Different Definitions of the Metabolic Syndrome and Risk of First

Different Definitions of the Metabolic Syndrome and Risk of First-Ever Acute Ischaemic Non-Embolic Stroke In Elderly SubjectsHaralampos Milionis, MD ; M.S. Kostapanos, MD ; E.N. Liberopoulos, MD ; J. Goudevenos, MD ; V.G. Athyros, MD ; D.P. Mikhailidis, MD ; M.S. Elisaf, MDPosted: 04/01/2007; Updated: 07/03/2007; Int J Clin Pract CME. 2007;61(4):545-551. © 2007 Blackwell PublishingSummary

To investigate which of the three recently proposed definitions of the metabolic syndrome (MetS) is related to the excessive risk of ischaemic non-embolic stroke in elderly individuals, and thus may be more appropriate to implement in clinical practice. In a population-based case-control study of subjects aged older than 70 years (163 patients vs. 166 controls), we evaluated the association of first-ever acute ischaemic non-embolic stroke with the MetS defined by using recent definitions as proposed by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the International Diabetes Federation (IDF) and the National Heart, Lung and Blood Institute/American Heart Association (NHLBI/AHA). By applying the NCEP ATP III, NHLBI/AHA and IDF definitions, the prevalence of MetS in the patient group was 46%, 57.1% and 69.9%, respectively, compared with 15.7%, 18.1% and 30.7% in the control group (p < 0.001 for all comparisons). After adjusting for multiple risk factors, the odds ratio (OR) for ischaemic stroke was 2.59 [95% confidence interval (CI): 1.24-5.42, p = 0.012] for NCEP ATP III-defined MetS and 3.18 (95% CI: 1.58-6.39, p = 0.001) for NHLBI/AHA-defined MetS. However, the association of IDF-defined MetS with ischaemic stroke was not significant (OR 1.18, 95% CI: 0.50-2.78, p = 0.71). The implementation of the IDF (unlike NCEP ATP III and NHLBI/AHA) MetS definition substantially increases the number of elderly subjects labelled as having MetS without contributing to the identification of those at high risk of stroke.

What's Known

The metabolic syndrome (MetS) is characterised by a clustering of cardiovascular risk factors and is associated with the development of diabetes and cardiovascular disease (CVD), including stroke.

New definitions, such as that of the National Heart, Lung, and Blood Institute and the American Heart Association (NHLBI/AHA), and especially that proposed by the International Diabetes Federation (IDF) have raised concerns as to the whether they can identify high-risk population for CVD who should benefit from intensive behavioural and/or pharmacological treatment.

What's New

The ageing populations are considered most vulnerable to atherosclerotic vascular disease, including stroke.

Our analysis indicates that both the NCEP ATP III and NHLBI/AHA definitions are useful in identifying subjects with MetS and high CVD prevalence.

The identification of individuals with MetS using simple diagnostic criteria may provide opportunities to intervene earlier with abnormalities that predispose individuals to ischaemic stroke.

Introduction

The metabolic syndrome (MetS) is a cluster of interrelated cardiovascular risk factors[1,2] and is associated with an increased risk of coronary heart disease (CHD) and stroke.[3-13] Most studies were based on the standardised definitions of the World Health Organization (WHO), and the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III (1). New definitions such as that of the National Heart, Lung and Blood Institute and the American Heart Association (NHLBI/AHA),[14] and especially that proposed by the International Diabetes Federation (IDF)[15] (Table 1) have raised concerns as to the whether they can identify high-risk population for cardiovascular disease (CVD) who should benefit from intensive behavioural and/or pharmacological treatment.[14-16]

Table 1.

NCEP ATP III (2001)

NHLBI/AHA (2005) IDF (2005)

Three or more of the following


The first plus any two of the

following

Central obesity

Waist circumference

Men >102 cm >102 cm* ?94 cm*

Women >88 cm >88 cm* ?80 cm*

Hypertension BP ?135/85 mmHg

BP ?135/85 mmHg or specific

medication

BP ? 135/85 mmHg or specific

medication

Triglycerides ?150 mg/dl (1.7 mmol/l)

?150 mg/dl (1.7 mmol/l) or

specific medication


specific medication

HDL-cholesterol

Men <40 mg/dl (1.03

mmol/l)

<40 mg/dl (1.03 mmol/l)

<40 mg/dl (1.03 mmol/l)

Women <50 mg/dl (1.29

mmol/l)

<50 mg/dl (1.29 mmol/l) or

specific medication


specific medication

Fasting plasma glucose

?110 mg/dl (6.1 mmol/l)

?100 mg/dl (5.6 mmol/l)

?100 mg/dl (5.6 mmol/l)

Comparison of the Definitions of the Metabolic Syndrome

*For subjects of European origin. BP = blood pressure; HDL = high-density lipoprotein; IDF = International Diabetes Federation; NCEP ATP = National Cholesterol Education Program Adult Treatment Panel; NHLBI/AHA = National Heart, Lung and Blood Institute/American Heart Association.

The IDF retained three of the five the NCEP ATP III diagnostic criteria, i.e. for hypertension, hypertriglyceridaemia and low high-density lipoprotein (HDL) cholesterol (Table 1). However, the IDF set lower thresholds for the remaining two diagnostic criteria; for abdominal obesity (waist circumference â¥94 cm for Europid men �and â¥80 cm for Europid women) and fasting plasma glucose �[â¥5.6 mmol/l (100 mg/dl)], as was previously suggested by the �American Diabetes Association (ADA). It also established specific values for waist circumference for different ethnic groups.[11-15] A diagnosis of MetS using the IDF criteria requires the presence of abdominal obesity plus any two of the other four criteria (Table 1).

Table 1.

NCEP ATP III (2001)





following

Central obesity

Waist circumference

Men >102 cm >102 cm* ?94 cm*

Women >88 cm >88 cm* ?80 cm*



medication


medication



specific medication


specific medication

HDL-cholesterol

Men <40 mg/dl (1.03

mmol/l)

<40 mg/dl (1.03 mmol/l)

<40 mg/dl (1.03 mmol/l)


mmol/l)


specific medication


specific medication


?110 mg/dl (6.1 mmol/l)

?100 mg/dl (5.6 mmol/l)

?100 mg/dl (5.6 mmol/l)



Table 1.

NCEP ATP III (2001)





following

Central obesity

Waist circumference

Men >102 cm >102 cm* ?94 cm*

Women >88 cm >88 cm* ?80 cm*



medication


medication



specific medication


specific medication

HDL-cholesterol

Men <40 mg/dl (1.03

mmol/l)

<40 mg/dl (1.03 mmol/l)

<40 mg/dl (1.03 mmol/l)


mmol/l)


specific medication


specific medication


?110 mg/dl (6.1 mmol/l)

?100 mg/dl (5.6 mmol/l)

?100 mg/dl (5.6 mmol/l)



The NHLBI/AHA definition retained most of NCEP ATP III criteria and suggested an adjustment of waist circumference to lower thresholds only in some ethnic groups, such as Asians, as well as a lower threshold for elevated fasting glucose [â¥5.6 �mmol/l (100 mg/dl)] (Table 1).[14]

Table 1.

NCEP ATP III (2001)





following

Central obesity

Waist circumference

Men >102 cm >102 cm* ?94 cm*

Women >88 cm >88 cm* ?80 cm*



medication


medication



specific medication


specific medication

HDL-cholesterol

Men <40 mg/dl (1.03

mmol/l)

<40 mg/dl (1.03 mmol/l)

<40 mg/dl (1.03 mmol/l)


mmol/l)


specific medication


specific medication


?110 mg/dl (6.1 mmol/l)

?100 mg/dl (5.6 mmol/l)

?100 mg/dl (5.6 mmol/l)



In a recent population-based case-control study, we reported a significant association of MetS with first-ever-in-a-lifetime acute ischaemic non-embolic stroke in individuals older than 70 years living in a non-industrialised area in the north-west of Greece.[12] However, the association between MetS and stroke may depend on the definition used to diagnose MetS. Therefore, we assessed the association between the different current definitions of MetS and acute ischaemic stroke in elderly persons.

Methods

The evaluation involved 163 elderly stroke patients (88 men and 75 women) who were consecutively hospitalised over a 5-year period for first-ever-in-a-lifetime acute ischaemic non-embolic stroke and 166 controls (87 men and 79 women) consecutively evaluated in the primary care setting.[12] The study was based on all the available eligible consecutive patients that we could assemble over a period of 5 years.

Criteria for inclusion in the study were: (i) subjects aged older than 70 years; (ii) residing in the prefecture of Ioannina; (iii) known to attend the Public Primary Care Health Centre facilities regularly for the last 5 years prior to enrollment; and (iv) patients reaching the Emergency Department of the University Hospital of Ioannina (the referral centre for patients with cerebrovascular disease over 65 years old in the region) within 12 h from the onset of symptoms.[10,11] The diagnosis of first-in-a-lifetime acute ischaemic/non-embolic stroke was based upon history (clinical course, associated symptoms), physical examination (including neurologic and cardiac assessment) and radiologic study [initial non-contrast brain computed tomography (CT) scan]. Further confirmation involved full cardiac evaluation (history and physical, electrocardiogram and a transthoracic echocardiogram) and carotid Doppler ultrasound to exclude a cardiac and/or carotid artery source of emboli, and a new brain CT scan where appropriate.[10,11]

Subjects with a history of vascular disease (previous stroke, angina, myocardial infarction, revascularisations and peripheral artery disease), active infections, neoplasia, renal or liver disease, thyroid dysfunction, chronic obstructive pulmonary disease, chronic inflammatory bowel disease and excessive alcohol consumption were excluded. Stroke patients and controls with a known or possible cardiac source of emboli (atrial fibrillation, heart valve disease and patients receiving anticoagulant treatment) were also excluded. None of the participants was receiving specific lipid lowering treatment (i.e. a statin or a fibrate). All subjects gave informed consent and the study protocol was approved by the Institutional Ethics Committee.

Fifty-four (33.1%) patients with large artery atherosclerosis and 93(57.1%) patients with small vessel disease (p < 0.01) were identified according to the TOAST classification [trial of ORG 10172 in acute stroke treatment.[17]] Hypertensive patients were recorded according to the medical history and relevant drug treatment. Seventy-seven out of 163 stroke patients(47.2%) vs. 61 of 166 controls(36.7%) were diagnosed as hypertensives (p = 0.07).[12] Seventy(90.9%) hypertensive patients vs. 58(95.1%) hypertensive controls were on thiazide diuretics, 28(36.4%) vs. 22(36.1%) on beta blockers, 31(40.2%) vs. 29(47.5%) on calcium channel blockers, and 37(48.0%) vs. 31(50.8%) were on angiotensin converting enzyme (ACE) inhibitors, respectively. Diabetes mellitus was coded as present according to the medical records and/or relevant treatment. Diabetes was recorded in 46(28.2%) stroke patients vs. 34(20.5%) controls (p = 0.1).[12] Thirty-eight(82.6%) patients vs. 29(80.5%) controls received a biguanide, 21(45.6%) vs. 15(44.1%) were on a sulfonylurea, while seven(15.2%) vs. five(14.7%) were insulin treated, respectively. Three definitions were applied to diagnose MetS in the study population (Table 1). Hypertension as a component of the MetS was diagnosed according to patient's history and/or antihypertensive treatment.

Table 1.

NCEP ATP III (2001)





following

Central obesity

Waist circumference

Men >102 cm >102 cm* ?94 cm*

Women >88 cm >88 cm* ?80 cm*



medication


medication



specific medication


specific medication

HDL-cholesterol

Men <40 mg/dl (1.03

mmol/l)

<40 mg/dl (1.03 mmol/l)

<40 mg/dl (1.03 mmol/l)




mmol/l) specific medication

specific medication


?110 mg/dl (6.1 mmol/l)

?100 mg/dl (5.6 mmol/l)

?100 mg/dl (5.6 mmol/l)



