Low Cobalamin Research Articles

Clinical significance of low cobalamin levels in older hospital patients

Background: It is still a commonly held belief that many of the frequently found low cobalamin (Cbl, vitamin B12) levels in older people do not represent deficiency and are therefore without clinical significance and should not be treated. In this study this notion will be challenged.Methods: In this prospective observational cohort design we studied 28 patients aged 65 years and older with low plasma Cbl (≤150 pmol/l). A number of haematological (Hb, MCV, five- and six-lobed granulocytes), metabolic (plasma levels of methylmalonic acid and homocysteine), and gastrointestinal (plasma pepsinogen A and C and protein-bound and free Cbl absorption) parameters, and the response to Cbl treatment, were measured. Cbl deficiency was considered to be present when at least one of the following three criteria was fulfilled: (1) haematological or metabolic abnormalities compatible with Cbl deficiency; (2) Cbl malabsorption or atrophic gastritis; (3) a response to Cbl supplementation.Results: Haematological or metabolic abnormalities were identified in 27 patients. Atrophic gastritis and Cbl malabsorption were identified in, respectively, 15 and 23 patients. Each treated patient showed a haematological or metabolic response to Cbl supplementation. All patients were considered Cbl deficient: 18 patients (64%) fulfilled three criteria of Cbl deficiency, eight (29%) fulfilled two criteria and two (7%) fulfilled one criterion.Conclusions: According to the generally accepted and a wide variety of criteria, we found that older patients with low Cbl levels were cobalamin deficient. Therefore, these patients should receive Cbl supplementation.

Current concepts in cobalamin deficiency.

The application of sensitive metabolic tests, such as the deoxyuridine suppression test and measurement of homocysteine and methylmalonic acid, to cobalamin status has identified the entity of mild, preclinical cobalamin deficiency. This state, common in the elderly, responds to cobalamin therapy. Preclinical deficiency may exist within the nervous system as well, although this requires further study. Nevertheless, it is well to remember that not all low cobalamin levels and not all abnormal metabolite results reflect cobalamin deficiency. Interpretation of metabolic results still requires caution, as do proposals to raise the cut-off point for low cobalamin levels to capture some normal levels that are associated with metabolic abnormality. The recognition of mild, preclinical deficiency has opened up many important issues. These include identifying its causes, what should be done about it, and what the clinical impact of the hyperhomocysteinemia itself is. Although malabsorptive disorders, especially food-cobalamin malabsorption, underlie about half of all cases of preclinical deficiency, no cause can be found in the remainder of these cases; poor dietary intake appears to be uncommon. In addition, unusual states of neurologically symptomatic cobalamin deficiency are being recognized, such as nitrous oxide exposure in patients with unrecognized deficiency and severe deficiency in children of mildly deficient mothers. All of these have broadened and complicated the picture of cobalamin deficiency while providing greater opportunities for prevention.

Serum cobalamin, homocysteine, and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities

Low cobalamin concentrations and mild hyperhomocysteinemia are common in the elderly but ethnic differences have not been defined. Our objective was to determine the demographic characteristics of cobalamin deficiency in the elderly and its role in their hyperhomocysteinemia. We measured serum cobalamin, total homocysteine (Hcys), and methylmalonic acid (MMA) concentrations in 725 subjects >60 y old, and folate concentrations in 520 subjects. After exclusion of subjects taking cobalamin supplements or with renal insufficiency, high prevalences of low cobalamin (11.8%), high MMA (16.6%), and high Hcys (26.1%) concentrations were seen. Most cobalamin concentrations <140 pmol/L appeared to reflect deficiency because 78. 3% of them were accompanied by abnormal metabolites. Subjects with cobalamin concentrations of 140-258 pmol/L had significantly fewer metabolic abnormalities. A low cobalamin concentration and renal insufficiency were the strongest predictors of abnormal Hcys concentrations. Elderly men had higher Hcys concentrations than did women (P = 0.0001). Whites and Latin Americans had lower cobalamin concentrations than did blacks and Asian Americans (P < 0.005). Whites also had higher Hcys concentrations than all the other groups (P < 0.05). When included in the analysis, renal insufficiency in subjects was associated with 23.8% of all high Hcys and 25.5% of all high MMA concentrations; most with renal insufficiency were Asian American and black men. Mild cobalamin deficiency is most common in elderly white men and least common in black and Asian American women. Hyperhomocysteinemia, which is most strongly associated with low cobalamin concentrations, is also most common in elderly whites, whereas that associated with renal insufficiency is more common in blacks and Asian Americans. Ethnic differences in cobalamin deficiency and the Hcys patterns associated with it or with renal insufficiency warrant consideration in supplementation strategies. Extending suspicion of deficiency to persons with cobalamin concentrations of 140-258 pmol/L appears to provide more disadvantages than advantages.

