lung and Blood Institute, 2001 (NIH publ. no. 01-3670).
6Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003;9:237-52.
7Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; American Heart Association; National Heart, Lung, and Blood Institute. Definition of Metabolic Syndrome. Report of the National Heart, Lung and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433-8.
8Tan CE, Ma S, Wai D, Chew SK, Tai ES. Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of the metabolic syndrome to Asians? Diabetes Care 2004;27:1182-6.
9Zhou BF, Wu YF, Li Y, Zhang LF. The cut-off point of waist circumference for identifying metabolic syndrome in Chinese adults. Zhonghua Xin Xue Guan Bing Za Zhi 2005;33:81-5.
10Matsuzawa Y. Metabolic syndrome-definition and diagnostic criteria in Japan. J Atheroscler Thromb 2005;12:301.
11Barbosa PJ, Lessa I, de Almeida Filho N, Magalhães LB, Araújo J. Criteria for central obesity in a Brazilian Population: Impact on the metabolic syndrome. Arq Bras Cardiol 2006;87:366-73.
12Misra A, Wasir JS, Pandey RM, An. Evaluation of candidate definitions of the metabolic syndrome in adult Asian Indians. Diabetes Care 2005;28:398-403.
13The IDF consensus worldwide definition of the metabolic syndrome. Available from: http://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf [Last accessed on 2011 June 11].
14Kahn R, Buse J, Ferrannini E, Stern M; American Diabetes Association; European Association for the Study of Diabetes. The metabolic syndrome: Time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28:2289-304.
15Lau DC, Yan H, Dhillon B. Metabolic syndrome: A marker of patients at high cardiovascular risk. Can J Cardiol 2006;22 Suppl B:85B-90B.
16Tong PC, Kong AP, So WY, Yang X, Ho CS, Ma RC, et al. The usefulness of the International Diabetes Federation and the National Cholesterol Education Program′s Adult Treatment Panel III definitions of the metabolic syndrome in predicting coronary heart disease in subjects with type 2 diabetes. Diabetes Care 2007;30:1206-11.
17Koutsovasilis A, Protopsaltis J, Triposkiadis F, Kokkoris S, Milionis HJ, Zairis MN, et al. Comparative performance of three metabolic syndrome definitions in the prediction of acute coronary syndrome. Intern Med 2009;48:179-87.
18Jayasinghe SR, Jayasinghe SH. Variant metabolic risk factor profile leading to premature coronary disease: time to define the syndrome of accelerated atherocoronary metabolic syndrome in Asian Indians. Singapore Med J 2009;50:949-55.
19Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP; San Antonio Heart Study. National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation 2004;110:1251-7.
20Oda E, Abe M, Veeraveedu PT, Watanabe K. Considerable disagreement among definitions of metabolic syndrome for Japanese. Circ J 2007;71:1239-43.
21Moebus S, Hanisch JU, Aidelsburger P, Bramlage P, Wasem J, Jöckel KH. Impact of 4 different definitions used for the assessment of the prevalence of the Metabolic Syndrome in primary healthcare: The German Metabolic and Cardiovascular Risk Project (GEMCAS). Cardiovasc Diabetol 2007;6:22.
22Hwu CM, Hsiung CA, Wu KD, Lee WJ, Shih KC, Grove J, et al. Diagnosis of insulin resistance in hypertensive patients by the metabolic syndrome: AHA vs. IDF definitions. Int J Clin Pract 2008;62:1441-6.
23Deepa M, Farooq S, Datta M, Deepa R, Mohan V. Prevalence of metabolic syndrome using WHO, ATPIII and IDF definitions in Asian Indians: the Chennai Urban Rural Epidemiology Study (CURES-34). Diabetes Metab Res Rev 2007;23:127-34.
24Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the Metabolic Syndrome. A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5.
25Oizumi T, Daimon M, Wada K, Jimbu Y, Kameda W, Susa S, et al. A proposal for the cutoff point of waist circumference for the diagnosis of metabolic syndrome in the Japanese population. Circ J 2006;70:1663.
26Hara K, Matsushita Y, Horikoshi M, Yoshiike N, Yokoyama T, Tanaka H, et al. A proposal for the cutoff point of waist circumference for the diagnosis of metabolic syndrome in the Japanese population. Diabetes Care 2006;29:1123-4.
27Oh JY, Sung YA, Lee HJ, Oh JY, Chung HW, Park H. Optimal waist circumference for prediction of metabolic syndrome in young Korean women with polycystic ovary syndrome. Obesity (Silver Spring) 2010;18:593-7.
28Koh JH, Koh SB, Lee MY, Jung PM, Kim BH, Shin JY, et al. Optimal waist circumference cutoff values for metabolic syndrome diagnostic criteria in a Korean rural population. J Korean Med Sci 2010;25:734-7.
29Azizi F, Hadaegh F, Khalili D, Esteghamati A, Hosseinpanah F, Delavari A, et al. Appropriate definition of metabolic syndrome among Iranian adults: Report of the Iranian National Committee of Obesity. Arch Iran Med 2010;13:426-8.
30Mansour AA, Al-Hassan AA, Al-Jazairi MI. Cut-off values for waist circumference in rural Iraqi adults for the diagnosis of metabolic syndrome. Rural Remote Health 2007;7:765.
31Medina-Lezama J, Pastorius CA, Zea-Diaz H, Bernabe-Ortiz A, Corrales-Medina F, Morey-Vargas OL, et al. Optimal definitions for abdominal obesity and the metabolic syndrome in Andean Hispanics: The PREVENCION study. Diabetes Care 2010;33:1385-8.
32Parikh RM, Joshi SR, Menon PS, Shah NS. Index of central obesity - A novel parameter, Med Hypotheses 2007;68:1272-5.
33Parikh RM, Joshi SR, Menon PS, Shah NS. Metabolic Syndrome Among Indian Type 2 Diabetic Patients. J Gen Med 2009;(21):16-9.
34Parikh RM, Joshi SR, Pandia K. Index of central obesity is better than waist circumference in defining metabolic syndrome. Metab Syndr Relat Disord 2009;7:525-7.
35Kagawa M, Byrne NM, Hills AP. Comparison of body fat estimation using waist: Height ratio using different ′waist′ measurements in Australian adults. Br J Nutr 2008;100:1135-41.
36Niebisz-Cie?lak AB, Karnafel W. Insulin sensitivity in chronic pancreatitis and features of insulin resistance syndrome. Pol Arch Med Wewn 2010;120:255-63.
37MacKay, Meredith F. Evaluating alternate anthropometric measures as predictors of incident type 2 diabetes mellitus (T2DM): The Insulin Resistance Atherosclerosis Study (IRAS)UNIVERSITY OF TORONTO, 2008, 158 pages; MR58808. Available from: http://www.gateway.proquest.com/openurl%3furl_ver=Z39.88-2004%26res_dat=xri:pqdiss%26rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation%26rft_dat=xri:pqdiss:MR58808 [Last accessed online on 14 th Jun 2011].
38Abdullah A, Abd El-Baky A, Bakry S, Abd-El Hay E. Adiponectin and liptin levels and their risk in coronary artery diseases in obese Egyptian men. Res J Med Med Sci 2009;4:526-32.
39Veigas NM, Dharmalingam M, Marcus SR. Oxidative stress in obesity and metabolic syndrome in Asian Indians. J Med Biochem 2011;30:115-20.
40Hsieh SD, Yoshinaga H. Waist/height ratio as a simple and useful predictor of coronary heart disease risk factors in women. Intern Med 1995;34:1147-52.
41Sant′anna MS, Tinôco AL, Rosado LE, Sant′ana, LF, Brito IS, Araújo LF, et al. Effectiveness of the conicity index and waist to height ratio to predict the percentage of body fat in children. J Braz Soc Food Nutr 2010;35:67-80.
42Manios Y, Kourlaba G, Kafatos A, Cook TL, Spyridaki A, Fragiadakis GA. Associations of several anthropometric indices with insulin resistance in children: The Children Study. Acta Paediatr 2008;97:494-9.
43Parikh R, Mohan V, Joshi S. Should Waist Circumference (WC) be replaced by Index of Central Obesity (ICO) in definition of metabolic syndrome? Diabetes Metab Res Rev 2011 Jun 22. doi: 10.1002/dmrr.1227. [Epub ahead of print].
44Mohan V, Deepa R, Deepa M, Somannavar S, Datta M. A simplified Indian diabetes risk score for screening for undiagnosed diabetic subjects. J Assoc Physicians India 2005;53:759-63.
45Mohan V, Sandeep S, Deepa M, Gokulakrishnan K, Datta M, Deepa R. A diabetes risk score helps identify metabolic syndrome and cardiovascular risk in Indians - the Chennai Urban Rural Epidemiology Study (CURES-38). Diabetes Obes Metab 2007;9:337-43.
46Ioachimescu AG, Brennan DM, Hoar BM, Hoogwerf BJ. The lipid accumulation product and all-cause mortality in patients at high cardiovascular risk: A PreCIS database study. Obesity (Silver Spring) 2010;18:1836-44.
47Kahn HS. The lipid accumulation product is better than BMI for identifying diabetes: A population-based comparison. Diabetes Care 2006;29:151-3.
48Tellechea ML, Aranguren F, Martínez-Larrad MT, Serrano-Ríos M, Taverna MJ, Frechtel GD. Ability of lipid accumulation product to identify metabolic syndrome in healthy men from Buenos Aires. Diabetes Care 2009;32:e85
49Bozorgmanesh M, Hadaegh F, Azizi F. Predictive performances of lipid accumulation product vs. adiposity measures for cardiovascular diseases and all-cause mortality, 8.6-year follow-up: Tehran lipid and glucose study. Lipids Health Dis 2010;9:45.