spacer
home > ict > spring 2014 > meta data
PUBLICATIONS
International Clinical Trials

Meta Data

Metabolic syndrome is a serious health condition which is defined as a cluster of metabolic risk factors that can increase the risk of developing cardiovascular diseases and diabetes. It impacts everyone to different degrees: children and adults of all genders, races and ethnicities. The prevalence of metabolic syndrome is rising dramatically – according to the American Heart Association (AHA), it now affects about one in three US adults.

As with many conditions, awareness, early diagnosis and early treatment can be critical – and clinical laboratories are well-equipped to aid with diagnosis by providing quality lab testing. The potential for successful management of metabolic syndrome is very good as treatments are simple, and can improve and save lives.

Diagnostic Criteria

As early as 250 years ago, long before the syndrome was defined, the Italian physician and anatomist Morgagni identified the link between abdominal obesity, atherosclerosis and hypertension – known today as the key risk factors of metabolic syndrome. Since then, the terminology and the definitions have evolved.

Metabolic syndrome was once known as plurimetabolic syndrome, syndrome X, deadly quartet, insulin resistance syndrome and dysmetabolic syndrome (1). The first official definition was provided by the World Health Organization (WHO) in 1989, followed by the European Group for the Study of Insulin Resistance (EGIR), the American Association of Clinical Endocrinologists (AACE), the US National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and, most recently, the International Diabetes Federation (IDF) (2-7).

These five official definitions agree on the point that people with multiple metabolic conditions are at higher risk of developing cardiovascular disease and diabetes. However, they disagree on the type and number of metabolic risk factors needed in order to be classified as metabolic syndrome. While each of the five official diagnostic criteria has its merits, it also has its weaknesses – ensuring ongoing debate around metabolic syndrome.

In the US, the metabolic syndrome definition provided by NCEP-ATP III in 2005 is the most widely used (8). It defines the syndrome as the presence of any three of the five traits such as abdominal obesity, high triglyceride levels, low serum high-density lipoprotein (HDL) cholesterol level, high blood pressure and high fasting plasma glucose.

Laboratory Testing


Methodologies and instrumentation available in clinical laboratories have evolved enormously in the past couple of years. Today, labs are well-equipped with state-ofthe-art instrumentation that can provide rapid and most accurate results, enabling metabolic syndrome to be quickly and easily detected.

Most clinical labs will provide glucose and lipid measurements. Their cut-off points have been established and standardised. Instead of giving triglycerides and HDL cholesterol measurements only, labs will usually provide lipid panel measurements that will help doctors with the overall cardiovascular and diabetes risk assessments and diagnosis.

Triglyceride Analysis

Lipids of dietary origin are transported in the bloodstream by complexes known as lipoproteins. They have to travel in micelle-like complexes composed of phospholipids and proteins on the outside, with cholesterol, cholesterol esters and triglycerides on the inside because they are not soluble in the plasma water (8).

The first direct triglyceride measurement method was published by Van Handel and Zilversmit in 1957. It was a manual method in which the phospholipids were removed from the lipid extract by an absorbent, with the triglycerides determined by measuring the amount of glycerol released by saponification with potassium hydroxide.

This method was modified by others, automated, and was once the most widely used. Over time, however, chemical triglyceride analysis has been simplified by the introduction of automated enzymatic methods, where stepwise enzymatic conversions of triglycerides are leading to a formation of coloured complex which can be measured by spectrophotometry. At present, there is no officially recognised reference method for triglyceride determinations.

Interferences due to haemolysis, icterus and lipemia of the sample have been documented. The contamination of the samples with glycerol from hand creams, glycerolcoated stoppers or any other origin can cause interference in some methods of triglyceride measurements (8).

The performance criteria of triglycerides methods are regulated by the Clinical Laboratory Improvement Amendments (CLIA), which require labs to be accurate to within +/- 25 per cent of the peer-group mean (9). The NCEP Laboratory Standardization Panel recommends the standards for precision and accuracy to be less than five per cent coefficient of variation (CV) and within +/- five per cent from the reference-method values (10). The recent College of American Pathologists (CAP) survey, based on results from laboratories across the US, shows that these quality goals are achievable by clinical labs (11).

Good Cholesterol

HDL cholesterol is known as ‘good’ cholesterol because it is believed to help remove ‘bad’ cholesterol from the body. By definition, HDL is the densest of the lipoproteins, composed of about 50 per cent protein, 25 per cent phospholipid, 25 per cent cholesterol and five per cent triglyceride. Ultracentrifugation and gravimetry of isolated HDL particles are the direct HDL measurement methods. However, they are lengthy, laborious techniques and so are rarely performed by clinical labs. Instead, the isolated HDL fractions are measured indirectly.

