Metabolic cobalamin deficiency in patients with low to low-normal plasma cobalamins

Moelby, L.; Nielsen, Gert; Rasmussen, Karsten; Jensen, Mogens Krogh; Pedersen, Katja Venborg

doi:10.3109/00365519709060029

Cited by 11 publications

(10 citation statements)

References 23 publications

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“…9 Their accidental coexistence with a suspected clinical finding can sometimes be misconstrued. 12 The initial task is to document the clinical and laboratory findings and prove their connection to cobalamin deficiency. Metabolic tests, such as serum methylmalonic acid (MMA) or plasma homocysteine, can be useful when the clinical picture is equivocal but are sometimes unreliable themselves.…”

Section: Pathophysiologically Based Management Of the Cobalamin-deficmentioning

confidence: 99%

How I treat cobalamin (vitamin B12) deficiency

Carmel

2008

Blood

286

233

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The challenges in medical management of cobalamin deficiency lie in attention to the unique pathophysiology that underlies cobalamin deficiency, more than in the mechanics of therapy. The central physiologic principles are that clinically important deficiency is more likely to occur (and progress) when intrinsic factor-driven absorption fails than when diet is poor and that most causes take years to produce clinically obvious deficiency. Transient defects have little clinical impact. The key management principle is the importance of follow-up, which also requires knowing how the deficiency arose. The virtues of these principles are not always fully appreciated. Recent developments have made diagnosis and management more difficult by diminishing the ability to determine cobalamin absorption status. Clinicians must also grapple with premature medicalization of isolated, mild biochemical changes that added many asymptomatic cases of still undetermined medical relevance to their caseload, often expanded by inflated cobalamin level criteria. The potential for misattribution of cobalamin-unrelated presentations to nongermane cobalamin and metabolite abnormalities has grown. Pathophysiologically based management requires systematic attention to each of its individual components: correctly diagnosing cobalamin deficiency, reversing it, defining its underlying cause, preventing relapse, managing the underlying disorder and its complications, and educating the patient. (Blood. 2008;112: 2214-2221)

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Section: Pathophysiologically Based Management Of the Cobalamin-deficmentioning

confidence: 99%

How I treat cobalamin (vitamin B12) deficiency

Carmel

2008

Blood

286

233

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“…Only one-half or fewer of low cobalamin concentrations are explained by malabsorption of either free or food-bound cobalamin, and dietary insufficiency is uncommon even among the elderly (2)(3)(4)(5)(6). Moreover, metabolic studies indicate that 15-40% of patients with low serum cobalamin do not have cobalamin deficiency (1,2,(7)(8)(9)(10), which suggests that as many as 15-40% of cobalamin values below the reference interval may be diagnostically misleading. This diagnostic dilemma is not resolved by changing reference intervals for cobalamin because low concentrations that represent true metabolic deficiency and malabsorption are not always lower than low concentrations that do not.…”

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confidence: 99%

Mild Transcobalamin I (Haptocorrin) Deficiency and Low Serum Cobalamin Concentrations

Carmel

2003

Clinical Chemistry

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Background: Low cobalamin concentrations are common, but their causes are often unknown. Transcobalamin I/haptocorrin (TC I/HC) deficiency, viewed as a rare cause, has not been examined systematically in patients with unexplained low serum cobalamin. Methods: Total TC I/HC was measured by RIA in three subgroups of 367, 160, and 38 patients with different categories of low cobalamin concentrations and three comparison subgroups of 112, 281, and 119 individuals with cobalamin concentrations within the reference interval. Additional studies, including family studies, were done in selected patients found to have low TC I/HC concentrations. Results: Low TC I/HC concentrations suggestive of mild TC I/HC deficiency occurred in 54 of 367 (15%) patients with low cobalamin identified by clinical laboratories and 24 of 160 (15%) patients whose low cobalamin was unexplained after absorption and metabolic evaluation, but in only 2 of 38 patients with malabsorptive causes of low cobalamin concentrations (5%). The prevalence was only 3% (8 of 281 plasma samples) to 5% (6 of 112 sera) in patients with cobalamin concentrations within the reference interval and 3% (4 of 119) in healthy volunteers. Three patients with low cobalamin (0.6%) had severe TC I/HC deficiency with undetectable TC I/HC. Presumptive heterozygotes for severe TC I/HC deficiency in two families had the findings of mild TC I/HC deficiency; mild deficiency was also found in at least three of seven studied families of patients with mild TC I/HC deficiency. Conclusions: Mild TC I/HC deficiency is frequently associated with low cobalamin, is often familial, and its biochemical phenotype appears identical to the heterozygous state of severe TC I/HC deficiency. Severe TC I/HC deficiency also appears to be more common

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“…Concerning MMA, fairly extensive conclusions were drawn on the background of these non-controlled studies. The major problem occurred when several authors suggested that vitamin B-12 deficiency could be defined as an increased level of MMA that decreased after administration of vitamin B-12 [5,20,27,28]. This definition was based on the analysis under evaluation, and the usefulness of MMA had become a self-fulfilling prophecy.…”

Section: Discussionmentioning

confidence: 98%

Health technology assessment in clinical biochemistry. Methylmalonic acid: a Danish showcase

Hvas¹,

Ellegaard²,

Lous

et al. 2003

Scandinavian Journal of Clinical and Laboratory Investigation

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In 1992 plasma methylmalonic acid (MMA) was introduced in Denmark for diagnosing vitamin B-12 deficiency. Now, 10 years later, we report on a health technology assessment (HTA) suggesting that the clinical usefulness of MMA is uncertain. MMA is an obvious component for measurement in the diagnosis of vitamin B-12 deficiency because MMA accumulates when there is a lack of vitamin B-12, and technologically the analysis is of high quality. The diagnostic sensitivity of MMA is high, whereas the diagnostic specificity is debatable, and our results suggest it to be relatively low. The organizational aspect implies that both MMA and P-cobalamins have been increasingly employed, though no consensus on the use of the analyses has emerged. The benefit to the patient is not obvious. An increased level of MMA does not predict further increases over time, and vitamin B-12 treatment shows limited clinical benefit in individuals with a moderately increased MMA. The economic consequences of introducing MMA were an increase in the costs of MMA and P-cobalamins of 12% per year during 1992-2000 and an increase in the turnover of vitamin B-12 preparations of 9% per year. In conclusion, MMA was introduced on sound grounds for both pathophysiological considerations and analytical quality. Our HTA shows that the resources employed to diagnose and to treat vitamin B-12 deficiency have increased considerably, but yet we have no evidence to suggest the clinical benefit.

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Metabolic cobalamin deficiency in patients with low to low-normal plasma cobalamins

Cited by 11 publications

References 23 publications

How I treat cobalamin (vitamin B12) deficiency

How I treat cobalamin (vitamin B12) deficiency

Mild Transcobalamin I (Haptocorrin) Deficiency and Low Serum Cobalamin Concentrations

Health technology assessment in clinical biochemistry. Methylmalonic acid: a Danish showcase

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