Experimental Gerontology 69 (2015) 221–225
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Vitamin B12 deficiency in the institutionalized elderly: A regional study C.W. Wong ⁎, C.Y. Ip, C.P. Leung, C.S. Leung, J.N. Cheng, C.Y. Siu Caritas Medical Centre (Hospital Authority), Wing Hong Street, Shum Shiu Po, Kowloon, Hong Kong, China
a r t i c l e
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Article history: Received 2 February 2015 Received in revised form 21 June 2015 Accepted 22 June 2015 Available online 27 June 2015 Editor: Borg Holly M Brown Keywords: Vitamin B12 Vitamin B12 deficiency Folate Macrocytosis Anaemia Elderly Institution
a b s t r a c t The prevalence of vitamin B12 deficiency increases with age and is suggested to be even higher in the elderly living in institutions. This retrospective study evaluated the vitamin B12 and folate status of 1996 institutionalized elderly residents aged over 65 years. Among them, 34.9% had vitamin B12 deficiency (serum vitamin B12 b 150 pmol/L), 11.8% had folate deficiency (serum folate b6.8 nmol/L), and 4.9% had both. The majority of vitamin B12 deficient residents (68%) had serum vitamin B12 between 100 pmol/L and 149 pmol/L. Macrocytosis was found in 24.2% of vitamin B12 deficient residents. A significant increase in macrocytosis was associated with a decrease in serum vitamin B12 below 100 pmol/L. Macrocytosis was most common in those with vitamin B12 ≦69 pmol/L (50.9%). Overall, vitamin B12 deficiency is common in the institutionalized elderly, however macrocytosis cannot predict deficiency. More liberal testing for vitamin B12 status in the institutionalized elderly may be warranted. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Elderly people are at risk of vitamin B12 deficiency owing to an increased prevalence of pernicious anaemia, and high prevalence of gastric atrophy, which in turn impairs the release of vitamin B12 from food protein for absorption (Baik and Rusell, 1999; Carmel, 1995). Although the prevalence of vitamin B12 deficiency varies among studies, it appears to increase with age (Baik and Rusell, 1999). The prevalence varies between 5% and 40% in the elderly, depending on the definition of vitamin B12 deficiency used and the population groups studied (Lindenbaum et al., 1994; Baik and Rusell, 1999; Carmel, 2000; Chui et al., 2001; Clarke et al., 2003, 2004; Loikas et al., 2007). The institutionalized elderly represent a group of frail elderly people with multiple comorbidities increasing disabilities and dependency, which is distinct from those who are free-living. The prevalence of vitamin B12 deficiency among the elderly living in institutions has been suggested to be even higher reaching 30 to 40% (Matthews, 1995; Dali-Youcef and Andrè, 2009). Vitamin B 12 is essential for the metabolism of all cells in the body. In humans, two enzymatic reactions are dependent on vitamin B12: methylmalonyl coenzyme A mutase reaction and 5methyltetrahydrofolate-homocysteine methyltransferase reaction. They are important in the extraction of energy from protein and fat in the mitochondrial citric acid cycle, maintaining integrity of the nervous ⁎ Corresponding author. E-mail address:
[email protected] (C.W. Wong).
http://dx.doi.org/10.1016/j.exger.2015.06.016 0531-5565/© 2015 Elsevier Inc. All rights reserved.
