Metabolic syndrome: an update on prevalence, criteria, and laboratory testing.

A 48-year-old male with chronic renal failure presented to the emergency department in the early morning with complaints of fatigue, chest pain, and difficulty in breathing upon waking. The patient's serial laboratory results for cardiac markers indicated a myocardial infarction that was subsequently confirmed by electrocardiogram. Other laboratory results (see Table 1) demonstrated evidence of hypertriglyceridemia, low HDL cholesterol, and an elevated glucose (fasting). The patient also displayed hypertension and abdominal obesity with a measured waist circumference of 45.28 inches.

These features, when seen together, describe the term metabolic syndrome as defined by the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). (1,2)

As a result of these findings, the patient's physician recommended a significant lifestyle intervention aimed at weight loss combined with treatment of his individual risk factors (dyslipidemia and hypertension). Since cardiovascular disease had already been established in this patient, a nutrition consult, and recommendation for moderate exercise were initiated to decrease the probability of further complications including an increase in overall mortality risk. The purpose of this article is to provide a brief comprehensive overview of the prevalence, updates, and laboratory testing involved with the metabolic syndrome.

Prevalence and updates of the metabolic syndrome

Metabolic syndrome, also referred to as Reaven's syndrome, (metabolic) syndrome X, the insulin-resistance syndrome, the deadly quartet, or the obesity-dyslipidemia syndrome, is the name given to a group of risk factors linked to obesity. (3) Together, these factors increase the chance for heart disease and other health problems such as diabetes and stroke. (1,4,5) A strong link exists between obesity and the associated risk factors for metabolic syndrome, such as dysfunctional insulin effects (seen in type 2 diabetes), adverse coronary events, as well as dyslipidemias. (1,2,6,7,8) This correlation is apparent when comparing obesity trends and the prevalence of diabetes in the United States. Figure 1 shows the extreme increase in the prevalence of obesity from 1990 to 2001 in the United States has paralleled the increase in prevalence of diabetes. (8,9) A recent study by the Centers for Disease Control and Prevention (CDC) found a 61% increase in diagnosed diabetes (including gestational) in Americans and a 74% increase in obesity from 1991 to 2001, reflecting the strong correlation between obesity and the development of diabetes. (10) Studies also suggest that the number of diagnosed cases of diabetes in the United States will increase by 165%, reaching a staggering 29 million by the year 2050. (11) In addition, those patients demonstrating glucose intolerance contribute to the increased prevalence of the metabolic syndrome.

[FIGURE 1 OMITTED]

There are currently several definitions for the metabolic syndrome. Organizations involved in defining its criteria include the World Health Organization (WHO) Diabetes Group, the ATP III, which is used mainly in the United States today, and the International Diabetes Federation (IDF). Table 2 lists the most recent criteria required by each organization's definition for metabolic syndrome. Each organization's criteria focuses on different elements; however, clinical-laboratory testing has a role in each definition. Insulin resistance, impaired glucose tolerance, or diabetes are included in the WHO definition, (6) whereas the essential element in the IDF definition is central obesity, with different waist-circumference thresholds set for different ethnic groups. (7) The ATP III focuses explicitly on the risk of cardiovascular disease, and does not require evidence of glucose or insulin abnormalities, although hyperglycemia is one of the criteria. (1) Additionally, in 2005 the ATP III updated its criteria for defining the metabolic syndrome by lowering the threshold value of a fasting plasma glucose from 110 mg/dL (6.1 mmol/L) to 100 mg/dL (5.5 mmol/L) in accordance with the American Diabetes Association criteria for impaired fasting glucose, as well as explicitly including diabetes in the hyperglycemia trait definition, and including the use of drugs for lipid control or blood-pressure control in the dyslipidemia and hypertension trait definitions. (2)