Today, numerous automated rapid techniques are available. They are all based on simple steps, such as isolation of the HDL and quantitation of the cholesterol in the isolated HDL. High levels of triglycerides, haemoglobin and bilirubin do not seem to interfere up to certain levels, although specimens with atypical lipoprotein patterns have been reported to interfere. In addition, unreliable results could be measured in samples from patients with Waldenstrom’s macroglobulinemia and polyclonal gammopathy. However, interpreting the results for these patients should be carried out with caution (8).

The HDL measurements are also regulated by CLIA, which require that laboratories be within +/- 30 per cent of the peer group mean (9). The NCEP Laboratory Standardization Panel recommends that total error be within 13 per cent, with≥ five per cent bias and ≥ four per cent CV (10). According to the recent CAP survey, these goals can be achieved by clinical labs (11).

Glucose Measurement


Enzymatic methods are the preferred approach for measuring glucose, with hexokinase or glucose oxidase most used by modern laboratories. Current methods have all been automated and point-of-care options are available.

The gold standard method for glucose measurement is isotope dilution mass spectrometry. Although highly accurate and precise, it is difficult to perform, and so is rarely used by clinical laboratories. This technique is mainly used by external quality assurance programmes to set the target values for their material, and by manufacturers to accurately determine glucose concentrations in their calibrators.

A number of substances can interfere with glucose measurements, including substances such as bilirubin, ascorbic acid and uric acid. However, modern chemistry analysers are well-equipped and can minimise the effect of these substances by performing kinetic measurements of glucose (8).

Glucose is a regulated analyte, and CLIA acceptable performance criteria require that labs be accurate to within ± 6mg/dl or ± 10 per cent (greater) of the peer group mean (9). According to the recent CAP survey, most labs can achieve these performance criteria (11).

Point-of-Care Meters


Recently, point-of-care glucose meters have become very popular because modern society demands rapid results at the patient’s bedside, and self-monitoring of blood glucose improves the lives of diabetic patients. But it is important to note that glucose meters are not as accurate and precise as laboratory analysers.

The Clinical and Laboratory Standards Institute uses the ISO 15197 guidelines, which recommend results for meters to be within 15mg/dl for glucose concentrations less than 75mg/dl and within 20 per cent for higher glucose levels (12).

Currently, the US Food and Drug Administration and other regulatory agencies are reviewing performance criteria of the meters, and more stringent criteria are expected to be implemented in the near future. Whole blood glucose levels are 10-15 per cent lower than the values obtained from plasma samples, but many modern meters are capable of automatically adjusting their glucose readings.

Insulin Resistance

Insulin resistance can be defined as an inappropriate glucose response of the body to the endogenous or exogenous insulin, with these measurements mainly used in research settings by clinical trial sponsors. The euglycemic insulin clamp, the intravenous glucose tolerance test and the insulin tolerance/suppression tests are all impractical for routine clinical use. In addition, there are no established cut-off values and a lack of standardised universal assays for insulin measurements.

The homeostasis model assessment (HOMA) of insulin resistance has been derived from the measurements of insulin and fasting glucose values. There are two equations currently in use by clinical trial sponsors: the first model, HOMA-1, was calibrated to an insulin assay used in the 1970s, while the second model, HOMA-2, was readjusted to the current insulin assays and improved (13).

Many limitations in the use of insulin resistance indexes lead to their removal from the diagnostic criteria in the newer definitions for metabolic syndrome. Nevertheless, insulin resistance measurements can provide valuable information for sponsors, if used appropriately.

Available Treatments

Metabolic syndrome is becoming increasingly common, but fortunately the treatments are simple. The ATP III, AHA, National Institutes of Health (NIH) and the Endocrine Society recommend treating the underlying causes – for example, obesity and physical inactivity. The cardiovascular risk factors also need special attention. If the lifestyle modifications such as diet, physical exercise and stopping smoking do not change the metabolic risk factors, then cardiovascular risk factors have to be treated. They can be reduced by treating hypertension, glycemic control in patients with diabetes, and lowering of cholesterol (5,14-17).

Metabolic syndrome is a serious condition that can lead to fatal outcomes if not detected and treated. Clinical laboratories are playing a central role in detecting it, and current technologies allow these labs to provide healthcare providers and/or clinical trial sponsors with rapid and accurate results to aid prevention and treatment.

