High prevalence of cobalamin deficiency in elderly outpatients.

OBJECTIVE: To measure the prevalence of cobalamin (vitamin B12) deficiency in geriatric outpatients as documented by both low serum cobalamin levels and elevations of serum methylmalonic acid and homocysteine and to determine the response to cobalamin treatment. DESIGN: Prospective study screening elderly subjects for cobalamin deficiency using radiodilution cobalamin assays as well as stable isotope dilution gas chromatography-mass spectrometry methylmalonic acid and homocysteine assays. In patients with serum cobalamin levels < or = 300 pg/mL, the response to cobalamin treatment in the group with levels of methylmalonic acid and/or homocysteine > 3 standard deviations (SD) above the mean for normals was compared with that of those without such elevations. SETTING: Outpatient geriatric clinics at the VA Medical Center and University Health Sciences Center, Denver, CO. PATIENTS: One-hundred and fifty-two consecutive outpatients, ages 65 to 99, were screened. Twenty-nine subjects with serum cobalamin levels < or = 300 pg/mL were prospectively evaluated and treated with cobalamin. MAIN OUTCOME MEASURES: Cobalamin, methylmalonic acid, homocysteine, complete blood counts, neurologic examination, and neuropsychological testing. RESULTS: The prevalence of cobalamin deficiency as defined by a serum cobalamin level < or = 300 pg/mL and levels of serum methylmalonic acid and/or homocysteine elevated to > 3 SD was 14.5% of the screened outpatients. A similar proportion of patients with low normal serum cobalamin levels (between 201 and 300 pg/mL) demonstrated elevated metabolites > 3 SD (56%) compared with patients with low serum cobalamin levels (< or = 200 pg/mL) (62%). Cobalamin therapy caused a marked fall or complete correction of the elevated methylmalonic acid and homocysteine levels in each patient who was treated prospectively. Results for complete blood count, lactate dehydrogenase, bilirubin, baseline neurologic score, and baseline neuropsychologic scores did not differ in the group of patients with elevated metabolites compared with those with normal metabolites. The mean red cell volume fell significantly in the patients with elevated metabolites after 6 months of cobalamin treatment. One patient with elevated metabolites had marked improvement in his neurologic abnormalities after 6 months of cobalamin treatment. CONCLUSION: There was a high (14.5%) prevalence of cobalamin deficiency as demonstrated by elevations in serum methylmalonic acid and homocysteine in addition to low or low normal serum cobalamin levels in elderly outpatients. The serum cobalamin level was insensitive for screening since similar numbers of patients with low normal serum cobalamin levels of 201-300 pg/mL compared with patients with low cobalamin levels (< or = 200 pg/mL) had markedly elevated metabolites which fell with cobalamin treatment. Additional studies will be required to define the full clinical benefit from treatment with Cbl in elderly subjects.     

Cobalamin absorption and serum homocysteine and methylmalonic acid in elderly subjects with low serum cobalamin

Abstract: We prospectively studied 41 consecutive elderly patients with serum cobalamin (vitamin B₁₂) levels lower than 125 pmol/l. The protein-bound cobalamin absorption test (PBAT) was performed in 34 of them and in 27 selected elderly control patients. The lower decision limit was 0.18% and an abnormal test was detected in only 9 (26%) of the 34 patients with low serum cobalamin level. When the PBAT was compared to the Schilling (Dicopac method) test, a concordant result was found in 80 %. Serum methylmalonic acid and/or total homocysteine concentrations were elevated in 75% (26/35) of the patients with low serum cobalamin levels but also in 30% (5/17) of the control patients. Of the 12 and 9 cobalamin-deficient patients with elevated serum levels of methylmalonic acid and homocysteine, normalization after cobalamin therapy was obtained in 11 and 5 respectively. In conclusion, determination of serum metabolites and their response to cobalamin therapy are a sensitive index of significant cobalamin deficiency and a useful means of distinguishing between cobalamin and folate deficiency. The PBAT offers little advantage over the Schilling test in diagnosing cobalamin malabsorption in elderly patients.     