Although these groups each have different criteria for the definition of the metabolic syndrome, they agree the disease is not the effect of a single underlying cause and the presence of one criterion of the metabolic syndrome should lead to the assessment for additional risk factors. A shocking 47 million U.S. residents are estimated to have the metabolic syndrome. (5) Unfortunately, this national problem does not appear to be subsiding. A recent retrospective study followed the incidence of metabolic syndrome (defined by ATP III 2005 revised criteria) for eight years in 3,323 Framingham Heart Study participants who did not have diabetes or cardiovascular disease at a baseline examination in the early 1990s. The initial prevalence of the metabolic syndrome was 26.8% in men and 16.6% in women. After eight years of follow-up, there was an age-adjusted 56% increase in prevalence among men and a 47% increase among women. (5) This study demonstrates the importance of recognizing the metabolic syndrome early so that preventive treatment options can be initiated. Furthermore, the clinical laboratory plays an important role in its early identification by performing tests that help to define the metabolic syndrome.

The metabolic syndrome and laboratory testing

The WHO, ATP III, and the IDF define the need for laboratory testing to aid in the diagnosis of the metabolic syndrome. Other analytes, however, that may be involved in the initiation or progression of metabolic syndrome are not used in the defining criteria. (12,13) These include monitoring the levels of vitamin D, calcium (14), and magnesium intake, (15,16) as well as levels of C-reactive protein (CRP), (16,17,18,19) interleukin (TL)-6, (19) IL-10, (20) adiponectin, (19) adipocyte-fatty acid binding protein (A-FABP), (21) and plasminogen activator inhibitor (PAI)-1. (22) Although glucose, insulin, and/or lipid (triglycerides and HDL cholesterol) values are required in one or more of the definitions set forth by these organizations, sometimes assay standardization issues limit their clinical testing and use.

Hyperinsulinemia is not an attractive testing target for clinical laboratories or clinicians. Currently, the lack of standardization of insulin assays hinders efforts to achieve consistent measures for treatment guidelines and precludes setting a specific insulin concentration above which a person is defined as insulin resistant. In rare instances, when normal representative data are available, the value defining the upper quartile of the fasting-insulin distribution among non-diabetic subjects may be used. In addition, insulin levels depend heavily on which assay is used. A recent study showed a two-fold variation in some insulin results, which may be related to specificity, manufacturers' calibration procedures or conversion factors (23) To put this into perspective, if a glucose value of 80 mg/dL was measured in one lab and in another lab the same sample were 160 mg/dL, such variation would preclude glucose control as a testing target. Efforts to understand the differences and achieve the desired consistency and harmonization among commercial insulin immunoassays are currently underway. (24)

Calcium and vitamin D levels have also been associated with metabolic syndrome risk. One study demonstrated that intake of calcium and vitamin D are related to the metabolic syndrome in middle-aged or older women who were free of cardiovascular disease, cancer, or diabetes and who never used post-menopausal hormones. (14) They showed that dietary vitamin D was inversely associated with the prevalence of metabolic syndrome but was not independent of total calcium intake, which suggested that calcium and dairy products may be associated with lower prevalence of the metabolic syndrome in middle-aged and older women. The same group examined whether magnesium intake is related to systemic inflammation and the metabolic syndrome. Results from this study suggested that magnesium intake is inversely associated with systemic inflammation and the prevalence of the metabolic syndrome in middle-aged and older women. (15)

The metabolic syndrome has been proposed to be a pro-inflammatory, prothrombotic state. While some studies, however, have shown that elevations in pro-inflammatory and prothrombotic mediators such as interleukin (IL)-6, (19) IL-10, (20) adiponectin, (1) A-FABP, (21) and PAI-1 (22) play a role in metabolic-syndrome pathogenesis and/or detection, others have not. Although their use appears promising, the lack of further investigation makes the value of their measurement in the setting of metabolic syndrome unknown. In addition, the use of these markers should be considered for clinical purposes only in the setting of coronary-vascular disease-risk assessment and reduction. One inflammatory protein, however, does show strong evidence demonstrating the potential for its use as a marker for the metabolic syndrome. This protein is CRP. (16,17,18,19) The relationship between the syndrome and inflammation has been strengthened since both metabolic syndrome and obesity are associated with elevated CRP levels. CDC guidelines, however, emphasize that CRP testing still belongs in the category of optional, based on clinical judgment rather than recommended routinely because the magnitude of its independent predictive power still remains uncertain and warrants further investigation. (25)

