Advice

Technology overview

Technology overview

This briefing describes the regulated use of the technology for the indication specified, in the setting described, and with any other specific equipment referred to. It is the responsibility of healthcare professionals to check the regulatory status of any intended use of the technology in other indications and settings.

About the technology

CE marking

The Abbott Diagnostics Active‑B12 assay for the ARCHITECT i2000SR or i1000SR system (Abbott Diagnostics) was CE marked in September 2011. The assay was previously CE marked for the Abbott AxSYM system, however this version is no longer available. The ARCHITECT assay is a chemiluminescent microparticle immunoassay (CMIA) using magnetic microparticles, whereas AxSYM assay was a microparticle enzyme immunoassay (MEIA) with latex microparticles. As part of the CE‑marking of the ARCHITECT assay, the manufacturer had to ensure that both assays gave equivalent results.

The product is regulated under the in vitro diagnostic medical device (98/79/EC) directive and is classed as a general device.

Description

The Abbott ARCHITECT Active‑B12 immunoassay is manufactured by Abbott Diagnostics. This is a high‑throughput format that is fully automated and can be run at 200 tests per hour. The assay is designed to be run on the Abbott ARCHITECT i2000SR or i1000SR analyser (Abbott Diagnostics). The assay kit contains all required reagents and these are loaded into the analyser along with the samples. The process of sample preparation, dilution and analysis is automated. In addition, standard laboratory supplies such as micro‑pipettes and plasticware are needed.

The Active‑B12 test uses a holotranscobalamin (holoTC)‑specific monoclonal antibody to capture holoTC from a serum sample. A second monoclonal antibody conjugate is used in the detection step. The assay uses 6 calibrators with defined pmol/l HoloTC concentrations then reads the sample signal against the calibration curve to calculate the sample concentration. A light signal generated from the detection step is directly proportional to the amount of holoTC in the serum sample. The analyser translates the light signal into a numerical sample concentration, expressed in pmol/l. No user input is needed. The output is stored on the instrument and can be printed out or sent directly to the laboratory information management system. The assay range is up to 128 pmol/l but this can be extended to 256 pmol/l by performing a 1:1 dilution. The diluent is an existing consumable called 'Multi‑Assay Diluent', which is used in many other ARCHITECT assays.

Setting and intended use

The Active‑B12 assay is a test for vitamin B12 deficiency. It could be used as a replacement for total vitamin B12 testing (Brady et al. 2008) as a first‑line or second‑line test, whenever testing for vitamin B12 deficiency is clinically indicated in primary or secondary care.

The analysis would be done in secondary care haematology laboratories. Tests would be run by appropriately trained clinical scientists or medical laboratory assistants in automated laboratories, supervised by medical laboratory scientists or clinical scientists.

Current NHS options

There is currently no standard test for measuring vitamin B12 deficiency. Recent guidelines for the diagnosis and treatment of cobalamin and folate disorders from the British Society for Haematology (Devalia et al. 2014) state that serum total vitamin B12 remains the first‑line test because of its wide availability and low cost, but that it lacks the sensitivity and specificity needed for a robust diagnostic test. Plasma methylmalonic acid testing is used to clarify uncertain results, however this may be falsely elevated in people with renal disease, haemoconcentration or small bowel bacterial overgrowth and the high cost of the test has prevented its widespread use (Devalia et al. 2014). The guidelines state that serum holoTC has the potential to be used as a first‑line test and may reduce the number of indeterminate results, particularly in people over 65 years. They further state that holoTC has the added advantage that it can be used in pregnant women and in women taking oral contraceptives, because the holoTC fraction of cobalamin does not seem to have the same physiological reduction over the course of pregnancy as total serum cobalamin. These guidelines state that further studies are needed to evaluate the clinical utility of holoTC in assessing vitamin B12 deficiency in a routine high‑output laboratory setting.

The NICE clinical knowledge summary on anaemia anaemia states that a diagnosis of vitamin B12 deficiency is generally made through the analysis of a person's clinical history. Signs and symptoms include:

  • a 'lemon tinge' to the skin

  • inflammation of the tongue

  • oropharyngeal ulcers

  • neuropsychiatric and neurological symptoms including peripheral neuropathy.

A full blood count should be taken if blood tests show a low haemoglobin level and high mean cell volume (MCV), and serum vitamin B12 and serum folate levels should be checked. In people with a low haemoglobin level and normal or low MCV, ferritin, vitamin B12 and folate levels should be tested.