system, and for DNA synthesis. Hence, in vitamin B12 deficiency, multiorgan systems are affected concomitant with a wide spectrum of clinical manifestations. The clinical manifestations are usually non-specific and highly variable. Routine testing of macrocytosis and anaemia associated with vitamin B12 deficiency is infrequently seen in clinical practice (Thompson et al., 1987; O Broin et al., 1990; Stott et al., 1997). Possibly related to the fact that the majority of the vitamin B12 deficiency is of a mild degree, which is not severe enough to cause macrocytosis or anaemia, especially when the folate status is normal (Herbert, 1994). However, data is lacking confirming that macrocytosis is found more frequently in those with a more severe degree of vitamin B12 deficiency. In this study, we evaluated the vitamin B12 and folate status in the elderly residents living in long term care institutions. We also explored the association of vitamin B12 concentration with macrocytosis in the vitamin B12 deficient residents. 2. Methods Caritas Medical Centre is a regional public hospital under the management of Hospital Authority in Hong Kong serving a population of 380,000. The majority of residents (around 4000) living in the long term care institutions in the serving district are under the care of the outreach team of Caritas Medical Centre. We retrospectively reviewed the electronic clinical records of the institutionalized residents under the care of the outreach team. Residents aged 65 and over with serum vitamin B12 concentration measured during the period 2011–2013 were included. Patients receiving vitamin
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B12 or folate supplements before vitamin B12 or folate blood tests were excluded. Patients put on tube feeding were evaluated separately. The clinical notes of all these residents were reviewed to determine the reason for serum vitamin B12 and folate measurement. Laboratory data on serum vitamin B12 and folate concentration, complete blood counts (CBC) and red cell indices (within 2 weeks before vitamin B12 measurement) were collected. In addition, age, medical disease including thalassaemia trait and iron deficiency, and medications at the time of vitamin B12 and folate measurement were also collected. This retrospective study has been approved by the Research Ethics Committee of Hospital Authority of Hong Kong before the start of study and the informed consent from the study subjects were waived. Serum vitamin B12 and folate were measured by Access 2 Immunoassay System (Beckman Coulter). The reference range for the vitamin B12 concentration was 133–675 pmol/L and for folate was N6.8 nmol/L. Vitamin B12 deficiency was diagnosed if the serum vitamin B12 was b 150 pmol/L (de Benoist, 2008; Selhub et al., 2008) and folate deficiency was diagnosed if the serum folate was b 6.8 nmol/L (Hao et al., 2003). CBC was performed by LH 750 haematology analyser (Beckman Coulter). Anaemia was defined as haemoglobin level b 13 g/dL for men and b11.5 g/dL for women. The normal mean corpuscular volume (MCV) range was 81 to 97 fL. Macrocytosis was defined as MCV above 99 fL and microcytosis as MCV below 80 fL. Macrocytic anaemia refers to macrocytosis with anaemia.
2.1. Statistical methods In the analysis of the influence of different serum vitamin B12 concentrations with macrocytosis and anaemia, residents with folate deficiency or iron deficiency, or haematological disease, or thalassaemia trait were excluded, as these can affect red cell indices and there is 8% thalassaemia carrier rate in our locality. Student's t test and ANOVA were used for comparisons between groups for continuous data. Chi-square test was used to compare the percentage of patients with macrocytosis and anaemia in different vitamin B12 concentration subgroups. Association of vitamin B12 concentration with age was assessed using linear regression.
3. Results During the period 2011–2013, 2176 institutionalized elderly residents aged 65 years or older had serum vitamin B12 concentration measured. 80 residents already receiving vitamin B12 supplements before vitamin B12 blood test performed were excluded. 100 residents on tube-feeding were evaluated independently. Of the remaining 1996 residents, 858 (43%) were men and 1138 (57%) were women (Table 1). All had serum vitamin B12 concentration measured but only 1885 residents had serum folate measured. The majority (N 70%) did not have clear indication for vitamin B12 and folate measurement. Most had vitamin B12 and folate measurement together with complete blood count, renal and liver function test and glucose, as a routine check-up.
3.1. Vitamin B12 and folate concentration and the prevalence of deficiency in the institutionalized elderly The mean serum vitamin B12 and folate concentration of the study population was 227 pmol/L and 16.2 nmol/L, respectively (Table 1). Among them, 34.9% (696) had vitamin B12 deficiency (serum vitamin B12 b150 pmol/L) and 11.8% had folate deficiency (serum folate b6.8 nmol/L). There was no significant difference in the prevalence of vitamin B12 deficiency between men and women but more men than women had folate deficiency (16.2% vs 8.5%, P b 0.001). The mean serum concentration of vitamin B12 in those with vitamin B12 deficiency was 110 pmol/L and 5.4 nmol/L for folate deficient residents. Only 4.9% had both vitamin B12 and folate deficiencies. Among vitamin B12 deficient residents, 11 residents (1.6%) had post-gastrectomy, 100 residents (14.4%) had metformin intake and 36 residents (5.2%) had proton pump inhibitor intake. Anti-intrinsic factor antibody and anti-parietal cell antibody were done in 301 of 696 residents with vitamin B12 deficiency. Only 20 residents had positive results for anti-intrinsic factor antibody and were presumed to have pernicious anaemia. There were no significant differences in serum vitamin B12 and folate concentration, and the prevalence of deficiencies by age even further
Table 1 Vitamin B12/folate status and selected characteristics of the institutionalized elderlya.