Schilling and protein-bound cobalamin absorption tests are poor instruments for diagnosing cobalamin malabsorption

Abstract. Lindgren A, Bagge E, Cederblad A, Nilsson 0, Persson H, Kilander AF (Boris Central Hospital, Sahlgrenska University Hospital, and Molndal Hospital, Sweden). Schilling and protein-bound cobalamin absorption tests are poor instruments for diagnosing cobalamin malabsorption. Objectives: To assess the advantage of a protein-bound cobalamin absorption test (PBAT) over the Schilling test in patients with suspeded cobalamin (vitamin B12) malabsorption. Design: Clinical study of consecutive patients referred from primary care units, medical and neurological clinics. Setting: The catchment area of Sahlgrenska University Hospital, Goteborg. Subjects. Referred patients (n = 155) with suspected cobalamin deficiency and at least one serum cobalamin value < 200 pmol L-l. Interventions: All patients were investigated with upper gastrointestinal endoscopy with biopsies taken upper gastrointestinal endoscopy with biopsies taken methylmalonic acid (h4MA) and homocysteine (Hcy) were determined in all 109 patients not on cobalamin substitution. A dual isotope cobalamin absorption test was then performed with the concomitant administration of crystalline (Schilling) and proteinbound cobalamin (PBAT). Main outcome measures: Number of patients with gastric body atrophy diagnosed with each absorption gastric body atrophy diagnosed with each absorption test and the relation between these results and functional cobalamin deficiency defined as elevated MMA and Hcy, that normalized after cobalamin substitution treatment. Results: The majority of patients with abnormal absorption tests had already developed elevated MMA and/or Hcy. PBAT was more sensitive than the Schilling test in identifyiog patients with gastric body atrophy but the sensitivity was too low for clinical use. About f of the patients with gastric body atrophy and normal absorption tests had already developed elevated MMA and/or Hcy. PBAT was more sensitive than the Schilling test in identifyiog patients with gastric body atrophy but the sensitivity was too low for clinical use. About f of the patients with gastric body atrophy and normal absorption tests had elevated MMA and/or Hcy, indicating cobalamin deficiency. Conclusion: PBAT may be somewhat more sensitive than the Schilling test but neither test is sensitive enough for diagnosing cobalamin malabsorption at an early stage.     

血清脂联素水平与老年人代谢综合征的相关性

目的 通过横断面研究,评估血清脂联素水平与老年人代谢综合征的相关性.方法 检测61例代谢综合征患者和140例非代谢综合征老年人血清脂联素、C反应蛋白、血糖、胆固醇、三酰甘油、高密度脂蛋白、低密度脂蛋白等,通过Logistic回归分析评价血清脂联素水平与老年人代谢综合征的关系,并采用等级相关统计方法比较血清脂联素水平. 结果 代谢综合征患者血清脂联素为(7.2±3.6)g/L,低于非代谢综合征组(10.0±3.9)g/L,代谢综合征1级、2级、3级的患者分别为27例(44.3%)、21例(34.4%)和13例(21.3%),脂联素水平分别为(8.5±2.7)g/L、(7.0±2.5)g/L和(4.9±2.4)g/L,随着代谢综合征组分的增多,脂联素的含量呈下降趋势,两两比较呈等级相关(均为P＜0.01).Logistic回归分析显示,在校正了年龄、体质指数和性别比后,高水平脂联素使代谢综合征患病风险降低.脂联素四分法表示中,高脂联素水平组患代谢综合征的风险较其他较低组降低96.0%(OR=0.04,95%可信区间0.023～0.056,P＜0.01).结论 老年人中,高水平脂联素使代谢综合征患病风险降低.     

In vitro effect of duodenal juice on R binders cobalamin complexes in subjects with pancreatic insufficiency: correlation with cobalamin absorption.

Absorption of cobalamin free or bound to chicken serum was assessed in nine patients with pancreatic insufficiency. Simultaneously the in vitro effect of duodenal juice collected from six patients and seven controls was tested on labelled cobalamin complexed to chicken serum or to R salivary binder. Malabsorption of free cobalamin was observed in one of nine patients and in four of nine patients when cobalamin was administered bound to chicken serum. The in vitro effect of duodenal juice on cobalamin complexed to chicken serum or to R salivary binder was studied: the percentage of free cobalamin released was significantly decreased in pancreatic insufficiency compared with controls whatever the binder used; the degradation of R salivary binder was different in pancreatic insufficiency and in controls. Despite the in vitro abnormalities observed in pancreatic insufficiency, these did not correlate with the in vivo absorption of cobalamin which was often normal in our patients.     

Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, and treatment with special focus on oral cobalamin therapy

The aim of this work was to review the literature concerning cobalamin deficiency in elderly patients. Articles were identified through searches of PubMed-MEDLINE (January 1990 to June 2006), restricted to: English and French language, human subjects, elderly patients (>65 years), clinical trial, review and guidelines. Additional unpublished data from our cohort with cobalamin deficiency at the University Hospital of Strasbourg, France, were also considered. All of the papers and abstracts were reviewed by at least two senior researchers who selected the data used in the study. In elderly people, the main causes of cobalamin deficiency are pernicious anemia and food-cobalamin malabsorption. The recently identified food-cobalamin malabsorption syndrome is a disorder characterized by the inability to release cobalamin from food or from its binding proteins. This syndrome is usually the consequence of atrophic gastritis, related or not to Helicobacter pylori infection, and of the long-term ingestion of antacids and biguanides (in around 60% of the patients). Management of cobalamin deficiency has been well established with the use of cobalamin injections. However, new routes of cobalamin administration (oral and nasal) are currently being developed, especially the use of oral cobalamin therapy to treat food-cobalamin malabsorption.     

Effects of cobalamin, cobalamin analogues and cobalamin binding proteins on P388D1 mouse leukemic cells in culture.

Cobalamin-deficient P388D1 mouse leukemic cells were created by propagation in a cyanocobalamin-free medium in which the original fetal bovine serum was replaced by bovine serum albumin. These cobalamin-deficient cells gradually ceased to multiply when the medium contained 5-methyltetrahydrofolate. The growth of cells that had been cultured with this coenzyme was recovered following the addition of cyanocobalamin (CNCbl), at concentrations above 37 pM. In contrast to the effect of CNCbl, cobinamide, and cobalamin analogues prepared from hydroxy cobalamin by reaction with ascorbic acid, did not have a growth-inducing effect on these cells, nor did these analogues inhibit CNCbl-dependent growth. Transcobalamin II-cobalamin complex had a remarkably stimulating effect on cell growth. The growth inducing effect became apparent with a cobalamin concentration of only 0.37 pM. This was about 1/100th the level of free cobalamin required for cell growth. However, no growth-inducing effect was seen at an R protein-bound cobalamin concentration of 37 pM, indicating that once cobalamin has been bound to R protein, it loses its growth-promoting effect on these cells in culture.     

Biliary excretion of cobalamin and cobalamin analogues in man

Using dialysis, gel filtration, isoelectrofocusing and radioaffinity assay, we studied the unsaturated and saturated binders of bile and the biliary concentration of cobalamin (Cbl) and Cbl analogues compared to the corresponding serum concentrations in 7 choledochodomized patients. Bile contained a single saturated or unsaturated R binder with a molecular mass of about 120,000. Differences in the isoelectrofocusing pattern were observed between unsaturated and saturated R binders and could correspond to two secretion origins, mucosal secretion and hepatocyte clearance, respectively. The concentration of total corrinoids is about 4 times higher in bile than in serum, and this could be explained by a hepatic clearance of serum Cbl analogue-R binder complexes, as previously described in the rabbit. Moreover, the enterohepatic circulation of Cbl seems likely in healthy individuals since the saturated biliary R binder is degraded by pancreatic juice.     

Neurologic aspects of cobalamin deficiency.

We reviewed 153 episodes of cobalamin deficiency involving the nervous system that occurred in 143 patients seen over a recent 17-year period at 2 New York City hospitals. Pernicious anemia was the most common underlying cause of the deficiency. Neurologic complaints, most commonly paresthesias or ataxia, were the first symptoms of Cbl deficiency in most episodes. The median duration of symptoms before diagnosis and treatment with vitamin B12 was 4 months, although long delays in diagnosis occurred in some patients. Diminished vibratory sensation and proprioception in the lower extremities were the most common objective findings. A wide variety of neurologic symptoms and signs were encountered, however, including ataxia, loss of cutaneous sensation, muscle weakness, diminished or hyperactive reflexes, spasticity, urinary or fecal incontinence, orthostatic hypotension, loss of vision, dementia, psychoses, and disturbances of mood. Multiple neurologic syndromes were often seen in a single patient. In 42 (27.4%) of the 153 episodes, the hematocrit was normal, and in 31 (23.0%), the mean corpuscular volume was normal. Neutropenia and thrombocytopenia were unusual even in anemic patients. In nonanemic patients in whom diagnosis was delayed, neurologic progression frequently occurred although the hematocrit remained normal. In 27 episodes, the serum cobalamin concentration was only moderately decreased (in the range of 100-200 pg/ml) and in 2 the serum level was normal. Neurologic impairment, as assessed by a quantitative severity score, was judged to be mild in 99 episodes, moderate in 39 and severe in 15. Severity of neurologic dysfunction before treatment was clearly related to the duration of symptoms prior to diagnosis. In addition, the hematocrit correlated significantly with severity, independent of the longer duration of symptoms in nonanemic patients. Four patients experienced transient neurologic exacerbations soon after beginning treatment with cyanocobalamin, with subsequent recovery. Followup evaluation was adequate to assess the neurologic response to vitamin B12 therapy in 121 episodes. All patients responded, and in 57 (47.1%), recovery was complete, with no remaining symptoms or findings on examination. The severity score was reduced by 50% or greater after treatment in 91% of the episodes. Residual long-term moderate or severe neurologic disability was noted following only 7 (6.3%) episodes. The extent of neurologic involvement after treatment was strongly related to that before therapy as well as to the duration of symptoms. The percent improvement over baseline neurologic status after treatment was inversely related to duration of symptoms and hematocrit. Some evidence of response was always seen during the first 3 months of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Blood haemoglobin declines in the elderly: implications for reference intervals from age 70 to 88