A Common Variant in Methionine Synthase Reductase Combined with Low Cobalamin (Vitamin B12) Increases Risk for Spina Bifida

Impairment of folate and cobalamin (vitamin B12) metabolism has been observed in families with neural tube defects (NTDs). Genetic variants of enzymes in the homocysteine remethylation pathway might act as predisposing factors contributing to NTD risk. The first polymorphism linked to increased NTD risk was the 677C→T mutation in methylenetetrahydrofolate reductase (MTHFR). We now report a polymorphism in methionine synthase reductase (MTRR), the enzyme that activates cobalamin-dependent methionine synthase. This polymorphorism, 66A→G (I22M), has an allele frequency of 0.51 and increases NTD risk when cobalamin status is low or when the MTHFR mutant genotype is present. Genotypes and cobalamin status were assessed in 56 patients with spina bifida, 58 mothers of patients, 97 control children, and 89 mothers of controls. Cases and case mothers were almost twice as likely to possess the homozygous mutant genotype when compared to controls, but this difference was not statistically significant. However, when combined with low levels of cobalamin, the risk for mothers increased nearly five times (odds ratio (OR) = 4.8, 95% CI 1.5–15.8); the OR for children with this combination was 2.5 (95% CI 0.63–9.7). In the presence of combined MTHFR and MTRR homozygous mutant genotypes, children and mothers had a fourfold and threefold increase in risk, respectively (OR = 4.1, 95% CI 1.0–16.4; and OR = 2.9, 95% CI 0.58–14.8). This study provides the first genetic link between vitamin B12 deficiency and NTDs and supports the multifactorial origins of these common birth defects. Investigation of this polymorphism in other disorders associated with altered homocysteine metabolism, such as vascular disease, is clearly warranted.

Supplementation with vitamin B 12 decreases homocysteine and methylmalonic acid but also serum folate in patients with end-stage renal disease

Hyperhomocysteinemia is frequently found in patients with end-stage renal disease (ESRD). Plasma total homocysteine (tHcy) concentrations may be reduced by supplementation with folic acid or combinations of folic acid, vitamin B 12, and vitamin B 6. Supplementation studies with vitamin B 12 alone in patients with ESRD have not yet been published. In this study, we investigated the effects of intravenous injection of cyanocobalamin (1 mg/wk for 4 weeks) in ESRD patients (N = 14) with low serum cobalamin concentrations (< 180 pmol/L). All patients had elevated levels of plasma tHcy, methylmalonic acid (MMA), and cystathionine before supplementation. After supplementation, plasma tHcy and MMA decreased 35% and 48%, respectively; however, cystathionine levels were unchanged. The extent of the plasma tHcy reduction tended to be influenced by the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR). Serum cobalamin increased significantly upon supplementation, whereas serum folate levels were substantially reduced by 47%. In contrast, red blood cell (RBC) folate was unchanged. This study shows that vitamin B 12 supplementation effectively decreases both MMA and plasma tHcy in ESRD patients with low B 12 levels. Furthermore, it illustrates the close interrelation between vitamin B 12 and folate metabolism.

Vitamin status of elderly people in Germany.

In the last decade several attempts (Nationale Verzehrsstudie, NVS; Verbundstudie Ernährungserhebung und Risikofaktoren-Analytik, VERA: Bethanien-Ernährungsstudie, BEST) have been made to assess the nutritional status of the elderly in Germany. A careful evaluation of those data describing the vitamin status clearly indicate that healthy older people are not at higher risk for vitamin deficiency compared to younger adults. The results of the NVS showed that, except for folic acid, mean intake of all vitamins exceeded 80% of the current recommendations. Only 5% of blood vitamin concentrations analyzed in a subpopulation (VERA-Study) were founded to be below the physiological range. Only the incidence of low cobalamin values increased with age, presumably due to gastrointestinal problems (atrophic gastritis). In contrast, geriatric patients showed markedly lower vitamin blood concentrations compared to healthy subjects of the same age (BEST-Study). This might be explained by physical and mental deterioration, handicaps, chronic diseases and multiple chronic drug use. Underrepresentation of very old people, lack of reliable reference values for biomarkers and uncertainties in data collection may have contributed to misinterpretations. Representative studies are needed to objectively assess the nutritional status of the elderly population in Germany.