References
1. Cripaldi G and Maggi S, The metabolic syndrome: a historical context, Diabetes Voice 51, 2006
2. Definition, diagnosis and classification of diabetes mellitus and its complications, Report of a WHO consultation, 1999
3. Balkau B and Charles MA, EGIR Comment on the provisional report from the WHO consultation, Diabet Med 16: pp442-443 ,1999
4. Executive summary of the third report of the NCEP expert panel on detection, evaluation and treatment of high blood cholesterol in adults (ATP III), JAMA 285: pp2,486-2,497, 2001
5. Grundy SM et al, National Heart, Lung and Blood Institute Diagnosis and management of the metabolic syndrome, Circulation 112(17): p2,735, 2005
6. American College of Endocrinology: Insulin resistance syndrome (position statement), Endocr Pract 9 (supplement 2): pp9-21, 2003
7. The IDF consensus worldwide definition of the metabolic syndrome, IDF, 2006
8. Kaplan LA and Pesce A, Clinical Chemistry, 5th edition, 2010
9. Visit: www.cms.gov/regulations-and-guidance/legislation/CLIA/ index.html?redirect=/clia
10. Recommendations for improving cholesterol measurement: a report from the Laboratory Standardization Panel of the NCEP, NIH Publication No. 90-2964, 1990
11. CAP Chemistry and Toxicology Survey, 2013
12. Sacks DB et al, Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus, Clin Chem 48: pp436-472, 2002
13. Wallace TM, Levy JC and Matthews DR, Use and abuse of HOMA modeling, Diabetes Care 27(6): 2004
14. Grundy SM et al, Report of the AHA/National Heart, Lung and Blood Institute/American Diabetes Association conference on scientific issues related to management, Circulation 109(4): p551, 2004
15. Rosenzweig JL et al, Primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab 93(10): p3,671, 2008
16. Pearson TA et al, AHA Guidelines for primary prevention of cardiovascular disease and stroke: 2002 update. Consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases, Circulation 106(3): p388, 2002
17. Eberly LE et al, Metabolic syndrome: risk factor distribution and 18-year mortality in the multiple risk factor intervention trial, Multiple Risk Factor Intervention Trial Research Group, Diabetes Care 29(1): p123, 2006
18. American Diabetes Association, Diabetes Care 36 (supplement 1), 2013
19. Clinical practice guideline for the evaluation and management of chronic kidney disease, KDIGO Kidney International Supplement, January 2013


Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

spacer
Dr Tatiana Souslova is a Diplomat of the American Board in Clinical Chemistry. She holds a doctorate in Neuroscience from the University of Ottawa, and has over 10 years of academic, industrial and diagnostic lab experience. At ACM Global Central Laboratory, Tatiana oversees all clinical chemistry and research activities, with an emphasis on providing high-quality, uniquely tailored solutions.


spacer
Dr Tatiana Souslova
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

ERT’s At-Home Cardiac Safety Assessment Ensures Clinical Trial Continuity

PHILADELPHIA – March 30, 2020 – ERT, a global data and technology company that captures critical endpoint data while minimizing uncertainty and risk in clinical trials, today announced a cardiac safety solution that helps biopharmaceutical researchers continue important clinical trials during current global ‘stay home’ mandates. The solution enables clinician-administered ECG readings ─ using ERT’s provisioned, FDA-cleared devices or other investigative site–owned equipment ─ to evaluate the safety of new vaccines and medical treatments from patients’ homes.
More info >>

White Papers

Is Your Biobank Ready for the Challenge of Biomarker-based Research?

BioFortis

Targeted and personalized studies with well-defined patient segmentation biomarkers are becoming the norm in clinical trials. This increased interest in molecular biomarker studies necessitates a rigor and sophistication in sample management within the clinical trial context that is often not supported either by traditional clinical trial management software (CTMS), or biobanking systems.  Download our Next Generation Biobanking whitepaper and learn about how to overcome the key challenges in clinical trial sample management from working in a distributed network of partners and stakeholder to managing consents and generating scientific insights.
More info >>

 
Industry Events

Clinical Operations in Oncology Trials West Coast

17-18 November 2020, Hilton San Francisco Airport Bayfront

Clinical Operations in Oncology Trials West Coast will be returning this April for another 2 day event full of thought-provoking presentations, discussions and roundtables. This years' conference highlights include the high-level, interactive immuno-oncology discussion panel where specialists from Shasta Bio Ventures, Abbvie and BeiGene shared their top tips on how to run successful and impactful immuno-oncology studies.
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement