Fructosamine


Article Author:
Verena Gounden


Article Editor:
Ishwarlal Jialal


Editors In Chief:
William Gossman


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
1/23/2019 11:29:03 AM

Introduction

Diabetes mellitus (DM), a global epidemic, is increasing at an alarming rate and is associated with both increased morbidity and mortality. It appears that only plasma glucose and glycated hemoglobin (HbA1c) are universally accepted as reliable measures of diabetes control. Data has been evolving with other measures that bridge the span of short-term glycemic control from an isolated glucose level to HBA1c which provided an index of glycemia over 2 to 3 months. Fructosamine is a measure of non-enzymatic glycation resulting in a ketamine linkage to circulating proteins including albumin, globulins and lipoproteins and glycated albumin (GA), is a measure of the percent albumin that is glycated; both provide a measure of glycemia of 2 to 3 weeks duration. Fructosamine and GA have a potential role in the diagnoses and management of diabetes.[1][2][3]

Pathophysiology

Fructosamine (1-amino-1-deoxy fructose), is a stable ketoamine, formed by the non-enzymatic reaction product of sugar (usually glucose) and the amino group of protein (usually albumin but includes globulins and lipoprotein). The attachment of the aldehyde group of the carbohydrate with the N terminal amino acid of the protein forms the reversible Schiff base and intermediate. The Schiff base may be converted back to glucose and protein or undergo the Amadori rearrangement to form stable fructosamine. This process is known as non-enzymatic glycation and is also referred to as the Maillard reaction. The Maillard reaction causes the browning phenomenon that occurs in milk and other food products when heated.

Glycated albumin refers to the formation of ketoamine specifically involving the major circulating protein albumin (3.5 g/dl to 5 g/dl).   Glycated albumin is an example of a fructosamine (FA). Because albumin is the most abundant of the serum proteins, fructosamine is predominantly a measure of glycated albumin. The formation of fructosamine and glycated albumin are post-translational modifications that occur to proteins. This is different from a  glycoprotein which is a protein molecule that contains a carbohydrate moiety(group). The formation of a glycoprotein is an enzymatic dependent reaction. The rate of non-enzymatic glycation of albumin is much higher than that of hemoglobin.[4][5]

Specimen Requirements and Procedure

Sample type: Serum or plasma are the sample types used for the measurement of fructosamine and glycated albumin. Fasting specimens are not required.

Testing Procedures

Fructosamine

The most common assays available for fructosamine involve a colorimetric methodology. The reaction occurs in an alkaline buffer where fructosamine as a reducing agent and involves a color change of the substrate which is measured spectrophotometrically.[6][7][8]

These assays are widely available, can be automated and fairly inexpensive. However, unlike HbA1c there is a serious lack of standardization across the different fructosamine assays.

Glycated Albumin

There are several different assay methodologies available for the analysis of glycated albumin. These include:

  • Enzymatic assay
  • High-performance liquid chromatography (HPLC) and affinity chromatography
  • Immunoassay, including quantification by radioimmunoassay
  • Enzyme-linked immunosorbent assay (ELISA)
  • Enzyme-linked boronate immunoassay (ELBIA)
  • Colorimetry
  • Electrochemical

Interfering Factors

Fructosamine assays are affected by changes in temperature and by the increased presence of reducing substances in serum, for example, vitamin C and bilirubin. Fructosamine and GA are both not standardized assays. Additionally, both fructosamine and glycated albumin are affected by the presence of any conditions that influence serum albumin concentrations. However, this is minimized for GA since GA is expressed as a percentage of total albumin. Fructosamine will be unreliable when serum albumin is less than 3.0 g/dl. This will include conditions where there is decreased albumin synthesis, for example, liver cirrhosis or albumin/protein loss such as nephrotic syndrome and protein-losing enteropathies. Fructosamine levels may also be affected by conditions with raised total protein levels such as in multiple myeloma (due to increased immunoglobulins) and polyclonal gammopathies.

Results, Reporting, Critical Findings

A  reference range for fructosamine in non-diabetic individuals is generally 200 to 285 umol/L.

While GA assays also suffer from standardization, a newer assay appears to be much improved such as the automated immunoassay developed by Asahi Kasei. According to this assay, normal persons have values around 14% and those with diabetes greater than 17%. Values in diabetes are generally two to five times upper limit of normal.

Clinical Significance

The clinical utility of fructosamine and GA includes monitoring of diabetes, diagnosis of pre-diabetes and prediction of both the microvascular and macrovascular complications. They have the advantage of not requiring a fasting sample.

Monitoring of  glucose control in diabetes

Fructosamine and glycated albumin can be utilized as short-term markers of glucose control.  Both correlate significantly with HBAIc levels. While HbA1c reflects glucose control over a period of the preceding 8 to 12 weeks, fructosamine reflects the average glycemia over the preceding 2 to 3 weeks. This is as a result of the inherent shorter half-life of albumin in comparison to hemoglobin in the erythrocyte.

Fructosamine has largely been used as an alternative to the use of HbA1c monitoring in the presence of certain conditions that preclude the use of HbA1c such as hemoglobin variants and alterations in erythrocyte lifespan. Fructosamine and glycated albumin are not affected by hemoglobin or red blood cell characteristics to which HbA1c is susceptible. This includes conditions such as hemoglobinopathies, sickle cell anemia and anemia related to iron or vitamin B12 deficiency.

