Guidelines for the diagnosis and treatment of cobalamin and
folate disorders (2014)
Cobalamin deficiency
In patients with classical megaloblastic anaemia, the presence of a low serum cobalamin level and objective assessment of response in terms of the rise in haemoglobin concentration clearly outlines the treatment pathway. However, the majority of patients do not have such a clear-cut picture. Neurological presentation (peripheral neuropathy, sub-acute combined degeneration of the cord) may occur in the absence of haema- tological changes, and early treatment is essential to avoid permanent neurological disability. Low cobalamin levels of uncertain significance may occur with non-specific symptoms and no anaemia. Furthermore, patients with strong clinical features of cobalamin deficiency may have serum cobalamin levels that lie within the reference range (false normal cobala- min level). As a result, other tests may be used to try and determine an underlying functional or biochemical deficiency (reviewed in Quadros, 2010; Fedosov, 2012). These tests, plasma homocysteine, plasma MMA and serum holotransco- balamin, may help but are not widely available currently and the cut-off points to indicate deficiency vary between different laboratories (Carmel, 2011; Heil et al, 2012). In addition, their role is not clearly defined in the routine diagnostic setting. Therefore, there is currently no 'gold standard’ test for the diagnosis of cobalamin deficiency (Solomon, 2005; Herrmann & Obeid, 2012).
Given that the biochemical pathways of cobalamin and folate are closely intertwined, with patients showing similar clinical features for both deficiencies, assessment of cobalamin and folate status is usually performed concurrently. In the presence of true cobalamin deficiency, the serum folate is often normal or can be elevated. However, a low serum cobalamin level may be found in the presence of folate deficiency.
Summary of key recommendations
1 The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no 'gold standard’ test to define deficiency.
2 Serum cobalamin currently remains the first-line test, with additional second-line plasma methylmalonic acid to help clarify uncertainties of underlying biochemical/functional deficiencies. Serum holotranscobalamin has the potential as a first-line test, but an indeterminate 'grey area’ may still
exist. Plasma homocysteine may be helpful as a second-line test, but is less specific than methylmalonic acid. The availability of these second-line tests is currently limited.
3 Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established.
4 In the presence of discordance between the test result and strong clinical features of deficiency, treatment should not be delayed to avoid neurological impairment.
5 Treatment of cobalamin deficiency is recommended in line with the British National Formulary. Oral therapy may be suitable and acceptable provided appropriate doses are taken and compliance is not an issue.
6 Serum folate offers equivalent diagnostic capability to red cell folate and is the first-line test of choice to assess folate status.
Investigations Recommendations
1 A blood film showing oval macrocytes and hyperseg- mented neutrophils in the presence of an elevated MCV may alert the clinician to the presence of underlying cobalamin or folate deficiency (Grade 2B).
2 Cobalamin and folate assays should be assessed concur- rently due to the close relationship in metabolism (Grade 1A).
3 The writing group recommends adoption of reporting for cobalamin assay results in pmol/l (Grade 2C).
4 A serum cobalamin cut-off level of either 148 pmol/l (200 ng/l) or one derived from a local reference range should be used as evidence of cobalamin deficiency in the presence of a strong clinical suspicion (Grade 2B).
5 The report providing the result of a serum cobalamin assay should include the following:
a The interpretation of the result should be consid- ered in relation to the clinical circumstances.
b Falsely low serum cobalamin levels may be seen in the presence of folate deficiency or technical issues.
c Neurological symptoms due to cobalamin deficiency may occur in the presence of a normal MCV (Grade 1B).
6 Plasma tHcy and/or plasma MMA, depending on avail- ability, may be considered as supplementary tests to determine biochemical cobalamin deficiency in the presence of clinical suspicion of deficiency but an inde- terminate serum cobalamin level (Grade 2B).
a Although plasma tHcy is a sensitive marker of cobal- amin deficiency, plasma MMA is more specific.
b Both assays have to be interpreted in relation to renal function.
7 HoloTC is suggested as a suitable assay for assessment of cobalamin status in a routine diagnostic laboratory in the future (Grade 1B).