If a diagnosis of vitamin B12 deficiency is confirmed, the current UK clinical practice is to offer treatment with intramuscular injections of hydroxycobalamin (Devalia et al. 2014; Hunt et al. 2014). Standard therapy is injections of 1000 micrograms given 3 times a week for 2 weeks for people without neurological impairment and the same dose on alternate days until there is no further improvement for people with neurological symptoms. Oral treatment may be considered in certain situations (Hunt et al. 2014).

NICE is aware of the following tests, which fulfil a similar purpose to the Active‑B12 (Abbott) test:

  • Axis‑Shield Active‑B12 enzyme immunoassay assay (EIA)

  • Biohit Active B12 enzyme‑linked immunosorbent assay (ELISA)

  • IBL International Active‑B12 (holotranscobalamin) ELISA.

Costs and use of the technology

According to the manufacturer, the expected cost of the Abbott ARCHITECT Active‑B12 is around £3.50 including VAT, although no formal list price was made available. The price depends on the type of test, number of samples and order size.

An Abbott ARCHITECT i2000SR or i1000SR analyser is needed to run the Active‑B12 assay. The cost of an analyser varies depending on whether it is bought through capital purchase or reagent rental, as well as on the length of the contract. ARCHITECT i2000SR and i1000SR analysers are commonly used in NHS laboratories.

Likely place in therapy

Currently vitamin B12 levels are tested when there is clinical suspicion of vitamin B12 deficiency and when monitoring patients during vitamin B12 supplementation therapy.

The Active‑B12 assay could be used as a replacement for the current standard test for serum total vitamin B12 levels. Holotranscobalamin levels may be more reliable than serum cobalamin in determining deficiency during pregnancy, and so the Active‑B12 test could be offered to this group when available (Devalia et al. 2014).

Specialist commentator comments

Specialist commentators commented that holoTC testing may be an appropriate replacement for total serum vitamin B12 testing. They noted that a large proportion of total vitamin B12 is in the inactive form and that this can mask a deficiency in bioavailable holoTC, and that holoTC may be the earliest marker for vitamin B12 deficiency.

Two commentators noted that holoTC testing does not eliminate the need for a second confirmatory test, MMA, if results are indeterminate, in which case additional serum creatinine testing may be needed to interpret the MMA result. The size of this indeterminate 'grey zone' is dependent on the holoTC cut‑off point chosen, but results that fall in this dynamic range are of uncertain biological significance and need confirmatory testing. One commentator noted that holoTC could be used as a second test for indeterminate total vitamin B12 levels between 150 pmol/l and 200 pmol/l, which may amount to 20% of results in older populations. This may be valuable if there is a discrepancy between a normal total vitamin B12 result and clinical signs of deficiency. However, a different commentator suggested that the use of the Active‑B12 assay to confirm indeterminate total vitamin B12 levels was inappropriate because a further group of indeterminate results will need more tests.

Two commentators stated that the assay was of particular value for detecting deficiency in pregnant women, because the holoTC levels, unlike total vitamin B12 levels, do not fall in the second and third trimesters. A second commentator thought that further experience is needed on interpretation of assays in pregnant women.

Commentators noted that although holoTC testing is being increasingly used, there are still discrepancies in the mode of application and the assignment of cut‑off values. One specialist commentator noted that variable 'normal' levels of vitamin B12, holoTC and MMA are to be expected in groups with different diets (Herrmann et al. 2003). This commentator stated that although the studies included in this briefing illustrate a range of cut‑off points; in their opinion, the cut‑off point should be between 19 pmol/l and 34 pmol/l as suggested by Heil et al. (2012) to get the optimal balance between sensitivity and specificity and reduce the need for additional testing with MMA. One commentator noted that individual laboratories should define normal ranges.

On costs, 1 commentator also stated that the price of an Active‑B12 assay is likely to be around £10 compared with their own estimate of £2.68 for total vitamin B12, and that the price depends on order size or sample throughput, which is inversely proportional to reagent prices. As such, they noted that the price may be a barrier to the uptake of this new test by NHS laboratories, which are unable to increase their prices to primary care and may be unable to establish a business case for using a better but more expensive test.

Equality considerations

NICE is committed to promoting equality and eliminating unlawful discrimination. In producing guidance, NICE aims to comply fully with all legal obligations to:

  • promote race and disability equality and equality of opportunity between men and women

  • eliminate unlawful discrimination on grounds of race, disability, age, sex, gender reassignment, pregnancy and maternity (including women post‑delivery), sexual orientation, and religion or belief (these are protected characteristics under the Equality Act 2010).

Testing for vitamin B12 deficiency is recommended for people of all ages in whom deficiency is clinically suspected. Vitamin B12 deficiency is more common in older people. Testing for holoTC may be particularly advantageous for pregnant women. Age, pregnancy and disability resulting from chronic conditions are protected characteristics under the 2010 Equality Act.