Fructosamine

Estimation of longer term patterns of glucose control is based upon measurement of stable combinations of glucose with circulating proteins. HbA1c is the most familiar and widely used of these, but has a number of limitations, for example spuriously low readings in people with shortened red cell life span or hemoglobinopathies. Furthermore, an apparently satisfactory HbA1c reading may conceal unwanted fluctuation between low and high glucose values. Fructosamine is formed by combination between glucose and circulating proteins, predominantly albumin, and reflects their more rapid rate of turnover - i.e.14-21 days as against 100-120 days for HbA1c. Fructosamine is therefore potentially useful in estimating short term changes in glucose control, although this is rarely needed in clinical practice. Disadvantages include the lability of circulating proteins in situations such as pregnancy, but fructosamine may prove useful in conditions affecting red cell turnover, including renal disease. It may also, when used in combination with other measures, find a role in identifying fluctuating glucose levels in those with a stable HbA1c.

0## Introduction

As with HbA1c, non-enzymatic glycation of serum proteins can take place, although in this instance the reaction is between the carbonyl group of glucose and the ε-amino groups of lysine side chains[1]. Albumin accounts for ~90% of the glycated protein in the circulation, and fructosamine measurement reflects a period of glucose exposure corresponding to the turnover of albumin, typically 14-21 days. This mode of glycation does not affect the charge of the molecule, and charge-dependent assay methods cannot therefore be used to measure it, in contrast with HbA1c.

Clinical Applications

Fructosamine is available as laboratory test which can be used as an alternative to HbA1C. [2] The normal range for Fructosamine is 258 - 317 μmol, equivalent to an HbA1C of 6-7%.[3]. Formulae relating Fructosamine to HbA1c have been developed in both the UK and US, as follows:

      Fructosamine = (A1C-1.61) x 58.82

Limitations of HbA1c

HbA1C is limited in its ability to determine or reflect short-term changes in glycemic control and it does not differentiate between fasting and post prandial glucose control. [4] In addition, certain hemoglobinopathies such as hemolytic anemia, sickle cell disease or variants can lead to a false or low A1C level.[5]

Fructosamine

Early studies with Fructosamine or glycosylated albumin for monitoring of glycemic control indicated the utility of the test over a short term period. There are however important limitations, including lack of a clear temporal relationship between mean glucose values and the test. Additionally, the test is affected by variation in serum albumin concentrations. Pregnancy, particularly in the first 24 weeks, affects serum albumin and can affect the results. [6][7]

A recent study involving 53 patients with type 2 DM had individuals utilize CGMS for 72 hours and also do Home Glucose Monitoring several times per day.
Multiple markers of glucose control were examined, including Fructosamine, and it was shown that was clinically relevant glucose variability and post-prandial hypo and hyperglycemia in apparently "well controlled" patients by HbA1C criterialevels. Fructosamine emerged as a potentially useful clinical tool in determining glucose control. The study concluded that more than 1 marker may be needed in the control of diabetes. [8]

An additional recent study by Shafi et al indicated that serum fructosamine would also be a useful indicator of increased mortality and morbidity in patients with end stage renal disease undergoing hemodialysis. An increase in fructosamine was associated with an increase in hospitalizations and all cause mortality in the 503 patients involved. The authors suggest that serum fructosamine should be included with HbA1C in the management of patients with diabetes who are undergoing hemodialysis.[9]

A third study involving patients with diabetes who are undergoing Peritoneal Dialysis (PD) indicated that fructosamine, used in conjunction with HbA1C, provides reliable evaluation of glycemic control.[10]

ARIC -Atherosclerosis Risk in Communities Study was a large study involving more than 2000 individuals and measured fructosamine, glycated albumin and A1C levels to determine both utility in prediction of incident DM and microvascular complications. The conclusions were that both fructosamine and glycated albumin were associated with incident DM and microvascular complications. Their prognostic value was similar to A1C. An accompanying editorial also indicated that "clinicians shoud be afraid to employ multiple measures of glucose control".[11][12]

Limitations of Fructoamine

Fructosamine reflects glucose changes over a shorter period of time than HbA1c[13], but diabetes treatment generally does not change markedly over the short term, and pharmacological agents may take months to have an effect on glucose control.