All biochemical analyses (including glucose, uric acid, albumin, iron and ferritin) were performed by commercially available standardised methods within 24 h after stroke onset using an Olympus AU560 analyser (Hamburg, Germany).[12] Plasma fibrinogen levels were measured by the Clauss method. Levels of total cholesterol (TC) and triglycerides (TG) were determined by an enzymatic colorimetric assay using a RA-1000 analyser (Technicon Instruments Ltd, Terrytown, NY, USA). High-density lipoprotein cholesterol (HDL-C) was determined enzymatically from the supernatant after precipitation of other lipoproteins with dextran sulphate magnesium. Levels of low-density lipoprotein cholesterol (LDL-C) were calculated using the Friedewald formula. Serum levels of apolipoprotein (Apo) A-I and B were measured by immunonephelometry using a Beckman array analyser (Beckman Instruments, Fullerton, CA, USA). The intra- and inter-assay coefficients of variation were 2.2% and 5.7%, respectively for Apo A-I, and 1.9% and 2.4% for Apo B. Lipoprotein (a) [Lp(a)] levels were measured on fresh samples using a monoclonal anti-[Lp(a)] antibody technique and enzyme-linked immunoassay (Terumo Medical Corporation Diagnostic Division, Elkron, MD, USA). The intra- and inter-assay coefficients of variation were <6.0% and 10.3%. The medical records of patients were investigated to validate the presence of serum lipid or glucose abnormalities within 6 months prior to the event. A clinical and laboratory re-evaluation visit was scheduled 3 months following discharge. If there was a 15% or greater difference between patient's records and blood glucose or lipid measurements, the mean value of admission and re-evaluation visit measurements was used for the determination. In case that the difference between measurements on admission and re-evaluation visit exceeded 15%, a third sample was taken and the last two values were used for the determination.

Statistical Analysis

Values were expressed as mean Â± standard deviation. A comparison of continuous variables was performed by an unpaired two-tailed Student's t-test for normally distributed variables and a Mann-Whitney test for non-normally distributed variables, while chi-squared tests were used for categorical variables. The strength of associations between MetS and acute ischaemic non-embolic stroke were assessed by means of logistic regression analysis (backward stepwise likelihood ratio) comparing stroke and control subjects. Multivariate analysis was performed by binary logistic regression analysis, which allows adjustment for confounding factors, such as age, sex, body mass index, smoking habits, the presence hypertension, serum lipids (TC, TG, LDL-C and HDL-C) and non-lipid serum metabolic variables (hyperglycaemia, fibrinogen, uric acid, albumin, ferritin and iron). Significance levels were set at p < 0.05. Analyses were performed using the spss 11.0 statistical package for Windows (SPSS Inc., 1989-2001, Chicago, IL, USA), and Statistica 6.0 (Statsoft, Inc., 1984-2001, Tulsa, OK, USA).

Results

By applying the different definitions according to NCEP ATP III, NHLBI/AHA and IDF, the prevalence of MetS in the stroke group was 46%, 57.1% and 69.9%, respectively, compared with 15.7%, 18.1% and 30.7% in the control group (p < 0.001 for all comparisons between stroke patients and controls). It is evident that the IDF definition almost doubled the prevalence of MetS in both the stroke and control groups.

Small vessel disease was more prevalent than large artery atherosclerosis in patients with the MetS according to NCEP ATP III [27(60.0%) vs. 45 (36.0%)], NHLBI/AHA [32(60.2%) vs. 56 (34.4%)] or the IDF [37(59.6%) vs. 68 (32.5%)] definition (p < 0.01 for all comparisons). The prevalence of either small or large vessel disease was not significantly different between patients with and without the MetS.

Table 2 summarises the prevalence of individual components and the number of components of the MetS based on the criteria of NCEP, NHLBI/AHA and IDF among patients and controls. The lower fasting glucose cut-off value increased the number of subjects fulfilling the diagnostic criteria of MetS according to NHLBI/AHA compared with the NCEP definition. It must be noted that different definitions resulted in a higher prevalence of abdominal obesity among IDF MetS subjects (either in the patient or the control group), and lower frequencies of hypertension, elevated TG and low HDL-C concentrations compared with non-IDF MetS subjects (Table 2).

Table 2.

Feature

NCEP ATP III (2001)N(%)

NHLBI/AHA (2005)N(%)

IDF (2005)N(%)

Patients (n = 75)

Controls (n =

26)

Patients (n =

93)

Controls (n =

30)

Patients (n = 114)

Controls (n =

51)

Abdominal obesity

44 (58.7)*

16 (61.5)

44 (47.3)†

16 (53.3)*

83 (72.8)

40 (78.4)

High TG 52 (69.3)†

14 (53.8)*

52 (55.9)*

14 (46.7)

48 (42.1)

14 (27.5)

Low HDL-C

66 (88.0)†

20 (76.9)*

66 (71.0)*

19 (63.3)

59 (51.8)

20 (39.2)

Hypertension

55 (73.3)†

19 (73.1)*

55 (59.1)*

18 (60.0)*

50 (43.9)

19 (37.3)

High fasting glucose

38 (50.7)

14 (53.8)

65 (69.9)*

24 (80.0)*

61 (53.5)

30 (58.8)

Number of MetS diagnostic features

Three 52 (69.4)

19 (73.1)

70 (75.3)

22 (73.3)

77 (67.5)

37 (72.6)

Four 16 (21.3)

6 (23.1) 16 (17.2)

6 (20.0) 28 (24.6)

12 (23.5)

Five 7 (9.3) 1 (3.8) 7 (7.5) 2 (6.7) 9 (7.9) 2 (3.9)

Prevalence of Individual Components and the Number of Components of the Metabolic Syndrome (MetS) Based on the Criteria of NCEP, NHLBI/AHA and IDF Among Patients and Controls

*p < 0.05 vs. IDF MetS(+) subjects. †p < 0.001 vs. IDF MetS(+) subjects. HDL-C = high-density lipoprotein cholesterol IDF = International Diabetes Federation NCEP ATP = National Cholesterol Education Program Adult Treatment Panel NHLBI/AHA = National Heart, Lung and Blood Institute/American Heart Association TG = triglycerides.

Table 2.

