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Health services administration Anatomy and physiology General medicine Hematologic diseases Medical practices
Volume 198 - Issue 11

Vitamin B12 and folate tests: the ongoing need to determine appropriate use and public funding

Authors:  Cameron D Willis, Michael P Metz, Janet E Hiller and Adam G Elshaug

Med J Aust 2013; 198 (11): 586-588. || doi: 10.5694/mja12.11328
Published online: 17 June 2013
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It’s not as simple as new for old: we need to follow a process for “disinvestment” in existing medical procedures, services and technologies

Criteria have been developed for assessing the safety, effectiveness and cost-effectiveness of new and emerging health interventions, but additional challenges exist in identifying opportunities for reducing the use of existing health technologies or procedures that are potentially overused, (cost-)ineffective or unsafe.1 Criteria have been proposed to flag technologies that might warrant further investigation under quality improvement programs.1 These criteria are: new evidence becomes available; there is geographical variation in use; variation in care between providers is present; the technology has evolved and differs markedly from the original; there exists a temporal trend in the volume of use; public interest or controversy is present; consultation with health care workers and funders raises concerns; new technology has displaced old technology; there is evidence of leakage (use beyond the restriction or indication); the technology or intervention is a “legacy item” that has never been assessed for cost-effectiveness; use is not in accordance with clinical guidelines; or the technology is nominated by clinical groups.

After such a nomination was made by members of the clinical laboratory community regarding vitamin B12 and folate tests, we sought to determine whether these tests met other criteria. We hope that this article will encourage debate and discussion about the appropriate use of these tests.

Testing for vitamin B12 and folate deficiency

Diagnosing vitamin B12 and folate deficiencies is difficult. The symptoms are diverse (such as malaise, fatigue and neurological symptoms), as are the signs (including megaloblastic anaemia and cognitive impairments). Defining target conditions is, therefore, also difficult. Tests include a full blood count and blood film examination, serum B12, serum folate and red-cell folate (RCF) assays, as well as examination of metabolic markers such as methylmalonic acid (MMA) and homocysteine (Hcy). Untreated vitamin B12 deficiencies may cause serious health problems, including permanent neurological damage (which may occur with low serum B12 levels without haematological changes). Maternal folate deficiencies have been associated with neural tube defects in infants. Potential vitamin B12 or folate deficiencies therefore need to be appropriately investigated and managed.

New evidence

The utility of a diagnostic test is influenced in part by its precision (the ability of a test to faithfully reproduce its own result) and its diagnostic accuracy (ability to discriminate between a patient with a target condition and a healthy patient). Evidence suggests serum B12 tests have poor discriminative ability in many situations, and debate is ongoing over which folate assay is most useful.

The only systematic review and meta-analysis of the diagnostic accuracy of serum B12 tests (conducted by members of our group) suggested that these tests often misclassify individuals as either B12 deficient or B12 replete.2 These findings are consistent with other reports in the literature. One recent report states:

Both false negative and false positive values are common (occurring in up to 50% of tests) with the use of the laboratory-reported lower limit of the normal range as a cutoff point for deficiency.3

And further:

There is often poor agreement when samples are assayed by different laboratories or with the use of different methods.3

Widespread CBLA (competitive-binding luminescence assay) malfunction has also been noted, with assay failure rates of 22% to 35%4 (interference due to intrinsic factor antibodies may explain some of this variation). While a critical overview has suggested that “falsely normal cobalamin concentrations are infrequent in patients with clinically expressed deficiency”, the author notes challenges in diagnosing subclinical deficiency5 (mild metabolic abnormalities without clinical signs or symptoms). Assessment of this evidence base is complicated by the lack of a universally accepted gold standard and by target conditions that are difficult to define, variable clinical presentations and variable cut-off values used to define deficiency.

For investigating folate status, RCF assays are thought to be less susceptible to short-term dietary intake than are assays for serum folate. However, it has been reported that:

The red cell folate assay is more complex to perform than the serum folate assay and requires more steps in sample handling before analysis, and this may be one of the reasons why the precision of the red cell folate assay is less than that of the serum folate assay.6

As discussion continues over which folate test is preferable, new evidence related to the prevalence of folate deficiencies in countries with mandatory food fortification has shifted the focus toward whether there is a need to perform any folate investigations in these jurisdictions. In Australia, mandatory fortification of wheat flour with folic acid was introduced in September 2009.7 Prevalence estimates from a sample of inpatients and outpatients suggested that folate deficiency stood at 0.5% in April 2010, showing an 85% reduction in absolute numbers since April 2009.7 While there is currently no evidence to suggest that the prevalence of megaloblastic anaemia caused by folate deficiency has been reduced, the low frequency of low serum RCF test results in countries where there is mandatory fortification of grain products with folic acid supports the perspective that “there is no longer any justification in ordering folate assays to evaluate the folate status of the patients”.8

Technology development

Over time, multiple technologies for analysing vitamin B12 status have become available, including assays for measuring holotranscobalamin (holoTC, the bioavailable form of vitamin B12), as well as metabolic markers such as MMA and Hcy.3,5 However, like all tests, these are imperfect: holoTC is expensive, not routinely available, itself reliant on poorly defined serum B12 reference ranges, and is yet to be confirmed as a superior test to the serum B12 assay.5 Hcy measurement is subject to artefactual increases due to collection practices, and reference ranges are variable. The availability of MMA tests is restricted to some clinical and research laboratories. As a result, the optimal procedure for measuring vitamin B12 is unclear. As noted above, while a number of approaches exist for assessing folate status, there is currently no consensus on the most appropriate laboratory investigation process.