Summary and conclusion

In this clinical issue, we have provided a brief yet comprehensive overview of the prevalence, updates, and laboratory testing involved with the metabolic syndrome. This complex condition is identified as encompassing the criteria of one of three definitions set forth by either the WHO, (6) ATP III, (1,2) or IDF. (7) The prevalence of the metabolic syndrome in the United States has dramatically increased and prospective studies indicate that these numbers will continue to rise. The laboratory plays a pivotal role in the diagnosis of the metabolic syndrome since each of the three organizations' definitions includes laboratory test values for either glucose, lipids (triglycerides and HDL cholesterol), or insulin. Standardization issues, however, may limit the clinical use of some insulin assays, making the WHO Diabetes Group definition for metabolic syndrome, which includes this criterion, disadvantageous. Efforts are underway, however, for laboratories to overcome these limitations. In addition, many new analytes that monitor inflammation, such as CRP, are considered as promising metabolic syndrome markers and may possibly be used clinically for this purpose in the near future.

References

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2. Grundy SM, Cleeman JI, Daniels SR, Donato KA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112(17):2735-2752.

3. Hoefner DM. The ruthless malady:metabolic syndrome. Medical Laboratory Observer. 2003: 35(10):12-21.

4. Wilson PW, D'Agostino RB, Parise H, Sullivan L, et al. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005;112(20):3066-3072

5. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Examination Survey. JAMA. 2002;287(3):356-359.

6. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998; 15(7):539-553.

7. Alberti, KG, Zimmet, P, Shaw, J; IDF Epidemiology Task Force Consensus Group. The metabolic syndrome--a new worldwide definition. Lancet. 2005; 366(9491):1059-1062.

8. Mokdad AH, Ford ES, Bowman BA, Dietz WH, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003; 289(1):76-79.

9. Center for Disease Control Behavioral Risk Factor Surveillance System (BRFSS). www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/obesity_2006.pdf. Accessed September 15, 2007.

10. New state data show obesity and diabetes still on the rise [press release]. Atlanta, GA: Centers for Disease Control and Prevention. December 30, 2002.

11. Boyle JP, Honeycutt AA, Naryan KM, Hoerger TJ, et al. Projection of diabetes burden through 2050:impact of changing demography and disease prevalenve in the U.S. Diabetes Care. 2001;24:1936-1940.

12. Langenberg C, Bergstrom J, Scheidt-Nave C, Pfeilschifter J, Barrett-Connor E. Cardiovascular death and the metabolic syndrome: role of adiposity-signaling hormones and inflammatory markers. Diabetes Care. 2006; 29(6):1363-1369.

13. Koh KK, Han SH, Quon MJ. Inflammatory markers and the metabolic syndrome insights from therapeutic interventions. J Am Coll Cardiol. 2005; 46(11):1978-1985.

14. Liu S, Song Y, Ford ES, Manson JE, et al. Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care. 2005; 28(12):2926-2932.

15. Ford ES, Li C, McGuire LC, Mokdad AH, et al. Intake of dietary magnesium and the prevalence of the metabolic syndrome among U.S. adults. Obesity 2007; 15(5):1139-1146.

16. Song Y, Ridker PM, Manson JE, Cook NR, et al. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care. 2005; 28(6):1438-1444.

17. Rutter MK, Meigs JB, Sullivan LM, D'Agostino RB Sr, Wilson PW. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation 2004; 110(4):380-385.

18. Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, et al. C-reactive protein and its role in metabolic syndrome: mendelian randomisation study. Lancet. 2005; 366(9501):1954-1959.

19. Nishida M, Moriyama T, Sugita Y, Yamauchi-Takihara K. Interleukin-10 associates with adiponectin predominantly in subjects with metabolic syndrome. Circ J. 2007; 71(8):1234-1238.

20. Nishida M, Moriyama T, Ishii K, Takashima S, et al. Effects of IL-6, adiponectin, CRP and metabolic syndrome on subclinical atherosclerosis. Clin Chim Acta. 2007; 384(1-2):99-104.

