Diagnosis of Cobalamin Deficiency

Cobalamin deficiency is suspected in individuals who display the typical manifestations of deficiency of the vitamin as described in the section above on the effects of deficiency. In addition to the symptoms that may be experienced by individuals that are related to anemia (easy fatigue, shortness of breath, palpitations) and neuropathy (sensory and motor disturbances and memory loss) there are features that may be detected by a physician, including skin pallor (from anemia), abnormalities in neurological examination (sensory loss, abnormal balance and reflexes, mental changes), and epithelial changes (skin pigmentation, smooth tongue). On the basis of any combination of such changes, cobalamin deficiency may be suspected but confirmation is necessary using laboratory tests because other conditions may give rise to effects that closely resemble cobalamin deficiency. This need to confim suspected cobalamin deficiency applies also in individuals who have abnormalities in their blood count results with anemia and macrocytosis (larger than normal red blood cells).

The standard screening test for cobalamin deficiency consists of direct measurement of circulating levels of cobalamin. Serum levels less than 150pmoll~1 are considered deficient and 150-250 pmol l_1 are considered borderline. Serum or plasma cobalamin concentration can be measured in several ways and this has evolved from early microbial growth assays through competitive binding assays that were first radioisotopic and are now enzyme-linked or based on chemiluminescence detection. The sensitivity and specificity of these assays is imperfect, such that measurement of serum cobalamin levels does not always detect the presence of deficiency, nor does the finding of a low serum cobalamin always connote true deficiency. There are several reasons for this including the distribution of cobalamin between the binding proteins in circulation (Table 1), imperfections in the assays for its measurement, and various poorly understood factors relating to exchange of cobala-min between cellular and circulatory compartments. Regarding the distribution of cobalamin between plasma-binding proteins, since transcobalamin is responsible for cobalamin delivery to cells, the fraction of the total cobalamin that is associated with transcobalamin (holoTC), even though small in comparison with the haptocorrin-associated fraction, is more likely to be indicative of cobalamin status than is the total serum cobalamin. Some studies bear this out, although technical difficulties with measuring holoTC levels have only recently been overcome.

The other approach to identification of cobalamin deficiency is indirect, based on the detection of raised levels of compounds in the blood or urine that require adequate tissue levels of cobalamin for

Table 3 Laboratory identification of cobalamin deficiency their metabolic disposal. The compounds most commonly measured for identification of possible coba-lamin deficiency are methylmalonic acid and homocysteine. These are the substrates in two coba-lamin-dependent reactions shown in Figure 2. Since the identification of these metabolic roles for coba-lamin, it has been apparent that deficiency of coba-lamin or disturbances in its metabolism would result in accumulation of these substances and a variety of assays for these metabolites is now available. Of the two compounds, elevation of the levels of methyla-malonic acid is the more specific for identification of cobalamin deficiency; however, renal insufficiency can cause raised levels of methylmalonate in the blood. In addition to cobalamin deficiency, several other conditions also can cause raised homocysteine levels in the blood, including deficiencies of folate and of vitamin B6, lack of thyroid hormone, and renal insufficiency (see 00151).

Table 3 shows the idealized usefulness of the various tests commonly available for detection of cobalamin deficiency.

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