Feature

NCEP ATP III (2001)N(%)

NHLBI/AHA (2005)N(%)

IDF (2005)N(%)

Patients (n = 75)

Controls (n =

26)

Patients (n =

93)

Controls (n =

30)

Patients (n = 114)

Controls (n =

51)

Abdominal obesity

44 (58.7)*

16 (61.5)

44 (47.3)†

16 (53.3)*

83 (72.8)

40 (78.4)

High TG 52 (69.3)†

14 (53.8)*

52 (55.9)*

14 (46.7)

48 (42.1)

14 (27.5)

Low HDL-C

66 (88.0)†

20 (76.9)*

66 (71.0)*

19 (63.3)

59 (51.8)

20 (39.2)

Hypertension

55 (73.3)†

19 (73.1)*

55 (59.1)*

18 (60.0)*

50 (43.9)

19 (37.3)

High fasting glucose

38 (50.7)

14 (53.8)

65 (69.9)*

24 (80.0)*

61 (53.5)

30 (58.8)

Number of MetS diagnostic features

Three 52 (69.4)

19 (73.1)

70 (75.3)

22 (73.3)

77 (67.5)

37 (72.6)

Four 16 (21.3)

6 (23.1) 16 (17.2)

6 (20.0) 28 (24.6)

12 (23.5)

Five 7 (9.3) 1 (3.8) 7 (7.5) 2 (6.7) 9 (7.9) 2 (3.9)

Prevalence of Individual Components and the Number of Components of the Metabolic Syndrome (MetS) Based on the Criteria of NCEP, NHLBI/AHA and IDF Among Patients and Controls

*p < 0.05 vs. IDF MetS(+) subjects. †p < 0.001 vs. IDF MetS(+) subjects. HDL-C = high-density lipoprotein cholesterol IDF = International Diabetes Federation NCEP ATP = National Cholesterol Education Program Adult Treatment Panel NHLBI/AHA = National Heart, Lung and Blood Institute/American Heart Association TG = triglycerides.

Demographic and clinical characteristics of subjects with the MetS according to the three definitions are shown in Table 3. Stroke patients with the MetS (as established by any definition) had a more atherogenic lipid profile compared with controls as a group (with and without the MetS) (Table 3). Specifically, serum TC, LDL-C and Apo B levels were similar in either group; however, stroke patients with the MetS had higher values of TG and Lp(a) and lower concentrations of HDL-C and Apo A-I (Table 3). In addition, stroke patients with the MetS had increased serum uric acid and plasma fibrinogen levels compared with controls in general (Table 3).

Table 3.

Stroke patients Controls

All (n = 163)

NCEP/ATP

III MetS (n = 75)

NHLBI/AHA MetS (n = 93)

IDF Met

S (114

)

All (n =

166)

NCEP/ATP

III MetS (n = 26)


IDF MetS (n

= 51)

Sex

Male

88 37 47 59 87 10 13 32

Female

75 38 46 55 79 16 17 29

Age (years)

78 (70–90)

77.6 (71–90)

77 (69–90)

78 (69–90)

78 (69–90)

79.6 (70–79)

79 (70–92)

78(69–92)

BMI (kg/m2)

26.6 ±

3.1*

27.2 ± 3.6*

26.8 ± 3.5*

26.2 ±

3.3†

25.5 ± 2.6

26.8 ± 2.9*

26.8 ± 3.0*

26.0 ±

2.7†

Waist circumference (cm)

Men

92.7 ±

11.0

95.8 ± 11.9

94.5 ± 11.5

92.6 ±

11.1

92.9 ±

11.7

97.0 ± 15.5

98.7 ± 14.5

92.4 ±

12.4

Women

82.7 ±

11.1

87.2 ± 11.4†

85.7 ± 11.4†

83.0 ±

11.2

80.8 ± 9.4

87.6 ± 11.3†

86.2 ± 10.8†

83.9 ±

9.4†

Raised BP (?130/85)

77 (47.2%)

74 (98.7%)

74 (79.6%

)

74 (64.9%)

61(36.7%)

19 (73.0%)

21 (70.0%

)

32 (62.7%)

Systolic BP (mmHg)

147.7 ± 16.5

*

153.0 ±

14.7*

151.0 ± 15.8*

149.7 ± 16.3

*

135.2 ±

13.5

147.6 ±

13.5*

144.8 ± 14.0*

142.5 ± 14.0

*

Diastolic BP (mmHg)

83.2 ±

8.2

85.1 ± 8.5†

84.6 ± 8.7†

83.5 ±

8.5

81.7 ± 6.2

86.1 ± 6.9†

85.0 ± 6.9†

84.2 ±

7.1†

TC (mmol/l)

5.4 ±

1.3

5.5 ± 1.3

5.4 ± 1.3

5.4 ±

1.3

5.4 ± 1.1

5.2 ± 1.1

5.3 ± 1.1

5.3 ±

0.9

LDL-C (mmol/l)

3.4 ±

1.1

3.5 ± 1.2

3.5 ± 1.1

3.5 ±

1.1

3.4 ± 1.2

3.4 ± 0.9

3.4 ± 0.9

3.4 ±

0.9

HDL-C (mmol/l)

1.0 ±

0.3*

1.0 ± 0.3*

0.9 ± 0.2*

0.9 ±

0.2*

1.3 ± 0.3

1.1 ± 0.2

1.2 ± 0.3

1.2 ±

0.3

TG (mmol/l)

2.0 ±

0.8*

2.1 ± 0.9*

2.1 ± 0.8*

2.2 ±

0.9*

1.4 ± 0.9

1.7 ± 0.6†

1.5 ± 0.6†

1.6 ±

0.6†

Apo A-I (mg/dl)

130.0 ± 24.3

126.6 ± 25.8

125.0 ± 25.3

125.1 ± 23.8

150.0 ±

22.0

139.8 ±

25.0†

145.3 ± 28.3

144.9 ± 24.0†

Apo B (mg/dl)

131.6 ± 24.2

134.2 ± 31.1

135.3 ± 34.5

134.3 ± 35.0

126.8 ±

25.6

120.5 ±

25.5†

123.5 ± 23.8

122.9 ± 21.6

Lp(a) (mg/dl)

12.2 (0.8

–65.3)*

14.8 (0.8–65.3)*

15.4 (0.8–65.3)*

16.9 (0.8

–65.3)*

7.1 (0.8–48)

9.8 (0.8–48)†

8.3 (0.8–48)

8.6 (0.8–48)

Fasting glucose (mmol/l)

5.3 ±

1.8

5.7 ± 1.4

5.4 ± 1.6

5.4 ±

1.5

5.1 ± 1.6

5.5 ± 1.3

5.4 ± 1.5

5.4 ±

1.4

HbA1C(%)

5.3 ±

1.6

5.5 ± 1.8

5.5 ± 1.5

5.4 ±

1.5

5.4 ± 1.3

5.6 ± 1.4

5.4 ± 1.3

5.5 ±

1.3

Fibrinogen (g/l)

4.3 (1.3

–6.3)

*

4.0 (1.7–5.6)*

4.1 (1.7–6.1)*

4.3 (1.7

–5.6)

*

3.0 (1.1–6.1)

2.8 (2.0–3.7)

2.9 (1.3–4.9)

3.0 (1.1

–4.9)

Uric acid (?mol/l)

333.1 ± 101.