In contrast to HbA1C, there is little standardization of this test. The reference values could depend on age, gender and test method. In addition, fructosamine may need to be adjusted if serum albumin levels are abnormal.[14] This makes interpretation of the results, if used separately, difficulty to interpret. For this reason, fructosamine is not widely used in clinical practise at present.

Future Prospects

Fructosamine could however find wider use as an alternative marker of both glycemic control and the risk of diabetes, particularly if used with other tests, to include glycated albumin and 1,5-AG (Glycomark), FA [15]

Additional studies may be necessary to prove the continued utility of fructosamine as a measure of glucose control. At the present time, it does appear that it may be useful as an adjunct to other tests, particularly in individuals with renal impairment.

References

  1. ^ Dolhofer R, Wieland OH. Glycosylation of serum albumin: elevated glycosyl-albumin in diabetic patients. FEBS Lett 1979;103:282-6

  2. ^ Zafon, C.; Ciudin, A.; Valladares, S.; Mesa, J.; and Simo, R.: Variables Involved in the Discordance between HbA1c and Fructosamine: The Glycation Gap Revisitee: PLOSone e66696; 2013

  3. ^ National Quality Measures Clearinghouse: 12-31-2007

  4. ^ Derr, R.; Garret, E.; Stacy, GA; Saudek, CD: Is HbA1c Affected by Glycemic Instability?: Diabetes Care 2728; 2003

  5. ^ Sacks, D.B.: Hemoglobin Variants and hemoglobin A1c analysis: Problem Solved?: Clinical Chemistry 49 (8): 1245-1247; 2003

  6. ^ Ziel, F.H. and Davidson, M.B.; The Role of Glucosylated Serum Albumin in Monitoring Glycemic Control in Stable Insulin-Requiring Diabetic Out-Patients: Journal of Clinical Endocrinology and Metabolism 64(2): 269-273; 1987

  7. ^ Morris M.A. et al.;Longitudinal Assessment of Glycosylated Blood Protein Concentrations in Normal Pregnancy and Gestational Diabetes Diabetes Care 9: 107, 1986

  8. ^ Chon, S.; Lee, YJ; Fraterrigo, G.; et al: Evaluation of Glycemic Variability in Well-Controlled Type 2 Diabetes Mellitus: Diabetes Techonology and Therapeutics 15 (6): 455; 2013

  9. ^ Shafi, T; Sozio, S; et al: Serum Fructosamine and Glycated Albumin and Risk of Mortality and Clinical Outcomes in Hemodialysis Patients: Diabetes Care 1522-1533; 2013

  10. ^ Lee, S-Y; Chen, Y-C; Tsai, I-C et al: Glycosylated Hemoglobin and Albumin-Corrected Fructosamine Are Good Indicators for Glycemic Control in Peritoneal Dialysis Patients: PLOSone 8(3): e57762; 2013

  11. ^ Selvin, E., Rawlings, A.M., Grams, M., Klein, R., Sharrett, A.R., Steffes, M. and Coresh, J.; Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC); www.thelancet.com/diabetes-endocrinology; http://dx.doi.org/10.1016/s2213-8587(13)70199-2

  12. ^ Cohen, R.M. and Herman, W.H.; Are glycated serum proteins ready for prime time?: www.thelancet.com/diabetes-//dx.doi.org/10.1016/s2213-8587(14)70003-8

  13. ^ Ashby, J.P and Frier, B.M.; Is serum fructosamine a clinically useful test?: Diabetes Medicine 118; 1988

  14. ^ Howey, JE; Browning, MC; Fraser, CG: Assay of serum fructosamine that minimizes standardization and matrix problems: use to assess components of biological variation: Cinical Chemistry 33: 269 1987

  15. ^ Juraschek, SP; Steffes, MS; Miller, ER and Selvin, E.: Alternative Markers of Hyperglycemia and Risk of Diabetes: Diabetes Care:35(11); 2265, 2012

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