The objective was to determine whether Hb declines in healthy elderly men and women and if this influences health-related reference intervals. A representative population sample, comprising 30% of all 70-yr-old subjects in a Swedish city with 420,000 inhabitants (n = 1148, participation rate 85%), was followed at 1-5-yr intervals for 18 yr within a longitudinal population study. Age-related changes in Hb were calculated after exclusion of non-healthy probands and by multivariate analyses in the total study group. Mean Hb declined between age 70 and 88 from 149 to 138 g/L in men (annual decline 0.69 g/L, p = 0.000), and from 139 to 135 g/L in women (annual decline 0.06 g/L, n.s.). Healthy men declined from 152 to 141 g/L (annual decline 0.53 g/L, p = 0.038), for women from 140 to 138 g/L (annual decline 0.05 g/L, n.s.). Age and body mass index correlated, in multivariate analysis, independently to Hb in both men and women, as did variables indicating a non-healthy state. Epidemiological decision limits for anaemia declined for men from 128 to 116 g/L, for women from 118 to 114 g/L. Anaemia, thus defined, occurred in 3.2 to 9.7% of the subjects, whereas 28.3% of the 88-yr-old men had anaemia according to the WHO definition. In conclusion, there is a significant age-related decline in Hb from age 70 to 88 among healthy men, and a less pronounced decline among women. This justifies the use of lower epidemiological decision limits for anaemia of about 115 g/L for both men and women from age 80-82.     

Serum transferrin receptor in the megaloblastic anemia of cobalamin deficiency.

In order to further study the relation between transferrin receptor and erythropoiesis we examined serum receptor levels in megaloblastic anemia, which is the classic example of ineffective erythropoiesis. We studied 33 patients with unequivocal cobalamin deficiency, only 22 of whom were anemic. High serum transferrin receptor levels were found in 12 patients, all of whom were anemic and had high lactate dehydrogenase (LDH) levels; in contrast, only 10 of the 21 patients with normal receptor levels were anemic. Receptor correlated most strongly with LDH (r = 0.573, p < 0.001) and, inversely, with hemoglobin values (r = -0.560, p < 0.001); it also correlated with ferritin and total bilirubin levels, but not with cobalamin, MCV or erythropoietin. No association was found with the hemolytic component of megaloblastic anemia, represented indirectly by haptoglobin levels. Changes induced by cobalamin therapy were also examined in 13 patients. Transferrin receptors rose in all 6 patients who initially had high levels and in 2 of 3 patients who had borderline levels, but not in the 4 patients with initially normal levels. The receptor levels began to rise within 1-3 days, peaked at about 2 weeks and returned to normal at about the 5th wk. The findings indicate that serum transferrin receptor levels reflect the severity of the megaloblastic anemia. The elevated receptor levels rise further with cobalamin therapy, however, as effective erythropoiesis replaces ineffective erythropoiesis, and these persist until the increased erythropoiesis returns to normal.     

Long-term effect of Helicobacter pylori eradication on plasma homocysteine in elderly patients with cobalamin deficiency