1

345.0 ±

107.1*

339.0 ± 101.1*

339.0 ± 101.1*

285.5 ±

83.3

297.4 ±

71.4†

291.4 ± 65.4

303.3 ± 89.2†

Albumin (g/l)

38.0 ±

5.0*

37.8 ± 5.4*

37.7 ± 5.4*

37.5 ±

5.2*

41.0 ± 6.0

42.7 ± 4.7

42.4 ± 5.0

42.0 ±

5.2

Iron (?mol/l)

11.6 ±

5.3

11.5 ± 5.2

11.5 ± 5.3

11.6 ±

5.3

11.5 ± 4.9

11.4 ± 4.8

11.4 ± 4.9

11.5 ±

4.8

Ferritin (?g/l)

42.9 ±

18.9

40.3 ± 16.9

42.2 ± 18.9

41.1 ±

18.8

41.6 ±

17.3

42.3 ± 20.5

42.7 ± 21.4

41.5 ±

20.1

Clinical and Laboratory Characteristics of the Study Population

Values represent means ± standard deviation, except for age, Lp(a) and fibrinogen where median and ranges are shown. *p < 0.001 compared with ‘all' controls. †p < 0.01 compared with ‘all' controls. Apo = apolipoprotein; BMI = body mass index; BP = blood pressure; HbA1C = glycosylated haemoglobin; HDL-C = high-density lipoprotein cholesterol; IDF = International Diabetes Federation; Lp(a) = lipoprotein(a); LDL-C = low-density lipoprotein cholesterol; MetS, metabolic syndrome; NCEP ATP = National Cholesterol Education Program Adult Treatment Panel; NHLBI/AHA = National Heart, Lung and Blood Institute/American Heart Association; TC = total cholesterol; TG = triglycerides.

Table 3.


All (n = 163)

NCEP/ATP

III MetS (n =


IDF Met

S (114

)

All (n =

166)

NCEP/ATP

III MetS (n =


IDF MetS (n

= 51)

75) 26)

Sex

Male

88 37 47 59 87 10 13 32

Female

75 38 46 55 79 16 17 29

Age (years)

78 (70–90)

77.6 (71–90)

77 (69–90)

78 (69–90)

78 (69–90)

79.6 (70–79)

79 (70–92)

78(69–92)

BMI (kg/m2)

26.6 ±

3.1*

27.2 ± 3.6*

26.8 ± 3.5*

26.2 ±

3.3†

25.5 ± 2.6

26.8 ± 2.9*

26.8 ± 3.0*

26.0 ±

2.7†


Men

92.7 ±

11.0

95.8 ± 11.9

94.5 ± 11.5

92.6 ±

11.1

92.9 ±

11.7

97.0 ± 15.5

98.7 ± 14.5

92.4 ±

12.4

Women

82.7 ±

11.1

87.2 ± 11.4†

85.7 ± 11.4†

83.0 ±

11.2

80.8 ± 9.4

87.6 ± 11.3†

86.2 ± 10.8†

83.9 ±

9.4†

Raised BP (?130/85)

77 (47.2%)

74 (98.7%)

74 (79.6%

)

74 (64.9%)

61(36.7%)

19 (73.0%)

21 (70.0%

)

32 (62.7%)

Systolic BP (mmHg)

147.7 ± 16.5

*

153.0 ±

14.7*

151.0 ± 15.8*

149.7 ± 16.3

*

135.2 ±

13.5

147.6 ±

13.5*

144.8 ± 14.0*

142.5 ± 14.0

*

Diastolic BP (mmHg)

83.2 ±

8.2

85.1 ± 8.5†

84.6 ± 8.7†

83.5 ±

8.5

81.7 ± 6.2

86.1 ± 6.9†

85.0 ± 6.9†

84.2 ±

7.1†

TC (mmol/l)

5.4 ±

1.3

5.5 ± 1.3

5.4 ± 1.3

5.4 ±

1.3

5.4 ± 1.1

5.2 ± 1.1

5.3 ± 1.1

5.3 ±

0.9

LDL-C (mmol/l)

3.4 ±

1.1

3.5 ± 1.2

3.5 ± 1.1

3.5 ±

1.1

3.4 ± 1.2

3.4 ± 0.9

3.4 ± 0.9

3.4 ±

0.9

HDL-C (mmol/l)

1.0 ±

0.3*

1.0 ± 0.3*

0.9 ± 0.2*

0.9 ±

0.2*

1.3 ± 0.3

1.1 ± 0.2

1.2 ± 0.3

1.2 ±

0.3

TG (mmol/l)

2.0 ±

0.8*

2.1 ± 0.9*

2.1 ± 0.8*

2.2 ±

0.9*

1.4 ± 0.9

1.7 ± 0.6†

1.5 ± 0.6†

1.6 ±

0.6†

Apo A-I (mg/dl)

130.0 ± 24.3

126.6 ± 25.8

125.0 ± 25.3

125.1 ± 23.8

150.0 ±

22.0

139.8 ±

25.0†

145.3 ± 28.3

144.9 ± 24.0†

Apo B (mg/dl)

131.6 ± 24.2

134.2 ± 31.1

135.3 ± 34.5

134.3 ± 35.0

126.8 ±

25.6

120.5 ±

25.5†

123.5 ± 23.8

122.9 ± 21.6

Lp(a) (mg/d

12.2 (0.8

14.8 (0.8–

15.4 (0.8–

16.9 (0.8

7.1 (0.8–

9.8 (0.8–

8.3 (0.8–

8.6 (0.8

l) –65.3)*

65.3)* 65.3)* –65.3)*

48) 48)† 48) –48)


5.3 ±

1.8

5.7 ± 1.4

5.4 ± 1.6

5.4 ±

1.5

5.1 ± 1.6

5.5 ± 1.3

5.4 ± 1.5

5.4 ±

1.4

HbA1C(%)

5.3 ±

1.6

5.5 ± 1.8

5.5 ± 1.5

5.4 ±

1.5

5.4 ± 1.3

5.6 ± 1.4

5.4 ± 1.3

5.5 ±

1.3

Fibrinogen (g/l)

4.3 (1.3

–6.3)

*

4.0 (1.7–5.6)*

4.1 (1.7–6.1)*

4.3 (1.7

–5.6)

*

3.0 (1.1–6.1)

2.8 (2.0–3.7)

2.9 (1.3–4.9)

3.0 (1.1

–4.9)

Uric acid (?mol/l)

333.1 ± 101.