Additionally, fructosamine has clinical utility in conditions where information regarding short-term glucose control is important in the management of the patient such as in pregnancy. FA and GA also useful in monitoring people with diabetes with fluctuating or poorly controlled diabetes.

Diagnosis of Diabetes

Recent studies have evaluated the use of the alternate glycaemic markers of fructosamine and glycated albumin for the diagnosis of diabetes. It has been reported that in the diagnosis of diabetes, serum GA measurements can be used to ascertain the need for an oral glucose tolerance test (OGTT).  There appears to be a negative correlation between GA and body mass index (BMI), and hence it could potentially underestimate glycemia in the obese. Currently, no guidelines support the use of GA or FA for the diagnosis of diabetes or pre-diabetes.

Diabetes Outcome

Previously there was little evidence of the relationship of fructosamine and glycated albumin with diabetes complications and long-term outcomes. Recent studies, for example, the Atherosclerosis Risk in Communities Study (ARIC), have demonstrated that fructosamine and glycated albumin were strongly associated with retinopathy as well as being significantly associated with risk of incident chronic kidney disease and incident diabetes.  In addition, both Fructosamine and GA, even following adjustment for HBAIc, significant prognosticators of cardiovascular outcomes and mortality.

Quality control and Lab Safety

Commerical assays for fructosamine and glycated albumin have internal quality control materials available for use. Additionally,  laboratories measuring these assays would subscribe to a recognized proficiency testing scheme to monitor test performance.

Enhancing Healthcare Team Outcomes

Healthcare workers including the nurse practitioner should be familiar with the diagnosis of diabetes. Fructosamine and GA have utility as alternate markers in those patients where the HbA1c assay is unreliable. Also, they can identify poor glucose control more rapidly than HbA1c, i.e., short-term hyperglycemia. A major promise will be their ability to predict those pre-diabetic patients who go on to clinical diabetes since this could lead to major lifestyle and pharmacological interventions to prevent the onset of diabetes and its complications. Finally, they may also have a role in pregnancy for the management of diabetes given that they can provide a measure of glycemia over 2 to 3 weeks rather than 8 to 12 weeks.  

Glycated albumin has been reported to be a better marker than HbA1c  for the assessment of glucose control in people with diabetes with chronic kidney disease and those on hemodialysis and peritoneal dialysis.


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Fructosamine - Questions

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Which of the following is a reliable measure of glycemic control over the last 2.5 weeks in a patient newly diagnosed type1 diabetes mellitus started on insulin?



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Which of the following disease states render a fructosamine assay unreliable in assessing diabetes control?



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Which of the following test is an indicator of glycemic control over a 2 to 3 week period preceding the collection of the blood sample?



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What would be the most appropriate marker of glycemic control to use for a 17-year-old male with type 2 diabetes mellitus and sickle cell anemia?



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A 5-day old neonate was diagnosed with breast milk jaundice. The infant had a normal vaginal delivery with no complications. Weight, height, and head circumference were just above the 50th percentile and remained there on the follow-up visit. The mother did not have any issues with the exclusive breastfeeding and the baby was latching adequately and drinking sufficiently at each feed. Blood investigations were performed. Apart from the moderately raised unconjugated bilirubin, the serum creatinine result was 0.0 mg/dL. The reference interval for neonate 0.2-0.9 mg/dl.



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Fructosamine - References

References

Neelofar K,Ahmad J, A comparative analysis of fructosamine with other risk factors for kidney dysfunction in diabetic patients with or without chronic kidney disease. Diabetes     [PubMed]
Garrahy A,Mijares Zamuner MB,Byrne MM, An evolving spectrum of diabetes in a woman with GCK-MODY. Endocrinology, diabetes     [PubMed]
Pedrosa W,Sander Diniz MFH,Barreto SM,Vidigal PG, Establishing a blood fructosamine reference range for the Brazilian population based on data from ELSA - Brasil. Practical laboratory medicine. 2019 Jan;     [PubMed]
Muñoz-Prieto A,Escribano D,Cerón JJ,Martínez-Subiela S,Tvarijonaviciute A, Glucose, fructosamine, and insulin measurements in saliva of dogs: variations after an experimental glucose administration. Domestic animal endocrinology. 2019 Jan;     [PubMed]
Gingras V,Rifas-Shiman SL,Switkowski KM,Oken E,Hivert MF, Mid-Pregnancy Fructosamine Measurement-Predictive Value for Gestational Diabetes and Association with Postpartum Glycemic Indices. Nutrients. 2018 Dec 18;     [PubMed]
Rivera-Velez SM,Hwang J,Navas J,Villarino NF, Identification of differences in the formation of plasma glycated proteins between dogs and humans under diabetes-like glucose concentration conditions. International journal of biological macromolecules. 2019 Feb 15;     [PubMed]
González-Lao E,Corte Z,Simón M,Ricós C,Coskun A,Braga F,Aarsand AK,Carobene A,Bartlett WA,Boned B,Asland B,Díaz-Garzón J,Marqués-García F,Minchinela J,Perich C,Fernández-Calle P,Roraas T,Fernández-Fernández P,Jonker N,Sandberg S, Systematic review of the biological variation data for diabetes related analytes. Clinica chimica acta; international journal of clinical chemistry. 2019 Jan;     [PubMed]
Gyurászová M,Kovalčíková A,Janšáková K,Šebeková K,Celec P,Tóthová Ľ, Markers of oxidative stress and antioxidant status in the plasma, urine and saliva of healthy mice. Physiological research. 2018 Dec 18;     [PubMed]

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