Case of the season

A THIRTY-FIVE-YEAR-OLD woman presented with a 3-month history of progressive dysesthesia of her feet, unsteadiness in the gait, and generalized weakness. There was no history of any surgery or drug intake. On examination, there was moderate pallor. Fine touch, position, and vibration sense were impaired below the anterior superior iliac spines. Romberg's sign was positive. There was mildly reduced motor power (4/5) in both lower limbs. Deep tendon reflexes of lower limbs were exaggerated. Plantars were equivocal. Laboratory tests revealed macrocytic anemia with hemoglobin of 8.6 g/dL, elevated mean corpuscular volume (117 fl), hypersegmented neutrophils, low serum cobalamin (<100 pg/mL), and elevated serum folate levels (22 ng/mL). Magnetic resonance imaging (MRI) of the spine was performed. Figure 1 is a sagittal T2-weighted fast spin-echo (FSE) image showing an abnormal increased signal intensity of the dorsal and lower cervical spinal cord. Figure 2 is an axial T2weighted FSE image at the upper dorsal region showing that the signal abnormality is located in the posterior columns of the spinal cord. Barium meal gastrointestinal series was normal.

Cerebrospinal fluid methylmalonic acid concentrations in neurological patients with low and normal serum cobalamin concentrations

To determine whether cerebrospinal fluid (CSF) methylmalonic acid (MMA) is increased in neurological patients with low serum cobalamin (Cbl, vitamin B12) concentrations as opposed to neurological patients with normal serum Cbl concentrations. We measured MMA concentrations in serum and CSF of neurological patients with low serum cobalamin concentrations, but without overt cobalamin related manifestations such as anemia or combined disease of the cord, and neurological patients with normal serum cobalamin concentrations (controls). Serum and CSF MMA concentrations were significantly higher in patients than in controls. Serum MMA was elevated in 4 patients of whom 3 had clearly elevated CSF MMA concentrations. Strong indications for cobalamin deficiency can be found not only in serum but also in CSF of patients with seemingly asymptomatic low serum cobalamin concentrations.

Hyperhomocysteinemia in terms of steady-state kinetics.

The plasma level of homocysteine (Hcy) and its oxidized products, i.e., plasma total Hcy (tHcy), is a function of the influx rate of Hcy to plasma and the plasma tHcy clearance. In vitro experiments show that proliferating cells usually export more Hcy than stationary cells and that the Hcy export increases in response to high methionine, low folate or low cobalamin level, and to agents interfering with Hcy remethylation. Comparison between various cell types suggests that hepatocytes have a unique ability to increase the Hcy export in response to extracellular methionine, probably due to its capacity to form adenosylmethionine. Some but not all cell types have an ability to use extracellular Hcy as a methionine source. Clearance studies in healthy subjects indicate that about 1.2 mmol Hcy is supplied from the cells to plasma per 24 h, which is only about 5-10% of total Hcy formed. Comparison of area under the curves after administration of Hcy and methionine shows that about 10% of the methionine administered is released to plasma as Hcy. Notably, only a few percent of Hcy from plasma is excreted unchanged in the urine, and this shows that most tHcy in plasma is metabolized. Folate or cobalamin deficient patients have normal plasma tHcy clearance, which suggests that their elevated tHcy level is due to increased Hcy export from tissues into the plasma compartment. In contrast, the hyperhomocysteinemia in renal failure is accounted for by a marked reduction in tHcy clearance, suggesting an important role of kidney in elimination of Hcy from plasma.

Reply from the Authors

Reply from the Authors: We thank Dr. Gilbert for his interest in our patient. [1] We agree that serum levels of methylmalonic acid and homocysteine would have been informative. These levels are useful markers for deficiency states in patients with low normal cobalamin levels. [3] We are unsure if these levels correlate highly with the extent of metabolic tissue injury, as suggested by …

Plasma methylmalonic acid in relation to serum cobalamin and plasma homocysteine in a psychogeriatric population and the effect of cobalamin treatment.