BACKGROUND: Helicobacter pylori gastritis may lead to impairment of the production of pepsinogen and acid, which are essential to cobalamin absorption. In turn, cobalamin deficiency leads to hyperhomocysteinaemia, a risk factor for cardio and cerebrovascular diseases. AIM: To evaluate the effect of H pylori eradication on plasma homocysteine levels in elderly patients. PATIENTS: Sixty-two H pylori-positive elderly patients with cobalamin deficiency were prospectively studied. METHODS: Homocysteine and cobalamin concentrations were determined before, 6 and 12 months after H pylori eradication. RESULTS: Corpus atrophy was observed in a few patients; otherwise, in most of them, the degree of corpus gastritis was moderate to severe. The initial homocysteine mean (SD) levels decreased from 41.0 (27.1) to 21.6 (10.1) micromol/l at the 6 month follow-up (p<0.001) and to 13.1 (3.8) micromol/l 12 months after H pylori eradication (p<0.001). Conversely, initial cobalamin mean levels increased from 145.5 (48.7) pmol/l to 209.8 (87.1) pmol/l and to 271.2 (140.8) pmol/l, 6 and 12 months after treatment, respectively (p<0.001 for both). Although the erythrocyte mean corpuscular volume was within reference intervals, it decreased significantly 6 (p = 0.002) and 12 (p<0.001) months after treatment. CONCLUSIONS: The results of the current study demonstrated that the eradication of H pylori in elderly patients with cobalamin deficiency is followed by increasing of cobalamin and decreasing of homocysteine blood levels.     

Low serum cobalamin levels in primary degenerative dementia. Do some patients harbor atypical cobalamin deficiency states?

Serum cobalamin (vitamin B12) levels were analyzed retrospectively in 17 patients with primary degenerative dementia and 11 with specific demonstrable causes of dementia (secondary dementia). The prevalence of low cobalamin levels was significantly increased in primary dementia (29% vs 0% in secondary dementia). Because typical findings of deficiency often seemed absent, we prospectively studied two other patients with primary dementia and low cobalamin levels. Neither of these two had megaloblastic anemia; one had a normal Schilling test while the other's was borderline. Despite this absence of the expected findings, the deoxyuridine suppression test gave biochemical evidence of cobalamin deficiency in both cases. Our survey of 28 patients thus established that low serum cobalamin levels are frequent in primary dementia. Our findings in the two prospectively studied cases (as well as in some of the patients in the survey) indicate that these levels are associated in at least some cases with an atypical deficiency state rather than with disorders such as pernicious anemia. Such atypical deficiency states cannot be identified by classic hematological criteria or by the Schilling test.     

The effect of smoking-related hyperhomocysteinemia on spirometric declines in chronic obstructive pulmonary disease in elderly Japanese

Smoking is implicated in chronic obstructive pulmonary disease (COPD) and hyperhomocysteinemia. To elucidate the role of hyperhomocysteinemia in COPD, we examined the relationship between plasma total homocysteine (tHcy) and spirometric declines in patients with COPD. We recruited 7 male never-smokers, 16 male control smokers, and 24 male patients with COPD. We investigated whether or not smoking might induce hyperhomocysteinemia in subjects predisposed to COPD, and then prospectively examined the relationship between plasma tHcy concentration and annual decline in FEV(1.0) in the COPD group. We found that plasma tHcy concentrations declined among groups in the following order: COPD group > control group > never-smoker group. Furthermore, plasma tHcy concentrations in the COPD group were significantly correlated with %FEV(1.0) (r(s) = 0.46). Also, COPD patients with severe airflow limitation showed a significant decrease in PaO2, which might be involved in the decreased tHcy in those patients. The prospective analysis revealed that plasma tHcy concentration, but not a history of smoking, were significantly correlated with the annual decline in FEV(1.0) calculated by the difference in FEV(1.0) between the first examination and an examination the following year (r(s) = 0.40). The present study suggests that smoking might increase plasma tHcy concentrations, leading to spirometric declines in subjects predisposed to COPD.     

Food cobalamin malabsorption occurs frequently in patients with unexplained low serum cobalamin levels

Malabsorption of food-bound or protein-bound cobalamin with normal absorption of free cobalamin has been described in studies of patients with gastric dysfunction. We used the egg-yolk cobalamin absorption test to study 47 patients selected not because of known gastric disorders but because they had low serum cobalamin levels with normal Schilling test results. Their egg test results were significantly lower than in normal controls, while Schilling test results were normal. Twenty of the subjects had egg test excretion below 1.5%. No features distinguished them from the 27 who excreted more than 1.5% other than the presence of lower pepsinogen I:II ratios. Eight of 19 tested patients with food cobalamin malabsorption had no evidence of abnormal gastric status by blood tests and/or gastric analysis. Also noteworthy was the finding of food cobalamin malabsorption in 60% of tested patients who had neurologic, cerebral, or psychiatric abnormalities. Food cobalamin malabsorption appears to be associated frequently with otherwise unexplained low cobalamin levels. Low cobalamin levels in patients with normal Schilling test results cannot be dismissed as insignificant without also testing for food cobalamin malabsorption, whether or not the patients have known gastric dysfunction.