Age (years) Age 65–74 years (n) Age ≧ 75 years (n) Serum vitamin B12 (pmol/L) • Vitamin B12 deficiencyc Vitamin B12 deficiency (n) Serum folate (nmol/L) • Folate deficiency d Folate deficiency† (n) Both vitamin B12 and folate deficiencies† (n) Haemoglobin (g/dL) Anaemiae (n) MCV (fL) Macrocytosis (MCV N99 fL) (n) Thalassaemia trait (n) Post-gastrectomy (n) Vegetarian (n) Metformin (n) Proton pump inhibitor (n)
Total n = 1996
Men n = 858 (43%)
Women n = 1138 (57%)
P valueb
83.3 ± 7.6 267 (13.4%) 1729 (86.6%) 227 ± 155 110 ± 29 696 (34.9%) 16.2 ± 13.1 5.4 ± 1.1 222 (11.8%) 93 (4.9%) 11.8 ± 2 1126 (53.7%) 92.6 ± 10.4 397 (20%) 135 (6.4%) 19 (1%) 1 188 (9.4%) 173 (8.7%)
80.4 ± 7.2 185 (21.6%) 673 (78.4%) 222 ± 150 112 ± 25 301 (35.1%) 14.8 ± 15.2 5.4 ± 1.1 130 (16.2%) 54 (6.8%) 12.2 ± 2 561 (63.3%) 93.3 ± 9.4 191 (22.3%) 50 (5.6%) 9 (1%) 0 73 (8.5%) 72 (8.4%)
85.5 ± 7.2 82 (7.2%) 1056 (92.8%) 230 ± 158 109 ± 32 395 (34.7%) 17.2 ± 11.2 5.3 ± 1.2 92 (8.5%) 39 (3.6%) 11.5 ± 1.7 565 (46.7%) 92.6 ± 11.1 206 (18.1%) 85 (7%) 10 (1%) 1 115 (10.1%) 101 (8.9%)
b0.001 b0.001 b0.001 0.21 0.17 0.86 b0.001 0.62 b0.001 0.002 b0.001 b0.001 0.014 0.021 0.201 0.516 – 0.227 0.477
*Abbreviations: MCV, Mean corpuscular volume; n, number. a Mean and standard deviation, number and percentage of the pathological results. Vitamin B12 deficiency is defined by serum vitamin B12 b150 pmol/L and folate deficiency is defined by serum folate b6.8 nmol/L. b Difference between men and women (Student's t test for continuous data; chi-square test for categorical data). c Serum vitamin B12 concentration in residents with vitamin B12 deficiency. d Serum folate concentration in residents with folate deficiency. e Anaemia: haemoglobin b 13 g/dL for men and b11.5 g/dL for women. † Only 1885 residents had serum folate measured.
Number of residents
C.W. Wong et al. / Experimental Gerontology 69 (2015) 221–225 473 (68%)
500 450 400 350 300 250 200 150 100 50 0
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Table 3 Haematological indices by various vitamin B12 concentration subgroupsa. Serum vitamin B12 concentration (pmol/L) 65-74 years
157 (22.5%)
Macrocytosis Macrocytic anaemia Anaemia (overall)
70-99
100-149
Vitamin B12 concentration(pmo/L)
Figure 1. Vitamin B12 concentration of 696 vitamin B12 deficient residents by age.
sub-classified the elderly into different age groups (65–69, 70–74, 75–79, 80–84, 85–89, and 90 years and older). The majority of vitamin B12 deficient residents (68%) had vitamin B12 concentration between 100 pmol/L and 149 pmol/L (Figure 1). This finding did not differ by age. It is interesting to note, none of the residents on tube feeding had vitamin B12 or folate deficiency. On the contrary, serum vitamin B12 and folate concentration were high with mean serum vitamin B12 of 660 pmol/L and mean serum folate of 37.7 nmol/L. 3.2. Vitamin B12 deficiency and macrocytosis Among the 546 vitamin B12 deficient residents, after excluding those with folate deficiency, iron deficiency, haematological disease, or thalassaemia trait, the majority of vitamin B12 deficient residents (73.4%) were normocytic and only 24.2% were macrocytic (Table 2). The macrocytic group had significantly lower serum vitamin B12 (99.6 pmol/L) than those in the microcytic and normocytic groups (P b 0.001). Vitamin B12 deficient residents were further classified according to the descending serum vitamin B12 concentrations (100–149 pmol/L, 70–99 pmol/L, ≦69 pmol/L) (Table 3). A significant increase in vitamin B12 deficient residents with macrocytosis and macrocytic anaemia was associated with a decrease in serum vitamin B12 below 100 pmol/L. An even higher percentage of vitamin B12 deficient residents had macrocytosis and macrocytic anaemia when serum vitamin B12 was ≤69 pmol/L (50.9% and 30.2%) than those with serum vitamin B12 70–99 pmol/L (30.4% and 18.3%). There was no association between the vitamin B12 concentration and overall anaemia. 4. Discussion The prevalence of vitamin B 12 deficiency (serum vitamin B 12 b150 pmol/L) among the institutionalized elderly in this study was 34.9%, comparable to reports reaching 30% to 40% (Matthews, 1995; Dali-Youcef and Andrè, 2009). More residents with vitamin B12 deficiency are expected to be detected if additional more sensitive indicators of vitamin B12 deficiency, such as serum total homocysteine, methylmalonic acid or holotranscobalamin level were used in those with borderline serum vitamin B12 concentration (Savage et al., 1994; Snow, 1999; Klee, 2000; Hermann et al., 2003; Nexo and Hoffmann-Lücke, 2011). Nevertheless, the prevalence was higher than Table 2 Vitamin B12 concentration of 546 vitamin B12 deficient residents by red cell morphologya.
Number of patients Vitamin B12 (pmol/L)
70–99 (n = 115)
100–149 (n = 378)
≧150 (n = 1006)
27 (50.9%) P b 0.001 16 (30.2%) P b 0.001 29 (54.7%) P = 0.503
35 (30.4%) P = 0.005 21 (18.3%) P = 0.023 61 (53%) P = 0.536
70 (18.5%) P = 0.71 29 (7.7%) P = 0.065 173 (45.8%) P = 0.16
195 (19.4%)
75 years Total
66 (9.5%)
69
≦69 (n = 53)
Microcytosis
Normocytosis
Macrocytosis
13 (2.4%) 110.8 ± 20.5 P b 0.001
401 (73.4%) 113.9 ± 28.6 P b 0.001
132 (24.2%) 99.6 ± 31.1
a Mean and standard deviation, number and percentage of the pathological results. Vitamin B12 concentration in patients with microcytosis and normocytosis were compared with those with macrocytosis by Student's t test.
111 (11%) 502 (50%)
a Number and percentage of the pathological results. The percentage of patients with various vitamin B12 deficiency subgroups were compared with vitamin B12 ≧150 pmol/L group by chi-square test.
in studies performed in the free-living elderly using a similar definition for vitamin B12 deficiency (serum vitamin B12 b150 pmol/L) in which the prevalence was between 5.3% and 20% (Lindenbaum et al., 1994; Clarke et al., 2003, 2004; Loikas et al., 2007). In a local study, the prevalence of serum vitamin B12 b 140 pmol/L was 6.6% in free living people older than 70 years (Chui et al., 2001). Unlike other studies (Chui et al., 2001; Clarke et al., 2003, 2004; Loikas et al., 2007), our study did not show the prevalence of vitamin B12 deficiency increased with age among elderly residents. This is probably due to the fact that the majority (86.6%) of residents in the study were already in the advanced age range of ≧ 75 years. Furthermore, the institutionalized and free-living elderly residents represent two distinct elderly populations. Institutionalized elderly residents tend to have poor health status and are more frail and dependent on others for daily life activities. Very often, they are encouraged to drink milk or nutritional supplements supposedly associated with a lower prevalence of deficiency. However, multiple comorbidities and the chronic disease state are detrimental to nutritional status in the body and may increase the body's vitamin requirements (Rajan et al., 2002; Obeid et al., 2004). Anorexia and dysphagia with poor dietary intake can further compromise the vitamin status. Long term usage of medications, such as proton pump inhibitors, histamine (H2) blockers, metformin and phenytoin, for treatment of comorbidities can interfere or reduce vitamin B12 absorption and metabolism (Schumann, 1999; Bausman et al., 2000). Iron deficiency anaemia is prevalent in the elderly (Mukhopadhyay and Mohanaruban, 2002) whilst prolonged iron deficiency can cause damage to gastric mucosa and lead to gastric atrophy and diminished vitamin B12 absorption due to loss of gastric acid and intrinsic factor secretion (Herbert, 1994). Moreover, the level of skilled nursing care provided and the amount of care they received can also affect the vitamin B12 status of the residents (Baik and Rusell, 1999). As a result, the institutionalized elderly are more prone to vitamin B12 deficiency and the aged-related change in vitamin B12 status among them becomes less obvious. The majority (68%) of the vitamin B12 deficiency was of a relatively less severe degree (vitamin B12 100–149 pmol/L). This finding is in accordance with the reports that food-cobalamin (vitamin B12) malabsorption is the most common cause of vitamin B12 deficiency in the elderly and tends to cause a less severe degree of vitamin B12 deficiency (Carmel, 2000; Andrè et al., 2005; Dali-Youcef and Andrè, 2009). Long term use of common medications for comorbidities, such as metformin and proton pump inhibitor can also contribute to vitamin B12 deficiency, however in the present study they only accounted for deficiency in 14.4% and 5.2%, respectively. Food-cobalamin deficiency is characterized by the inability to release vitamin B12 from food or from its binding protein (Carmel, 1995). It thus accounts for 40–70% of cases of vitamin B12 deficiency according to various studies (Carmel, 2000; Andrè et al., 2005; Dali-Youcef and Andrè, 2009). It is caused mainly by atrophic gastritis, which in turn reduces gastric acid and pepsin secretion, to separate the vitamin B12 from the binding protein (Andrè et al., 2005). Although associated with poor absorption of
