Fructosamine

Fructosamine is the product of non-enzymatic glycation of serum proteins, mostly albumin, which forms ketoamine linkages with glucose. It is measured by the reduction of nitroblue tetrazolium in alkaline solution. Because albumin has a half life of about 20 days, the result reflects mean glucose over the preceding 2 to 3 weeks. This is shorter than HbA1c and independent of red cell lifespan and haemoglobin structure.

It is used when HbA1c is unreliable, and to monitor glycaemia over a short interval. It is not accepted for the diagnosis of diabetes, and it is affected by anything that changes serum albumin concentration or turnover.

Indications.

• Haemoglobinopathies (HbS, HbC, HbE, thalassaemia) and other conditions that shorten red cell life (haemolytic anaemia, hypersplenism, recent blood loss or transfusion).
• Chronic kidney disease with anaemia treated by erythropoiesis stimulating agents.
• Pregnancy with pre-existing or gestational diabetes, where the 2 to 3 week window is useful.
• Assessment after a change in treatment, when 4 to 6 weeks of HbA1c data is not yet available.
• Discordance between HbA1c and home glucose readings.

Specimen. Serum, or plasma in some methods. Fasting is not needed. The sample is stable for several days at 2 to 8 °C and for longer when frozen.

Reference range. About 200 to 285 micromol/L in non-diabetic adults. Ranges are assay specific, and local limits take precedence.

Relation to HbA1c. A fructosamine of about 285 micromol/L corresponds roughly to an HbA1c of 48 mmol/mol (6.5%), and about 320 micromol/L to 53 mmol/mol (7.0%). The relationship is approximate, varies between people and assays, and is weakest when albumin is abnormal. There is no universal target, and trends over time in the same person are more useful than single values.

Interpretation.

• Values under the usual range with high HbA1c: check for protein loss or abnormal albumin turnover.
• High fructosamine with a normal HbA1c: raised glucose in recent weeks, or an HbA1c lowered by red cell turnover.
• A fall of about 10% or more after a change in therapy suggests a response.

Causes of falsely low results. Hypoalbuminaemia from nephrotic syndrome, protein losing enteropathy, cirrhosis, malnutrition, severe illness and burns, hyperthyroidism (faster protein turnover), and high dose vitamin C in some methods.

Causes of falsely high results. Hyperalbuminaemia (rare), hyperbilirubinaemia, haemolysis, lipaemia, high urate, and monoclonal IgA in some methods. Fructosamine may be unreliable in paraproteinaemia.

Albumin adjustment. Several adjustments for serum albumin have been proposed. None has been validated well enough for routine use, so the result is read together with albumin.

Critical findings needing immediate action. None specific. A markedly raised value with symptoms needs the same day glucose and ketone assessment that applies to a high HbA1c.

Pitfalls.

• Variation in serum albumin is the main limitation, and reference ranges change with albumin concentration.
• Methods differ in sensitivity to bilirubin, lipaemia and haemolysis, so serial values should come from the same assay.
• It does not show glucose variability or hypoglycaemia.
• The link between fructosamine and long term complications is less well established than for HbA1c.
• It is not used to screen for or diagnose diabetes.

Special groups.

• Pregnancy: albumin falls, so values run lower for the same glucose, and the evidence for use is limited.
• Chronic kidney disease and nephrotic syndrome: albumin loss lowers results.
• Liver disease: reduced albumin synthesis lowers results.
• Children: reference ranges are age specific.
• Haemoglobinopathies: it is the main alternative when HbA1c is unreliable, alongside glycated albumin and continuous glucose monitoring.

Follow up tests. HbA1c, serum albumin, glycated albumin, continuous glucose monitoring or home glucose records, full blood count, haemoglobin electrophoresis, urine albumin-to-creatinine ratio, liver function tests, serum protein electrophoresis when a paraprotein is suspected.