Cobalamin deficiency seems to be a relatively common condition in psychogeriatric patients. To elucidate the diagnostic possibility of cobalamin deficiency we have in this study analysed three markers for cobalamin deficiency, plasma methylmalonic acid, plasma homocysteine and serum cobalamin, in 96 psychogeriatric patients. Patients were divided into four groups according to serum cobalamins above or below 150 pmol/l and normal (< 19.9 mumol/l) or increased plasma homocysteine. The upper reference limit (95th percentile) for plasma methylmalonic acid in 100 healthy subjects was established to 0.42 mumol/l. The mean value of methylmalonic acid was increased only in the group of patients with serum cobalamin below 150 pmol/l and increased plasma homocysteine compared to the other groups. In this group six (46%) out of 13 patients exhibited increased plasma methylmalonic acid, whereas in the other groups the frequency of increased plasma methylmalonic acid only varied from 10 to 13%. During cobalamin supplementation the most pronounced decrease of plasma methylmalonic acid also occurred in the group of patients with low serum cobalamin levels and increased plasma homocysteine. Only 39% of the initial mean value for plasma methylmalonic acid was noted after 7-10 days of cobalamin administration.

A Review of 20 Years of Jejunoileal Bypass

Background: The long-term effects of jejunoileostomy for morbid obesity were studied 15–20 years after surgery, in 60 patients. Methods: A total of 141 patients underwent surgery during the years 1973 to 1979. Thirty-four (24%) had had bowel continuity reestablished because of side effects. Eight (5.6%) were dead, 4 (2.8%) had emigrated, and 11 (7.8%) lived in remote areas, leaving 84 patients for follow-up. Sixty of these patients agreed to participate in the study. Seventy-seven per cent of the study population were women, with a mean age of 50 years. Results: The average weight loss was 50.2 kg; only one patient had regained the preoperative weight. The average weight was 84.2 kg. Reported side effects were 1) gastrointestinal: diarrhoea (61.7%), bad defecation smells (60%), and meteorism (11.7%), and 2) systemic: arthralgia (18.3%) and symptomatic nephro/cholelithiasis (18.3%). Forty-two patients (70% of the participants) found the results acceptable/satisfactory. Nine patients (15%) had vitamin B12 injections regularly; another 22 (35%) were found to have a low cobalamin level, and 35 patients (58%) had reduced P-magnesium. The 25-hydroxycholecalciferol level was low in 26 patients (43%), and parathyroid hormone values were increased in 18 (30%). Fifty-seven patients (95%) had a P-carotene value lower than the normal limit. Conclusion: These results stress the need for continuous control and supplementary therapy.

Hormone replacement therapy and cobalamin status in elderly women

Serum cobalamin concentrations are frequently low in the elderly but the cause is often not apparent. Because oral contraceptives have been associated with low cobalamin concentrations in young women, we compared hormone use with cobalamin status in elderly women to determine whether it could account for their unexplained low cobalamin concentrations. Thirty-eight of the 111 women had abnormal cobalamin status (defined by low cobalamin, elevated methylmalonic acid, and/or elevated homocysteine concentrations) and 73 had normal status. There was no difference in hormone use between the two groups: 7 (18.4%) of the 38 cobalamin-deficient subjects used estrogens compared with 20 (27.4%) of the 73 control subjects. No differences in hormone use were apparent either when analysis was confined to abnormal serum cobalamin concentrations alone. Similarly, the 27 women taking hormones and the 84 women not taking hormones did not have significantly different serum cobalamin or serum total homocysteine concentrations. Indeed, hormone users had slightly, though not significantly, higher cobalamin concentrations and lower homocysteine concentrations than nonusers; furthermore, hormone users also had significantly lower serum methylmalonic acid concentrations. Thus, neither cobalamin concentrations nor cobalamin metabolic status were significantly worse in elderly women taking estrogen than in those not taking it (and, if anything, may have been slightly better). Hormone use does not appear to be a significant contributor to the low cobalamin concentrations or the mild metabolic evidence of cobalamin deficiency so often seen in the elderly.