1

345.0 ±

107.1*

339.0 ± 101.1*

339.0 ± 101.1*

285.5 ±

83.3

297.4 ±

71.4†

291.4 ± 65.4

303.3 ± 89.2†

Albumin (g/l)

38.0 ±

5.0*

37.8 ± 5.4*

37.7 ± 5.4*

37.5 ±

5.2*

41.0 ± 6.0

42.7 ± 4.7

42.4 ± 5.0

42.0 ±

5.2

Iron (?mol/l)

11.6 ±

5.3

11.5 ± 5.2

11.5 ± 5.3

11.6 ±

5.3

11.5 ± 4.9

11.4 ± 4.8

11.4 ± 4.9

11.5 ±

4.8

Ferritin (?g/l)

42.9 ±

18.9

40.3 ± 16.9

42.2 ± 18.9

41.1 ±

18.8

41.6 ±

17.3

42.3 ± 20.5

42.7 ± 21.4

41.5 ±

20.1



Table 3.


All (n = 163)

NCEP/ATP

III MetS (n = 75)


IDF Met

S (114

)

All (n =

166)

NCEP/ATP

III MetS (n = 26)


IDF MetS (n

= 51)

Sex

Male

88 37 47 59 87 10 13 32

Fem 75 38 46 55 79 16 17 29

ale

Age (years)

78 (70–90)

77.6 (71–90)

77 (69–90)

78 (69–90)

78 (69–90)

79.6 (70–79)

79 (70–92)

78(69–92)

BMI (kg/m2)

26.6 ±

3.1*

27.2 ± 3.6*

26.8 ± 3.5*

26.2 ±

3.3†

25.5 ± 2.6

26.8 ± 2.9*

26.8 ± 3.0*

26.0 ±

2.7†


Men

92.7 ±

11.0

95.8 ± 11.9

94.5 ± 11.5

92.6 ±

11.1

92.9 ±

11.7

97.0 ± 15.5

98.7 ± 14.5

92.4 ±

12.4

Women

82.7 ±

11.1

87.2 ± 11.4†

85.7 ± 11.4†

83.0 ±

11.2

80.8 ± 9.4

87.6 ± 11.3†

86.2 ± 10.8†

83.9 ±

9.4†

Raised BP (?130/85)

77 (47.2%)

74 (98.7%)

74 (79.6%

)

74 (64.9%)

61(36.7%)

19 (73.0%)

21 (70.0%

)

32 (62.7%)

Systolic BP (mmHg)

147.7 ± 16.5

*

153.0 ±

14.7*

151.0 ± 15.8*

149.7 ± 16.3

*

135.2 ±

13.5

147.6 ±

13.5*

144.8 ± 14.0*

142.5 ± 14.0

*

Diastolic BP (mmHg)

83.2 ±

8.2

85.1 ± 8.5†

84.6 ± 8.7†

83.5 ±

8.5

81.7 ± 6.2

86.1 ± 6.9†

85.0 ± 6.9†

84.2 ±

7.1†

TC (mmol/l)

5.4 ±

1.3

5.5 ± 1.3

5.4 ± 1.3

5.4 ±

1.3

5.4 ± 1.1

5.2 ± 1.1

5.3 ± 1.1

5.3 ±

0.9

LDL-C (mmol/l)

3.4 ±

1.1

3.5 ± 1.2

3.5 ± 1.1

3.5 ±

1.1

3.4 ± 1.2

3.4 ± 0.9

3.4 ± 0.9

3.4 ±

0.9

HDL-C (mmol/l)

1.0 ±

0.3*

1.0 ± 0.3*

0.9 ± 0.2*

0.9 ±

0.2*

1.3 ± 0.3

1.1 ± 0.2

1.2 ± 0.3

1.2 ±

0.3

TG (mmol/l)

2.0 ±

0.8*

2.1 ± 0.9*

2.1 ± 0.8*

2.2 ±

0.9*

1.4 ± 0.9

1.7 ± 0.6†

1.5 ± 0.6†

1.6 ±

0.6†

Apo A-I (mg/dl)

130.0 ± 24.3

126.6 ± 25.8

125.0 ± 25.3

125.1 ± 23.8

150.0 ±

22.0

139.8 ±

25.0†

145.3 ± 28.3

144.9 ± 24.0†

Apo B (mg/dl)

131.6 ± 24.2

134.2 ± 31.1

135.3 ± 34.5

134.3 ± 35.0

126.8 ±

25.6

120.5 ±

25.5†

123.5 ± 23.8

122.9 ± 21.6

Lp(a) (mg/dl)

12.2 (0.8

–65.3)*

14.8 (0.8–65.3)*

15.4 (0.8–65.3)*

16.9 (0.8

–65.3)*

7.1 (0.8–48)

9.8 (0.8–48)†

8.3 (0.8–48)

8.6 (0.8–48)

Fasting glucose

5.3 ±

1.8

5.7 ± 1.4

5.4 ± 1.6

5.4 ±

1.5

5.1 ± 1.6

5.5 ± 1.3

5.4 ± 1.5

5.4 ±

1.4

(mmol/l)

HbA1C(%)

5.3 ±

1.6

5.5 ± 1.8

5.5 ± 1.5

5.4 ±

1.5

5.4 ± 1.3

5.6 ± 1.4

5.4 ± 1.3

5.5 ±

1.3

Fibrinogen (g/l)

4.3 (1.3

–6.3)

*

4.0 (1.7–5.6)*

4.1 (1.7–6.1)*

4.3 (1.7

–5.6)

*

3.0 (1.1–6.1)

2.8 (2.0–3.7)

2.9 (1.3–4.9)

3.0 (1.1

–4.9)

Uric acid (?mol/l)

333.1 ± 101.

1

345.0 ±

107.1*

339.0 ± 101.1*

339.0 ± 101.1*

285.5 ±

83.3

297.4 ±

71.4†

291.4 ± 65.4

303.3 ± 89.2†

Albumin (g/l)

38.0 ±

5.0*

37.8 ± 5.4*

37.7 ± 5.4*

37.5 ±

5.2*

41.0 ± 6.0

42.7 ± 4.7

42.4 ± 5.0

42.0 ±

5.2

Iron (?mol/l)

11.6 ±

5.3

11.5 ± 5.2

11.5 ± 5.3

11.6 ±

5.3

11.5 ± 4.9

11.4 ± 4.8

11.4 ± 4.9

11.5 ±

4.8

Ferritin (?g/l)

42.9 ±

18.9

40.3 ± 16.9

42.2 ± 18.9

41.1 ±

18.8

41.6 ±

17.3

42.3 ± 20.5

42.7 ± 21.4

41.5 ±

20.1



Table 3.


