Several goals have been envisioned: two pertaining to concerns about Cbl deficiency and the other two to neural-tube-defect-related concerns. The most immediate goal is to prevent neurologic progression of unrecognized Cbl deficiency because of exposure to folic acid fortification. The second, broader, goal is to reduce the high frequency of mild Cbl insufficiency that especially often affects the elderly. Third, some have suggested that Cbl may itself contribute to preventing neural tube defects (Thompson et al. 2009
). Finally, fortification may remove the Cbl deficiency-related constraints on further raising folic acid intake and thereby perhaps increase folate’s ability to prevent neural tube defects.
The validities of these goals and expectations require a clear understanding of Cbl physiology and the pathophysiology of Cbl deficiency. The most important of the concepts are outlined in . The chief points are that Cbl bioavailability is limited under normal circumstances and becomes even more limited under abnormal ones. Absorptive capacity plays a critical role: the classic Cbl deficiencies, the ones that feature megaloblastic anemia and/or neurologic dysfunction, are almost invariably caused by significant malabsorption (94% of clinically expressed deficiency in the survey by Savage et al. 1994
), usually reflecting loss of gastric intrinsic factor (pernicious anemia) or interference with its intestinal uptake. Moreover, years must pass before stores become sufficiently depleted because daily losses are so small relative to body stores, and this is usually achieved only when malabsorption is chronic and does not fluctuate (); often, the underlying causes are irreversible.
Important facts of cobalamin (Cbl) physiology and pathophysiology relevant to understanding Cbl deficiency and its health implications
This classic and typically malabsorptive, and hence progressive, deficiency state characterized by megaloblastic anemia and/or neurologic dysfunction is too uncommon a condition to justify population-wide intervention. As a serious medical disease, it requires individualized medical intervention instead, including injections or very large oral doses of Cbl. Such deficiency is rarely preventable or curable by dietary fortification. Not only is classic deficiency such as pernicious anemia the only Cbl deficiency state with proven, consistent health consequences, it is also the only state in which neurologic complications after folic acid therapy have been described (Chanarin 1979
). The only form of Cbl deficiency common enough to warrant fortification and that might respond to small oral doses is the mild asymptomatic deficiency first identified in the 1980s (Carmel and Karnaze 1985
; Carmel et al. 1987
). This subclinical Cbl deficiency state usually involves only biochemical changes. As importantly, it rarely arises from intrinsic-factor-related absorption failure (Carmel et al. 1987
; Karnaze and Carmel 1990
; Carmel 2000
). Instead, subclinical deficiency is usually nonmalabsorptive or, in 30–50% of cases, features mild malabsorption confined to food-bound Cbl (FBCM) (Carmel and Karnaze 1985
; Carmel et al. 1987
; Carmel 1995
). FBCM is a partial (and occasionally reversible by antibiotics) malabsorption resulting from impaired release of Cbl from food and leading to very slowly progressive and perhaps even fluctuating Cbl deficiency (Carmel 1995
If subclinical deficiency, currently defined only by biochemical changes, is the only target suitable for Cbl fortification, the appropriateness of fortification depends on proving the health consequences of subclinical deficiency and their responsiveness to small oral doses of Cbl. There are undoubted reasons to be concerned enough about the issue to justify efforts to obtain definitive answers. The most commonly expressed rationales reflexively assume that, left untreated, asymptomatic deficiency inevitably progresses to clinically expressed deficiency with megaloblastic anemia and neurologic dysfunction, just as early preclinical pernicious anemia with its permanent loss of intrinsic factor always does. However, no basis exists for equating the two. Progression of irreversible, malabsorptive conditions is inevitable, but subclinical Cbl deficiency, the causes of which are unknown in >50% of cases (Carmel 1995
), has an uncertain and often static natural history. Progression of subclinical deficiency to clinical deficiency seems surprisingly infrequent (see Carmel 2000
). Even the mild biochemical changes that define subclinical deficiency remain stable for years, and they reverse spontaneously much more often than they progress (44% vs. 16% of cases), with the rest remaining static over 4 years of study (Hvas et al. 2001
). Subclinical deficiency’s occasional origin in very early pernicious anemia may explain much of whatever modest risks of progression exist (Carmel 2000
). Moreover, when subclinical deficiency caused by FBCM or dietary insufficiency progresses, it is likely to do so very slowly. The natural history of subclinical deficiency and its risk of progression to clinical deficiency remain undefined, but they require definition in order to understand this common condition and to justify Cbl fortification.
The second frequently expressed reason for concern is that hidden health hazards may exist even in the asymptomatic but biochemically deficient state. Indeed, manifestations at or near the threshold of clinical expression, such as mild evoked potential and electroencephalographic abnormalities of unknown clinical relevance but which often reverse with Cbl injections, have been described (Carmel et al. 1987
; Karnaze and Carmel 1990
; van Asselt et al. 2001
). They remain murky, however. To illustrate, a prospective study of 16 patients with dementia found high frequencies of mild neuropathy that often responded to Cbl, along with the electrophysiologic and metabolic abnormalities, whereas the dementia never improved (Carmel et al. 1995
). However, the study was uncontrolled, some patients had mild Cbl-responsive macrocytic anemia as well, absorption status could not be tested in the demented individuals, and Cbl therapy was parenteral and intensive; all this suggested that the deficiency may not have been subclinical, and the likelihood that small oral doses could have produced similar improvement is unknown.
Even murkier are the meanings of statistical associations of Cbl levels with mild cognitive deficits or even loss of brain volume in the elderly. Cognitive associations have been inconsistent (Raman et al. 2007
), confounders are frequent, other explanations and influences have been suggested, and Cbl levels are often only relatively rather than absolutely low as in Cbl deficiency (see, for example, Vogiatzoglou et al. 2008
). Most importantly, nearly all the neurocognitive studies, even when prospective and impressive, have been observational, so the associations may identify markers rather than causes. Proposed nonneurological associations with subclinical deficiency, such as osteoporosis, diabetes in offspring, and tinnitus, are murkier still.
As to the neurocognitive impact of high folic acid intake on Cbl deficiency (Chanarin 1979
; Reynolds 2006
), it is unknown if the risks thus far reported only in patients with pernicious anemia, whose deficiency always progresses relentlessly, extend to subclinical deficiency. The question has been tackled broadly, but thus far inconclusively, by epidemiologic surveys, which do not lend themselves to sufficiently informative clinical, neurologic, and hematologic assessments (Carmel 2009
). Whereas high folate levels appear to be associated with worse metabolic Cbl status in individuals with low Cbl levels than do normal folate levels (Selhub et al. 2007
; Miller et al. 2009
), only one survey (Morris et al. 2007
) found cognitive dysfunction to also be more frequent with high folate status; two others did not (Clarke et al. 2008
; Miller et al. 2009
). All the cross-sectional findings await clarification (Carmel 2009
Despite the legitimacy of the concerns, data have been insufficient to provide a basis for informed decisions about mandatory fortification with Cbl. Information that oral cobalamin actually modifies any of the proposed health risks of subclinical deficiency, not just its mild biochemical abnormalities, is badly needed (). Given the unsettled state of knowledge, the idea that randomized placebo-controlled trials of subclinical deficiency are unethical (Eussen et al. 2005
) must be vigorously resisted. We need only recall the compelling associations of homocysteine with cardiovascular disease that failed to survive examination by clinical trials.
Issues that require clarification before deciding about mandatory cobalamin (Cbl) fortification