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vitamin B12 from food protein, absorption of free vitamin B12 or crystalline vitamin B12 is entirely unaffected (Carmel, 2000; Andrè et al., 2005; Dali-Youcef and Andrè, 2009). This is reflected in our finding that none of the tube feeding patients had vitamin B12 deficiency but rather had high serum vitamin B12 concentration. It is because the tube feeding formula contains recommended or even higher than daily requirement of vitamin B12 in the form of cyanocobalamin (crystalline vitamin B12) which can be readily absorbed in the body. Since food-cobalamin malabsorption often produces a slowly progressive depletion of vitamin B12, it usually causes a mild deficient state (Carmel, 2000). In the present study, 20% of all the study residents (Table 1) and 19.4% of the non-vitamin B12 deficient residents (Table 3) had macrocytosis, which is comparable to that of vitamin B12 deficient residents (24.2%) (Table 2). This finding is in accordance with the observation that macrocytosis cannot predict the presence of vitamin B12 deficiency (Oosterhuis et al., 2000; Chui et al., 2001; Kwok et al., 2002). Macrocytosis has been shown to have low sensitivity of 17%–30% for detection of vitamin B12 deficiency and up to 84% of the deficiency would be missed undetected if macrocytosis was used to screen for the deficiency (Oosterhuis et al., 2000). Although MCV cannot be an indicator of vitamin B12 deficiency, it seems that severe vitamin B12 deficiency was associated with more macrocytosis. Our study found that a significant increase in macrocytosis occurred when serum vitamin B12 was below 100 pmol/L. Macrocytosis was also associated with a much lower serum vitamin B12 concentration or a more severe degree of vitamin B12 deficiency (50.9% in those with vitamin B12 ≦69 pmol/L vs 30.4% with vitamin B12 70–99 pmol/L and 18.5% in those with serum vitamin B12 100–149 pmol/L) (Table 3). Herbert (1994) described 4 stages of vitamin B12 deficiency, starting from stage I) serum depletion (low serum holotranscobalamin concentration), stage II) cell store depletion (decreasing holohaptocorrin and low red cell vitamin B12 concentrations), stage III) biochemistry deficiency (elevated serum homocysteine and methylmalonic acid concentrations), and finally to stage IV) clinical deficiency (anaemia and macrocytosis) (Herbert, 1994). Low serum total vitamin B12 concentration indicates stage II to IV deficiency whilst macrocytosis represents the final stage of vitamin B12 deficiency. Thus, serum vitamin B12 concentration decreases before macrocytosis occurs and may need to decrease further to a lower level before macrocytosis occurs. Furthermore, different quantities of vitamin B12 are stored in different organs, thus not all organ-systems are at the same stage of vitamin B12 deficiency simultaneously (Herbert, 1994). For example, the vitamin B12 stored in the nervous system is depleted earlier than in the bone marrow storage, thus cognitive dysfunction and neurological disorder precede the development of haematological disorders (Lindenbaum et al., 1988; Herbert, 1994). Therefore, if we look for vitamin B12 deficiency when macrocytosis and anaemia occur, we may miss an undetected significant proportion of patients with vitamin B12 deficiency that might have already developed neuropsychiatric disorders. Since vitamin B12 deficiency is prevalent in the elderly and early detection with prompt treatment can reverse the damage before it becomes extensive and irreversible, more liberal tests and screening for vitamin B12 deficiency may be warranted. However, diagnosis of vitamin B12 deficiency is not straight forward as there is no consensus or guideline for diagnosis. Serum vitamin B12 concentration b150 pmol/L for defining vitamin B12 deficiency is derived from National Health and Nutritional Examination survey. It is based on serum vitamin B12 concentration below which the serum metabolites (serum total homocysteine and methylmalonic acid) become elevated and is endorsed by The World Health Organization (de Benoist, 2008; Selhub et al., 2008). However, serum vitamin B12 concentration is known for its lack of sensitivity to identify genuine or tissue vitamin B12 deficiency in the body. On the other hand, elevated serum homocysteine and methylmalonic acid concentrations, and decrease in serum holotranscobalamin concentration are more sensitive and earlier markers for vitamin B12 deficiency (Savage et al., 1994; Snow, 1999; Klee, 2000; Hermann et al., 2003; Nexo and Hoffmann-Lücke, 2011). Unfortunately, these tests are