All (n = 163)

NCEP/ATP

III MetS (n = 75)


IDF Met

S (114

)

All (n =

166)

NCEP/ATP

III MetS (n = 26)


IDF MetS (n

= 51)

Sex

Male

88 37 47 59 87 10 13 32

Female

75 38 46 55 79 16 17 29

Age (years)

78 (70–90)

77.6 (71–90)

77 (69–90)

78 (69–90)

78 (69–90)

79.6 (70–79)

79 (70–92)

78(69–92)

BMI (kg/

26.6 ±

27.2 ± 3.6*

26.8 ± 3.5*

26.2 ±

25.5 ± 2.6

26.8 ± 2.9*

26.8 ± 3.0*

26.0 ±

m2) 3.1* 3.3† 2.7†


Men

92.7 ±

11.0

95.8 ± 11.9

94.5 ± 11.5

92.6 ±

11.1

92.9 ±

11.7

97.0 ± 15.5

98.7 ± 14.5

92.4 ±

12.4

Women

82.7 ±

11.1

87.2 ± 11.4†

85.7 ± 11.4†

83.0 ±

11.2

80.8 ± 9.4

87.6 ± 11.3†

86.2 ± 10.8†

83.9 ±

9.4†

Raised BP (?130/85)

77 (47.2%)

74 (98.7%)

74 (79.6%

)

74 (64.9%)

61(36.7%)

19 (73.0%)

21 (70.0%

)

32 (62.7%)

Systolic BP (mmHg)

147.7 ± 16.5

*

153.0 ±

14.7*

151.0 ± 15.8*

149.7 ± 16.3

*

135.2 ±

13.5

147.6 ±

13.5*

144.8 ± 14.0*

142.5 ± 14.0

*

Diastolic BP (mmHg)

83.2 ±

8.2

85.1 ± 8.5†

84.6 ± 8.7†

83.5 ±

8.5

81.7 ± 6.2

86.1 ± 6.9†

85.0 ± 6.9†

84.2 ±

7.1†

TC (mmol/l)

5.4 ±

1.3

5.5 ± 1.3

5.4 ± 1.3

5.4 ±

1.3

5.4 ± 1.1

5.2 ± 1.1

5.3 ± 1.1

5.3 ±

0.9

LDL-C (mmol/l)

3.4 ±

1.1

3.5 ± 1.2

3.5 ± 1.1

3.5 ±

1.1

3.4 ± 1.2

3.4 ± 0.9

3.4 ± 0.9

3.4 ±

0.9

HDL-C (mmol/l)

1.0 ±

0.3*

1.0 ± 0.3*

0.9 ± 0.2*

0.9 ±

0.2*

1.3 ± 0.3

1.1 ± 0.2

1.2 ± 0.3

1.2 ±

0.3

TG (mmol/l)

2.0 ±

0.8*

2.1 ± 0.9*

2.1 ± 0.8*

2.2 ±

0.9*

1.4 ± 0.9

1.7 ± 0.6†

1.5 ± 0.6†

1.6 ±

0.6†

Apo A-I (mg/dl)

130.0 ± 24.3

126.6 ± 25.8

125.0 ± 25.3

125.1 ± 23.8

150.0 ±

22.0

139.8 ±

25.0†

145.3 ± 28.3

144.9 ± 24.0†

Apo B (mg/dl)

131.6 ± 24.2

134.2 ± 31.1

135.3 ± 34.5

134.3 ± 35.0

126.8 ±

25.6

120.5 ±

25.5†

123.5 ± 23.8

122.9 ± 21.6

Lp(a) (mg/dl)

12.2 (0.8

–65.3)*

14.8 (0.8–65.3)*

15.4 (0.8–65.3)*

16.9 (0.8

–65.3)*

7.1 (0.8–48)

9.8 (0.8–48)†

8.3 (0.8–48)

8.6 (0.8–48)


5.3 ±

1.8

5.7 ± 1.4

5.4 ± 1.6

5.4 ±

1.5

5.1 ± 1.6

5.5 ± 1.3

5.4 ± 1.5

5.4 ±

1.4

HbA1C(%)

5.3 ±

1.6

5.5 ± 1.8

5.5 ± 1.5

5.4 ±

1.5

5.4 ± 1.3

5.6 ± 1.4

5.4 ± 1.3

5.5 ±

1.3

Fibrin 4.3 4.0 4.1 4.3 3.0 2.8 2.9 3.0

ogen (g/l)

(1.3–

6.3)*

(1.7–5.6)*

(1.7–6.1)*

(1.7–

5.6)*

(1.1–6.1)

(2.0–3.7)

(1.3–4.9)

(1.1–

4.9)

Uric acid (?mol/l)

333.1 ± 101.

1

345.0 ±

107.1*

339.0 ± 101.1*

339.0 ± 101.1*

285.5 ±

83.3

297.4 ±

71.4†

291.4 ± 65.4

303.3 ± 89.2†

Albumin (g/l)

38.0 ±

5.0*

37.8 ± 5.4*

37.7 ± 5.4*

37.5 ±

5.2*

41.0 ± 6.0

42.7 ± 4.7

42.4 ± 5.0

42.0 ±

5.2

Iron (?mol/l)

11.6 ±

5.3

11.5 ± 5.2

11.5 ± 5.3

11.6 ±

5.3

11.5 ± 4.9

11.4 ± 4.8

11.4 ± 4.9

11.5 ±

4.8

Ferritin (?g/l)

42.9 ±

18.9

40.3 ± 16.9

42.2 ± 18.9

41.1 ±

18.8

41.6 ±

17.3

42.3 ± 20.5

42.7 ± 21.4

41.5 ±

20.1



The association between MetS and first-ever-in-a-lifetime acute ischaemic non-embolic stroke was determined by multivariate logistic regression modelling after adjusting for potential confounding factors (Table 4). This association was robust when MetS was defined according to NCEP ATP III or NHLBI/AHA criteria. Specifically, the adjusted odds ratio (OR) for a first-ever acute ischaemic stroke was 2.59 [95% confidence interval (CI): 1.24-5.42, p = 0.012] for NCEP ATP III-defined MetS, and 3.18 (95% CI: 1.58-6.39, p = 0.001) for NHLBI/AHA-defined MetS. In contrast, the association of IDF-defined MetS with ischaemic stroke was not significant (adjusted OR 1.18, 95% CI: 0.50-2.78 and p = 0.71) (Table 4).