Cobalaminopenia in a postindustrial society: minimal incidence, age distribution, and differences by sex

The aim of this study was to obtain a conservative estimate of the current incidence of low serum cobalamin levels (cobalaminopenia) in a modern, postindustrial region in Sweden. All serum cobalamin determinations made during 1993 in one health care area (Umeå) with 131,393 inhabitants were analyzed. These analyses were all performed in a single laboratory; data were available for 6451 serum samples from 5225 patients. Serum cobalamin levels <145 pmol/L (corresponding to the lowest decile determined in previous years) were identified in 582 samples from 473 patients. Data from these samples were further investigated to determine distributions of cobalaminopenia based on age and sex. The overall minimal incidence of low serum cobalamin levels (<145 pmol/L) was 0.36%; the incidence increased with age. Low serum cobalamin levels occurred significantly more frequently in women aged 15 to 44 years than in men in the same age group. In contrast, men older than 70 years of age were more prone to cobalaminopenia than women of the same age. The current minimal incidence of low serum cobalamin values suggests adequate functioning of social and health care networks, with an overall minimal incidence of cobalaminopenia of 0.36% and a projected incidence of cobalaminopenia in the Umeå health care area of approximately 1%.

Spouses of demented patients with low cobalamin levels: a new risk group for cobalamin deficiency.

Low serum cobalamin levels are common in conditions such as dementia and often represent mild deficiency. We surveyed serum cobalamin levels prospectively in spouses and blood relatives of demented patients to determine if any familial predisposition exists for the low levels. Cobalamin status in most of the relatives found to have low levels was assessed further by means of blood counts, metabolic tests, neurologic evaluation, absorption studies and response to cobalamin therapy. Serum cobalamin levels in 36 spouses correlated with those of the 36 demented patients related to them (r = 0.46, p = 0.004). A significant association was not seen in 34 blood relatives of 34 demented patients (r = 0.27). Most importantly, 67% of the spouses of demented patients with low serum cobalamin had low values themselves, compared with only 3% of the spouses of patients with normal levels (p = 0.001). Detailed study of 4 of the 5 spouses (and 3 blood relatives) with low cobalamin levels showed no anemia in any case. Nevertheless, 4 of the subjects had metabolic evidence of deficiency and one had electrophysiological abnormalities; all these defects improved with cobalamin therapy. These observations identify a hitherto unsuspected group of people at high risk for cobalamin deficiency and suggest that spouses of demented patients with low cobalamin levels should also have their cobalamin levels measured. The increased frequency of low serum cobalamin levels in spouses of demented patients with low levels represents in most cases a true, mild cobalamin deficiency that responds to treatment.

Neutrophil nuclear segmentation in mild cobalamin deficiency: relation to metabolic tests of cobalamin status and observations on ethnic differences in neutrophil segmentation.

Neutrophil hypersegmentation is considered the most sensitive peripheral blood cell marker of cobalamin deficiency. However, its diagnostic value in the mild deficiency states that accompany most low cobalamin levels and its relation to metabolic test of cobalamin status are unknown. The authors compared neutrophil lobe averages and percent neutrophils with 5 or more lobes (%5+ lobes) in 169 subjects with their mean corpuscular volume (MCV) and serum cobalamin, methylmalonic acid (MMA), homocysteine, and folate levels and, in 65 cases, with the deoxyuridine suppression test (dUST). Only 9 subjects had hypersegmentation by lobe average and 20 subjects by %5+ lobes. They were not more often cobalamin-deficient than subjects without hypersegmentation. Moreover, only one of 34 subjects with dUST results diagnostic for cobalamin deficiency had neutrophil hypersegmentation. Both indices of neutrophil segmentation in the 169 subjects correlated significantly with homocysteine levels. They also showed weak inverse correlation with cobalamin levels, but did not correlate with MMA, folate, or MCV values. Cobalamin therapy for 6 months did not significantly change neutrophil lobe averages in 35 subjects with mild deficiency, compared with 8 nondeficient controls, and only marginally improved the %5+ lobes. A surprising, incidental observation was that blacks had significantly greater neutrophil segmentation by both criteria than did whites and others. This difference was unrelated to cobalamin or folate status. Our results indicate that dUST abnormalities precede all morphologic changes of deficiency, including hypersegmentation. Although a tendency exists for neutrophil segmentation to increase very slightly as some serum values, especially homocysteine, start to worsen in mild cobalamin deficiency, the metabolic changes precede overt hypersegmentation. Neutrophil nuclear segmentation is insufficiently sensitive in relation to metabolic evidence of deficiency to be used as a clinical tool in the diagnosis of mild cobalamin deficiency.