Temporal, geographical and provider variations

Australian Medicare utilisation data have shown substantial growth in the use of item 66602, which relates to the combined use of serum B12 and folate tests. Between the financial years 2000–01 and 2009–10, use increased from 1082 services per 100 000 population to 7243 services per 100 000 population (21.78% average annual growth rate).9 Over the same period, spending on pathology services overall grew at an average annual rate of 6.3%.

Geographical variation was also present, with the number of services reimbursed for item 66602 ranging from 1962 per 100 000 population in the Northern Territory to 8658 per 100 000 population in the Australian Capital Territory in 2009–10.9 While some of this variation may be due to demographic differences and populations known to have access to fewer health services (eg, Indigenous Australians), the substantial temporal and geographical differences in use raise more questions about appropriate use of these tests, and whether or not they are underused or overused.

Guidelines

Guidelines related to the use of vitamin B12 and folate tests vary widely in their recommendations. While some recommend B12 and folate tests as screening tools in commonly encountered illnesses such as dementia, others suggest restricting testing to patients who have already undergone pretest investigations (such as full blood examinations; however, we note that neurological damage may occur in patients with low serum B12 levels and without haematological changes).10,11 Guidelines may differ on key recommendations, such as the preferred first-line investigation for establishing folate status, while some question the utility of folate investigations at all in jurisdictions where food is fortified with folate.12-14

Leakage

With wide variability in guideline recommendations, and with few appearing to consider the diagnostic accuracy of B12 or folate tests, determining the extent to which services have “leaked” beyond their clinical indications is difficult. Possible leakage is evidenced by the use of serum B12 tests among patients presenting with weakness and tiredness, which is not supported by any available guidelines.15 A large study of general practitioners indicated that between April 2000 – March 2002 and April 2006 – March 2008 their use of serum B12 tests among patients presenting with weakness and tiredness increased by 105%.15

Discussion

Tests for investigating patients’ vitamin B12 and folate status have become widely used in clinical practice. Yet existing evidence suggests that the diagnostic accuracy of serum B12 tests is difficult to determine and may be highly variable. While other tests are available for investigating suspected B12 and folate deficiency (such as holoTC, MMA and Hcy), the diagnostic accuracy of these tests is also contested. Challenges in examining the diagnostic accuracy of serum B12 tests include highly variable clinical presentations, lack of a gold standard and inconsistent cut-off values used to define deficiency. While it remains under debate whether the serum or red-cell folate test is most useful for investigating folate status, mandatory folate fortification in Australia may call into question any use of these tests.

Temporal variation in use and geographical differences in how these tests are employed are both evident in Australian data. Moreover, available clinical guidelines are highly inconsistent in their recommendations. Collectively, the issues of test accuracy, wide variability in test use, and inconsistent guideline recommendations suggest that the use of vitamin B12 and folate tests is an area with much scope for quality improvement.

To improve the use of these tests, further assessment is needed that examines the complexity associated with clinical decision making and the various factors influencing why doctors request these tests. The decision to request an investigation such as a B12 or folate test may be driven by a range of factors, including ease of use, cost, absence of significant patient risk, the perceived need to respond to patient requests, lack of appreciation of the diagnostic accuracy of the tests, or ready availability of results.16 Understanding how these factors influence the use of B12 and folate tests may best be achieved through direct consultation with general practitioners, pathologists, specialists and consumers and is a critical step in advancing the assessment of these tests.

Authors

  • Cameron D Willis PhD1,2
  • Michael P Metz MD3
  • Janet E Hiller MPH, PhD4
  • Adam G Elshaug MPH, PhD1,5,6
  • 1. Discipline of Public Health, School of Population Health, University of Adelaide, Adelaide, SA.
  • 2. School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
  • 3. Clinpath Laboratories, Adelaide, SA.
  • 4. Faculty of Health Sciences, Australian Catholic University, Melbourne, VIC.
  • 5. Department of Health Care Policy, Harvard University, Boston, Mass, USA.
  • 6. Commonwealth Fund, New York, NY, USA.

Correspondence: cameron.willis@adelaide.edu.au

Competing interests

Janet Hiller and Adam Elshaug are Co-Chief Investigators, Michael Metz is an Associate Investigator, and Cameron Willis is a former Senior Research Fellow of the ASTUTE Health study. Adam Elshaug and Janet Hiller contribute to the Australian Government Department of Health and Ageing’s Safety, Quality and Sustainability Forum and the Comprehensive Management Framework for the Medicare Benefits Schedule. Vitamin B12 and folate blood tests have been selected for review within that framework. Janet Hiller is a member of the Protocol Advisory Sub-Committee of the Medical Services Advisory Committee.

Acknowledgements

The Assessing Service and Technology Use To Enhance Health (ASTUTE Health) study, within which vitamin B12 and folate blood tests are a case study, is funded by the National Health and Medical Research Council (NHMRC grant 565327). The findings and views expressed in this article are those of the authors and do not necessarily represent those of the Commonwealth Fund. Cameron Willis and Adam Elshaug hold NHMRC Fellowships (1013165 and 627061, respectively). Cameron Willis was supported by funding from the NHMRC Health Care in the Round Capacity Building Grant (565501). We acknowledge the valuable contributions made by Amber Watt, Dagmara Riitano and Heather Buchan. We also acknowledge the contributions made by the ASTUTE Health study group: Annette Braunack-Mayer, John Moss, Jackie Street, Tracy Merlin and Jonathan Karnon.

References

Provenance: Not commissioned; externally peer reviewed.

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