Table 4.

Definition Adjusted OR (95% CI)* p-value

NCEP ATP III (2001) 2.59 (1.24–5.42) 0.012

NHLBI/AHA (2005) 3.18 (1.58–6.39) 0.001

IDF (2005) 1.18 (0.50–2.78) 0.71

Odds Ratios (OR) of Acute Ischaemic Non-Embolic Stroke According to Different Definitions of the Metabolic Syndrome

*After adjustment for sex, age, body mass index, smoking habits, the presence of hypertension, lipids (total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol) and non-lipid serum metabolic parameters (fasting glucose, fibrinogen, uric acid,

albumin, ferritin and iron). CI = confidence interval; HDL = high-density lipoprotein; IDF = International Diabetes Federation; LDL = low-density lipoprotein; NCEP ATP = National Cholesterol Education Program Adult Treatment Panel; NHLBI/AHA = National Heart, Lung and Blood Institute/American Heart Association.

Table 4.

Definition Adjusted OR (95% CI)* p-value

NCEP ATP III (2001) 2.59 (1.24–5.42) 0.012

NHLBI/AHA (2005) 3.18 (1.58–6.39) 0.001

IDF (2005) 1.18 (0.50–2.78) 0.71

Odds Ratios (OR) of Acute Ischaemic Non-Embolic Stroke According to Different Definitions of the Metabolic Syndrome

*After adjustment for sex, age, body mass index, smoking habits, the presence of hypertension, lipids (total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol) and non-lipid serum metabolic parameters (fasting glucose, fibrinogen, uric acid, albumin, ferritin and iron). CI = confidence interval; HDL = high-density lipoprotein; IDF = International Diabetes Federation; LDL = low-density lipoprotein; NCEP ATP = National Cholesterol Education Program Adult Treatment Panel; NHLBI/AHA = National Heart, Lung and Blood Institute/American Heart Association.

Discussion

In the present study, we demonstrated that the IDF definition markedly increased MetS prevalence compared with the NCEP ATP III or NHLBI/AHA diagnostic criteria. In contrast to the latter two MetS definitions, the association between IDF-defined MetS and ischaemic stroke was not significant. This was due to a substantial increase in the number of subjects labelled as having the MetS.

The IDF MetS definition, if embraced worldwide, is expected to considerably raise the prevalence of the MetS. A study conducted by the Hellenic Atherosclerosis Society (the MetS-Greece study), showed that adopting this definition increased the prevalence of MetS by 77% (p < 0.0001) compared with the NCEP ATP III criteria (43.4% vs. 24.5%, respectively) in a total of 9669 subjects representing the Greek population.[7,18] Consequently, the IDF-MetS could then be considered a ânormal variant' if it is present in ��about half of the general population.

The findings of the present analysis are in agreement with the estimated risk (using the Framingham and PROspective Cardiovascular Munster risk engines) for subjects of the MetS-Greece study. In that study, the estimated CVD risk for subjects having the NCEP ATP III-defined MetS was almost double that of subjects having the IDF-definedMetS.[18] A further analysis of the MetS-Greece study showed that MetS as defined using either the NCEP ATP III or the NHLBI/AHA criteria was associated with the greatest increase in CVD prevalence (23.3% and 22.6%, respectively).[18] In subjects with IDF (+) MetS, a smaller increase in CVD prevalence(18.3%) was mainly due to the inclusion of subjects having the NCEP ATP III (+) or NHLBI/AHA (+) MetS. Specifically, the CVD prevalence in IDF (+) but NCEP ATP III (â') / NHLBI/AHA (â') MetS subjects(11.2%) was not higher � �compared with that of the whole study population.(11.4%)

In the same context, implication of the IDF definition in the prospective Japan Diabetes Complication Study (n = 1424 Japanese patients with type 2 diabetes followed-up for 8 years for CHD and stroke events) did not improve the prediction of adverse CVD events compared with the NCEP ATP III and WHO definitions.[16] Specifically, MetS diagnosis by the IDF definition was not predictive for CVD events in either male or female patients in this study.[18] It should be noted, however, that this study included only diabetic patients and applied the waist circumference values proposed for Japanese subjects, which are different for those proposed for individuals of European ancestry.

In general, MetS not only predicts an increased CVD risk, but is also associated with an increased incidence of type 2 diabetes.[19,20] In a recent analysis of the Insulin Resistance Atherosclerosis Study (n = 822, follow-up: 5.2 years), the IDF definition was as good as the NCEP ATP III and WHO definitions in predicting new-onset type 2 diabetes.[21] Therefore, although IDF definition may not be as useful as the others in predicting CVD risk, it seems to maintain its power to predict incident diabetes.

In August 2005, the ADA and the European Association for the Study of Diabetes issued a statement discouraging the use of the term âmetabolic syndrome'.�� [22] According to this statement, there is no evidence that the CVD risk associated with MetS is greater than that of the sum of its parts.[22] In our study both the NCEP ATP III and the NHLBI/AHA definitions were significantly associated with increased stroke risk even after adjustment for all MetS components as well as other risk factors. However, this was not the case with the IDF definition.

Study Limitations

Only subjects of Caucasian origin were included in the study; accordingly the waist circumference cut-off values for different ethnic groups (proposed by the IDF and NHLBI/AHA) were not tested. Furthermore, this was a case-control study and its results may not accurately reflect the ability of these definitions to predict future stroke. Therefore, there is a need for larger prospective studies designed to test the usefulness of the proposed MetS definitions in predicting stroke risk.[23]

Concluding Remarks

A simple, practical and unified definition for the MetS is needed. We believe that either the NCEP ATP III or the NHLBI/AHA definitions constitute the most applicable set of criteria in everyday clinical practice, at least in Caucasian populations.

Address

Haralampos Milionis, Department of Internal Medicine, Medical School, University of Ioannina, GR 451 10 Ioannina, Greece Tel.: + 30 26510 97509 Fax: + 30 26510 97016 Email: [email protected]

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Int J Clin Pract CME. 2007;61(4):545-551. © 2007 Blackwell Publishing

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