21. Xu A, Tso AW, Cheung BM, Wang Y, et al. Circulating adipocyte-fatty acid binding protein levels predict the development of the metabolic syndrome: a 5-year prospective study. Circulation. 2007;27;115(12):1537-1543.

22. Festa A, D'Agostino R Jr, Tracy RP, Haffner SM. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes. 2002; 51(4):1131-1137.

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24. Marcovina S, Bowsher RR, Miller WG, Staten M; Insulin Standardization Workgroup. Standardization of insulin immunoassays: report of the American Diabetes Association Workgroup. Clin Chem. 2007; 53(4):711-716.

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Ross J. Molinaro, PhD, MT(ASCP), is a Clinical Chemistry Fellow/AACC Past Presidents' Scholar, who works in the Department of Pathology and Laboratory Medicine of the Emory University School of Medicine in Atlanta, GA.

By Ross J. Molinaro, PhD, MT (ASCP)

Table 1. Patient laboratory results

Analyte            Result                   Reference ranges

Triglycerides      320 mg/dL (3.60 mmol/L)  <150 mg/dL (1.69 mmol/L)
HDL cholesterol     35 mg/dL (0.87 mmol/L)   >60 mg/dL (0.90 mmol/L)
Glucose (fasting)  145 mg/dL (8.05 mmol/L)  <100 mg/dL (5.56mmmol/L)

World Health          2001 National               International
Organization          Cholesterol                 Diabetes
Diabetes Group        Education Program/ATP III   Federation

Guidelines developed  Guidelines developed in     Guidelines developed
  in 1998               2001, updated in 2005       in 2004
Criteria:               Criteria is any three of  Criteria:
* Hyperinsulinemia        the following five      * Increased waist
  (upper quartile of      traits:                   circumference based
  a measure of        * Abdominal obesity,          on ethnicity
  insulin resistance    defined as a waist        PLUS any two of the
  in the                circumference in men        following:
  non-diabetic          >102 cm (40 in) and in    * Elevated serum
  population), OR       women >88 cm (35 in)        triglycerides, >150
* Fasting plasma      * Elevated serum              mg/dL (1.7 mmol/L)
  glucose, 110 mg/dL    triglycerides, 150 mg/      or treatment for
  (6.1 mmol/L) or a     dL (1.7 mmol/L) or drug     elevated
  plasma glucose two    treatment for elevated      triglycerides
  hours after an        triglycerides             * Low serum HDL
  oral glucose        * Low serum HDL               cholesterol, <40 mg/
  tolerance test 200    cholesterol,                dL (1.03 mmol/L) in
  mg/dL (11.1 mmol/     <40 mg/dL (1 mmol/L)        men or <50 mg/dL
  L)                    in men and <50 mg/dL        (1.29 mmol/L) in
PLUS at least two of    (1.3 mmol/L) in women or    women, or treatment
  the following:        drug treatment for low      for low HDL
* Abdominal obesity,    HDL-C                     * High blood pressure,
  waist-to-hip ratio  * High blood pressure,        systolic blood
  >0.90, a body mass    130/85 mmHg or drug         pressure >130,
  index 30 kg/          treatment for elevated      diastolic blood
  [m.sup.2], or a       blood pressure              pressure > 85, or
  waist girth 94 cm   * Fasting plasma glucose,     treatment for
  (37 in)               >100 mg/dL (5.5 mmol/L)     hypertension
* Dyslipidemia,         or drug treatment for     * Fasting plasma
  defined as serum      elevated blood glucose      glucose, >100 mg/dL
  triglyceride 150                                  (5.6 mmol/L), or
  mg/dL (1.7 mmol/L)                                previously diagnosed
  or high-density                                   type 2 diabetes. An
  lipoprotein HDL                                   oral glucose
  cholesterol <35mg/                                tolerance test is
  dL (0.9 mmol/L)                                   recommended for
* High blood                                        patients with an
  pressure, 140/90                                  elevated fasting
  mmHg or the                                       plasma glucose, but
  administration of                                 not required
  antihypertensive
  drugs

Table 2. Criteria-based definitions of the metabolic syndrome. Adapted
from (1,2,6,7)