Why Vitamin B12 Deficiency Should be on your Radar Screen

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<strong>Vitamin</strong> <strong>B12</strong> <strong>Deficiency</strong> The vitamin <strong>B12</strong> literature contains many articles on the relative merits and limitations of the various laboratory testing options. Some tests are used more commonly for the initial assessment, while others, <strong>be</strong>cause of their cost, inconvenience, or difficulty of interpretation, are reserved for confirmatory testing in ambivalent situations or are used only in the research setting. Initial Assessment After conducting a thorough history and physical examination, if you suspect vitamin <strong>B12</strong> deficiency, you should include a complete blood count (CBC), peripheral blood smear, and serum cobalamin (<strong>B12</strong>) as part of the initial laboratory assessment.(58) The serum cobalamin test is readily available and generally affordable, and can detect low serum vitamin <strong>B12</strong> levels even among patients who are not anemic.(59, 60) However, not all patients with a vitamin <strong>B12</strong> deficiency will have hematologic manifestations. As Carmel succinctly noted, “the proscription that cobalamin deficiency should not <strong>be</strong> diagnosed unless megaloblastic changes are found is akin to requiring jaundice to diagnose liver disease.”(11) While serum vitamin <strong>B12</strong> concentrations are generally accurate,(61) many conditions can complicate the interpretation of vitamin <strong>B12</strong> laboratory values. Falsely low values have <strong>be</strong>en associated with multiple myeloma, oral contraceptives,(62-64) folate deficiency,(58, 59) and pregnancy.(10) Additionally, a low serum <strong>B12</strong> level does not automatically mean a deficiency. From 20%– 40% of elderly people with low serum <strong>B12</strong> levels have normal metabolite (homocysteine [Hcy] and methylmalonic acid [MMA]) levels and should not <strong>be</strong> considered as having a B deficiency.(11) 12 Sometimes, a true cobalamin deficiency will not <strong>be</strong> detected by the serum vitamin <strong>B12</strong> test. Some examples of falsely normal serum cobalamin results might <strong>be</strong> seen with (but not limited to) liver disease,(58) myeloproliferative disorders,(58) and renal insufficiency.(4, 65) If a patient has clinical e vidence of a vitamin <strong>B12</strong> deficiency and a normal serum <strong>B12</strong> level, it is important to evaluate further. 29 The complete blood count, smear, and serum cobalamin (<strong>B12</strong>) test should <strong>be</strong> included in the initial laboratory assessment of vitamin <strong>B12</strong> Oral contraceptive users generally have lower serum vitamin <strong>B12</strong> levels than nonusers; however, the evidence of tissue depletion, as detected by high values of methylmalonic acid and homocysteine, is lacking. “Accepted lower limits of serum <strong>B12</strong> levels in adults range <strong>be</strong>tween 170 and 250 pg/ml; however, higher levels (but less than 350 pg/ml) have <strong>be</strong>en recorded in 15% of ostensibly healthy elderly patients with other findings suggestive of a deficiency state, most notably increased levels of serum methylmalonic acid. The true lower limits of normal serum <strong>B12</strong> would therefore appear to <strong>be</strong> somewhat poorly defined.” Ward, 2002
<strong>Vitamin</strong> <strong>B12</strong> <strong>Deficiency</strong> Opinions differ as to the optimal laboratory cutpoint for the serum vitamin <strong>B12</strong> test, due in part to the insidious onset and slow progression of the disorder and limitations of current assays. Research studies and clinical laboratories have tended to dichotomize low values at 200 picograms per milliliter(pg/mL).(18, 66, 67) Stabler and Allen noted the following ranges of serum cobalamin levels among patients with a clinically confirmed <strong>B12</strong> deficiency (defined as those who “have objective clinical responses to appropriate therapy”): less than 100 pg/mL, approximately 50%; 100–200 pg/mL, approximately 40%; 200–350 pg/mL, approximately 10%; and more than 350 pg/mL, approximately 0.1% to 1%.(7) Adequate follow-up for suspect normal or low-normal results is needed through either additional confirmatory testing or a prolonged therapeutic trial followed by metabolic and clinical reassessment. Confirmatory Testing When the serum vitamin <strong>B12</strong> results are suspect, it is helpful to obtain more information.(1) Several tests can <strong>be</strong> used to rule out a vitamin <strong>B12</strong> deficiency either among patients with borderline serum cobalamin levels or among symptomatic patients with normal serum cobalamin levels. Homocysteine (Hcy) and Methylmalonic Acid (MMA) By far, the most common, accurate, and widely used confirmatory tests for identifying vitamin <strong>B12</strong> deficiency are tests for Hcy and MMA.(1) Because cobalamin is necessary for the synthesis of methionine from Hcy, low levels of vitamin <strong>B12</strong> lead to increases in total serum Hcy. The total serum Hcy test is a sensitive indicator for a vitamin <strong>B12</strong> deficiency; however, its utility is limited as a sole confirmatory test <strong>be</strong>cause elevated Hcy levels among patients also can <strong>be</strong> caused by familial hyperhomocysteinemia, levodopa therapy,(68) renal insufficiency, and folate deficiency.(1, 7, 69, 70) The serum MMA test is more specific for vitamin <strong>B12</strong> deficiency than the Hcy test.(1, 2, 7, 69, 70) MMA levels also increase in the presence of low vitamin <strong>B12</strong> levels 30
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Why Vitamin B12 Deficiency Should be on your Radar Screen

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