Folic Acid Fortification of Food

<h3>To the Editor.</h3> —Dr Boushey and colleagues¹report an increased risk of coronary artery disease in people with increased plasma homocysteine levels and suggest that this risk may be reduced by both supplementation and food fortification with folic acid. The dangers of these suggestions prompt us to point out the following. The quoted incidence of pernicious anemia of one in 5000 in a 1985 Mayo Clinic study²is a marked underestimation because that study based the diagnosis of pernicious anemia on anemia and/or typical neurologic manifestations. Many patients with cobalamin (vitamin B₁₂) deficiency have no anemia and no classical neuropathy. Rather, they may have "dementia" usually ascribed to aging.³In 1992, Pennypacker et al⁴described low cobalamin and/or increased homocysteine and methylmalonic acid serum levels in 14.5% of elderly outpatients. A more recent study found undiagnosed true pernicious anemia in 3% of elderly outpatients or

Subtle Cobalamin Deficiency

Subtle Cobalamin Deficiency

Risk Factors for Dideoxynucleoside-Induced Toxic Neuropathy in Patients with the Human Immunodeficiency Virus Infection

Dideoxynucleosides induce a dose-related toxic neuropathy; however, there is a paucity of information on whether other risk factors influence the development of neuropathy. We reviewed the records of 103 patients at an AIDS Clinical Trials Unit who were taking didanosine and/or zalcitabine to determine the risk factors for dideoxynucleoside-induced toxic neuropathy. Most were homosexual or bisexual (85%) men with a mean age of 39 years. The median CD4+ lymphocyte count was 59 cells/mm3, and 35% had a previous diagnosis of AIDS. Toxic neuropathy was more common in patients taking zalcitabine compared with those taking didanosine (14 of 51 versus seven of 55, p = 0.08). In the patients who took zalcitabine, those who had a low baseline serum cobalamin level, a history of heavy ethanol consumption, or a history of symptoms of peripheral nerve dysfunction were more likely to develop a toxic neuropathy (10 of 14 versus 12 of 37, p = 0.01). Conversely, there were no factors associated with the development of didanosine-induced toxic neuropathy. Dideoxynucleoside-induced toxic neuropathy is a common problem that can be disabling but is usually reversible. A history of symptoms of peripheral nervous system disease, heavy ethanol consumption, or a low serum cobalamin level may be useful in distinguishing patients at higher risk of developing zalcitabine-induced toxic neuropathy.

10 Malabsorption of food cobalamin

Food-cobalamin malabsorption is marked by the inability to release cobalamin from food, which therefore cannot be taken up by intrinsic factor for absorption. The defect is not detectable by classical clinical tests like the Schilling test which are all based on the absorption of free, crystalline cobalamin. Tests of food-cobalamin absorption have been devised, the most popular ones using cobalamin bound to eggs or to chicken serum. The disparity between the abnormal results of these tests and the normal results with the Schilling test defines the disorder of food-cobalamin malabsorption. Release of cobalamin from food requires acid and pepsin, and most food-cobalamin malabsorptive states can be traced to gastric defects. However, other mechanisms may also play a role. The malabsorption is limited to food cobalamin and any free cobalamin, presumably including recycled biliary cobalamin, will be absorbed normally, which may explain its frequently insidious nature. The effect on cobalamin status covers a broad spectrum. At one extreme, some individuals, perhaps in the earliest stages, have normal cobalamin status, while at the other extreme may be found deficiency every bit as severe as in the most florid case of pernicious anaemia. Most often, however, the deficiency is mild, frequently marked by only a low serum cobalamin level, mild evidence of metabolic insufficiency and, sometimes, minimal clinical sequelae. Moreover, in some cases the gastric defect progresses and intrinsic factor secretion is affected, thus transforming into classical pernicious anaemia; this is not inevitable, however, and probably occurs in only a minority of patients. The course of food-cobalamin malabsorption is therefore a varied one. Nevertheless, it may be the most common cause of subtle or mild cobalamin deficiency and it is also sometimes associated with severe deficiency. Its identification and treatment need to be considered more widely in the clinical setting.