less readily available. The lack of easily available and reliable diagnostic tools further hinders screening. The strength of the present study is notable for the large sample size of patients recruited and the serum vitamin B12 obtained as part of routine clinical care. About half of the institutionalized elderly population in our serving district was recruited into the study. In view of the increasing prevalence of vitamin B12 deficiency in the elderly, especially in those that are institutionalized; in the recent 5 years testing for vitamin B12 status is performed more liberally in our setting, even when there is no clear indication, as it is part of the routine tests (complete blood count, renal and liver function test, blood glucose, vitamin B12 and folate blood test, thyroid function test, chest XR and ECG) for new patients under our care. Accordingly, our findings are likely to reflect the real situation in this population. However, a possible patient recruitment bias is inherent with the retrospective nature of the study. Additionally the lack of metabolite assays to detect early or subclinical vitamin B12 deficiency may affect the derived prevalence. Furthermore, confounding factors that may have influenced haemoglobin and MCV levels, such as iron deficiency and renal impairment status of the residents, could not be excluded from the analysis, as iron status was infrequently tested and a significant proportion of residents had various degrees of renal impairment. To overcome these setbacks, it would be preferable to conduct a prospective study with a standard set of tests and also to recruit the free-living elderly from the same setting for direct comparison with the institutionalized elderly that would generate meaningful results. 5. Conclusion Vitamin B12 deficiency is common in the institutionalized elderly with a prevalence of 34.9% by serum assay derived from the present study. The majority was of a mild to moderate degree of deficiency, which is likely to be related to food-cobalamin (vitamin B12) malabsorption. The haematological manifestations of vitamin B12 in terms of anaemia and macrocytosis seem to be trivial, and haemoglobin level and MCV are not useful indicators of vitamin B12 deficiency. Traditional recommendation for vitamin B12 measurement when there are overt signs and symptoms, such as macrocytosis and anaemia, may miss the detection of a significant proportion of patients with vitamin B12 deficiency or delay the diagnosis. Thus, more liberal testing for vitamin B12 status or universal prescription of vitamin B12 supplement to the institutionalized elderly residents may be warranted. However, the cost-effectiveness of detecting and treating subclinical or asymptomatic vitamin B12 deficiency among institutionalized elderly residents versus universal supplementation of vitamin B12, and the daily dosage recommended, remain to be determined. Financial support None. Conflict of interest None. References Andrè, E., Affenberger, S., Vinzio, S., Kurtz, J.E., Noel, E., Kaltenbach, G., Maloisel, F., Schlienger, J.L., Blicklé, J.F., 2005. Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. Am. J. Med. 118, 1154–1159. Baik, H.W., Rusell, R.M., 1999. Vitamin B12 deficiency in the elderly. Annu. Rev. Nutr. 19, 357–377. Bausman, W.A., Shaw, S., Jayatilleke, E., Spungen, A.M., Herbert, V., 2000. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 23, 1227–1231. Carmel, R., 1995. Malabsorption of food cobalamin. Baillieres Clin. Haematol. 8, 639–655. Carmel, R., 2000. Current concepts in cobalamin deficiency. Annu. Rev. Med. 51, 357–375. Chui, C.H., Lau, F.Y., Wong, R., Soo, O.Y., Lam, C.K., Lee, P.W., Leung, H.K., So, C.K., Tsoi, W.C., Tang, N., Lam, W.K., Cheng, G., 2001. Vitamin B12 deficiency — need for a new guideline. Nutrition 17, 917–920.
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